Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4](O)=[O:5].O1CCCC1.[NH3:17]>O>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH2:17])=[O:5]
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: N
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(N)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 15 g of 2-amino-5-methylbenzoic acid, 16 g of 1,1-carbonyldiimidazole and 500 ml of tetrahydrofuran was stirred for 2 hours at room temperature and then saturated with anhydrous ammonia with ice bath cooling. After 24 hours, 50 ml of water was added and the mixture was concentrated under reduced pressure to a solid residue. This solid Was partially dissolved in 500 ml of dichloromethane and then washed with 200 ml of 0.1 N sodium hydroxide and 200 ml of water. The dichloromethane solution was dried and concentrated to a solid Which Was crystallized from ethyl acetate/hexane, giving 3.0 g of 2-amino-5-methylbenzamide as straw-colored crystals, mp 171°-174° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:16][NH2:17]>>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([NH:17][CH3:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C1CCC(c2ccc(CO)cc2)CC1
Reactant: CN
Product: CN[C@H]1CC[C@H](c2ccc(CO)cc2)CC1

Procedure:
from 4-(4-hydroxymethylphenyl)cyclohexanone and methylamine. Melting point: 131°-134° C.
Reaction SMILES: [CH3:1][N:2]([C:26]([C:28]1[N:29](CC2C=CC=CC=2)[CH:30]=[C:31]([O:35]CC2C=CC=CC=2)[C:32](=[O:34])[CH:33]=1)=[O:27])[NH:3][S:4]([NH:7][C:8]([N:10]1[CH2:13][C@H:12]([NH:14]C(OCC2C=CC=CC=2)=O)[C:11]1=[O:25])=[O:9])(=[O:6])=[O:5].[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53]>CN(C)C=O.[Pd]>[F:50][C:51]([F:56])([F:55])[C:52]([OH:54])=[O:53].[NH2:14][CH:12]1[CH2:13][N:10]([C:8]([NH:7][S:4]([NH:3][N:2]([CH3:1])[C:26]([C:28]2[NH:29][CH:30]=[C:31]([OH:35])[C:32](=[O:34])[CH:33]=2)=[O:27])(=[O:5])=[O:6])=[O:9])[C:11]1=[O:25]
Reactant: CN(NS(=O)(=O)NC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C1=O)C(=O)c1cc(=O)c(OCc2ccccc2)cn1Cc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CN(NS(=O)(=O)NC(=O)N1CC(N)C1=O)C(=O)c1cc(=O)c(O)c[nH]1
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of 2 g of (S)-1,4-dihydro-4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)-2-pyridinecarboxylic acid, 1-methyl-2-[[[[2-oxo-3-[[(phenylmethoxy)carbonyl]amino]-1-azetidinyl]carbonyl]amino]sulfonyl]hydrazide in 60 ml of dimethylformamide, 1.1 ml of trifluoroacetic acid was added, followed by one gram of palladium on charcoal (10%). After flushing with nitrogen, hydrogen was passed through the solution for 60 minutes with stirring, the catalyst was removed by filtration, the filtrate evaporated in vacuo and the residue triturated with ether to yield 1.1 g of crude title compound. Yield: 86.6%.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][O:7][C@@H:6]1[N:19]=[N+]=[N-])(=[O:3])[CH3:2].[H][H]>CO.[C].[Pd]>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][O:7][C@@H:6]1[NH2:19])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](N=[N+]=[N-])OC[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](N)OC[C@@H]1OC(C)=O
Yield: 29.6 %

