Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C=O)C>[OH:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:6]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To a solution of 2-hydroxy-4-(trifluoromethyl)benzoic acid (0.5 g, 2.4 mmol) in CH2Cl2 (8 mL0 was added oxalyl chloride (0.46 g, 3.6 mmol) and 2 drops of DMF. The reaction was stirred (RT, 2 h) and then concentrated. The resulting residue was dissolved in CH2Cl2 (8 mL) and tert-butyl 2-aminoethylcarbamate (0.39 g, 2.4 mmol) and diisopropylethylamine (0.41 g, 3.2 mmol) were added. The reaction was stirred (RT, 16 h) and then partitioned between CH2Cl2 and brine. The aqueous layer was extracted with CH2Cl2 and the combined organic extracts were dried over MgSO4. The crude material was purified by silica chromatography (0-10% MeOH/CH2Cl2) to afford 0.55 g of tert-butyl 2-(2-hydroxy-4-(trifluoromethyl)benzamido)ethylcarbamate. Mass calculated for C15H19F3N2O4=348.32; found: [M+Na]+=371.1. This was then dissolved in CH2Cl2 (10 mL) and TFA (4 mL). The reaction was stirred (RT, 3 h) and concentrated and dried to afford 0.7 g of N-(2-aminoethyl)-2-hydroxy-4-(trifluoromethyl)benzamide as a clear oil. Mass calculated for C10H11F3N2O2=248.20; found: [M+H]+=249.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].O[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C@H:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:22][CH2:21]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[C@H:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:22][CH2:21]3)[CH:5]=[CH:4][C:3]=1[C:13]([F:16])([F:14])[F:15]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Reactant: OCCCNc1ccc(C(F)(F)F)c(Cl)n1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3ccc(C(F)(F)F)c(Cl)n3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
To a solution of 3-{[6-chloro-5-(trifluoromethyl)-2-pyridinyl]amino}-1-propanol (Example 301) (2.0 g, 7.85 mmol) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 0.87 g, 3.93 mmol) in THF (20 mL) were added triphenylphosphine (1.35 g, 5.11 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (1.30 g, 5.11 mmol) under argon. The golden yellow mixture was stirred at rt for 18 h, and then concentrated under reduced pressure. The product (1.15 g, 64%) was isolated after column chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD3OD) δ 7.58 (d, 1H), 6.94 (d, 1H), 6.77 (d, 1H), 6.61 (dd, 1H), 6.42 (d, 1H), 4.16 (q, 2H), 4.01 (t, 2H), 3.55 (q, 2H), 3.55-3.420 (m, 1H), 2.92-2.68 (m, 3H), 2.42-2.30 (m, 2H), 2.08 (qt, 2H), 1.78-1.68 (m, 1H), 1.27 (t, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([NH:20][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccccc1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Product: CCOc1cc2ncc(C#N)c(Nc3ccccc3)c2cc1OCC

Procedure:
In the manner of Example 105 reaction of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile with aniline gave the title compound as a tan solid, mp 168-170° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C1(N=C=NC2CCCCC2)CCCCC1.[C:32]([NH:42][C@H:43]([C:45](O)=[O:46])[CH3:44])([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>C(Cl)Cl>[C:32]([NH:42][C@H:43]([C:45]([N:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH2:2][CH2:3]2)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:46])[CH3:44])([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]
Reactant: CCOC(=O)CNc1ccc2c(c1)CCC2
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)[C@H](C)NC(=O)OCc1ccccc1)c1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl N-(5-indanyl)-glycinate (10.6 g, 48.4 mmol) and N,N'-dicyclohexylcarbodiimide (10.5 g, 50.8 mmol) in 200 ml CH2Cl2 at 0° C. was added dropwise a solution of N-carbobenzyloxy-L-alanine (11.3 g, 50.8 mmol) in 100 ml CH2Cl2. After the addition was completed the solution was stirred 10 min., warmed to room temperature and stirred overnight. The solution was filtered and concentrated in vacuo. The residue was dissolved in ether, filtered, washed with saturated NaHCO3, 10% aqueous HCl (5x), brine and dried MgSO4). Concentration of the volatiles in vacuo provided the product.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]1>N1C=CC=CC=1>[C:1]([NH:8][C@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@@H]1CC[C@H](N)C1
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1CC[C@H](NC(C)=O)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.9 %

