Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]([N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[CH:16]1)=[CH2:14].[CH:24](OCC)=[O:25].C(O)(=O)C>CCCCCC.O1CCCC1.C(OCC)(=O)C.O>[CH:13]([N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[CH:24]=[O:25])=[CH2:14]
Reactant: CCOC=O
Reactant: C=Cn1cnc2ccccc21
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: O
Solvent: CC(C)NC(C)C
Product: C=Cn1c(C=O)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
To a cold (-78° C.) solution of dry tetrahydrofuran (300 ml) containing 13.27 ml (94.6 mmoles) of diisopropylamine was added 37.86 ml of 2.5M solution of n-butyl lithium in hexane and the mixture stirred for 30 minutes. 1-Vinylbenzimidazole (13.6 g, 94.6 mmoles) in 50 ml of tetrahydrofuran was added and the mixture stirred for 30 minutes. Ethyl formate (8.4 ml, 104.1 mmoles) was then added and the reaction mixture stirred, allowing to warm to room temperature, overnight. Acetic acid (5.4 ml, 99.6 mmoles) was added and the reaction added to 500 ml of water and 300 ml of ethyl acetate. The organic layer was separated, the water layer extracted with additional ethyl acetate (2×100 ml), and the organic phases combined, dried over magnesium sulfate and concentrated to an oil, 17 g. The residue was purified by chromatographing on 700 g of silica gel using ethyl acetate-chloroform (1:9; v:v) as the eluent to give 6.7 g of product as a light brown solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19](Cl)[N:18]=1>>[Cl:16][C:17]1[N:18]=[C:19]([O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([NH:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=2)[CH:20]=[N:21][CH:22]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(=O)Nc1ccc(O)c2ccccc12
Product: CC(=O)Nc1ccc(Oc2cncc(Cl)n2)c2ccccc12
Yield: 68.2 %

Procedure:
Method DD was followed (in a round-bottomed flask, reaction time: 20 hours) with N-(4-hydroxynaphthalen-1-yl)acetamide (1.22 g, 6.08 mmol) and 2,6-dichloropyrazine (1.09 g, 7.30 mmol). The DMF was evaporated in vacuo. The resulting crude was dissolved in a mixture (hot) of AcOEt (25 mL) and acetone (175 mL) and filtered. The volume of the filtrate was reduced to 100 mL and this filtrate crystallised upon storage at low temperature to yield the title compound (1.30 g). Yield: 68%. 1H NMR (500 MHz, DMSO-d6) δ 2.21 (s, 3H), 7.42 (d, 1H, J=8.2 Hz), 7.57 (t, 1H, J=7.5 Hz), 7.64 (t, 1H, J=7.6 Hz), 7.72 (d, 1H, J=8.1 Hz), 7.90 (d, 1H, J=8.3 Hz), 8.16 (d, 1H, J=8.5 Hz), 8.52 (s, 1H), 8.72 (s, 1H), 10.02 (s, 1H). 13C NMR (125.8 MHz, DMSO-d6) δ 23.42, 117.59, 121.40, 121.65, 123.42, 126.53, 126.71, 126.85, 128.90, 131.85, 133.59, 137.50, 144.40, 145.04, 158.92, 169.04. m/z 314.0 [(M+H)+ calcd for C16H12ClN3O2 313.1].
Reaction SMILES: C1([C@H]([N:9]2[CH2:14][CH2:13][O:12][C@@H:11]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)=[CH:17][CH:16]=3)[CH2:10]2)C)C=CC=CC=1.C([O-])=O.[NH4+].CO.O>O1CCCC1.[Pd]>[NH:9]1[CH2:14][CH2:13][O:12][C@@H:11]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:19][CH:20]=2)[CH2:10]1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(Nc3ccccn3)cc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(Nc2ccc([C@H]3CNCCO3)cc2)nc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of N-(4-((2S)-4-((1R)-1-phenylethyl)morpholin-2-yl)phenyl)-pyridin-2-amine (0.89 g, 2.5 mmol) and ammonium formate (0.78 g, 12.5 mmol) in tetrahydrofuran (15ml)-methanol (24 ml)-water (18 ml) was added 10% palladium on carbon (wet, 200 mg) and the mixture was stirred at 95° C. for one hour. After filtration, the solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was concentrated under reduced pressure to yield N-(4-((2S)-Morpholin-2-yl)phenyl)pyridin-2-amine (0.60 g, 94%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([I:13])[CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23]([CH:25]2[CH2:27][CH2:26]2)=[O:24])=[CH:17][C:16]=1[NH:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>C(Cl)Cl>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23]([CH:25]2[CH2:27][CH2:26]2)=[O:24])=[CH:17][C:16]=1[N:28]([C:7](=[O:8])[NH:6][C:4](=[O:5])[C:3]1[CH:9]=[CH:10][C:11]([I:13])=[CH:12][C:2]=1[F:1])[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C2CC2)ccc1Cl
Reactant: O=C=NC(=O)c1ccc(I)cc1F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN(C(=O)NC(=O)c1ccc(I)cc1F)c1cc(CNC(=O)C2CC2)ccc1Cl
Yield: 18.5 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-9 by using 2-fluoro-4-iodobenzoyl isocyanate (Intermediate-47, 0.500 g, 1.71 mmol), tert-butyl 2-(2-chloro-5-(cyclopropanecarboxamidomethyl)phenyl)hydrazine carboxylate (0.582 g, 1.71 mmol) and DCM (20 mL) to afford 0.200 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 0.69 (m, 4H), 1.42 (s, 9H), 1.56 (m, 1H), 4.17 (d, J=5.7 Hz, 2H), 6.58-6.63 (m, 2H), 7.18 (d, J=8.1 Hz, 1H), 7.30 (m, 3H), 7.63-7.79 (m, 2H), 8.53 (m, 1H), 8.90 (s, 1H); MS (m/z): 630.85 (M+H)+.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:24][C:25]([C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)[CH:26]=O>C1COCC1>[CH3:24][C:25]([C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)[CH2:26][CH:2]=[O:3]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(CC(C)(C=O)c2cccnc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccc(CC(C)(CC=O)c2cccnc2)cc1
Reaction time: 0.25 h

