Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([NH2:24])[C:18]([NH:21][CH2:22][CH3:23])=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:32](=N)(OCC)[CH3:33]>C(O)(=O)C>[C:25]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]4[N:21]([CH2:32][CH3:33])[C:22]([CH3:23])=[N:24][C:17]=4[CH:16]=3)[CH2:12][CH2:13]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCNc1ccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1N
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CC(=O)O
Product: CCn1c(C)nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4.8 parts of 4-[4-(diphenylmethyl)-1-piperazinylmethyl]-N1 -ethyl-1,2-benzenediamine and 25 parts of acetic acid is stirred at room temperature till all solid enters solution. Then there are added 1.73 parts of ethyl ethanimidate hydrochloride and stirring is continued first for one hour at room temperature and further for one hour at reflux. The reaction mixture is evaporated and the residue is stirred in water. The whole is alkalized with a sodium hydroxide solution and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 2.7 parts of 5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1-ethyl-2-methyl-1H-benzimidazole; mp. 152.9° C.
Reaction SMILES: Cl.C(OCC)(=O)C.C([O:12][C:13]1[C:14]([CH2:19][N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:36])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34][CH3:35])[CH2:22][CH2:21]2)=[N:15][CH:16]=[CH:17][N:18]=1)(C)(C)C.[OH-].[Na+]>ClCCl>[CH3:35][S:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][C:26]([CH:23]1[CH2:22][CH2:21][N:20]([CH2:19][C:14]2[C:13](=[O:12])[NH:18][CH:17]=[CH:16][N:15]=2)[CH2:25][CH2:24]1)=[O:36]
Reactant: CSc1ccccc1CC(=O)C1CCN(Cc2nccnc2OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CSc1ccccc1CC(=O)C1CCN(Cc2ncc[nH]c2=O)CC1
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
After adding 3 ml of 4N hydrogen chloride/ethyl acetate to 200 mg of 1-[1-(3-tert-butoxy-2-pyrazinylmethyl)piperidin-4-yl]-2-[2-(methylthio)phenyl]ethanone while cooling on ice, the mixture was stirred for 30 minutes. A 2N sodium hydroxide solution was added to the reaction solution for neutralization, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and the mixture was filtered to obtain the title compound (146 mg, 84% yield).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[N:17]=[C:11]3[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][N:26]([CH3:31])[C:27]=1[C:28](O)=[O:29])=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][N:26]([CH3:31])[C:27]=1[C:28](=[O:29])[NH:16][C:13]1[CH:14]=[CH:15][N:10]2[N:9]=[C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=3)[N:17]=[C:11]2[CH:12]=1)=[O:22])[CH3:19]
Reactant: Nc1ccn2nc(-c3cccc(F)n3)nc2c1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3cccc(F)n3)nc2c1
Yield: 40.4 %

Procedure:
The product was prepared in the same manner as described in example 44d using 2-(6-fluoropyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine (350 mg, 1.53 mmol) and 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (363 mg, 1.83 mmol) as starting materials. The reaction affords 5-[2-(6-fluoro-pyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (253.1 mg, 40.5%) as white solid. mp.: 290° C., MS: m/z=410.0 (M+H+).
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[CH:10]=[C:11]([C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:13][C:14]=1[Br:15].[CH3:20][S:21]SC>C(Cl)(Cl)Cl>[Br:15][C:14]1[CH:13]=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[S:21][CH3:20]
Reactant: CSSC
Reactant: Nc1cc(C(F)(F)F)ccc1Br
Agent: CC(C)(C)ON=O
Solvent: ClC(Cl)Cl
Product: CSc1cc(C(F)(F)F)ccc1Br

Procedure:
t-Butyl nitrite (3 ml) was added to a mixture of 3-amino-4-bromobenzotrifluoride (4 g) and dimethyl disulphide (15 ml) in chloroform. The mixture was warmed until reaction started when t-butyl nitrite (11 ml) and a solution of 3-amino-4-bromobenzotrifluoride (16 g) in chloroform were added simultaneously. The resultant mixture was stirred for 24 hours, washed with water, hydrochloric acid (2M), water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was distilled to give 4-bromo-3-(methylsulphenyl)benzotrifluoride (16.4 g) as a yellow oil, b.p. 84°-88° C. at 2 mm Hg.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S(C2C=C([N+:33]([O-])=O)C=CC=2Cl)=O)C=CC=CC=1>>[C:1]1([S:7]([C:9]2[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][C:14]=2[NH2:33])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cc(S(=O)c2ccccc2)ccc1Cl
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)c2ccccc2)c1
Product: Nc1ccc([N+](=O)[O-])cc1S(=O)c1ccccc1
Reaction time: 20 h