Procedure:
Acetic anhydride (0.07 ml, 7.00 mmol) was added to a stirred solution of (1R,3S)-methyl 3-aminocyclopentanecarboxylate (200 mg, 1.39 mmol) in pyridine (5 ml) and stirred for 15 h at ambient temperature. The reaction mixture was concentrated under reduced pressure, water and CHCl3 were added. The organic layer was separated and washed with saturated sodium bicarbonate solution, brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 180 mg (69%) of (1R,3S)-methyl 3-acetamidocyclopentanecarboxylate as brown oil.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([S:14]([O-:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)[CH2:4]1.[Li+].C1C(=O)N([Cl:25])C(=O)C1.CN1CCC2C(=C(N)C=CC=2)C1>ClCCl>[CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([S:14]([Cl:25])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)[CH2:4]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC1CCN(c2cccc(S(=O)[O-])c2)C1
Agent: CN1CCc2cccc(N)c2C1
Agent: [Li+]
Solvent: ClCCl
Product: COC1CCN(c2cccc(S(=O)(=O)Cl)c2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Into a 250 mL round bottom flask was placed a solution of lithium 3-(3-methoxypyrrolidin-1-yl)benzenesulfinate (12 g, 29.15 mmol) in dichloromethane (100 mL). To the above was added NCS (4.48 g, 33.56 mmol) in several batches, while cooling to a temperature of 0° C. over a time period of 10 minutes. The resulting solution was allowed to react, with stirring, for 15 minutes while the temperature was maintained at 0° C. in a bath of H2O/ice, then the ice bath was removed and the solution was allowed to react for an additional 25 minutes at room temperature. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether 5=1:1). The resulting mixture was washed 2 times with 50 mL of NaHSO3 and 2 times with 50 mL of brine. The mixture was dried over Na2SO4 and concentrated by evaporation under vacuum using a rotary evaporator. The residue was purified by eluting through a column with a 2:3 ethyl acetate/petroleum ether solvent system. This resulted in 6.6 g (82.5%) of 3-(3-methoxypyrrolidin-1-yl)benzene-1-sulfonyl chloride as yellow oil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:35])[C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([C:31]([F:34])([F:33])[F:32])[CH:25]=2)=[O:20])[CH2:15]1>>[F:30][C:28]1[CH:29]=[C:24]([CH:25]=[C:26]([C:31]([F:34])([F:32])[F:33])[CH:27]=1)[C:23]([NH:22][CH2:21][C:19](=[O:20])[NH:18][CH:16]1[CH2:17][N:14]([CH:10]2[CH2:11][CH2:12][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)[CH2:15]1)=[O:35]
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: O=C(CNC(=O)c1cc(F)cc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cc(F)cc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-phenyl-cyclohexanone (Aldrich) and N-(azetidin-3-ylcarbamoylmethyl)-5-fluoro-3-trifluoromethyl-benzamide (as prepared in the previous step) using the procedure described in Step C of Example 4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH3:21])[C:8]3[C:13]([S:14][C:15]=2[C:16]=1[CH:17]=[O:18])=[CH:12][C:11]([O:19][CH3:20])=[CH:10][CH:9]=3.[BH4-].[Li+].COC1C=CC2N(C)C3C(SC=2C=1CO)=CC(OC)=CC=3.[CH3:45][O:46][CH2:47][CH2:48][O:49][CH2:50]Cl>O1CCCC1.C([Li])CCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH3:21])[C:8]3[C:13]([S:14][C:15]=2[C:16]=1[CH2:17][O:18][CH2:45][O:46][CH2:47][CH2:48][O:49][CH3:50])=[CH:12][C:11]([O:19][CH3:20])=[CH:10][CH:9]=3
Reactant: COc1ccc2c(c1)Sc1c(ccc(OC)c1C=O)N2C
Reactant: COCCOCCl
Agent: COc1ccc2c(c1)Sc1c(ccc(OC)c1CO)N2C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCOCOCc1c(OC)ccc2c1Sc1cc(OC)ccc1N2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
A solution of 1.90 g (6.32 mmol) of 3,7-dimethoxy-10-methyl-phenothiazine-4-carbaldehyde in 30 ml of tetrahydrofuran was reduced with 7.6 ml of lithium borohydride solution (1M in tetrahydrofuran) analogously to that described in Example 4.1.1.da. The resulting 3,7-dimethoxy-10-methyl-phenothiazine-4-methanol was dissolved in 20 ml of tetrahydrofuran, whereupon 4.36 ml of n-butyllithium solution (1.6M in hexane) were added at -78°. The reaction mixture was brought slowly to 0°, then treated with 1.02 g (8.19 mmol) of 2-methoxy-ethoxymethyl chloride, stirred at room temperature for 2 hours and finally poured into ice-water/saturated sodium hydrogen carbonate solution. After three-fold extraction with diethyl ether the combined organic phases were washed with sodium chloride solution, dried over magnesium sulphate and evaporated. The residue was chromatographed on silica gel with diethyl ether/hexane (3:2), whereupon 2.09 g (84.6%) of 3,7-dimethoxy-4-(2-methoxy-ethoxymethoxymethyl)-10-methyl-phenothiazine were obtained as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=O)[CH:8]=[CH:7]2.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][NH2:22]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([F:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](/[CH:12]=[N:22]/[NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=1)[CH:8]=[CH:7]2
Reactant: NNc1ccccn1
Reactant: O=Cc1ccc2cc(F)cc(Br)c2n1
Solvent: CCO
Product: Fc1cc(Br)c2nc(/C=N/Nc3ccccn3)ccc2c1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
8-Bromo-6-fluoroquinoline-2-carbaldehyde (100 mg, 0.39 mmol) and 1-(pyridin-2-yl)hydrazine (43 mg, 0.39 mmol) were dissolved in 15 mL of absolute EtOH, and heated to reflux for 2 hours, at which time all starting material had been consumed. The reaction was then cooled to ambient temperature, and the yellow/orange product was collected by filtration (wash EtOH), affording (100 mg, 73.6% yield) as a yellow solid. MS APCI (+) m/z 345.1 and 347 (M+1 of each Br isotope) detected.
Reaction SMILES: [Br-:1].[CH:2]1([C:8]([OH:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][N+:13]2([CH3:27])[CH:17](C2C=NC=CN=2)[C:18](=[O:20])[NH2:19])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Br-].[OH:36][C@@H:37]1[CH2:41][CH2:40][N+:39](C)(C(C2C=NC=CN=2)C(=O)N)C1.[Br-].O[C@@H]1CC[N+](CC(=O)NC2C=CON=2)(C)C1>>[Br-:1].[CH:2]1([C:8]([OH:34])([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:9]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][N+:13]2([CH2:17][C:18](=[O:20])[NH:19][C:40]2[CH:41]=[CH:37][O:36][N:39]=2)[CH3:27])=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: C[N+]1(C(C(N)=O)c2cnccn2)CC[C@@H](O)C1
Reactant: C[N+]1(C(C(N)=O)c2cnccn2)CCCC1OC(=O)C(O)(c1ccccc1)C1CCCCC1
Agent: C[N+]1(CC(=O)Nc2ccon2)CC[C@@H](O)C1
Agent: [Br-]
Product: C[N+]1(CC(=O)Nc2ccon2)CCCC1OC(=O)C(O)(c1ccccc1)C1CCCCC1

