Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](F)=[CH:4][C:5](F)=[C:6](C=1)[C:7](NS(C)(=O)=O)=[O:8].[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.C1(CCO)CCC1>>[Cl:17][C:18]1[C:19]([O:8][CH2:7][CH2:6][CH:5]2[CH2:2][CH2:3][CH2:4]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Agent: OCCC1CCC1
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCCC2CCC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with 2-cyclobutylethanol, the title compound was obtained as a colorless solid (0.12 g, 32%): 1H NMR (300 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.72 (d, J=7.5 Hz, 1H), 7.22 (d, J=12.4 Hz, 1H), 4.08 (t, J=6.3 Hz, 2H), 2.87 (s, 6H), 2.47-2.40 (m, 1H), 2.10-1.99 (m, 2H), 1.89-1.63 (m, 6H); MS (ES−) m/z 377.2, 379.2 (M−1).
Reaction SMILES: P([O-])([O-])([O-])=[O:2].[K+].[K+].[K+].[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:11]=1[C:12]#[N:13]>>[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:11]=1[C:12]([NH2:13])=[O:2]
Reactant: N#Cc1c(F)cccc1F
Reactant: O=P([O-])([O-])[O-]
Agent: [K+]
Product: NC(=O)c1c(F)cccc1F

Procedure:
The suspension of the bacterial cells (corresponding to 5.92 mg of the dry cells) obtained in Example 8 was added to 4 ml of the reaction solution containing 10 mM of a potassium phosphate buffer (pH 8.0) and 0.5 M of 2,6-difluorobenzonitrile, and the reaction was conducted at 25° C. with adding 0.5 M of 2,6-difluorobenzonitrile to the reaction solution after 2,4,6 and 8 hours from the initiation of the reaction, respectively. After 22 hours from the initiation of the reaction, 2.5 M (393 g/lit.) of 2,6-difluorobenzamide was produced with a 100% conversion.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3].[H][H]>CN(C)C(=O)C.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)=[O:3]
Reactant: O=C(Cl)c1ccc2c(c1)COC2=O
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CC(=O)N(C)C
Product: O=Cc1ccc2c(c1)COC2=O
Temperature: 60 °C
Reaction time: 40 h
Yield: 63.1 %

Procedure:
To a solution of 8.58 g (0.043 mole) of 5-chlorocarbonylphthalide in 120 ml of N,N-dimethylacetamide in a hydrogenator 1 g of 5% Pd/BaSO4 is added and hydrogen at 2.5 bar is charged thereinto. The mixture is heated to 60° C., kept at this temperature for 40 hours at 2.5÷3 bar, then cooled, filtered to remove the catalyst and concentrated under vacuum at 75° C. The residue is taken up with 50 ml of deionized water, then the suspension is neutralized with 10% ammonium hydroxide solution to a pH=7.5 and the product is filtered to give 4.4 g (63%) of 5-formylphthalide with m.p.=162÷163° C.
Reaction SMILES: [CH2:1]([NH:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1([N:16]=[C:17]=[S:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)(C)C>[CH2:1]([N:8]([C:17]([NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[S:18])[NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C=Nc1ccccc1
Reactant: NNCc1ccccc1
Solvent: CC(C)O
Product: NN(Cc1ccccc1)C(=S)Nc1ccccc1
Reaction time: 1 h