Procedure:
997.2 mg (3.31 mmol) of 2,3,4-tri-O-acetyl-β-L-xylopyranosyl azide was dissolved in 30 ml of methanol, and the solution was allowed to react at 45° to 50° C. for 2 hours in a hydrogen gas stream in the presence of 300 mg of 5% palladium carbon catalyst. The reaction solution was then filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in 60 ml of pyridine, and 10 ml of acetic anhydride was added. The mixture was allowed to react at room temperature for 4 hours. The reaction mixture was then concentrated under reduced pressure and the residue extracted with chloroform (100 ml). The chloroform layer was washed with 2N aqueous hydrochloric acid solution (100 ml), 10% aqueous sodium carbonate solution (100 ml) and water in the stated order, dehydrated over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (Waggle C-200, 30 g) and eluted with chloroform-methanol (300:1). The eluate was crystallized from ethyl acetate-hexane to obtain 309.9 mg (0.98 mmol, 30%) of 2,3,4-tri-O-acetyl-β-L-xylopyranosylamine as a colorless needle crystal. The physicochemical properties of this crystalline compound were as follows.
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][C:5]([NH:7][NH:8][C:9]([SH:12])=[N:10][CH3:11])=O.Cl>CCO>[SH:12][C:9]1[N:10]([CH3:11])[C:5]([CH2:4][OH:3])=[N:7][N:8]=1
Reactant: CN=C(S)NNC(=O)CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(S)nnc1CO
Temperature: 60 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
5N NaOH (50 mmol) was added to a solution of 2-(2-hydroxyacetyl)-N-methylhydrazinecarbimidothioic acid (8.15 g, 50 mmol) in EtOH, and then the mixture was stirred for 4 hr at 60° C. The mixture was cooled in an ice bath and the pH was adjusted to ˜5-6 with concentrated HCl. The precipitated solid was filtered, washed with EtOH, and dried under vacuum to give the title compound. Yield: 83%. 1H NMR (DMSO-d6, 400 MHz) δ: 5.64 (s, 1H), 4.46 (s, 2H), 3.44 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:12][C:13]1[CH:14]=[C:15]([NH2:21])[C:16]([NH2:20])=[CH:17][C:18]=1[CH3:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]2[NH:20][C:10]([C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=3)=[N:21][C:15]=2[CH:14]=1
Reactant: N#Cc1ccc(C=O)cc1F
Reactant: Cc1cc(N)c(N)cc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1cc2nc(-c3ccc(C#N)c(F)c3)[nH]c2cc1C
Yield: 65.2 %

Procedure:
To a solution of 2-fluoro-4-formylbenzonitrile 1 (100 mg, 0.7 mmol) and 4,5-dimethyl benzene-1,2-diamine 2 (109 mg, 0.8 mmol) in ethanol (10 ml) was added a catalytic amount of p-toluenesulfonic acid (0.5 mg, 0.5 mmol). The mixture was stirred reflux for 2 hours and concentrated by rotor evaporation. The crude material was purified through column chromatography with 40% ethyl acetate in hexane to yield compound 3 as white solid (68% yield, 121 mg, confirmed by LCMS: 266.20).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[CH:3]=1.[CH3:10][C:11](=[O:14])[C:12]#[CH:13].C(NC(C)C)(C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:13]#[C:12][C:11](=[O:14])[CH3:10])[CH:5]=[C:4]([Cl:9])[CH:3]=1
Reactant: Clc1cc(Cl)cc(I)c1
Reactant: C#CC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(=O)C#Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 1,3-dichloro-5-iodo-benzene (3.44 g, 12.6 mmol) in THF (220 mL) was added PdCl2(PPh3)2 (904 mg, 1.29 mmol), 3-butyn-2-one (2.18 g, 32.0 mmol), copper(I)iodide (380 mg, 2 mmol) and diisopropylamine (44 mL). The reaction mixture was stirred at room temperature for 48 hours, filtered and evaporated. The residue was purified by column chromatography using methylene chloride:hexanes (1:1) as eluent. The desired 4-(3,5-dichloro-phenyl)-3-butyn-2-one product was isolated in 977 mg yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([F:27])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:28]#[N:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[C:37]1([N:43]=[C:44]=[O:45])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(#N)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:44]([NH:43][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:45])=[C:22]([F:27])[CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:28]#[N:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1OCc1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccccc4)c(F)c3)ccnc2cc1OCc1ccccc1