Procedure:
This compound is prepared by an analogous method to (1R/S,3R)-3-((R/S)-(2-cyclohexyl-2-hydroxy-2-phenyl-acetoxy)-1-methyl-1-(pyrazin-2-ylcarbamoylmethyl)-pyrrolidinium bromide (Example 1) by replacing (1R/S,3R)-3-hydroxy-1-methyl-1-(pyrazin-2-yl-carbamoylmethyl)-pyrrolidinium bromide (Intermediate B) with (1R/S,3R)-3-hydroxy-1-(isoxazol-3-ylcarbamoyl-methyl)-1-methyl-pyrrolidinium bromide (Intermediate D).
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:11][C:12]1([CH3:26])[C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:16]=2[NH:15][C:14](=[O:25])[O:13]1>>[CH3:11][C:12]1([CH3:26])[O:13][C:14](=[O:25])[NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:2]3[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][CH:3]=3)=[CH:18][C:17]1=2
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3ccc(S(N)(=O)=O)s3)cc21

Procedure:
Prepared according to procedure B from 5-bromothiophene-2-sulphonamide and (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid. White solid: mp 258-260° C.; 1H-NMR (DMSO-d6) δ 10.41 (s, 1H), 7.71 (s, 2H), 7.58 (m, 2H), 7.52 (d, 1H, J=3.9 Hz), 7.48 (d, 1H, J=8.16 Hz), 6.95 (d, 1H, J=8.16 Hz), 1.66 (s, 6H); MS m/z 337 (M−H). Anal. Calc. for C14H14N2O4S2: C, 49.69; H, 4.17; N, 8.28. Found: C, 49.90; H, 4.28; N, 8.12.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:25](Cl)[C:26]#[CH:27]>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:27][C:26]#[CH:25])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: C#CCCl
Product: C#CCn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 24.5 %

