Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CS(O[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)(=O)=O.[OH-].[Na+]>CCCCCC.C1COCC1>[C:22]([N:19]1[CH2:20][CH2:21][CH:16]([CH2:15][S:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:17][CH2:18]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CS(=O)(=O)OCC1CCN(C(=O)c2ccccc2)CC1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1ccccc1)N1CCC(CSc2ccccc2)CC1
Reaction time: 0.25 h
Yield: 93.1 %

Procedure:
4.27 g (0.1068 mol) of sodium hydride (60% dispersion in oil) were washed twice with hexane, suspended in 160 ml of THF and treated with 10.3 ml (0.1068 mol) of thiophenol. The mixture was stirred for 15 min. and then a solution of 5.95 g (0.02 mol) of 1-benzoylpiperidin-4-yl-methyl methanesulfonate in 20 ml of THF was added. The mixture was boiled at reflux for 18 hrs. The reaction mixture was treated with 250 ml of 2N aqueous NaOH and extracted with ether. The organic phase was washed with 2N aqueous NaOH and saturated sodium chloride solution, dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane (1:3) as the eluent. 5.8 g (93%) of 1-benzoyl-4thio-phenoxymethylpiperidine were obtained as yellow crystals; m.p. 76°-79°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16]O)=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.S(Cl)(Cl)=O.[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.[K]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][N:32]1[C:28](=[O:38])[C:29]3[C:30](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:31]1=[O:33])=[C:5]2[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1CN1C(=O)c2ccccc2C1=O
Temperature: 55 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of (6-bromo-2-isobutyl-4-phenylquinolin-3-yl)methanol (1.6 g, 4.2 mmol) in toluene (30 ml) was added thionyl chloride (0.61 ml, 8.4 mmol), and the mixture was heated under reflux for 30 min. The solvent was evaporated and the residue was dissolved in N,N-dimethylformamide (30 ml). Potassium phthalimide (1.2 g, 6.3 mmol) was added and the mixture was stirred at 55° C. for 1 hr. The reaction mixture was partitioned between ethyl acetate (50 ml) and water (50 ml) and the aqueous layer was extracted with ethyl acetate (50 ml). The extract and the organic layer were combined and the mixture was washed with saturated aqueous sodium hydrogen carbonate (50 ml) and then saturated brine (50 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated and toluene (20 ml)-ethyl acetate (10 ml) was added to the residue. Insoluble materials were filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and crystallized from diisopropyl ether to give 2-[(6-bromo-2-isobutyl-4-phenylquinolin-3-yl)methyl]-1H-isoindole-1,3(2H)-dione (1.7 g, yield 82%) as pale-yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]([O:25]C)=[O:24].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]([OH:25])=[O:24]
Reactant: COC(=O)C(CCc1ccccc1)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2c(C(CCc3ccccc3)C(=O)O)c(C)nc3sc4c(c23)CCCC4)cc1
Temperature: 60 °C
Yield: 2.4 %

Procedure:
To a solution of methyl [2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-4-phenylbutanoate (0.128 g; 0.272 mmol) in methanol (2.7 mL) was added a solution of sodium hydroxide 5 N (0.54 mL) and the mixture was heated at 60° C. for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was acidified with HCl (1N) until pH 1. The organic layer was washed with brine, water, dried over magnesium sulphate and concentrated under reduced pressure. A purification by Preparative TLC using a mixture ethyl acetate/heptane (1:1)+0.5% AcOH furnished 0.003 g (2%) of the title compound as a light yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][CH:11]([C:19]([OH:21])=[O:20])[CH2:12][CH:13]=[CH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].Cl>C(O)C.[Pd]>[NH2:1][C@H:2]([C:8]([NH:10][CH:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:19]([OH:21])=[O:20])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: NCCCC[C@H](N)C(=O)NC(CC=CCC(=O)O)C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCCCC[C@H](N)C(=O)NC(CCCCC(=O)O)C(=O)O
Yield: 82.9 %