Procedure:
Benzylhydrazine (30 g, 0.0245 mole) and phenyl isothiocyanate (33.1 g, 0.0245 mole) were dissolved in 200 ml of isopropanol and cooled to 0°-5° C. The phenyl isothiocyanate was then added dropwise in 50 ml of petroleum ether. The title compound precipitated from solution during this phase of the operation. After addition, the reaction mixture was stirred at 40°-45° C. for one hour. The title product was filtered off as a white solid, m.p. 121°-3° C., yield 43 g.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=O.C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)C(=O)C1.C(N(CC)CC)C.[NH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1>C(#N)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1)=[O:9]
Reactant: O=C(O)CCCCCBr
Reactant: NCCc1ccc(O)cc1
Agent: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(CCCCCBr)NCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6-bromohexanoic acid (4.51 g, 23.1 mmol) in acetonitrile (50 mL) is added N,N'-disuccinimidyl carbonate (6.5 g, 25 mmol) and triethylamine (3.2 mL, 23 mmol). The solution is stirred at room temperature for 4 hours and tyramine (3.2 g, 23 mmol) is added and stirred continued at room temperature overnight, evaporated in vacuo, re-dissolved in ethyl acetate (100 mL) and washed with water (6×50 mL) and saturated sodium chloride solution (2×25 mL). The ethyl acetate solution is dried with sodium sulfate, filtered, and evaporated in vacuo to give a light brown gum. The crude product is purified by silica gel chromatography to give 6-bromo-N-[2-(4-hydroxyphenyl)-ethyl]-hexanamide (II) as a light amber syrup.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)=[N:4]1)[CH3:2]>C(O)(=O)C.[Zn]>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc([N+](=O)[O-])cc2)n1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of 4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine (59 mmol) in glacial acetic acid (25 mL) was treated with zinc dust (41 mmol) and stirred for 1 h at room temperature. The reaction was then filtered and concentrated in vacuo. The resultant residue was suspended in a 1:1 solution of ethyl acetate (10 mL) and saturated sodium bicarbonate (10 mL) and stirred 30 minutes. The organic layer was separated, filtered, washed with brine (1×5 mL), dried over sodium sulfate, and concentrated. Purification of the residue by flash chromatography (80-100% ethyl acetate/hexanes) provided the title product as a white powder (85%). ESMS [M+H]+: 304.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[CH3:28][S:29][CH2:30][C:31]1[N:32]=[CH:33][C:34]([NH2:37])=[N:35][CH:36]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:37][C:34]2[CH:33]=[N:32][C:31]([CH2:30][S:29][CH3:28])=[CH:36][N:35]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CSCc1cnc(N)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSCc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 84.3 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 581.7 mg, 1.758 mmol) in methylene chloride (8.6 mL) was cooled to 0° C. The reaction mixture was then treated with oxalyl chloride (310 mL, 3.554 mmol) and N,N-dimethylformamide (2 drops). The reaction mixture was stirred at 0° C. for 45 min and then slowly warmed to 25° C. over 6 h. The solution was then concentrated in vacuo. The resulting yellow slurry was dissolved in methylene chloride (7 mL) and then cooled to 0° C. To this solution was added a solution of 5-methylsulfanylmethyl-pyrazin-2-ylamine (267.2 mg, 1.721 mmol) and pyridine (174 μL, 2.151 mmol) in methylene chloride (8.6 mL), followed by a methylene chloride rinse (1.7 mL). The pH of the reaction was roughly 3–4, and a second aliquot of pyridine (50 μL, 0.618 mmol) was added to adjust the pH to roughly 5. The reaction mixture was stirred at 0° C. and slowly warmed to 25° C. overnight. The reaction was then quenched with water (10 mL), stirred at 25° C. for 10 min, and concentrated in vacuo. The reaction slurry was partitioned between ethyl acetate (250 mL) and a 1N aqueous hydrochloric acid solution (250 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (250 mL), a saturated aqueous sodium bicarbonate solution (250 mL), water (250 mL), and a saturated aqueous sodium chloride solution (250 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 1/2 ethyl acetate/hexanes) afforded the desired chiral 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methylsulfanylmethyl-pyrazin-2-yl)-propionamide (679.0 mg, 84%) as a white foam: mp 75.0–76.7° C. (foam to gel); (ES)+-HRMS m/e calcd for C21H26ClN3O3S2 (M+H)+ 468.1177, found 468.1180.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.[F:10][C:11]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=1[NH2:13]>>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:13][C:12]1[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:11]=1[F:10])=[O:9]
Reactant: O=C(O)c1sccc1Br
Reactant: COc1ccc(N)c(F)c1
Product: COc1ccc(NC(=O)c2sccc2Br)c(F)c1
Yield: 86.5 %

Procedure:
Following Step 1 from General Procedure A, 3-bromothiophene-2-carboxylic acid (7.3 g, 35 mmol) was reacted with 2-fluoro-4-methoxyaniline (5.0 g, 35 mmol) to afford the desired product (10 g, 90%) as an orange solid: ESI MS m/z 331 [C12H1FNO2S+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][CH2:14][N:15]([CH3:19])[C:16](=[O:18])[CH3:17])[N:5]=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[O:28][C:29]([CH3:37])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[CH3:30])[NH2:24]>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[O:12][CH2:13][CH2:14][N:15]([CH3:19])[C:16](=[O:18])[CH3:17])[N:5]=[CH:4][N:3]=2)[CH:25]=[CH:26][C:27]=1[O:28][C:29]([CH3:30])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[CH3:37]
Reactant: CC(C)(Oc1ccc(N)cc1Cl)c1ccccn1
Reactant: CC(=O)N(C)CCOc1cccc2ncnc(Cl)c12
Product: CC(=O)N(C)CCOc1cccc2ncnc(Nc3ccc(OC(C)(C)c4ccccn4)c(Cl)c3)c12
Yield: 31 %