Procedure:
The title compound (0.014 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 2-propynyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C16H16ClN3, 285.10; found, m/z 286.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.38-7.32 (m, 4H), 7.13 (t, J=6.4 Hz, 1H), 5.48 (d, J=6.4 Hz, 2H), 2.93-2.91 (m, 4H), 2.84-2.81 (m, 2H), 2.68-2.65 (m, 2H).
Reaction SMILES: [N:1]([CH2:10][C:11]([OH:13])=O)([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].C(OC(=O)C)(=O)C.[Br:21][C:22]1[C:23]([CH3:31])=[C:24]([C:26]([CH3:30])=[CH:27][C:28]=1[CH3:29])[NH2:25]>N1C=CC=CC=1>[Br:21][C:22]1[C:23]([CH3:31])=[C:24]([NH:25][C:11](=[O:13])[CH2:10][N:1]([CH2:2][C:3]([OH:5])=[O:4])[CH2:6][C:7]([OH:9])=[O:8])[C:26]([CH3:30])=[CH:27][C:28]=1[CH3:29]
Reactant: O=C(O)CN(CC(=O)O)CC(=O)O
Reactant: Cc1cc(C)c(Br)c(C)c1N
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: Cc1cc(C)c(NC(=O)CN(CC(=O)O)CC(=O)O)c(C)c1Br
Temperature: 50 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
A suspension of 9.56 g of nitrilotriacetic acid in pyridine (dried over molecular sieves) is prepared with the exclusion of moisture (CaSO4 drying tube) and heated to 50° C. Acetic anhydride (5.11 g) is added dropwise. The reaction mixture clears and is heated to 100° C. After maintaining the temperature for 40 minutes, the reaction mixture is cooled to 55° C. and a solution of 10.7 g 3-bromo-2,4,6-trimethylaniline in 25 ml of dry pyridine is added slowly. The reaction is heated to 100° C. and after 1.5 hours at this temperature, the solution is cooled in an ice-bath. The reaction mixture is rotary evaporated to a semisolid which is dissolved in 125 ml of 10% sodium hydroxide w/v. The basic layer is then extracted with two 100 ml portions of methylene chloride. Distilled water (100 ml) is added to the basic layer which is then brought to pH 3 with concentrated hydrochloric acid to give a precipitate. After refrigeration for about 16 hours, the crude product is filtered, washed with cold distilled water and dried under vacuum at 40° C. The crude product is dissolved in 100 ml of 60% aqueous ethanol, treated with 3.0 g of Darco and filtered hot through a Hyflo-bed to give a solution. Crystals precipitate and are filtered, washed with three 25 ml portions of 50% aqueous ethanol and dried under vacuum at 40° C. The reaction yields 9.1 g of the title compound, melting point 198°-200° C., dec.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](C(C)(C)C)[CH:8]=[CH:7][C:6]=1[OH:15])(C)(C)[CH3:2].C(OC[N:22](COCC(C)C)C)C(C)C>C1(C)C=CC=CC=1>[O:15]1[C:6]2=[CH:7][CH:8]=[CH:9][CH2:10][CH:5]2[CH2:1][CH2:2][NH:22]1
Reactant: CC(C)COCN(C)COCC(C)C
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Product: C1=CCC2CCNOC2=C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 189.8 %

Procedure:
A 1000 ml four-neck flask was initially charged with 206 g of 2,4-di-tert-butylphenol at room temperature in 400 ml of toluene. 203 g of N,N-di(isobutoxymethyl)-N-methylamine from example 1 were added rapidly. The flask contents were stirred at 80° C. for 60 minutes. The solution was concentrated by evaporation at 120° C. and 5 mbar. 260 g of product were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:13])[C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[NH:18][N:17]=1>>[CH3:13][N:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:18]2[C:19]3[CH2:20][CH2:21][CH2:22][CH2:23][C:24]=3[C:16]([C:15]([F:14])([F:26])[F:25])=[N:17]2)=[CH:3][CH:4]=1)[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)N(C)Cc1ccc(Br)cc1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Product: CC(=O)N(C)Cc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1