Procedure:
678 mg of 6-(L-lysylamino) 3-heptenedioic acid prepared as in Example 9 were dissolved at ambient temperature in 70 ml of ethanol and 2.1 ml of N hydrochloric acid and then 140 mg of palladium on active carbon were added, followed by hydrogenation under 1100 millibars for an hour and a half. The residue, after filtering, was evaporated to dryness, rinsed with ethanol then with water, dried and concentrated to dryness under reduced pressure. The residue was dissolved in water, and the pH was adjusted to 6 with ammonium hydroxide. The mixture was purified by passing through Dowex 50 W×8 ion-exchange resin and eluting with water and then with 0.5N ammonia, evaporation to dryness and lyophilized to obtain 566 mg of the expected product with a specific rotation of [α]D =+29°±1.5° (c=0.7% in H2O).
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:25])=[C:6]([C@@H:14]2[CH2:18][CH2:17][N:16]([CH3:19])[C@H:15]2[CH2:20][O:21][C:22](=[O:24])[CH3:23])[C:7]([O:12][CH3:13])=[CH:8][C:9]=1[O:10][CH3:11])(=[O:3])[CH3:2].[Cl:26][C:27]1[C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=[CH:29][N:28]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:22]([O:21][CH2:20][C@H:15]1[C@H:14]([C:6]2[C:7]([O:12][CH3:13])=[CH:8][C:9]([O:10][CH3:11])=[C:4]([C:1](=[O:3])[CH3:2])[C:5]=2[O:25][C:33](=[O:34])[C:32]2[CH:31]=[CH:30][CH:29]=[N:28][C:27]=2[Cl:26])[CH2:18][CH2:17][N:16]1[CH3:19])(=[O:24])[CH3:23]
Reactant: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2COC(C)=O)c(O)c1C(C)=O
Reactant: O=C(O)c1cccnc1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2COC(C)=O)c(OC(=O)c2cccnc2Cl)c1C(C)=O

Procedure:
(+/−)-trans-Acetic acid 3-(3-acetyl-2-hydroxy-4,6-dimethoxy-phenyl)-1-methyl-pyrrolidin-2-ylmethyl ester (1.65 g, 4.7 mmol) was reacted with 2-chloro-pyridine-3-carboxylic acid (2.44 g, 15.49 mmol) in the presence of dry pyridine (25 mL) and POCl3 (2.1 mL, 23.43 mmol) using the conditions described in example 52 to get trans-2-Chloro-nicotinic acid 2-(2-acetoxymethyl-1-methyl-pyrrolidin-3-yl)6-acetyl-3,5-dimethoxy-phenyl ester. This was converted in situ to the title compound (66) using NaH (1.29 g, 26.86 mmol) in 1,4-dioxane (25 mL) as described in example 26.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=O)[CH:5]=[C:4]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:3]=1.CO>C1COCC1>[C:16]([C:4]1[CH:5]=[C:6]([CH2:8][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:7]=[C:2]([NH2:1])[CH:3]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1cc(N)nc(C(=O)N2CCOCC2)c1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(N)nc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
Suspend (6-amino-4-tert-butyl-pyridin-2-yl)-morpholin-4-yl-methanone (6.02 g, 22.86 mmol) in 40 mL anhydrous THF. Add 2 M solution of BH3-Me2S complex in THF (34.3 mL, 68.6 mmol, 3 eq) dropwise at room temperature. On BH3-Me2S/THF solution addition, the suspension turns clear and bright yellow after complete addition. Stir overnight at room temperature under nitrogen atmosphere. Carefully quench reaction with slow addition of MeOH (24 mL), stir 3 hours at 60° C. and concentrate in vacuo. Purify the residue on 300 g silica cartridge with a gradient of 0→2% MeOH in dichloromethane over 2 minutes, followed by 2→10% MeOH in dichloromethane over 40 minutes. Concentrate and dry clean fractions to give 2.0 g (35%) of the title compound as a white solid. LCMS (ES) m/z 250 (M+1).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].[C:8]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:13]=[CH:12][C:11]([N:14]2[C:18]3=[N:19][CH:20]=C(C#N)[CH:22]=[C:17]3[C:16]3([CH2:29][CH2:28][N:27]([CH2:30][C:31]4[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][N:32]=4)[CH2:26][CH2:25]3)[C:15]2=[O:38])=[CH:10][CH:9]=1.S(=O)(=O)(O)O.[OH-].[Li+].Cl>O.C1COCC1.C(O)C>[C:8]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:9]=[CH:10][C:11]([N:14]2[C:18]3=[N:19][CH:20]=[C:2]([C:3]([OH:5])=[O:4])[CH:22]=[C:17]3[C:16]3([CH2:29][CH2:28][N:27]([CH2:30][C:31]4[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][N:32]=4)[CH2:26][CH2:25]3)[C:15]2=[O:38])=[CH:12][CH:13]=1
Reactant: Cc1cccnc1CN1CCC2(CC1)C(=O)N(c1ccc(-c3ccccc3)cc1)c1ncc(C#N)cc12
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccnc1CN1CCC2(CC1)C(=O)N(c1ccc(-c3ccccc3)cc1)c1ncc(C(=O)O)cc12
Temperature: 100 °C