Procedure:
Under N2 Lithium bis(trimethylsilyl)amide solution (10.5 ml, 10.5 mmol, 1.0M in THF) was added to a mixture of methoxy methyltriphenyl phosphonium chloride (3.43 g, 10 mmol) in 25 ml THF dropwise at 0° C. After 15 min, it was added to a solution of the product of STEP 4 (1.65 g, 6.5 mmol) in 15 ml THF at 0° C. The reaction was stirred for 1 h and quenched with brine. The product was extracted with ethyl acetate. The organic layer was concentrated. The residue was dissolved in 50 ml THF and 50 ml 2N HCl solution. The reaction was stirred at room temperature for 18 h, and THF was evaporated. The residue was dilute with ethyl acetate and basified with 1N NaOH solution. The product was extracted thoroughly with ethyl acetate. The organic layer was washed with brine, and dried with MgSO4, and concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate/hexane=3/1) to yield a brown oil in 1.37 g. NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][C@H:9]1[C:25]([N:27]1[CH2:31][CH2:30][S:29][CH2:28]1)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(C1C=CC(S(N[C@@H]2CN[C@H](C(N3CCSC3)=O)C2)(=O)=O)=CC=1)#N.C(=O)([O-])[O-].[K+].[K+].[C:63]([C:65]1[CH:72]=[CH:71][C:68]([CH2:69]Br)=[CH:67][CH:66]=1)#[N:64].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:69][C:68]2[CH:71]=[CH:72][C:65]([C:63]#[N:64])=[CH:66][CH:67]=2)[S:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=2)(=[O:15])=[O:16])[CH2:10][C@H:9]1[C:25]([N:27]1[CH2:31][CH2:30][S:29][CH2:28]1)=[O:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NS(=O)(=O)c2ccc(C#N)cc2)C[C@H]1C(=O)N1CCSC1
Agent: Cl
Agent: N#Cc1ccc(S(=O)(=O)N[C@@H]2CN[C@H](C(=O)N3CCSC3)C2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](N(Cc2ccc(C#N)cc2)S(=O)(=O)c2ccc(C#N)cc2)C[C@H]1C(=O)N1CCSC1
Reaction time: 4 h
Yield: 84.3 %