Procedure:
The procedure described in Example 20 is followed, except that as a starting material instead of phenyl-(4-chloro-3-nitrophenyl) sulfoxide a corresponding amount of phenyl-(2-chloro-5-nitrophenyl) sulfoxide is employed, and the reaction is carried out at 140° C. for 20 hours.
Reaction SMILES: [Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[Cl:12][CH2:13][CH2:14][C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:16]>>[Br:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:16][C@@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH2:13][Cl:12])[CH:3]=1
Reactant: O[C@H](CCCl)c1ccccc1
Reactant: N#Cc1cc(F)c(Br)cc1F
Product: N#Cc1cc(F)c(Br)cc1O[C@H](CCCl)c1ccccc1

Procedure:
This was prepared by the method of Example 43(a) using 4-bromo-2,5-difluorobenzonitrile and (R)-α-(2-chloroethyl)benzenemethanol.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[N:12][C:13]([NH:16][C:17]([NH2:19])=[S:18])=[CH:14][CH:15]=1)(=[O:9])=[O:8].Br[CH2:21][C:22](=O)[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1>CN(C=O)C.CC(O)=O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][C:22]2[N:19]=[C:17]([NH:16][C:13]3[N:12]=[CH:11][C:10]([S:7]([NH:6][C:2]4[S:1][CH:5]=[CH:4][N:3]=4)(=[O:8])=[O:9])=[CH:15][CH:14]=3)[S:18][CH:21]=2)=[CH:25][CH:26]=1
Reactant: O=C(CBr)Cc1ccc(Cl)cc1
Reactant: NC(=S)Nc1ccc(S(=O)(=O)Nc2nccs2)cn1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=S(=O)(Nc1nccs1)c1ccc(Nc2nc(Cc3ccc(Cl)cc3)cs2)nc1
Temperature: 95 °C

Procedure:
The mixture of the 6-Thioureido-pyridine-3-sulfonic acid thiazol-2-ylamide (27 mg, 0.000086 mol) and 1-Bromo-3-(4-chloro-phenyl)-propan-2-one (25 mg, 0.00010 mol) in DMF/AcOH (1:1) was heated at 95° C. for 20 min. The reaction solution was directly purified on Gilson (semi-prep, reverse phase, Phenomenex 100×21.2 mm 10 micron C18 column, 20 mL/min, Gradient 85% A to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8 TFA). Fractions were checked by LC/MS and found no pure desired product was isolated. Fractions with the desired product were combined and then dried on a lyophilizer to give the product (1126-8-P1) as a yellow powder. The product (a mixture) was purified again by chromatography (silica gel, 5% Ethyl acetate in hexanes to 100% Ethyl acetate) to give a cleaner product (1126-8-P2), which was purified by Prep TLC (25% Ethyl acetate in hexanes, then 100% Ethyl acetate) to give the final pure product (1126-8-P-3) as a yellow solid.
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)=O.Cl.[C:15]([NH2:23])(=[NH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[K+]>O1CCCC1.O>[C:16]1([C:15]2[NH:22][C:2]([CH3:13])=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N=C(N)c1ccccc1
Reactant: CC(Br)C(=O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1[nH]c(-c2ccccc2)nc1-c1ccc(Cl)c(Cl)c1
Reaction time: 2 h

Procedure:
A solution of 86.6 g (0.307 mol) of the above-mentioned crude 2-bromo-3′,4′-dichloropropiophenone in 120 ml of tetrahydrofuran was added dropwise over 40 minutes into a suspension, under reflux with heating, of 48.1 g (0.307 mol) of benzamidine hydrochloride, 123.4 g (1.23 mol) of potassium bicarbonate in 450 ml of tetrahydrofuran and 110 ml of water. After the addition was complete, further refluxing with heating was carried out for 2 hours. The reaction solution was evaporated to dryness under reduced pressure, to give a residual solid. This solid was successively washed with water and toluene, to give 65.3 g (71.3% crude yield) of crude crystals of the desired product. The crude crystals were recrystallized using acetonitrile, to give a purified white powder.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[C:24]2[C:5]([CH2:6][C:7]3([C:17]42[NH:21][C:20](=S)[C:19]([CH3:23])=[N:18]4)[CH2:12][CH2:11][CH:10]([C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[NH3:26]>>[Br:1][C:2]1[CH:25]=[C:24]2[C:5]([CH2:6][C:7]3([C:17]42[N:21]=[C:20]([NH2:26])[C:19]([CH3:23])=[N:18]4)[CH2:12][CH2:11][CH:10]([C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: N
Reactant: CC1=NC2(NC1=S)c1cc(Br)ccc1CC21CCC(C(F)(F)F)CC1
Product: CC1=NC2(N=C1N)c1cc(Br)ccc1CC21CCC(C(F)(F)F)CC1
Temperature: 110 °C
Yield: 21.5 %

