Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O.[H][H]>CO.[C].[Pd]>[CH2:8]1[C@H:4]2[C:3](=[O:2])[NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:19])[N:5]2[CH2:6][CH2:7]1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)c1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C1Nc2ccccc2C(=O)N2CCC[C@@H]12
Yield: 76.4 %

Procedure:
To a solution of 6.4 g of (2S)-1-(2-nitrobenzoyl) proline methyl ester in 250 ml of methanol, there was added 1.5 g of a 10% palladium-carbon catalyst and then the resulting mixture was stirred at room temperature for 6 hours in a hydrogen gas atmosphere. The catalyst present in the reaction solution was filtered off and the filtrate was concentrated under reduced pressure to give 3.8 g (yield 75.2%) of the title compound as white crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.O>C(#N)C>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: C1CNCCN1
Reactant: COc1ccnc(Cl)n1
Solvent: CC#N
Solvent: O
Product: COc1ccnc(N2CCNCC2)n1
Yield: 90 %

Procedure:
A suspension of 2-chloro-4-methoxypyrimidine (21.5 g) and piperazine (64.0 g) in acetonitrile (200 ml) was refluxed for 30 min. The reaction mixture was poured into water (500 ml) and extracted with chloroform (400 ml). The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound (26.0 g) as a pale-yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[C:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:23])=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[CH3:24][C:25]([CH3:30])([CH3:29])[C:26](Cl)=[O:27]>>[O:22]=[C:20]1[NH:19][C:18](=[O:23])[C:17](=[CH:16][C:13]2[CH:12]=[CH:11][C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][N:2]([CH3:1])[C:26](=[O:27])[C:25]([CH3:30])([CH3:29])[CH3:24])[CH:5]=3)=[CH:15][CH:14]=2)[S:21]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CNCc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Product: CN(Cc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)C(=O)C(C)(C)C
Yield: 65.3 %

Procedure:
In a manner similar to that of Example 1(d), by reacting 500 mg (0.9 mmol) of 5-(3′-methylaminomethylbiphenyl-4-ylmethylene)thiazolidine-2,4-dione (prepared in Example 12(c)) with 0.3 ml (2.3 mmol) of 2,2-dimethylpropionyl chloride, 240 mg (65%) of the expected product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH:5]([OH:34])[CH2:6][NH:7][CH:8]([CH3:33])[CH2:9][C:10]1[CH:32]=[CH:31][C:13]([O:14][CH2:15][C:16]2O[CH:18]=[C:19]([O:23]CC3C=CC=CC=3)[C:20](=[O:22])[CH:21]=2)=[CH:12][CH:11]=1.[CH3:38][NH2:39]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[CH:5]([OH:34])[CH2:6][NH:7][CH:8]([CH3:33])[CH2:9][C:10]1[CH:32]=[CH:31][C:13]([O:14][CH2:15][C:16]2[N:39]([CH3:38])[CH:18]=[C:19]([OH:23])[C:20](=[O:22])[CH:21]=2)=[CH:12][CH:11]=1
Reactant: CN
Reactant: CC(Cc1ccc(OCc2cc(=O)c(OCc3ccccc3)co2)cc1)NCC(O)c1cccc(Cl)c1
Product: CC(Cc1ccc(OCc2cc(=O)c(O)cn2C)cc1)NCC(O)c1cccc(Cl)c1

Procedure:
A suspension of 2-[4-[2 [(3-chloro-β-hydroxyphenethyl)amino]propyl]phenoxymethyl]-5-benzyloxy-4H-pyran-4-one (1.0 g) in 33% ethanolic methylamine solution (15 ml), was heated to 120° in a sealed vessel for 18 hours. The solvent was evaporated in vacuo and the residue purified by column chromatography on silica using chloroform, then 10% methanol:chloroform as eluent. The resulting gum was dissolved in methanol and 2M hydrochloric acid was added dropwise to bring the pH to 1.5-2.0. The solution was then hydrogenated at room temperature and pressure over 10% palladium on charcoal. After filtration and evaporation of solvent in vacuo the residue was treated with 1.2M sodium hydrogen carbonate solution (5 ml), and extracted with ethyl acetate (3×50 ml), and dried (MgSO4). After filtration and evaporation of solvent the residue was triturated with acetone to give 2-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino]propyl]phenoxymethyl]-5-hydroxy-1-methyl-1H-pyrid-4-one (0.7 g) as a (40:60) mixture of diastereoisomers.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([OH:25])[C@@:10]2([N:22]=[N+:23]=[N-:24])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.S(O)(C(F)(F)F)(=O)=O>C1CCCCC1.C(Cl)Cl.CCOCC>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([O:25][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@:10]2([N:22]=[N+:23]=[N-:24])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2]
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: CCOC(=O)[C@H]1[C@@H]2C[C@@H](O)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOCC
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)[C@H]1[C@@H]2C[C@@H](OCc3ccccc3)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Reaction time: 5 h
Yield: 26.6 %