Procedure:
The title compound was prepared from N-[(4-bromophenyl)methyl]-N-methylacetamide and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similar procedure to that described for Example 1.
Reaction SMILES: Br[CH:2]([CH2:10][CH2:11][CH2:12][Cl:13])[C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:14][C:15]([NH2:17])=[S:16]>CC(C)=O>[NH2:17][C:15]1[S:16][C:2]([CH2:10][CH2:11][CH2:12][Cl:13])=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:14]=1
Reactant: CCOC(=O)C(=O)C(Br)CCCCl
Reactant: NC(N)=S
Solvent: CC(C)=O
Product: CCOC(=O)c1nc(N)sc1CCCCl
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a solution of ethyl 3-bromo-6-chloro-2-oxohexanoate (23A) (0.845 g, 3.11 mmol) in acetone (6 mL) was added thiourea (0.284 g, 3.73 mmol) and refluxed overnight. The reaction mixture was concentrated under reduced pressure. EtOAc and hexanes in a ratio of 1:9 was added and stirred for 1 hour. Added acetone to dissolve material and concentrated under reduced pressure to give 0.718 g (93%) of the desired product ethyl 2-amino-5-(3-chloropropyl)thiazole-4-carboxylate (23B): LC/MS (APCI): m/z 249.5 (M+H).
Reaction SMILES: Br[CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C:13](=[O:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]([OH:35])=[S:34])[CH2:28][CH2:27]1>CC(C)=O>[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]([S:34][CH2:2][C:3](=[O:25])[C@@H:4]2[C@:21]3([CH3:22])[C@H:7]([C@H:8]4[C@H:18]([C:19](=[O:23])[CH2:20]3)[C@:16]3([CH3:17])[C@H:11]([CH2:12][C:13](=[O:24])[CH2:14][CH2:15]3)[CH2:10][CH2:9]4)[CH2:6][CH2:5]2)=[O:35])[CH2:28][CH2:27]1
Reactant: OC(=S)CN1CCOCC1
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Solvent: CC(C)=O
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CSC(=O)CN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
21-Bromo-5α-pregnane-3,11,20-trione (1.04 g.) was refluxed in dry acetone (100 ml) with morpholino thioacetic acid (600 mg) for 15 minutes. The reaction mixture was concentrated, partitioned between ethyl acetate, water, pH 8, the organic layer was washed, dried (MgSO4) and evaporated to an off white solid (1.26g.)
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[C:9]([O:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[CH:18][CH:17]=3)[C:10](Br)=[CH:11][CH:12]=2)[CH2:7][CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2].CC1(C)OB([C:32]2[CH:33]=[N:34][N:35]([CH:37]3[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]3)[CH:36]=2)OC1(C)C.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[C:9]([O:15][C:16]3[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH2:22])=[CH:18][CH:17]=3)[C:10]([C:32]3[CH:33]=[N:34][N:35]([CH:37]4[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:41][CH2:42]4)[CH:36]=3)=[CH:11][CH:12]=2)[CH2:7][CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)c(Oc3ccc(C(N)=O)cc3)c2CC[C@@H]1C
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1c2ccc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c(Oc3ccc(C(N)=O)cc3)c2CC[C@@H]1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
A mixture of 4-[[(2S)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-5-yl]oxy]benzamide (0.080 g, 0.20 mmol), tert-butyl 4-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (0.090 g, 0.24 mmol), potassium carbonate (0.082 g, 0.59 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.016 g, 0.02 mmol) in 1,4-dioxane (20 mL) and water (2 mL) stirred overnight at 100° C. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, and concentrated under vacuum. The residue was purified via preparative thin layer chromatography (eluting with 50% ethyl acetate-petroleum ether) to afford tert-butyl 4-[4-[(2S)-1-acetyl-5-(4-carbamoylphenoxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl]-1H-pyrazol-1-yl]piperidine-1-carboxylate (0.080 g, 70%) as a yellow oil. MS (ESI, pos. ion) m/z 574 [M+H]+.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27](O)=[O:28])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:33]>>[C:34]1([C:32]2[N:33]=[C:27]([CH:13]3[CH2:14][CH:15]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=4)[CH2:16][N:11]([C:9]([N:6]4[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]4)=[O:10])[CH2:12]3)[O:28][N:31]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Reactant: NC(=NO)c1ccccc1
Product: N#CC1CCN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(-c4ccccc4)no3)C2)CC1

Procedure:
100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 38.5 mg (0.269 mmol) of N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 84.2 mg (66% of theory).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][NH:14][CH2:15][C@@H:10]3[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][C:6]=2[CH:20]=1.Br[CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34]>>[C:25]1(=[O:34])[N:24]([CH2:23][CH2:22][N:14]2[CH2:13][CH2:12][N:11]3[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:20][C:6]=4[CH2:7][C:8]4[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=4[C@H:10]3[CH2:15]2)[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]12
Reactant: Fc1ccc2c(c1)Cc1ccccc1[C@H]1CNCCN21
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Product: O=C1c2ccccc2C(=O)N1CCN1CCN2c3ccc(F)cc3Cc3ccccc3[C@H]2C1
Yield: 91 %

Procedure:
Following a procedure similar to that described in Preparation 14(a), but using (14bS)-8-fluoro-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine and N-(2-bromoethyl)phthalimide, the title compound was obtained in a yield of 91%.