Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][N:14]1[C:19](=[O:20])[C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:24][CH:23]=2)=[C:17]([CH2:36][CH2:37][CH3:38])[N:16]2[N:39]=[CH:40][N:41]=[C:15]12>C(OCC)(=O)C>[CH3:13][N:14]1[C:19](=[O:20])[C:18]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[NH:3][C:4](=[O:7])[O:5][N:35]=3)=[CH:26][CH:27]=2)=[C:17]([CH2:36][CH2:37][CH3:38])[N:16]2[N:39]=[CH:40][N:41]=[C:15]12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A mixture of hydroxylammonium chloride (1.49 g), sodium hydrogen carbonate (2.4 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-[(4-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.52 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.28 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.24 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.24 g, 38%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:44][CH2:45][C:46]([NH2:48])=[O:47])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:40][CH2:39][N:38]([CH2:44][CH2:45][C:46]([NH2:48])=[O:47])[CH2:43][CH2:42]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: NC(=O)CCN1CCNCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCC(N)=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 3-piperazin-1-yl-propionamide (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C36H45Cl2N6O3 [(M+H)+] 679.2925, observed 679.2928.
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:4]([CH3:18])[C:3]=1[C:19]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:23][CH2:22]1)=[O:20].[N:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[N:34][CH:33]=1>>[CH3:18][N:4]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:23][CH2:22]2)=[O:20])=[C:2]([C:36]2[CH:37]=[N:32][CH:33]=[N:34][CH:35]=2)[N:6]=[C:5]1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=1
Reactant: OB(O)c1cncnc1
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Product: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(-c2cncnc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 19) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as colorless foam. MS: 501.1 (MH+).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[H][H].Cl[C:15]1[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=1>C1COCC1>[Cl:21][C:20]1[C:15]([O:3][CH2:4][CH2:5][N:6]2[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)=[N:16][CH:17]=[C:18]([Cl:22])[CH:19]=1
Reactant: OCCN1CCOCC1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cnc(OCCN2CCOCC2)c(Cl)c1
Yield: 94.9 %

Procedure:
97% sodium hydride (2.72 g. 0.11 mol) was suspended in THF (100 ml) under nitrogen and a solution of N-(2-hydroxyethyl)morpholine (14.4 g, 0.11 mol) in THF (15 ml) was added in portions. When hydrogen evolution had ceased, a solution of 2,3,5-trichloropyridine (18.2 g, 0.10 mol) in THF (25 ml) was added at such a rate as to maintain a gentle reflux. The reaction mixture was refluxed for 2 hours and the solvent was subsequently removed in vacuo. The residue was taken up in water/CH2Cl2, the organic layer was separated and the solvent was removed in vacuo to afford 26.3 g (94.9%) of 3.5-dichloro-2-[2-(4-morpholinyl]ethoxy]pyridine as a crystalline solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:15])[C:6]=2[N:16]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[S:31][CH2:32][CH2:33][C:34](ON2C(=O)CCC2=O)=[O:35])C=CC=CC=1>ClCCl>[NH2:15][C:7]1[C:6]2[N:16]=[C:3]([CH2:2][NH:1][C:34](=[O:35])[CH2:33][CH2:32][SH:31])[N:4]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:5]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1
Reactant: O=C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)ON1C(=O)CCC1=O
Reactant: NCc1nc2c(N)nc3ccccc3c2n1Cc1ccccc1
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1nc(CNC(=O)CCS)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(aminomethyl)-1-benzyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.3 mmol) and succinimido 3-(triphenylmethylthio)propanoate (2.2 g, 4.9 mmol) in dichloromethane (33 mL) was stirred overnight at room temperature. The reaction mixture was warmed and the solvent was removed under reduced pressure. Dichloromethane (30 mL) and trifluoroacetic acid (3 mL) were added and the mixture was stirred over the weekend. Additional trifluoroacetic acid was added. After 4 hours, the mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel (gradient elution with a solution of 2% ammonium hydroxide in methanol and chloroform) followed by crystallization from ethyl acetate/acetonitrile. HRMS (ESI) calcd for C21H21N5OS+H 392.1545, found 392.1534.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1.[C:20]([NH:30][C@H:31]([C:35]([O:37][CH:38]([CH2:42][O:43][C:44](=[O:60])[C@H:45]([CH:57]([CH3:59])[CH3:58])[NH:46][C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48])[C:39](O)=[O:40])=[O:36])[CH:32]([CH3:34])[CH3:33])([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:39](=[O:40])[CH:38]([O:37][C:35](=[O:36])[C@H:31]([CH:32]([CH3:34])[CH3:33])[NH:30][C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:42][O:43][C:44](=[O:60])[C@H:45]([CH:57]([CH3:59])[CH3:58])[NH:46][C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:48])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)O
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(OC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2′,3′-dideoxy-3′-fluoroguanosine (2.15 g, 8 mmole), 2,3-bis-(N-CBZ-L-valyloxy)-propanoic acid (6.2 g, 10.8 mmole), DMAP (244 mg, 2 mmole) and HOBT (1.46 g, 10.8 mmole) was coevaporated two times with DMF and reduced to about 120 ml. DCC (2.48 g, 12 mmole) was added and the mixture was stirred for two days at room temperature. The mixture was filtered and the solution was evaporated under reduced pressure. 150 ml ethyl acetate was added and the organic phase was washed twice with 5% acetic acid, with 5% sodium hydrogen carbonate and with water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 2.25 g=35%
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH2:10])[CH:2]=[CH2:3].C(Cl)(Cl)Cl.[CH3:15][NH:16][S:17]([C:20]1[CH:21]=[C:22]([C:30](Cl)=[O:31])[C:23]2[O:28][CH2:27][CH2:26][O:25][C:24]=2[CH:29]=1)(=[O:19])=[O:18]>O>[CH2:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[CH2:9][NH:10][C:30]([C:22]1[C:23]2[O:28][CH2:27][CH2:26][O:25][C:24]=2[CH:29]=[C:20]([S:17](=[O:19])(=[O:18])[NH:16][CH3:15])[CH:21]=1)=[O:31])[CH:2]=[CH2:3]
Reactant: C=CCN1CCCC1CN
Reactant: CNS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Solvent: O
Solvent: ClC(Cl)Cl
Product: C=CCN1CCCC1CNC(=O)c1cc(S(=O)(=O)NC)cc2c1OCCO2
Yield: 49 %