Procedure:
6′-Bromo-5″-methyl-4-(trifluoromethyl)-3′H-dispiro[cyclohexane-1,2′-indene-1′,2″-imidazole]-4″(3″H)-thione (Example 124 Step 2, 40 mg, 0.09 mmol) was dissolved in ammonia (7 M in MeOH) (2 mL, 14.0 mmol) in a microwave vial. The vial was capped, and heated to 110° C. for min in a microwave reactor. The solution was concentrated, and the residue dissolved in ammonia (7 M in MeOH) (2 mL, 14.0 mmol) and heated to 110° C. in a microwave reactor. This cycle (concentration, addition of ammonia and heating) was repeated until all starting material was converted to product (6 times). The reaction mixture was cooled to r.t., concentrated in vacuo and purified by preparative chromatography to give the title compound (8 mg, 21% yield): 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.38 (m, 4 H) 1.42-1.59 (m, 3 H) 1.84-1.92 (m, 1 H) 1.98 (m, 1 H) 2.20 (s, 3 H) 2.76-2.94 (m, 2 H) 6.55-6.62 (m, 3 H) 7.22 (m, 1 H) 7.34 (m, 1 H); MS (APCI+) 416 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[N:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1)(=[O:3])[NH2:2].[C:12]([CH2:15][C:16](=O)[CH3:17])(=O)[CH3:13]>C(O)C>[C:1]([C:4]1[N:5]=[N:6][C:7]([N:10]2[C:16]([CH3:17])=[CH:15][C:12]([CH3:13])=[N:11]2)=[CH:8][CH:9]=1)(=[O:3])[NH2:2]
Reactant: NNc1ccc(C(N)=O)nn1
Reactant: CC(=O)CC(C)=O
Solvent: CCO
Product: Cc1cc(C)n(-c2ccc(C(N)=O)nn2)n1
Reaction time: 3 h

Procedure:
A mixture of 1.53 g (0.01 moles) of 3-carbamoyl-6-pyridazinyl-hydrazine, 1.1 g (0.011 moles) of acetylacetone and 15 ml ethanol is heated to reflux under stirring for 3 hours. After cooling the separated crystals are filtered, washed with ethanol and dried. Yield: 2.05 g (95%); m.p.: 256°-257° C.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:7][O:8][C:9](=[O:27])[C@H:10]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:11][C:12](=[O:19])[C@H:13]([CH2:15][C:16](=[O:18])[OH:17])[NH2:14]>O1CCCC1>[CH3:7][O:8][C:9](=[O:27])[C@H:10]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[NH:11][C:12](=[O:19])[C@H:13]([CH2:15][C:16](=[O:17])[OH:18])[NH:14][C:4](=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: C=C1CC(=O)O1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)CC(C)=O
Reaction time: 20 h

Procedure:
4.5 parts of diketene were added dropwise to a stirred suspension of 14.7 parts α-L-aspartyl-L-phenylalanine methyl ester in 400 parts by volume of tetrahydrofuran and stirred for 20 hours at ambient temperatures. An additional 4.2 parts of diketene was added. After 18 hours, the solvent was removed under vacuum and the residue was purified by chromatography on silica gel to give N-acetoacetyl-α-L-aspartyl-L-phenylalanine methyl ester, mp. 118.5°-121° C. whch eluted in a 10:90:0.1 ethanol: methylene chloride:acetic acid mixture.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:19])=[O:5])[CH3:2].[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[N:19]1[C:23](=[O:24])[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]1=[O:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(CC)cc2)csc1N
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CCOC(=O)c1c(-c2ccc(CC)cc2)csc1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(4-ethylphenyl)-thiophene-3-carboxylic acid ethyl ester (2 mmol, Example 12, Part B) and phthalic anhydride (2.2 mmol) in glacial acetic acid (20 mL) is heated at reflux overnight. After cooling to room temperature, the acetic acid is removed in vacuo and the residue triturated with petroleum ether. The crude product is collected by filtration, suspended in acetyl chloride (5 mL), and heated to reflux for one hour. After removing the solvent in vacuo, the residue is dissolved in ethyl acetate (30 mL), washed sequentially with 5% aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Recrystallization affords the desired product.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[C:11]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:11][C:3]1([C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: COC(=O)C1CCCC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)C1(C)CCCC1=O
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A mixture of methyl 2-oxocyclopentanecarboxylate (67 g, 0.47 mol), K2CO3 (163 g, 1.18 mol) and MeI (167 g, 1.18 mol) in acetone (500 mL) was heated under reflux for 12 h. The mixture was cooled to ambient temperature and then concentrated. The residue was dissolved in EtOAc (800 mL) and the resulting solution was washed with saturated aqueous NaHCO3 (500 mL×3) and brine (300 mL×1), dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by distillation to afford methyl 1-methyl-2-oxocyclopentanecarboxylate (60.5 g, 82% yield).
Reaction SMILES: [Na].[CH3:2][O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH:8]([CH3:11])[C:7]1=[O:12])=[O:5].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=1>>[CH3:2][O:3][C:4]([C:6]1([CH2:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)[CH2:10][CH2:9][CH:8]([CH3:11])[C:7]1=[O:12])=[O:5]
Reactant: COC(=O)C1CCC(C)C1=O
Reactant: ClCc1ccc(Cl)cc1
Agent: [Na]
Product: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)C1=O