Procedure:
The procedure described in Example 126 was repeated using N-{2-[(4-chloroquinazolin-5-yl)oxy]ethyl}-N-methylacetamide (obtained as described in Example 126, preparation of starting materials, 47 mg, 0.170 mmol) and 3-chloro-4-(1-methyl-1-pyridin-2-ylethoxy)aniline (49 mg, 0.187 mmol) to give the title compound in 31% yield; NMR Spectrum (DMSO-d6, 400 MHz, 373K) 1.75 (s, 6H), 1.92 (s, 3H), 2.94 (s, 3H), 3.88 (t, 2H), 4.47 (t, 2H), 6.62 (d, 1H), 7.16 (d, 1H), 7.31 (ddd, 1H), 7.35 (d, 1H), 7.39 (dd, 1H), 7.70 (dd, 1H), 7.75 (dd, 1H), 7.83 (ddd, 1H), 7.99 (d, 1H), 8.46 (s, 1H), 8.58 (dd, 1H), 9.70 (s, 1H); Mass spectrum MH+ 506.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:14][CH:15]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[C:16]([OH:18])=[O:17])=[O:13])[C:7]1=[O:24].[CH3:29]O.S(Cl)(Cl)=O>>[CH3:29][O:17][C:16](=[O:18])[CH:15]([NH:14][C:12]([C:8]1[C:7](=[O:24])[N:6]([CH2:5][C:4]2[CH:25]=[CH:26][C:27]([F:28])=[C:2]([F:1])[CH:3]=2)[CH:11]=[CH:10][CH:9]=1)=[O:13])[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1
Reactant: CO
Reactant: O=C(NC(C(=O)O)c1cccs1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Solvent: O=S(Cl)Cl
Product: COC(=O)C(NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1cccs1

Procedure:
{[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-thiophen-2-yl-acetic acid (0.360 g, 0.000890 mol;) was dissolved in Methanol (10 mL, 0.2 mol;) then cooled to 0. Thionyl chloride (325 uL, 0.00445 mol;) was added and the reaction was allowed to stir o/n. The crude was concentrated then dissolved in ethyl acetate and washed with 1× citric acid, 1× saturated bicarbonate, and 1× brine. The ethyl acetate was then dried with magnesium sulfate and concentrated. The crude was then dissolved in methylene chloride and injected onto the combiflash for purification. The compound eluted at almost 100% EA using a 0-100% hexanes ethyl acetate gradient. Pure fractions were concentrated to give the pure product. ES (+) MS m/e=418.86.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH2:10]([Mg]Br)[CH3:11].B(F)(F)F.O>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2([NH2:9])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: CC[Mg]Br
Reactant: Cc1cnc(C#N)nc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(C2(N)CC2)nc1

Procedure:
To a solution of 5-methylpyrimidine-2-carbonitrile (200 mg, 1.7 mmol, 1 eq) in dry THF under an argon atmosphere was added titanium isopropoxide (0.58 ml, 2.0 mmol, 1.2 eq) slowly at ambient temperature and the reaction mixture was stirred for 15 mins Ethyl magnesium bromide (1M solution) in THF (4 ml, 4.0 mmol, 2.4 eq) was added via syringe slowly at ambient temperature. Then the reaction mixture was stirred for an hour. BF3.EtO (0.36 ml, 2.6 mmol, 1.5 eq) was added slowly through syringe to the mixture at 0° C. The mixture was allowed to attain ambient temperature and stirred for another one hour. 10 ml of water was added to the reaction mixture which was then filtered through Celite and the bed washed with water and ethyl acetate. The filtrate was basified with 10% NaOH solution (pH=9) then extracted with DCM. The organic was washed with brine solution, dried over sodium sulphate and concentrated to give the crude product which was taken for coupling reaction without further purification. Yield: 125 mg (crude).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=O.[F:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].[B][B][B][B][B][B][B][B][B][B]>CO>[F:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][CH2:1][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: Nc1ccccc1F
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: O=C(O)c1ccc(CNc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
A mixture of 4-formylbenzoic acid 47a (3.33 mmol, 500 mg), 2-fluoroaniline 47b (3.33 mmol, 370 mg), and decaborane (1 mmol, 122 mg) in 8 mL of MeOH was stirred at room temperature for 15 min. The mixture was concentrated and purified by preparative reverse-phase chromatography to afford 0.81 g (99%) of 47c.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:22][C:23]([C:25]2[CH:34]=[C:33]([OH:35])[C:32]3[C:27](=[CH:28][C:29]([CH3:36])=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:38]([O:45][C:46](=[O:50])[C@H:47](O)[CH3:48])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:22][C:23]([C:25]2[CH:34]=[C:33]([O:35][C@H:47]([C:46]([O:45][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:50])[CH3:48])[C:32]3[C:27](=[CH:28][C:29]([CH3:36])=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:14][C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccc(C)cc3n2)CC1
Reactant: C[C@@H](O)C(=O)OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)c2cc(O[C@@H](C)C(=O)OCc3ccccc3)c3ccc(C)cc3n2)CC1
Reaction time: 2 h