Procedure:
85 g of levorotatory 1-allyl-2-aminomethyl-pyrrolidine, 610 cm3 of chloroform, and gradually, 178 g of 7-methylsulfamoyl-1,4-benzodioxane-5-carbonyl chloride at a temperature of from 5°-10° C. were introduced into a balloon flask provided with an agitator and a thermometer. After agitation of the mixture 1.2 liters of water were added and then chloroform was distilled. The remaining solution was filtered and then the base was precipitated with 70 cm3 of 20% ammonia. The crystals formed were dried off and washed with water. After recrystallization from ethyl acetate, 117 g of levorotatory-N-(1-allyl-2-pyrrolidylmethyl)-7-methylsulfamoyl-1,4-benzodioxane-5-carboxamide was produced (M.P.: 101°-102° C.; yield: 49%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[F:9][C:10]1[C:15](B(O)O)=[CH:14][CH:13]=[CH:12][N:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:9][C:10]1[C:15]([C:2]2[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1cc(-c2cccnc2F)cs1
Temperature: 80 °C
Reaction time: 20 h
Yield: 53.5 %

Procedure:
A suspension of 4-bromothiophene-2-carbaldehyde (10.0 g), 2-fluoro-3-pyridineboronic acid (9.1 g), tetrakis(triphenylphosphine)palladium (0) (3.1 g) and sodium carbonate (13.7 g) in 1,2-dimethoxyethane (100 mL) and water (50 mL) was stirred at 80° C. for 20 hr under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give the title compound as a pale-yellow solid (yield 5.8 g, yield 53%).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].CN(C)C=O.[H-].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([O:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:8])[F:9])[S:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1sc(C(F)(F)F)cc1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C(F)(F)F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64 %

Procedure:
A mixture of 5B (5.0 g) and dimethylformamide (50 ml) is treated with sodium hydride (1.06 g). Benzylbromide (3.15 ml) was slowly added to the resulting reaction mixture and stirred at room temperature for 20 hours. The --reaction mixture was poured into water. The mixture was extracted with diethyl ether twice. The combined organic phases were washed with water, dried and concentrated in vacuo. The crude product was chromatographed (hexane / dichloromethane, 1/1) to give the product as a white solid (4.5 g, 64 %) with a melting point of 52-53.5 ° C.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([NH2:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:13]([NH:12][CH:10]1[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(NCc2ccccc2)C1
Temperature: 0 °C
Yield: 73.4 %