Procedure:
3-[(2S,4S)-1-tert-Butoxycarbonyl-4-(4-cyanophenylsulfonyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine [product of Example 123 (1), 856 mg] was dissolved in DMF (20 mL), and potassium carbonate (380 mg) and 4-cyanobenzyl bromide (400 mg) were added thereto at room temperature. The mixture was stirred for 4 hr. To the reaction mixture was added 10% citric acid solution, and the precipitate was collected by filtration to give 3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(4-cyanophenylmethyl)-N-(4-cyanophenylsulfonyl)amino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (900 mg) as a pale-yellow solid.
Reaction SMILES: C(OP([CH2:9][P:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.C([Li])CCC.C(OC([N:28]1[CH2:32][CH2:31][C:30](=O)[CH:29]1[C:34]([O:36]CC)=[O:35])=O)C>O1CCCC1>[CH2:16]([O:15][P:10]([CH2:9][O:36][C:34]([CH:29]1[CH:30]=[CH:31][CH2:32][NH:28]1)=[O:35])([O:12][CH2:13][CH3:14])=[O:11])[CH3:17]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: CCOC(=O)C1C(=O)CCN1C(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOP(=O)(COC(=O)C1C=CCN1)OCC
Temperature: 25 °C

Procedure:
A stirred solution of 5.3 ml of bis-(diethylphosphono)methane in 30 ml of anhydrous tetrahydrofuran (THF) under nitrogen is cooled to -78° and 8.5 ml of 2.5M butyl lithium is added dropwise. After stirring 5 minutes a solution of 4.64 g of ethyl 1-ethoxycarbonyl-3-oxo-pyrrolidine-2-carboxylate [J. Am. Chem. Soc. 86, 5297 (1964)] in 30 ml dry THF is added dropwise rapidly. The solution is heated at reflux for 18 hours, cooled to room temperature and concentrated; 40 ml of 1N hydrochloric acid is added and the mixture is extracted with 100 ml of methylene chloride. The organic fraction is washed with 25 ml water, dried over Na2SO4, filtered and concentrated. Purification by flash chromatography using ethyl acetate as solvent yields ethyl 1-ethoxycarbonyl-3-(diethylphosphonomethyl-2,5-dihydropyrrole-2-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][C:8](=[CH:13][N:14](C)[CH3:15])[C:7](=O)[C:6]=2[CH:18]=1.C(O)(=O)C.C(N)=[NH:24]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][C:8]3[CH:13]=[N:14][CH:15]=[N:24][C:7]=3[C:6]=2[CH:18]=1
Reactant: N=CN
Reactant: CN(C)C=C1CC(=O)Nc2ccc(Br)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Cc2cncnc2-c2cc(Br)ccc2N1
Yield: 83 %