Procedure:
To a solution of (1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (VII) (305 mg, 0.88 mmol) and benzyl 2,2,2-trichloroacetimidate (0.2 mL, 1.06 mmol) in cyclohexane (2.4 mL) and DCM (1.2 mL) was added TfOH (0.05 mL), whereupon the solution became hot and stirring was continued at 23° C. for 5 h. The reaction mixture was poured on ice, diluted with ether, washed with sat. NaHCO3 -sol., brine and dried over MgSO4. The crude product was purified by silica gel column chromatography with hexane/EtOAc 4:1 to give (1S,2R,3R,5R,6S)-2-azido-3-benzyloxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXIII-3) (102 mg, 27%) as a yellow oil. 1H-NMR (250 MHz, CDCl3) □1.25 (3H, t, J=7.1 Hz), 1.75 (1H, t, J=3.5 Hz), 2.06 (1H, m), 2.17-2.31 (3H, m), 3.60 (1H, bt, J=8 Hz), 4.12 (2H, q, j=7.1 Hz), 4.42 (1H, d, J=12 Hz), 4.57 (1H, d,J=12 Hz), 5.23 (1H, d,J=12 Hz), 5.34 (1H, d,J=12 Hz), 7.15-7.42 (10H, m); MS[ISP] 408 [(M+H-N2)+ ]; □D20 +2.03 ° (c=0.99, CHCl3).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:33]=[C:32](Br)[CH:31]=[CH:30][N:29]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:32]3[CH:31]=[CH:30][N:29]=[C:28]([Cl:27])[CH:33]=3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Br)ccn1
Reactant: Cc1cc(NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)cc(C)n2)ccn1
Product: Cc1cc(NC(=O)c2cc(-c3ccnc(Cl)c3)cc(C)n2)ccn1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide in accordance with the general method of example 131, step 2 using 2-Chloro-4-bromopyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white amorphous, MS (ISP): m/e=339.1, 341.1 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]([C:22](=[O:27])[NH:23][CH:24]3[CH2:26][CH2:25]3)[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO>[CH:24]1([NH:23][C:22](=[O:27])[CH:20]([C:17]2[CH:18]=[CH:19][C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:15][CH:16]=2)[CH3:21])[CH2:25][CH2:26]1
Reactant: CC(C(=O)NC1CC1)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: CO
Product: CC(C(=O)NC1CC1)c1ccc(C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 3.40 g (9.13 mmol) 4-[4-(1-cyclopropylcarbamoyl-ethyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (X.1) in 20 mL methanol are added 10.9 mL (13.7 mmol) 1.25 M HCl in methanol. The mixture is stirred for 12 h at rt. After that time, 2.0 mL 1.25 M HCl in methanol are added and the mixture is stirred for 2 d at 40° C. After that time, the solvent is evaporated, the residue taken up in 1N NaOH and extracted with EtOAc. After drying over sodium sulphate, the solvent is removed in vacuo to yield the desired product.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:4][N:5]([CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: CC1(c2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCCN1CCC(C)(c2ccccc2)CC1
Yield: 93.2 %