Procedure:
1-Boc-3-aminoazetidine (11) (2.2 gm, 12.78 mmol) was dissolved in DCM (20 ml) under nitrogen and cooled to 0° C. Then the solution was added benzaldehyde (12; 1.35 gm, 12.78 mmol) followed by sodium triacetoxyborohydride (8.13 gm, 38.34 mmol) under nitrogen atmosphere. The reaction mixture was then allowed to warm to room temperature and stirred over night. The reaction's completion was monitored by TLC. After completion of the reaction it was quenched by the addition of water (5 ml) and extracted with DCM. The organic layer was washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Crude product was then purified by column chromatography to give compound (13a) (2.46 gm, 72%). 1H NMR (400 MHz, CDCl3) δ: 1.40 (s, 9H), 3.60 (m, 3H), 3.73 (s, 2H), 4.05 (m, 2H), 7.3 (m, 5H); MS: m/z 263.20 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[C:20]([CH:21]3[CH2:23][CH2:22]3)=[N:19][NH:18][C:7]=2[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]2[C:20]([CH:21]3[CH2:23][CH2:22]3)=[N:19][N:18]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][O:24]3)[C:7]=2[N:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[CH:10]=1)=[O:4]
Reactant: C1=COCCC1
Reactant: COC(=O)c1cc(-c2ccc(O)cc2)nc2[nH]nc(C3CC3)c12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(-c2ccc(O)cc2)nc2c1c(C1CC1)nn2C1CCCCO1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
A mixture of 3-cyclopropyl-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid methyl ester (12.9 g), 3,4-dihydro-2H-pyran (5.26 g) and p-toluenesulfonic acid monohydrate (2.38 g) in THF (300 mL) was stirred at r.t. until the reaction was complete. Water was added and the mixture was extracted with ethyl acetate, the combined organic phases were washed with water and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed over a short path column (heptane/ethyl acetate gradient). 11.4 g (70%) of the title compound were obtained.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:38])[N:9]([CH2:18][C:19]1[CH:20]=[N:21][C:22]([CH3:37])=[C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=2)[C:24]=1C=O)[C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][CH:11]=1)([CH3:6])([CH3:5])[CH3:4].C(=O)(O)[O-:40].[Na+].[O:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1>>[CH3:45][O:44][C:48](=[O:40])/[CH:47]=[CH:46]/[C:24]1[C:19]([CH2:18][N:9]([C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:38])[C:10]2[CH:11]=[CH:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=2)=[CH:20][N:21]=[C:22]([CH3:37])[C:23]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]#[N:36])[CH:30]=1
Reactant: C1CCOC1
Reactant: O=C([O-])O
Reactant: Cc1ncc(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)c(C=O)c1OCc1cccc(C#N)c1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)/C=C/c1c(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)cnc(C)c1OCc1cccc(C#N)c1
Reaction time: 0.25 h
Yield: 738 %

Procedure:
To a solution of sodium hydride (124 mg, 60% in oil, 3.1 mmol) in anhydrous tetrahydrofuran (10 mL) was added methyl diethyl phosphonoacetate (661 mg, 3.1 mmol) at −78° C. under nitrogen atmosphere and stirred for 15 minutes. To the reaction mixture was added 5-(3-cyano-benzyloxy)-4-formyl-6-methyl-pyridin-3-ylmethyl]-(4-cyano-phenyl)-carbamic acid tert-butyl ester (109) (523 mg, 1.1 mmol) and stirred for 15 minutes. The reaction mixture was then poured into a cold solution of saturated aqueous sodium bicarbonate, and the crude product extracted with dichloromethane, dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a crude residue, which was purified by column chromatography on silica gel using a gradient mixture of ethyl acetate:hexane (0:1 to 1:1) as an eluant to give (E)-3-[5-{[tert-butoxycarbonyl-(4-cyano-phenyl)-amino]-methyl}-3-(3-cyano-benzyloxy)-2-methyl-pyridin-4-yl]-acrylic acid methyl ester (120) (428 mg, 738% yield) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.CN(C=O)C.C([O-])([O-])=O.[Cs+].[Cs+]>C(OCC)(=O)C.O>[Cl:1][C:2]1[C:3]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([F:12])[CH:18]=2)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: OB(O)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1cnc(-c2cccc(F)c2)c(Cl)c1
Temperature: 90 °C
Yield: 95.2 %