Procedure:
To a solution of 1 g of 4-{(S)-3-tert-Butoxycarbonyl-2-[(4-hydroxy-7-methyl-quinoline-2-carbonyl)-amino]-propionyl}-piperazine-1-carboxylic acid ethyl ester and 350 mg of (R)-2-Hydroxy-propionic acid benzyl ester in 20 ml of THF, 764 mg of Triphenyl-phosphane and 507 mg of Diethyl azodicarboxylate was added and stirred for 2 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1.3 g.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N+:4]([O-:12])[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-])=O.O.Cl>Cl.[Fe].C(O)C>[NH2:8][C:7]1[CH:6]=[C:5]([CH3:11])[N+:4]([O-:12])=[N:3][C:2]=1[CH3:1]
Reactant: Cc1n[n+]([O-])c(C)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1n[n+]([O-])c(C)cc1N
Reaction time: 20 h

Procedure:
3,6-dimethyl-4-nitropyridazine-N-oxide (1.0 g), 0.5 mL water, 5 mL ethanol, 0.025 mL conc HCl and 1.0 g Fe powder were stirred together and heated under reflux. After 30 minutes an additional 1.0 g of Fe and 2 drops conc HCl was added to the mixture. After 2 hours an additional 1 g Fe and 2 drops of conc HCl were added and heating continued for another 5 hours, whereupon 5 mL EtoH, 1 g Fe and 2 drops conc HCl were added. Reflux was continued for 20 hours. The reaction was cooled filtered through celite, the celite washed with CH3OH and the filtrate was evaporated to give an orange oil which crystallized on standing (0.88 g yield). Used without further purification. ##STR27##
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13]1[C:14]([Cl:19])=[N:15][CH:16]=[CH:17][CH:18]=1>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Zn]>[Cl:19][C:14]1[C:13]([CH2:12][C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)=[O:7])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Clc1ncccc1CBr
Agent: Cl[Pd]Cl
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: O=C(Cc1cccnc1Cl)c1ccc(F)cc1
Reaction time: 20 h
Yield: 12.6 %

Procedure:
To a stirred suspension of 4-fluorobenzoyl chloride (2.89 mL, 24.5 mmol), bis(triphenylphosphine)palladium (II) chloride (1.08 g, 1.54 mmol) and zinc dust (3.20 g, 49 mmol) in anhydrous dimethoxyethane (50 mL) was added a solution of the title compound of Step B (5.06 g, 24.5 mmol) in dimethoxyethane (50 mL) at room temperature under N2 over 45 min. After 20 h, the suspension was filtered through Celite® washed with ethyl acetate. The filtrate was washed with water and saturated aqueous NaCl, dried over MgSO4, and concentrated in vacuo to a yellow solid. Purification by flash chromatography eluting with 17-60% ethyl acetate/hexanes afforded the title compound of Step C as a yellow solid (0.77 g) which was somewhat impure by 1H NMR. 1H NMR (CDCl3, 300 MHz) δ8.30 (dd, 1H), 8.10 (m,2H), 7.6 (dd, 1H), 7.0-7.4 (m,3H), 4.40 (s,2H).
Reaction SMILES: CCN(CC)CC.Cl.[NH2:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:12].[CH2:22]([O:24][C:25](=[O:29])[C:26](Cl)=[O:27])[CH3:23]>CCOC(C)=O>[N+:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11](=[O:12])[CH2:10][NH:9][C:26](=[O:27])[C:25]([O:24][CH2:22][CH3:23])=[O:29])=[CH:18][CH:17]=1)([O-:21])=[O:20]
Reactant: CCOC(=O)C(=O)Cl
Reactant: NCC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)NCC(=O)c1ccc([N+](=O)[O-])cc1
Yield: 59 %