Procedure:
After adding 1.90 g of the 7-benzyloxy-6-cyano-4-(3-fluoro-4-aminophenoxy)quinoline obtained in Production Example 8 to 60 ml of toluene and 30 ml of acetonitrile, the mixture was heated to reflux. Next, 0.76 ml of phenyl isocyanate was added and the mixture was further heated to reflux for 1 hour. After cooling, the precipitated solid was filtered out and dried under reduced pressure to obtain 1.65 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:3]2[C:8]3[N:9]4[CH2:37][CH2:36][C:12]([CH3:38])([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([CH3:35])[O:19][C:20]5[CH:21]=[CH:22][C:23]([F:34])=[CH:24][C:25]=5[C:26]5[CH:33]=[C:30]([C:31]=1[N:32]=[C:4]2[CH:5]=[C:6]([CH3:49])[C:7]=3[C@H:39]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:40]([O:42][CH3:43])=[O:41])[CH:29]=[CH:28][CH:27]=5)[CH2:11][CH2:10]4.[Cl:50]N1C(=O)CCC1=O.C(OCC)(=O)C>C(#N)C>[Br:1][C:2]1[N:3]2[C:8]3[N:9]4[CH2:10][CH2:11][C:12]([CH3:38])([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([CH3:35])[O:19][C:20]5[CH:21]=[CH:22][C:23]([F:34])=[CH:24][C:25]=5[C:26]5[CH:33]=[C:30]([C:31]=1[N:32]=[C:4]2[C:5]([Cl:50])=[C:6]([CH3:49])[C:7]=3[C@H:39]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:40]([O:42][CH3:43])=[O:41])[CH:29]=[CH:28][CH:27]=5)[CH2:36][CH2:37]4
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3c(Br)n2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Cl)c2nc3c(Br)n2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Reaction time: 3 h
Yield: 57.4 %

Procedure:
Methyl(2S)-2-[(22S)-8-bromo-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]-2-(tert-butoxy)acetate (50 mg, 0.068 mmol, 1.0 equiv) was dissolved in acetonitrile (1357 μl). To this solution was added 1-chloropyrrolidine-2,5-dione (9.06 mg, 0.068 mmol, 1.0 equiv) and stirred for 3 hours. The mixture was diluted by 15 mL Ethyl Acetate, washed by NaHCO3 and brine. The organic layer was dried, concentrated, and purified on ISCO 12 g column (0-100% EtOAc [2% TEA]/Hexane) to give the product (30 mg, 0.039 mmol, 57.3% yield).
Reaction SMILES: [I-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].[C:10]1(=O)[O:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>>[OH:14][CH2:13][CH2:12][CH2:11][C:10]1[N:9]=[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]2[N:2]=1
Reactant: Nc1cccc[n+]1N
Reactant: O=C1CCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: OCCCc1nc2ccccn2n1
Reaction time: 8 h