Procedure:
The title compound of Example 4, 1′-biphenyl-4-yl-1-[(3-methylpyridin-2-yl)methyl]-2′-oxo-1′,2′-dihydrospiro[piperidine-4,3′-pyrrolo[2,3-b]pyridine]-5′-carbonitrile, (1 mmol) was combined with anhydrous ethanol (10 mL) and neat sulfuric acid (1 mL) was added drop wise to the solution over 2 minutes. The resulting mixture is heated in a sealed tube to 100° C., allowed to cool to room temperature and combined with ice water. The resulting mixture was extracted with methylene chloride, dried and concentrated. The crude oil is combined with THF (10 mL), water (5 mL) and lithium hydroxide (20 mmol) and heated to 50° C. for 5 h, acidified with 1 m HCl, concentrated and purified by preparative reverse phase HPLC (method C), which provided the title compound, isolated as a salt of trifluoroacetic acid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:24]=[CH:25][CH:26]=1)[C:15]([CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)=[O:16].C(N(CC)CC)C>O1CCCC1.C(OCC)(=O)C.[OH-].[Na+]>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:13]=[C:14]([CH:24]=[CH:25][CH:26]=2)[C:15]([CH:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)=[O:16])=[O:7])=[CH:4][CH:3]=1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(F)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
4-Fluorobenzoyl chloride (0.98 ml, 8.3 mmol) was added dropwise to a 0° C. solution of 4-[3-aminobenzoyl]-1-methylpiperidine (1.64 g, 7.5 mmol) and triethylamine (1.3 ml, 9.0 mmol) in tetrahydrofuran (20 ml). The reaction mixture stirred 2 h at room temperature, diluted with ethyl acetate and 1N sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate extracts were washed with water, brine, then dried over sodium sulfate. Solvent was removed under reduced pressure to give 2.5 g (98%) of a foam.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:19])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:26])[CH3:25]>C(O)C>[C:24]([NH:23][CH2:22][CH2:21][NH:20][C:6]([C:8]1[N:9]=[C:10]([Cl:19])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])(=[O:26])[CH3:25]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Reactant: CC(=O)NCCN
Solvent: CCO
Product: CC(=O)NCCNC(=O)c1nc(Cl)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 104 %

Procedure:
A mixture of 56 mg (0.2 mmol) of 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester from example B-1 c), 227 mg (2 mmol) of N-(2-amino-ethyl)-acetamide and 0.8 ml of absolute ethanol was stirred at ambient temperature for 3 days. Then the solvent was evaporated in vacuo, the residue suspended in 3 ml of water, and the pH of the mixture was adjusted 2 to 3 by the addition of aqueous 1N HCl. The mixture was extracted with 2×25 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated in vacuo to give a yellowish solid. 64 mg of the title compound were obtained; MS-(+)-ion: M+1=308.1.
Reaction SMILES: [CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[C:14]([CH2:15]2)=[CH:13][NH:12]4)[CH2:5][CH:4]([C:18]([O:20][CH3:21])=[O:19])[CH2:3]1.FC(F)(F)C(O)=O.[BH4-].[Na+].[OH-].[NH4+]>>[CH3:1][N:2]1[C@H:16]2[C@@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[C:11]4[C:17]=3[CH:14]([CH2:15]2)[CH2:13][NH:12]4)[CH2:5][CH:4]([C:18]([O:20][CH3:21])=[O:19])[CH2:3]1
Reactant: COC(=O)C1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Agent: [BH4-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1C[C@@H]2c3cccc4c3C(CN4)C[C@H]2N(C)C1