Procedure:
To a solution of 4-methyl-4-phenyl piperidine (1.61 g, 9.2 mmol) in 100 mL dioxane was added 3-bromo-N-tert-butoxycarbonyl-propylamine (2.25 g, 9.4 mmol) and K2CO3 (3.48 g, 25.2 mmol) and the resulting suspension was heated to reflux for 10 h. The suspension was allowed to cool, filtered and the solvent was evaporated to obtain yellow residue which was purified by column chromatography (Rf=0.4, 3:1 EtOAc/MeOH) to obtain 3-[4-methyl-4-phenyl-piperidin-1-yl]-N-tert-butoxycarbonyl-propylamine as a yellow oil (2.85 g). It was dissolved in 35 mL of CH2Cl2 and 6.0 mL of trifluoroacetic acid was added with stirring at room temperature under argon atmosphere. After 1 h the solvent was evaporated in vacuo and the residue was basified to pH 10 by adding minimum amount of 1 N KOH solution. The product was extracted with CH2Cl2 (3×35 mL), dried over MgSO4, filtered and the solvent was removed in vacuo to obtain 3-[4-methyl-4-phenylpiperidin-1-yl]propylamine as a viscous yellow oil (1.54 g, 73% for two steps). It was used in the next step without further purification. This step “d” is a representative procedure for putting propylamino tether on any piperidine.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:5][C:6]=1[CH3:7].[H-].[Na+].[CH3:16]I>C1COCC1>[Br:1][C:2]1[C:3]([CH3:13])=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:5]([CH3:16])[C:6]=1[CH3:7]
Reactant: CCOC(=O)c1[nH]c(C)c(Br)c1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)c(Br)c(C)n1C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylate (0.050 mL, 0.610 mmol) in THF (3 mL), was added NaH (36.6 mg, 0.914 mmol). The mixture was stirred for 10 min and then MeI (0.046 mL, 0.731 mmol) was added dropwise. The resulting mixture was stirred overnight. The reaction was quenched with sat. NH4Cl. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine (1×), dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Biotage Horizon, 12M, Si, ˜10 mL/min, 100% hexanes for 36 mL, gradient to 20% EtOAc in hexanes over 1032 mL) to afford ethyl 4-bromo-1,3,5-trimethyl-1H-pyrrole-2-carboxylate. 1H NMR (500 MHz, CDCl3): δ 4.31 (q, J=7.1 Hz, 2H); 3.82 (s, 3H); 2.31 (s, 3H); 2.26 (s, 3H); 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: COC(C1[C@@H](C2C=CC(C#N)=CC=2)N=C(NN)N(C2C=CC=C(C(F)(F)F)C=2)C=1C)=O.[CH3:32][O:33][C:34]([C:36]1[CH:37]([C:59]2[CH:64]=[CH:63][C:62]([C:65]#[N:66])=[CH:61][CH:60]=2)[N:38]=[C:39]([NH:53][NH:54][C:55]([O:57][CH3:58])=[O:56])[N:40]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:52])([F:51])[F:50])[CH:44]=2)[C:41]=1[CH3:42])=[O:35]>>[CH3:32][O:33][C:34]([C:36]1[C@@H:37]([C:59]2[CH:64]=[CH:63][C:62]([C:65]#[N:66])=[CH:61][CH:60]=2)[N:38]=[C:39]([NH:53][NH:54][C:55]([O:57][CH3:58])=[O:56])[N:40]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:50])([F:51])[F:52])[CH:44]=2)[C:41]=1[CH3:42])=[O:35]
Reactant: COC(=O)NNC1=NC(c2ccc(C#N)cc2)C(C(=O)OC)=C(C)N1c1cccc(C(F)(F)F)c1
Agent: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(NN)=N[C@@H]1c1ccc(C#N)cc1
Product: COC(=O)NNC1=N[C@H](c2ccc(C#N)cc2)C(C(=O)OC)=C(C)N1c1cccc(C(F)(F)F)c1

Procedure:
Intermediate 11 (381 mg) was prepared from Intermediate 10 (782 mg, 1.8 mmol) according to an analogous procedure to that described for Intermediate 3.
Reaction SMILES: [CH:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:27]([NH2:29])=[O:28])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])=[CH2:2].Cl.[CH3:31][O:32][NH2:33].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[I-].[Na+]>[CH3:31][O:32][NH:33][CH2:2][CH2:1][S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:27]([NH2:29])=[O:28])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4]
Reactant: CON
Reactant: C=CS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CS(C)=O
Product: CONCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Temperature: 80 °C
Yield: 45.3 %

Procedure:
The mixture of 3-[1-(ethenylsulfonyl)-4-piperidinyl]-5-phenyl-1H-indole-7-carboxamide (41 mg, 0.1 mmol) in DMSO (2.0 mL), were added O-methylhydroxylamine hydrochloride (83.5 mg, 1.0 mmol), K2CO3 (70.0 mg, 0.70 mmol) and sodium iodide (0.5 mg). The reaction solution was heated to 80° C. overnight. The reaction mixture was concentrated and purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (20.7 mg, 43%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:20]([CH3:38])[C@@H:21]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C@@H:22]([CH3:27])/[CH:23]=[CH:24]\[CH:25]=[CH2:26])[C@@H:3]([CH3:19])[C:4]([N:6]1[C@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][O:8][C:7]1=[O:18])=[O:5].N1C(C)=CC=CC=1C.C(Cl)Cl.[Si:50](OS(C(F)(F)F)(=O)=O)([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51]>CCOCC>[CH3:54][C:53]([Si:50]([CH3:52])([CH3:51])[O:1][C@@H:2]([C@H:20]([CH3:38])[C@@H:21]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)[C@@H:22]([CH3:27])/[CH:23]=[CH:24]\[CH:25]=[CH2:26])[C@@H:3]([CH3:19])[C:4]([N:6]1[C@H:10]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:9][O:8][C:7]1=[O:18])=[O:5])([CH3:56])[CH3:55]
Reactant: C=C/C=C\[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)[C@H](O)[C@@H](C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: Cc1cccc(C)n1
Product: C=C/C=C\[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 86.7 %