Procedure:
A mixture of 24 g of 1,2-diaminopyridinium iodide, 17.2 g of γ-butyrolactone and 57 g of potassium carbonate in 100 ml of diethylcellosolve was refluxed with stirring for 8 hours. The mixture was concentrated under reduced pressure to the residue, which was extracted by hot dichloromethane. The solvent was removed to give crude 2-(3-hydroxypropyl)-s-triazolo[1,5-a]pyridine, which was recrystallized from ethyl acetate to colorless needles (16 g, 90%), mp 71.5°-73° C. Anal. Calcd. for C9H11ON3 : C, 61.00; H, 6.24; N, 23.72. Found: C, 60.82; H, 6.14; N, 23.48.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([O:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[CH:32][CH:31]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3ccc(Cl)cc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 26.9 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 4-chlorophenol (6.40 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (3.3 mg, 26.9% yield) as a thick oil: 1H NMR 67 7.36 (s, 1H), 7.35–7.22 (m, 7H), 7.12 (m, 2H), 6.97 (apparent d, 1H, J=7.2 Hz), 6.77 (m, 2H), 5.23 (m, 1H), 3.18 (m, 2H), 2.70 (m, 2H), 2.50 (m, 2H), 2.40–1.80 (m, 8H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 491.4 (M+R)+.
Reaction SMILES: Cl.[F:2][C:3]([F:23])([F:22])[C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH:6]([O:13][CH:14]1[CH2:17][NH:16][CH2:15]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:24]([N:28]=[C:29]=[O:30])([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])[O-]>>[F:23][C:3]([F:2])([F:22])[C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH:6]([O:13][CH:14]1[CH2:17][N:16]([C:29]([NH:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:15]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: FC(F)(F)c1ccccc1C(OC1CNC1)c1ccccc1
Reactant: CC(C)(C)N=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Product: CC(C)(C)NC(=O)N1CC(OC(c2ccccc2)c2ccccc2C(F)(F)F)C1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)benzhydryloxy]azetidine hydrochloride (133) (0.33 mmol), tert-butyl isocyanate (0.33 mmol) and MP-carbonate (2.62 mmol/g, 0.98 mmol) using the procedure described for compound (10) (99.5 mg, 75%).
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1>>[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:2]2[C:10]3[NH:9][C:8]4[CH:11]5[CH2:17][CH2:16][N:14]([CH2:15][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]5)[CH:19]=1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Reactant: OB(O)c1cccnc1
Product: c1cncc(-c2cccc3c4c([nH]c23)C2CCN(CC2)C4)c1

Procedure:
The product of Example 1B (80 mg, 0.28 mmol) and pyridine-3-boronic acid (36 mg, 0.29 mmol; Aldrich) were processed as described in Example 4 to provide the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 2.00-2.14 (m, 4 H), 3.01-3.15 (m, 3 H), 3.20-3.28 (m, 2 H), 4.27 (s, 2 H), 7.04-7.09 (m, 1 H), 7.12 (t, J=7.3 Hz, 1 H), 7.37 (dd, J=7.5, 1.4 Hz, 1 H), 7.56 (dd, J=7.8, 5.1 Hz, 1 H), 8.05-8.12 (m, 1 H), 8.55 (dd, J=4.9, 1.5 Hz, 1H), 8.77-8.79 (m, 1 H); MS (ESI+) m/z 290 (M+H)+.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([NH:28][C:29]4[C:38]5[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH3:40])[CH:37]=5)[O:32][C:31](=[O:41])[CH:30]=4)[CH2:24][CH2:23]3)=[CH:20][C:15]=2[O:14][CH2:13]1.[Cl:42]N1C(=O)CCC1=O.C(O)(=O)C>C(#N)C>[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([NH:28][C:29]4[C:38]5[C:33](=[CH:34][CH:35]=[C:36]([O:39][CH3:40])[CH:37]=5)[O:32][C:31](=[O:41])[C:30]=4[Cl:42])[CH2:24][CH2:23]3)=[CH:20][C:15]=2[O:14][CH2:13]1
Reactant: COc1ccc2oc(=O)cc(NC3CCN(Cc4ccc5c(c4)OCO5)CC3)c2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1ccc2oc(=O)c(Cl)c(NC3CCN(Cc4ccc5c(c4)OCO5)CC3)c2c1