Procedure:
A solution of 0.7 g. of 6-methyl-8-carbomethoxyergoline in 50 ml. of trifluoroacetic acid was stirred and cooled to 5° c. in an ice-water bath. To the cold reaction mixture was added 1 g. of sodium borohydride in equal portions over about 1/2 hour. The reaction mixture was added 50 g. of ice and ammonium hydroxide was added to adjust the pH to 11. The aqueous alkaline reaction mixture was extracted with ethyl acetate, and the combined organic extracts were washed with water, dried, and the solvent was removed therefrom providing 2,3-dihydro-6-methyl-8-carbomethoxy-ergoline as an oil. The oil was added to a column containing 30 g. of florisil, and the column was eluted with chloroform containing 1 percent methanol. Fractions of 50 ml. each were collected, and fractions 25-35 were combined, the solvent was removed therefrom under reduced pressure to afford an oil which was crystallized from diethyl ether and hexane and shown to be 2,3-dihydro-6-methyl-8carbomethoxy-ergoline, M.P. 110°-120° C.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH3:10][CH:11]([CH3:15])[C:12](=O)[CH3:13].N1C=CC=CC=1.O>C(Cl)(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:10][CH:11]([CH3:15])[C:12](=[C:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])[CH3:13]
Reactant: COC(=O)CC(=O)OC
Reactant: CC(=O)C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)C(C(=O)OC)=C(C)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon and at 0° C., 10 g (75.7 mmol) of dimethyl malonate in 20 ml of chloroform were slowly added dropwise to a solution of 16.6 ml (151.4 mmol) of titanium tetrachloride in 60 ml of chloroform. After the addition had ended, the reaction solution was stirred at 0° C. for another 30 min. At 0° C., 6.52 g (75.7 mmol) of 3-methyl-2-butanone in 20 ml of chloroform were then added dropwise. The reaction mixture was slowly warmed to room temperature and stirred at this temperature for 4 h. The reaction solution was then once more cooled to 0° C., and 30.6 ml (378.5 mmol) of pyridine in 20 ml of chloroform were added. After the addition had ended, the solution was warmed to room temperature and stirred at this temperature overnight. The reaction solution was then once more cooled to 0° C., and 50 ml of water were added slowly. The resulting phases were separated, and the aqueous phase was extracted two more times with in each case about 50 ml of dichloromethane. The combined organic phases were washed with saturated sodium bicarbonate solution and with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 9.4 g (62% of theory) of the target compound.
Reaction SMILES: [N+:1]([C:4]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[H][H].CCCCCC.C(OCC)(=O)C>[Pd].C(O)C>[NH2:1][C:4]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: [H][H]
Reactant: N#Cc1cccc(O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: N#Cc1cccc(O)c1N
Reaction time: 1 h

Procedure:
A parr bottle was charged with palladium on activated carbon (5%, 0.196g). A solution of 2-nitro-3-hydroxybenzonitrile (1.31 g, 0.008 mol) in 40 ml of ethanol was added. The reaction mixture was placed under 25 psi of hydrogen gas and shaken for 1 hour. TLC (1:1 hexane:ethyl acetate) shows that no starting material remained. The mixture was filtered through Celite® and evaporated to yield 2-amino-3-hydroxybenzonitrile, 1.01 g (0.0075 mol, 94%).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[N+:9]([O-:11])=[O:10].C(N(CC)CC)C.[N:19]1([CH2:24][CH2:25][CH2:26][NH2:27])[CH:23]=[CH:22][N:21]=[CH:20]1>CN(C)C=O>[CH3:7][N:6]1[C:2]([NH:27][CH2:26][CH2:25][CH2:24][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[C:3]([N+:9]([O-:11])=[O:10])[C:4]([CH3:8])=[N:5]1
Reactant: NCCCn1ccnc1
Reactant: Cc1nn(C)c(Cl)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(NCCCn2ccnc2)c1[N+](=O)[O-]
Temperature: 105 °C
Yield: 56.7 %