Procedure:
Analogous to Scheme 1, from 7-bromo-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and formamidine acetate. Yield: 83%.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:17](Cl)(=[O:19])=[O:18])[CH:15]=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1.[N+:21]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)([O-:23])=[O:22]>N1C=CC=CC=1>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:17]([NH:28][C:27]4[CH:29]=[CH:30][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=4)(=[O:19])=[O:18])[CH:15]=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: Cc1nc2c(c(=O)[nH]1)-c1cc(S(=O)(=O)Cl)ccc1CC2
Solvent: c1ccncc1
Product: Cc1nc2c(c(=O)[nH]1)-c1cc(S(=O)(=O)Nc3ccc([N+](=O)[O-])cc3)ccc1CC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1,2,5,6-Tetrahydro-3-methyl-1-oxobenzo[f]quinazolin-9-sulfonyl chloride (0.53 g, 1.7 mmole) and p-nitroaniline (0.25 g, 1.8 ammole) (Eastman) were dissolved in pyridine (5 ml) and the reaction mixture stirred at room temperature for 48 hours. The pyridine was removed in vacuo, and the residue washed with water. The dried solid was subjected to chromatography on silica (80 g), eluting with methanol-methylene chloride(1:19). Fractions containing product were evaporated to dryness, the residue sonicated with ether (75 ml) and filtered. The beige solid was washed with ether and dried under high vacuum to yield 1,2,5,6-tetrahydro-3-methyl-4'-nitro-1-oxobenzo[f]qu- inazoline-9-sulfonanilide. (0.18 g, 26%). Mp>2400 C. 1H NMR (DMSO-d61 300 MHz) δ: 2.32 (s, 3H, CH3); 2.72 (m, 2H, Ar CH2J, 2.91 (m, 2H, ArCH2); 7.33 (d, J=9Hz, 2H, Ar); 7.43 (d, J=8Hz, 1H, Ar); 7.69(dd, J=2,8 Hz, Ar); 8.13 (d, J=9Hz, 2H, Ar); 9.23 (d, J=2Hz, 1H, Ar); 11.13 (s, 1H, NH); 12.73 (s, 1H, NH). Anal Calculated for C19H16N4 05S.13/25 H2O: C,54.10; H,4.07; N,13.28; S,7.60. Found: C,54.07; H,3.98; N,13.19; S,7.66.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].C([Li])CCC.[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26]>C1COCC1>[Cl:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]([OH:26])[C:4]1[C:3]([C:1]#[N:2])=[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[S:6][C:5]=1[C:14]([OH:16])=[O:15]
Reactant: N#Cc1cc(C(=O)O)sc1N1CCOCC1
Reactant: O=Cc1ccccc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1C(O)c1ccccc1Cl
Temperature: -70 °C
Reaction time: 2 h
Yield: 18.9 %

Procedure:
A solution of 4-cyano-5-morpholin-4-ylthiophene-2-carboxylic acid (0.1 g, 0.42 mmol) in anhydrous THF (1.5 mL) was cooled down to −70° C. To this cooled solution was added a 2.5 M solution of n-butyl lithium in hexanes (0.672 mL, 1.68 mmol) dropwise under nitrogen. The resulting solution was stirred at −70° C. for 2 h and 2-chlorobenzaldehyde (0.142 mL, 1.26 mmol) was added. The reaction mixture was stirred at −70° C. for a further 2 h and was quenched with water. The mixture was concentrated to a small volume and the aqueous residue was washed with EtOAc. The aqueous solution was separated, acidified with 1N HCl and extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by column chromatography to give 3-[(2-chlorophenyl)(hydroxy)methyl]-4-cyano-5-morpholin-4-ylthiophene-2-carboxylic acid (61) (0.03 g, 19%). LCMS: (FA) ES+ 319.0. 1H NMR (400 MHz, d6-DMSO) δ: 7.39-7.41 m, 1H), 7.31-7.33 (m, 1H), 7.23-7.27 (m, 2H), 6.19 (s, 1H), 5.74 (s, 1H), 3.70-3.72 m, 4H) and 3.38-3.40 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH:4]([C:18]([O:20][CH3:21])=[O:19])[CH2:3]1.[CH2:22](O)[CH2:23][OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:24]1[C:2]2([CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:9])[CH:4]([C:18]([O:20][CH3:21])=[O:19])[CH2:3]2)[O:1][CH2:22][CH2:23]1
Reactant: OCCO
Reactant: COC(=O)C1CC(=O)CCN1C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COC(=O)C1CC2(CCN1C(=O)OCc1ccccc1)OCCO2