Procedure:
The obtained sodium salt of 3-methyl-2-oxocyclopentanecarboxylic acid methyl ester is reacted with (4-chlorophenyl)methyl chloride to produce 1-[(4-chlorophenyl)methyl]-3-methyl-2-oxocyclopentanecarboxylic acid methyl ester.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH2:8][C@@H:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[C@@H:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2].[Br:30]N1C(=O)CCC1=O>O1CCOCC1>[C:1]([O:4][C@@H:5]1[C@@H:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2[Br:30])[CH2:8][C@@H:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[C@@H:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OC[C@@H]1C[C@H](n2cnc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: C1COCCO1
Product: CC(=O)OC[C@@H]1C[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 62.6 %

Procedure:
(±)(1R*,2S*,3S*,5S*)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (4.20 g, 9.48 mmol) was refluxed in dry dioxane (25 mL) while freshly recrystallized N-bromosuccinimide (3.37 g, 18.9 mmol) was added all at once. After 5 minutes of reflux, volatiles were removed in vacuo. The residue was partitioned between water and chloroform. The chloroform layer was dried (sodium sulfate), and evaporated to an oil which was chromatographed on silica gel with elution by 1:1 hexanesoethyl acetate. Resolidification from ethanol-water gave title compound as white powder (3.10 g, 63%), m.p. 157°-158.5° C.; 1H-NMR(DMSO-d6) identical to that of the sample described in Example 3.
Reaction SMILES: [H-].[Na+].C(S)C.[NH2:6][C:7]1[C:15]([Cl:16])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:17]C)[CH:8]=1>CN(C)C=O>[NH2:6][C:7]1[C:15]([Cl:16])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([OH:17])[CH:8]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: CN(C)C=O
Product: Nc1cc(O)c(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.4 %

Procedure:
A cooled (5° C.) suspension of 60% sodium hydride/oil dispersion (20.0 g, 0.50 mole) in anhydrous dimethylformamide (300 mL) under nitrogen was treated slowly dropwise with ethyl mercaptan (18.7 g, 0.30 mole) so as to maintain a pot temperature below 15° C., then stirred at room temperature for 15 minutes, cooled (5° C.), and treated in portions with 4-amino-5-chloro-2-methoxybenzoic acid (40.33 g, 0.20 mole). The mixture was heated to 105±5° C. for 4 hours, cooled, and concentrated in vacuo to remove most of the dimethylformamide, then plunged into water (500 mL). The aqueous solution was extracted with methylene chloride (2×150 mL), and ether (150 mL), acidified with concentrated HCl (55 mL), filtered, and the filter cake washed with water and dried in vacuo to afford 35.7 g of crude product. Crystallization from tetrahydrofuran/hexane afforded 31.3 g (83%) of white solid; mp 192° C.
Reaction SMILES: [C:1]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[N+](C1C=C(S(O[CH2:28][C@@H:29]2[CH2:31][O:30]2)(=O)=O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[O:30]1[CH2:31][C@H:29]1[CH2:28][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)c1ccccc1O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccccc1OC[C@@H]1CO1
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A mixture of tert-butyl salicylate (2.01 g, 10.3 mmol), (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (2.69 g, 10.4 mmol) and cesium carbonate (4.05 g, 12.4 mmol) in dimethylformamide (20 mL) was stirred at room temperture overnight. The reaction mixture was partitioned between ethyl acetetate and water. The organic layer was dried over sodium sulphate, Na2SO4, filtered, concentrated in vacuo. The residue was purified by silica gel flash chromatography (ethyl acetate 40%, heptane 60%) and gave the subtitle compound (2.3 g, 89%).
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]2=[C:6]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]=1[C:23](OCC)=[O:24])(=O)[CH3:2].[F:28][C:29]1[CH:37]=[CH:36][C:32]([CH2:33][NH:34][NH2:35])=[CH:31][CH:30]=1>C(O)(=O)C.C1(C)C=CC=CC=1>[CH2:16]([O:15][C:6]1[C:5]2[C:23](=[O:24])[N:34]([CH2:33][C:32]3[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=3)[N:35]=[C:1]([CH3:2])[C:4]=2[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]=12)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C(C)=O)CCN(C)C2=O
Reactant: NNCc1ccc(F)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: Cc1nn(Cc2ccc(F)cc2)c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O
Temperature: 120 °C