Procedure:
To a round bottom flask was added 5,6-dichloronicotinic acid (500 mg, 2.60 mmol), 3-fluorophenylboronic acid (364 mg, 2.60 mmol), DMF (25 mL), 2 M Cs2CO3 (6 mL) and Pd(Ph3)4 (30.1 mg, 0.0026 mmol). The reaction mixture was heated to 90° C. for 3 hrs and then allowed to cool to rt. The mixture was diluted with ethyl acetate/water and the layers separated. The organic layer was washed with brine, dried (MgSO4) and the solvent removed to give a solid, which was purified by chromatography (silica, DCM/MeOH) to give the desired product, 5-chloro-6-(3-fluorophenyl)nicotinic acid (623 mg, 95%). LC/MS (M+H)=252 observed, 252.02 expected.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:17])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])#[N:6]>C(OCC)(=O)C>[C:5]([C:7]1[CH:8]=[C:9]([N+:1]([O-:4])=[O:2])[C:10]([OH:17])=[C:11]([CH:16]=1)[C:12]([O:14][CH3:15])=[O:13])#[N:6]
Reactant: COC(=O)c1cc(C#N)ccc1O
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C#N)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To 25 ml of fuming nitric acid was added 2.50 g of methyl 5-cyano-2-hydroxybenzoate. This solution quickly turned dark orange, and the reaction was complete after stirring for 1 h. The solution was slowly transferred to 100 ml of ice-cold water. To the resultant suspension was added 100 ml of ethyl acetate and the biphasic mixture was shaken and separated. The aqueous layer was extracted with ethyl acetate (2×60 ml), and the combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was taken up in ethyl acetate (100 ml) and filtered through a small plug of silica gel, eluting with more ethyl acetate (50 ml). The eluent was concentrated in vacuo to provide the title compound (2.71 g, 87%). Mass spectrum (ESI) 221.2 (M−1).
Reaction SMILES: [NH2:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:19]=1[C:20](Cl)=[O:21].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:19]=1[C:20]([NH:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4])=[O:21]
Reactant: COC(=O)C(N)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(Cc1ccc([N+](=O)[O-])cc1)NC(=O)c1c(Cl)cccc1Cl
Reaction time: 2 h

Procedure:
To a solution of methyl 2-amino-3-(4-nitrophenyl)propanoate 2 (9.5 g) in CH2Cl2 (40 ml) is added, at 0° C., 2,6-dichlorobenzoyl chloride (7.71 g) dissolved in CH2Cl2 (40 ml). DIPEA (2 equ.) is then added dropwise to the mixture at 0° C. The reaction is then risen at RT and pH is brought to 7-8 by addition of DIPEA. The mixture is stirred for 2 h, then evaporated and the residue is placed in AcOEt (175 ml). The organic phase is washed one time with 5% NaHCO3 (150 ml), one time with water, one time with 10% KHSO4 (150 ml) and one time with brine, dried over MgSO4 and evaporated. No further purification is needed.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:36](Cl)=[O:37])[C:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)([CH3:28])[C:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)([CH3:20])[N:19]=2)=[C:11]([O:39][CH2:40][CH3:41])[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[N:44]1([CH2:50][C:51]([NH2:53])=[O:52])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([C:36]([N:47]3[CH2:48][CH2:49][N:44]([CH2:50][C:51]([NH2:53])=[O:52])[CH2:45][CH2:46]3)=[O:37])[C@@:17]([C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)([CH3:28])[C@@:18]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)([CH3:20])[N:19]=2)=[C:11]([O:39][CH2:40][CH3:41])[CH:10]=1)(=[O:7])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1cc(S(=O)(=O)NC(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: NC(=O)CN1CCNCC1
Agent: Cl
Product: CCOc1cc(S(=O)(=O)NC(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butylsulfamoyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazin-1-yl-acetamide dihydrochloride (Matrix Scientific) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C36H44N6O5SCl2 [(M+H)+] 743.2544, observed 743.2538.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9].[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][CH:30]=O)[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([CH2:29][CH2:30][N:13]2[CH2:14][CH2:15][CH:10]([C:8]([C:4]3[S:5][CH:6]=[CH:7][C:3]=3[Cl:2])=[O:9])[CH2:11][CH2:12]2)[CH2:27][CH2:28]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C(c1sccc1Cl)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3sccc3Cl)CC2)CC1

Procedure:
From (3-chloro-thiophen-2-yl)-piperidin-4-yl-methanone hydrochloride (100 mg) and [trans-4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (intermediate C, 91 mg) by procedure A.1. Yield: 85 mg (50%). White foam. MS (m/z): 455.3 ([M+H]+).