Procedure:
The 4-(1-Benzo[1,3]dioxol-5-ylmethyl-piperidin-4-ylamino)-6-methoxy-chromen-2-one para-toluene sulfonic acid salt (0.025 g, 0.043 mmol), N-chlorosuccinimide (0.0061 g, 0.046 mmol), and 0.2 mL Acetic Acid were shaken at room temperature overnight. Solution was diluted with Acetonitrile and purified on a C-18 RP HPLC. Product fractions were combined, treated with K2CO3, extracted with CH2Cl2, dried over sodium sulfate and concentrated to dryness to give the title compound as an off white solid. MS ESI(+)Q1MS m/z 451 (M−H)+; 1H NMR (300 MHz, CDCl3) δ ppm partially buried 1.47-1.78 (m, 2H), 2.03-2.21 (m, 4H), 2.8-2.91 (br d, 2H), 3.39-3.46 (s, 2H), 3.8-3.87 (s, 3H), 4.01-4.13 (m, 1H), 4.83-4.91 (br s, 1H), 5.93-5.97 (s, 2H), 6.71-6.78 (m, 2H), 6.83-6.86 (s, 1H), 7.05-7.16 (m, 2H), 7.27-7.36 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[C@@H:21]([OH:25])[CH2:22][CH2:23][OH:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])([CH3:28])[CH3:27].N1C=CN=C1.O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:15])[CH3:16])[CH2:10][C@H:9]1[C@@H:21]([OH:25])[CH2:22][CH2:23][O:24][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:32])[CH3:31])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1[C@@H](O)CCO
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1[C@@H](O)CCO[Si](C)(C)C(C)(C)C
Yield: 92 %

Procedure:
To a solution of (2S,4R)-1-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[(S)-1,3-dihydroxypropyl]pyrrolidine (16.95 g, 45.2 mmol) in methylene chloride (200 ml) were successively added tert-butylchlorodimethylsilane (6.81 g, 45.2 mmol), 4-N,N-dimethylaminopyridine (0.55 g, 4.5 mmol) and imidazole (3.08 g, 45.2 mmol) in a nitrogen atmosphere under cooling with ice under stirring. The mixture was stirred at room temperature for 1 h. Then, the reaction solution was poured into water (200 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was subjected to silica gel column chromatography (Wakogel™ C-300, heptane-ethyl acetate=9:1→4:1) to give (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[(S)-3-tert-butyldimethylsiloxy-1-hydroxypropyl]pyrrolidine (20.36 g, yield: 92.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9](O)=[O:10])=[C:4]([F:18])[CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:27])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([Cl:27])=[O:10])=[C:4]([F:18])[CH:3]=1
Reactant: C[C@H](C(C(=O)O)c1ccc(Cl)cc1F)C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](C(C(=O)Cl)c1ccc(Cl)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
660 mg (2.32 mmol) of (3R)-2-(4-chloro-2-fluorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid (diastereomer mixture) were dissolved in 2 ml of dichloromethane. After addition of a small drop of DMF, the reaction solution was cooled to from −5° C. to 0° C., and 0.4 ml (4.64 mmol) of oxalyl chloride was added dropwise. Cooling was removed and the reaction mixture was stirred at RT for 1 h until the evolution of gas had ceased. The mixture was then concentrated under reduced pressure. The residue was twice taken up in abs. dichloromethane, in each case reconcentrated under reduced pressure and the residue was finally dried under high vacuum. This gave 640 mg of the target product which was directly, without further purification, reacted further.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2([OH:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[N:7][CH:8]=1.Cl[C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][N:27]=2)[N:24]=1>>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2([OH:15])[CH2:10][CH2:11][N:12]([C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25]([C:28]([F:29])([F:31])[F:30])=[N:26][N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:6]=[N:7][CH:8]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: OC1(c2cncc(C(F)(F)F)c2)CCNCC1
Product: OC1(c2cncc(C(F)(F)F)c2)CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Yield: 75 %