Procedure:
A mixture of ethyl 6-acetyl-8-(benzyloxy)-2-methyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate (65 mg, 0.18 mmol) and 4-fluorobenzyl hydrazine (0.12 g, 0.88 mmol), and acetic acid (3 drops) in toluene (40 mL) was heated in a sealed tube at 120° C. overnight. The reaction mixture was concentrated under vacuum, and the residue was subjected to column chromatography on silica gel eluted with 1-5% methanol in ethyl acetate gradient to provide titled product.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][C@@H:8]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:7]12)C.[NH3:19].C(OCC)C>CO>[O:11]=[C:10]1[N:6]([CH2:5][C:4]([NH2:19])=[O:3])[C@H:7]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@H:8]2[CH2:9]1
Reactant: N
Reactant: CCOC(=O)CN1C(=O)C[C@@H]2CCCCCC[C@@H]21
Solvent: CO
Solvent: CCOCC
Product: NC(=O)CN1C(=O)C[C@@H]2CCCCCC[C@@H]21
Reaction time: 18 h

Procedure:
A solution of cis-decahydro-2-oxo-1H-cycloocta[b]pyrrole-1-acetic acid ethyl ester (4.0 g, 0.0157 mole) in methanol (30 ml) is saturated with anhydrous ammonia. The solution is stirred 18 hours. The solution is concentrated at reduced pressure to yield a solid. Trituration with anhydrous diethyl ether yields pure cis-decahydro-2-oxo-1H-cycloocta[b]pyrrole-1-acetamide with mp 110°-112° C.
Reaction SMILES: C([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([CH2:19][CH3:20])[C:13]=2[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[CH2:19]([N:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([OH:8])[C:17]=2[N:16]=[C:15]1[CH3:18])[CH3:20]
Reactant: CCn1c(C)nc2c(OCc3ccccc3)cccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCn1c(C)nc2c(O)cccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.9 %

Procedure:
To a solution of 4-benzyloxy-1-ethyl-2-methyl-1H-benzimidazole (370 mg) in ethyl acetate (3.7 ml) was added 10% palladium on carbon (18 mg), and the mixture was stirred for 5 hours at ambient temperature under hydrogen atmosphere. Insoluble material was filtered off, and the filtrate was concentrated in vacuo. The residue was crystallized with diisopropyl ether to give 1-ethyl-4-hydroxy-2-methyl-1H-benzimidazole (220 mg)
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][O:10][C:9]2=[C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=2)[NH:17][C:16]1=[O:25])=[O:4].[OH2:26]>N1CCOCC1>[Cl:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:25])[C:15]2=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:5]3[CH2:6][CH2:14][O:26][CH2:2][CH2:3]3)[CH:7]=2)[CH2:11][O:10]1
Reactant: O=C(CBr)Nc1ccc2c(c1)C(=C1C(=O)Nc3ccc(Cl)cc31)OC2
Reactant: O
Solvent: C1COCCN1
Product: O=C(CN1CCOCC1)Nc1ccc2c(c1)C(=C1C(=O)Nc3ccc(Cl)cc31)OC2
Temperature: 40 °C
Reaction time: 0.67 h
Yield: 94 %

Procedure:
A mixture of 2-bromo-N-[3-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-5-yl]-acetamide (63 mg, 0.15 mmol) in morpholine (1 ml) was stirred at 40° C. under nitrogen for 40 minutes. The mixture was poured into water (75 ml). The solid was filtered, washed with water and dried under vacuum to give N-[3-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-5-yl]-2-morpholin-4-yl-acetamide as a yellow solid (60 mg, 94%).