Procedure:
A solution of the product of stage (ii) (5.06 g) and 1,2-ethanediol (1.06 ml) in benzene (100 ml) containing 4-toluenesulphonic acid (0.2 g) was stirred at reflux temperature under a Soxhlet cup filled with 4 Å molecular sieves for 4 h. The reaction mixture was allowed to cool to 22°, washed with 2N sodium carbonate (2×20 ml), water (20 ml) and dried. The benzene solution was evaporated in vacuo to give the title compound as an oil (5.75 g).
Reaction SMILES: [NH2-].[Na+].C1(C)C=CC=CC=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]#[N:19])=[CH:13][CH:12]=1.Cl[C:21]1[S:22][CH:23]=[CH:24][N:25]=1>O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[C:18]#[N:19])=[CH:13][CH:12]=1
Reactant: Clc1nccs1
Reactant: N#CCc1ccc(Cl)cc1
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC(c1ccc(Cl)cc1)c1nccs1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
At 0°-5°C add a suspension of 28.5 g. of sodamide in 300 ml. of toluene to a stirred solution containing 50 g. of p-chlorphenylacetonitrile and 40 g. of 2-chlorothiazole in 400 ml. of toluene. Maintain the temperature at 20°C for 2 hrs. and finally at 60°C. for 1 hr. Consecutively add 100 ml. of water and 35 ml. of acetic acid at 0°-10°C and filter the resulting mixture. Separate the toluene layer, concentrate in vacuo and distill the residue to give α-(p-chlorphenyl)-2-thiazolylacetonitrile as a mobile yellow oil, b.p. 155°-160°C/1 mm.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[N+:7]([O-])[CH:8]=[CH:9][CH:10]=1.P(Cl)(Cl)([Cl:18])=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Cl:18][C:8]1[N:7]=[CH:6][C:5]([O:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[F:1])=[CH:10][CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cccc(Oc2ccccc2F)c1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Fc1ccccc1Oc1ccc(Cl)nc1

Procedure:
A solution of 25 g of 3-(o-fluorophenoxy)pyridine N-oxide in 50 ml of chloroform is added dropwise to 77 g of refluxing phosphorous oxychloride. The mixture is refluxed for 2 hours. The mixture is concentrated at reduced pressure. The oil is dissolved in 500 ml dichloromethane, washed with 50 ml of ice cold concentrated ammonium hydroxide and dried over anhydrous MgSO4. The organic phase is separated, concentrated at reduced pressure and distilled to yield the mixture of desired chlorinated pyridines as an oil, bp 92°-105° C. at 0.1 mm. The oil is dissolved in 50 ml of toluene and chromatographed over 450 g of silica gel in toluene to yield in the first eluate 6-chloro-3-(o-fluorophenoxy)pyridine. Continued elution with toluene yields 2-chloro-3-(o-fluorophenoxy)pyridine. Finally elution with toluene-methanol (50:50) yields 4-chloro-3-(o-fluorophenoxy)pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)=[CH:22][C:4]=1[CH2:5][NH:6][CH:7]1[CH2:12][CH2:11][CH:10]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:8]1.[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[C:42]([F:47])[C:36]=2[S:37][C:38]=1[C:39](Cl)=[O:40]>>[Cl:33][C:34]1[C:35]2[C:45]([F:46])=[CH:44][CH:43]=[C:42]([F:47])[C:36]=2[S:37][C:38]=1[C:39]([N:6]([CH2:5][C:4]1[CH:22]=[C:23]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)[CH:24]=[CH:25][C:3]=1[O:2][CH3:1])[CH:7]1[CH2:8][CH2:9][CH:10]([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH2:12]1)=[O:40]
Reactant: COc1ccc(-c2ccnc(C)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Product: COc1ccc(-c2ccnc(C)c2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Crude biaryl amine 88 (1.96 g, 4.45 mmol) is treated with acid chloride 8 (1.43 g, 5.35 mmol) using Method D to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[S:16][CH:15]=2)[N:11]([CH3:30])[N:10]=1.[Br:31]Br.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:23][CH:24]=3)[S:16][C:15]=2[Br:31])[N:11]([CH3:30])[N:10]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1csc(-c2ccc(OC(F)(F)F)cc2)c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1cc(-c2ccc(OC(F)(F)F)cc2)sc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.9 %

Procedure:
A solution of 3-(2-chloro-6-fluorophenyl)-1-methyl-5-[5-(4-trifluoromethoxyphenyl)thien -3-yl]-1H-1,2,4-triazole (0.26 g, 0.6 mmol) in glacial acetic acid (7 mL) was cooled to 6° C. Bromine (0.1 g, 32 μL, 0.6 mmol) was added to the reaction and allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was poured into water (50 mL) and extracted with ether (3×30 mL). The combined ethereal extracts were washed with water (100 mL), saturated aqueous sodium bicarbonate (100 mL), aqueous sodium bisulphite (10% solution, 50 mL) and brine (70 mL), dried over magnesium sulphate and concentrated. Column chromatography gave the product (297 mg, 97%) as a yellowish solid: mp 135-136° C.; 1H NMR (CDCl3) δ 7.57 (d, 1H), 7.25-7.40 (m, 5H), 7.12 (t, 1H), 4.04 (s, 3H); EI/MS 533 m/c (M+).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]([CH2:10][N+:11]([O-])=O)[CH2:7][CH2:8][CH3:9])C.[H][H]>CO>[CH2:7]([CH:6]1[CH2:10][NH:11][C:4](=[O:3])[CH2:5]1)[CH2:8][CH3:9]
Reactant: CCCC(CC(=O)OCC)C[N+](=O)[O-]
Reactant: [H][H]
Solvent: CO
Product: CCCC1CNC(=O)C1
Yield: 78.7 %