Procedure:
Et3N (8.88 ml) was added to a solution of 2-amino-1-(4-nitrophenyl)ethanone hydrochloride (step B product, 11.5 g) in EtOAc (115 ml). This was followed by drop wise addition of Ethylchlorooxoacetate (7.11 ml). The reaction mixture was refluxed for 2 hours. It was then cooled and quenched with water. The organic layer was separated, dried over Na2SO4 and the solvent was concentrated to get dark brown oil which was purified by column chromatography in 3:7 Ethyl acetate:Pet ether to get yellow solid. The solid was crystallized in ethyl acetate/pet ether to yield 8.9 g (59%) of the title compound. 1HNMR (DMSO-d6, 300 MHz): δ 9.21 (t, 1H), 8.35 (d, 2H), 8.24 (d, 2H), 4.78 (d, 2H), 4.29 (q, 2H), 1.29 (t, 3H).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[NH2:24]>CC#N>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:24][C:23]2[CH:25]=[CH:26][C:27]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[C:21]([Cl:20])[CH:22]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1ccc(N2CCOCC2)c(Cl)c1
Solvent: CC#N
Product: CCCCN1C(=O)C(Nc2ccc(N3CCOCC3)c(Cl)c2)=C(c2ccccc2)S1(=O)=O
Yield: 0 %

Procedure:
A solution of 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.025 g, 0.083 mmol) and 3-chloro-4-morpholinoaniline (0.039 g, 0.183 mmol) in MeCN (1 ml) was heated in a microwave reactor at 130° C. for 90 mins. The product was purified by preparative HPLC (Kromasil C8, 0.1M NH4OAc/MeCN, gradient). The combined product fractions were evaporated and freeze-dried to give the title compound (0.004 mg, 9%). 1H NMR (400 MHz, CD3CN): δ 7.74 (bs, 1H), 7.29-7.24 (m, 1H), 7.20-7.15 (m, 2H), 7.12-7.08 (m, 2H), 6.80-6.75 (m, 3H), 3.76-3.71 (m, 6H), 2.85-2.81 (m, 4H), 1.85-1.76 (m, 2H), 1.52-1.42 (m, 2H), 1.00 (t, 3H); Mass Spectrum: M+H+ 476.
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:25]3[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:24]=3[NH:23][C:22]2=[O:31])[CH2:17][CH2:16]1>C(O)C>[Cl:30][C:28]1[CH:27]=[CH:26][C:25]2[N:21]([CH:18]3[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][N:11]4[C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[NH:4][C:1]4=[S:3])[CH2:16][CH2:17]3)[C:22](=[O:31])[NH:23][C:24]=2[CH:29]=1
Reactant: S=C=S
Reactant: Nc1ccccc1NCCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Solvent: CCO
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(CCCn2c(=S)[nH]c3ccccc32)CC1
Yield: 45.5 %

Procedure:
A mixture of 38 parts of carbon disulfide, 6 parts of 1-[1-{3-[N-(2-aminophenyl)amino]propyl}-4-piperidinyl]-5-chloro-1,3-dihydro-2H-benzimidazol-2-one and 32 parts of ethanol is stirred and refluxed for 24 hours. The reaction mixture is evaporated and the residue is crystallized from ethanol. The product is filtered off and recrystallized from a mixture of N,N-dimethylformamide and water, yielding 3 parts (45.5%) of 5-chloro-1-{1-[3-(2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl)-propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 266.6° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:33][CH2:34][CH3:35])=[C:9]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH:36]1[CH2:41][CH2:40][NH:39][CH2:38][C:37]1=[O:42]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:33][CH2:34][CH3:35])=[C:9]([C:11]2[N:12]([C:30]([N:39]3[CH2:40][CH2:41][NH:36][C:37](=[O:42])[CH2:38]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1ccc(C(C)(C)C)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C1CNCCN1
Product: CCOc1ccc(C(C)(C)C)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
4-[(4S,5R)-2-(5-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one was prepared from (4S,5R)-2-(5-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12d) and 2-piperazinone (Avocado Organics) in an analogous manner as described in example 25. LR-MS: 593.3 [(M+H)+]