Procedure:
A solution of (4R)-3-[(2R,3S,4S,5S,6S,7Z)-3-hydroxy-5-[(4-methoxyphenyl)methoxy]-2,4,6-trimethyl-1-oxo-7,9-decadienyl]-4-(phenylmethyl)-2-oxazolidinone (3.4 g, 6.53 mmol), 2,6-lutidine (3.5 g, 32.65 mmol) and methylene chloride (100 mL) is cooled to 0° C. TBSOTf (7.12 g, 26.94 mmol)is added over 30 min and the resultant mixture is allowed to react overnight at 0° C. The mixture is diluted with ether (300 mL), washed with aqueous NaHSO4, brine, and concentrated. Flash chromatography affords the desired compound (3.6 g, 87%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8](SC)[C:9]3[C:10](=[CH:12][S:13][CH:14]=3)[NH:11][C:5]=2[CH:4]=1.O.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([N:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)[C:9]3[C:10](=[CH:12][S:13][CH:14]=3)[NH:11][C:5]=2[CH:4]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc2c(c1)Nc1cscc1C(SC)=N2
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(c1)Nc1cscc1C(N1CCN(C)CC1)=N2

Procedure:
A solution of 6-methoxy-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in excess N-methylpiperazine and glacial acetic acid is heated at reflux for 2 days. The solution is poured into water and the product is collected.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[C:17]([C:40]4[CH:45]=[CH:44][C:43]([CH2:46]O)=[CH:42][CH:41]=4)=[N:18][N:19]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1.[CH3:48][NH:49][CH3:50]>[O-2].[Mn+4].[O-2].C(Cl)(Cl)Cl>[CH3:48][N:49]([CH3:50])[CH2:46][C:43]1[CH:44]=[CH:45][C:40]([C:17]2[C:16]([C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)=[CH:8][N:9]=4)[CH:12]=3)=[CH:20][N:19]([C:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:18]=2)=[CH:41][CH:42]=1
Reactant: CNC
Reactant: OCc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CN(C)Cc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1

Procedure:
A mixture of 296 mg {4-[4-(3-pyridin-2-ylimidazo[1,2-a]pyridin-6-yl)-1-trityl-1H-pyrazol-3-yl]phenyl}methanol (compound in Example 359), 844 mg manganese (IV) oxide and 20 mL chloroform was heated for 1 hour under reflux. The reaction solution was cooled to remove insolubles, and the filtrate was evaporated. 264 mg crude product of 4-[4-(3-pyridin-2-ylimidazo[1,2-a]pyridin-6-yl)-1-trityl-1H-pyrazol-3-yl]benzaldehyde was obtained as a pale brown amorphous. From 100 mg of this aldehyde derivative and 35 μL dimethylamine (50% aqueous solution), 81 mg of the title compound was obtained as a colorless amorphous under the same conditions as in Production Example 153.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=O)[CH3:2].Cl.[S:10]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1)(=[O:13])(=[O:12])[NH2:11]>>[S:10]([C:14]1[CH:15]=[CH:16][C:17]([NH:20][N:21]=[C:1]([C:4]2[S:5][CH:6]=[CH:7][CH:8]=2)[CH3:2])=[CH:18][CH:19]=1)(=[O:13])(=[O:12])[NH2:11]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: CC(=O)c1cccs1
Agent: Cl
Product: CC(=NNc1ccc(S(N)(=O)=O)cc1)c1cccs1

Procedure:
A solution of 2-acetylthiophene (5 mmol) and 4-sulfamylphenylhydrazine hydrochloride is subjected to the General Procedure. The title compound is isolated as described in the general procedure.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[C:15]([NH2:17])[N:14]=[CH:13][N:12]=2)=[CH:6][CH:5]=1)[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[N:28]=[C:29]=[O:30]>>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[NH:28][C:29]([NH:17][C:15]1[CH:16]=[C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:18][CH3:19])=[CH:9][CH:8]=2)[N:12]=[CH:13][N:14]=1)=[O:30]
Reactant: CCN(CC)c1ccc(Nc2cc(N)ncn2)cc1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Product: CCN(CC)c1ccc(Nc2cc(NC(=O)Nc3c(Cl)cccc3Cl)ncn2)cc1