Procedure:
300 g (1.476 mol) of 3-nitromethyl-hexanoic acid ethyl ester (B) are diluted in methanol (500 ml). The mixture is transferred to an autoclave of 1 L. The reaction mixture is allowed to react at 55° C. under 50 bars of hydrogen pressure for 28 h. The catalyst is filtered on celite and washed with methanol. The filtrate is recovered with 500 ml of dichloromethane. Then, the solution is extracted with water (2×400 ml). The organic layers are dried with MgSO4, filtered and concentrated to afford an oil residue (177.12 g, HPLC purity=82.6%) which is purified by distillation (110° C., 7.10−2 mbar). 147.82 g of (C) are obtained (Yield=78.7%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[N+:17]([C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[O:22][CH2:23][CH:24]1[CH2:26][O:25]1)([O-])=O.C([O-])=O.[NH4+]>CCO.[Pd]>[NH2:17][C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[O:22][CH2:23][CH:24]([OH:25])[CH2:26][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:5][CH2:6]1
Reactant: O=[N+]([O-])c1ccccc1OCC1CO1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccccc1OCC(O)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
A solution of 1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one (0.434 g, 2.0 mmol), 2-[(2-nitrophenoxy)methyl]oxirane (0.390 g g, 2.0 mmol) in EtOH (95%, 3 ml, was stirred for 2 hours at 78° C. The reaction mixture was cooled and Pd—C (5%, 0.20 g) was added. Then ammonium formiate (1.26 g, 20 mmol) was added in portions during 5 min. After 90 min the reaction mixture was filtered through Celite, concentrated, partioned between dichloromethane and ammonium hydoxide (25%) and purified on silica (dichloromethane-methanol, 12:1, containing 1% of NH4OH (25%)) to give the subtitle compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:25]=[C:24]([Cl:26])[C:6]([C:7]([C:9]2[C:17]3[C:12](=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])=[C:5]([Cl:27])[CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][NH2:35]>C(#N)C.O>[Cl:27][C:5]1[CH:4]=[C:3]([CH2:2][NH:35][CH3:34])[CH:25]=[C:24]([Cl:26])[C:6]=1[C:7]([C:9]1[C:17]2[C:12](=[C:13]([NH:18][C:19]([CH:21]3[CH2:22][CH2:23]3)=[O:20])[N:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8]
Reactant: CN
Reactant: O=C(c1c(Cl)cc(CBr)cc1Cl)c1c[nH]c2c(NC(=O)C3CC3)nccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CNCc1cc(Cl)c(C(=O)c2c[nH]c3c(NC(=O)C4CC4)nccc23)c(Cl)c1
Yield: 15.7 %

Procedure:
To a solution of N-{3-[4-(bromomethyl)-2,6-dichlorobenzoyl]-1H-pyrrolo[2,3-c]pyridin-7-yl}cyclopropanecarboxamide (50 mg, 0.11 mmol) in acetonitrile, cesium carbonate (70 mg, 0.21 mmol) was added and stirred at same temperature. Methyl amine (6.8 mg, 0.21 mmol) was added at 0° C. The reaction mixture was then stirred at room temperature for 3 h. On completion, the reaction mixture was diluted with water and extracted with ethyl acetate, organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under vacuum. Purification by silica gel (100-200) column chromatography using dichloromethane and methanol gradient as eluent afforded N-(3-{2,6-dichloro-4-[(methylamino)methyl]benzoyl}-1H-pyrrolo[2,3-c]pyridin-7-yl)cyclopropanecarboxamide (7.2 mg, 16%).