Procedure:
A mixture of 4-[5-(trifluoromethyl)pyridin-3-yl]piperidin-4-ol and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by the method of Example 306 to give 4-[5-(trifluoromethyl)pyridin-3-yl]-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol in 75% yield.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](Cl)=[O:14])=[CH:8][CH:7]=1.[CH3:16][C:17]1([CH3:29])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH3:28])([CH3:27])[CH2:19][CH2:18]1.O>ClCCl>[CH3:16][C:17]1([CH3:29])[CH2:18][CH2:19][C:20]([CH3:28])([CH3:27])[C:21]2[CH:22]=[C:23]([C:13](=[O:14])[CH2:12][C:9]3[CH:10]=[CH:11][C:6]([Br:5])=[CH:7][CH:8]=3)[CH:24]=[CH:25][C:26]1=2
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C(=O)Cc3ccc(Br)cc3)ccc21
Reaction time: 0.5 h
Yield: 63 %

Procedure:
Aluminium trichloride (4.33 g, 32.5 mmol) and 4-bromophenylacetyl chloride (5.55 g, 23.2 mmol) are added successively at −30° C. to a solution of 1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (4.36 g, 23.2 mmol) in 300 ml of dichloromethane. The temperature is allowed to rise to 0° C. in 30 minutes, the reaction mixture is poured over 400 ml of a volume to volume mixture of ice and water and this is extracted with dichloromethane. The organic phase is dried over MgSO4, filtered and evaporated. The raw product is purified by crystallisation in hexane to obtain 5.69 g of a white solid, 4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-oxo-2-ethyl]bromobenzene (yield=63%).
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:55][O:56][CH2:57][CH2:58][CH2:59][O:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[OH:67]>ClCCl.CO>[Br:1][C:65]1[CH:64]=[CH:63][C:62]([OH:67])=[C:61]([O:60][CH2:59][CH2:58][CH2:57][O:56][CH3:55])[CH:66]=1
Reactant: COCCCOc1ccccc1O
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: COCCCOc1cc(Br)ccc1O
Reaction time: 0.5 h

Procedure:
6.9 g of tetrabutylammonium tribromide are added in portions, at room temperature, to a solution of 2.6 g of 2-(3-methoxypropyloxy)-phenol in 60 ml of dichloromethane and 40 ml of methanol, and the mixture is then stirred for 30 minutes. The reaction mixture is concentrated by evaporation and the residue is partitioned between diethyl ether and water. The combined organic phases are dried over magnesium sulfate and concentrated by evaporation, and the residue is purified by FC (700 g of silica gel, dichloromethane/diethyl ether=98:2), yielding the title compound: Rf (dichloromethane/diethyl ether=97:3)=0.50; HPLC Rt =14.32 minutes; FAB-MS (M+H)+ =262.
Reaction SMILES: Br[CH2:2][C:3](OCC)=[O:4].[F-].[K+].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[OH:20]>CN(C=O)C>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]2[NH:10][C:3](=[O:4])[CH2:2][O:20][C:12]=2[CH:13]=1)([O-:19])=[O:18]
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1COc2cc([N+](=O)[O-])ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, ethyl bromoacetate (7.2 ml, 65 mmol) was added to a solution of anhydrous potassium fluoride (10 g, 172.1 mmol) in 50 ml anhydrous DMF. The solution was stirred for 30 minutes at room temperature. 2-Amino-5-nitrophenol (Aldrich, 10 g, 65 mmol) was then dissolved in 25 ml of DMF and added dropwise to the reaction with stirring. After the final addition the reaction was warmed to 70 degrees and stirred for 16-24 hours. The reaction was then poured into 300 mls of an ice/water mixture with stirring. A yellow precipitate was formed immediately. The solid was filtered off and dried in vacuo. The product was recrystallized from hot THF. Collected 8.3 g (72.5%) of tan crystals: m.p. 227-230; 'H NMR (300 MHz, DMSO) δ 4.752 (s, 2H, CH2), 7.0835 (d, J=8.73, Hz, 1H, ACH), 7.769 (d, J=2.44 Hz, 1 H) 7.9185 (dd, J=2.525, 8.705 Hz, 1H, ACH); 13C NMR (300 MHz, DMSO) δ 66.560, 111.344, 115.776, 118.738, 134.464, 142.643, 142.861, 164.891. Mass spectrum (EI) m/z 194 M+