Procedure:
The title compound is prepared analogously as described in Example 105A from N-(4-diethylamino-phenyl)-pyrimidine-4,6-diamine and 2,6-dichlorophenyl isocyanate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[S:36]([C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=1)[C:42]([OH:44])=[O:43])(=[O:38])=[O:37]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[S:36]([C:39]3[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=3)[C:42]([OH:44])=[O:43])(=[O:38])=[O:37])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)S(=O)(=O)c3cccc(C(=O)O)c3)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, 3-(chlorosulfonyl)benzoic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=1[O:18][CH3:19])([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[C:30]([C:33](O)=[O:34])[NH:31][CH:32]=2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[C:30]([C:33]([NH:17][C:14]3[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][NH:7][C:6](=[O:20])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[C:12]([O:18][CH3:19])[CH:13]=3)=[O:34])[NH:31][CH:32]=2)=[CH:24][CH:23]=1
Reactant: COc1cc(N)ccc1OCCNC(=O)OC(C)(C)C
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Product: COc1cc(NC(=O)c2cc(-c3ccc(Cl)cc3)c[nH]2)ccc1OCCNC(=O)OC(C)(C)C

Procedure:
tert-Butyl-(4-amino-2-methoxyphenoxy)ethylcarbamate was converted to the title compound (80 mg) by acylation with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid (25 mg) following the procedure described in step C of Example 1. MS (ESI) 386 (M-Boc)+.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.Br[CH:35]([C:37]1[CH:42]=[CH:41][C:40]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH:39][CH:38]=1)[CH3:36].[I-].[Na+]>CN(C=O)C.C(OCC)(=O)C.CCOCC.O>[CH3:46][S:43]([C:40]1[CH:41]=[CH:42][C:37]([CH:35]([N:7]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[C:5]([CH2:4][C:3]([OH:2])=[O:15])=[C:6]2[CH3:14])[CH3:36])=[CH:38][CH:39]=1)(=[O:44])=[O:45]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: CC(Br)c1ccc(S(C)(=O)=O)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1c(CC(=O)O)c2cccnc2n1C(C)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
A solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((2.37 g, 11.12 mmol) in dry DMF (38 ml) at room temperature is treated with BEMP (4.39 ml, 15.19 mmol) dropwise. The reaction mixture is stirred at room temperature for 35 minutes and then 1-(1-bromo-ethyl)-4-methanesulfonyl-benzene (4.00 g, 15.18 mmol) and sodium iodide (12.29 g, 15.28 mmol) is added. After stirring at 60° C. for 1 hour, the reaction mixture is allowed to cool to room temperature and then diluted with ethyl acetate/ether (200 ml of a 1:1 mixture) and water (150 ml). The organic portion is washed with brine, dried (Na2SO4) and concentrated in vacuo and the resulting crude is purified by chromatography on silica eluting with ethyl acetate/iso-hexane (2:3 increasing to 1:1 ethyl acetate) to yield the titled product as a racemic mixture. The enantiomers are resolved using a chiralcel OD column eluting with 30% IPA in hexanes to afford enantiomer A (retention time=14.33 minutes) and enantiomer B (retention time=17.68 minutes)
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C@@H:11]([CH2:16][NH:17][C:18](=[O:37])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[C:12]([O:14]C)=[O:13])[CH2:7][CH2:6]1)(=[O:4])=[O:3].CS(N1CCN([C@@H](CNC(=O)C2C=CC(OCC3C=CC(F)=CC=3)=CC=2)C(O)=O)CC1)(=O)=O>>[CH3:1][S:2]([N:5]1[CH2:6][CH2:7][N:8]([C@@H:11]([CH2:16][NH:17][C:18](=[O:37])[C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=3)=[CH:23][CH:24]=2)[C:12]([OH:14])=[O:13])[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: COC(=O)[C@H](CNC(=O)c1ccc(OCc2ccc(C(F)(F)F)cc2)cc1)N1CCN(S(C)(=O)=O)CC1
Agent: CS(=O)(=O)N1CCN([C@@H](CNC(=O)c2ccc(OCc3ccc(F)cc3)cc2)C(=O)O)CC1
Product: CS(=O)(=O)N1CCN([C@@H](CNC(=O)c2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)C(=O)O)CC1

Procedure:
In a manner similar to example 2-5, starting from 240 mg (0.4 mmol) of methyl (S)-2-(4-methanesulphonylpiperazin-1-yl)-3-[4-(4-trifluoromethylbenzyloxy)-benzoylamino]propanoate, 200 mg (82%) of (S)-2-(4-methanesulphonylpiperazin-1-yl)-3-[4-(4-fluorobenzyl-oxy)benzoylamino]propanoic acid are obtained in the form of a white solid.