Procedure:
0.88 g of 5-chloro-1,3-dimethyl-4-nitro-1H-pyrazole (Aldrich), 1 molar equivalent of triethylamine, 1.1 molar equivalents of 3-imidazol-1-ylpropylamine and 5 ml of N,N-dimethylformamide were introduced into a 25 ml three-necked round-bottomed flask equipped with a magnetic stirrer, a thermometer and a condenser. The reaction medium was maintained at a temperature of about 105° C. for 6 hours. The solvent was evaporated off under vacuum. A black liquid was obtained, which was purified by chromatography on silica gel (ethyl acetate/methanol=4/1). 0.75 g of (2,5-dimethyl-4-nitro-2H-pyrazol-3-yl)(3-imidazol-1-yl-propyl)amine was obtained in the form of white crystals in a yield of 56.7%.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][CH:4]=1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K]>CN(C=O)C.O>[CH:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:15]2[C:11](=[O:21])[C:12]3[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:14]2=[O:16])=[CH:4][CH:5]=1)=[CH2:10]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=Cc1ccc(CCl)cc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: C=Cc1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 70 °C
Yield: 46 %

Procedure:
To a stirred solution of 1-(chloromethyl)-4-vinylbenzene (10 g, 66 mmol) in DMF (100 mL) was added potassium phthalimide (13.3 g, 72.1 mmol), and the resultant reaction mixture was heated at 70° C. for 16 h. The reaction mixture was diluted with H2O and extracted with CHCl3. The combined CHCl3 layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Recrystallization from MeOH afforded the title compound as an off-white solid (8 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.83 (m, 2H), 7.71 (m, 2H), 7.39 (m, 4H), 6.65 (dd, J=17.6, 10.8 Hz, 1H), 5.72 (d, J=17.6 Hz, 1H), 5.21 (d, J=10.8 Hz, 1H), 4.82 (s, 2H); GCMS m/z 263.2 ([M]+); IR (thin film) 3420, 1133, 718 cm−1.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[C:7]2[CH2:11][N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:9][C:8]=12)([OH:3])=[O:2].[BrH:22]>C(O)(=O)C>[BrH:22].[C:1]([C:4]1[S:5][CH:6]=[C:7]2[CH2:11][NH:10][CH2:9][C:8]=12)([OH:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)N2Cc3csc(C(=O)O)c3C2)cc1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1scc2c1CNC2
Temperature: 60 °C
Yield: 83 %

Procedure:
A mixture of 0.5 g (1.54 mmol) of 1-carboxy-5-tosyl-5,6-dihydro-4H-thieno[3,4-c]pyrrole and 5 ml of a 33% solution of hydrobromic acid in acetic acid, placed in a sealed tube, is heated at 60° C. in a water bath for 15 min. The reaction mixture is then cooled, the precipitate formed is filtered, washed twice with diethyl ether and dried. 0.32 g of product is obtained in the hydrobromide form. Yield 83%. Melting point: 281.3°-281.7° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6](C(OC(C)(C)C)=O)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH2:14][O:15][C:16](=[O:18])[CH3:17])=[CH:9][C:8]=2[N+:19]([O-:21])=[O:20])=[O:4].Cl>ClCCl>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH2:14][O:15][C:16](=[O:18])[CH3:17])=[CH:9][C:8]=2[N+:19]([O-:21])=[O:20])=[O:4]
Reactant: COC(=O)c1cc2cc(COC(C)=O)cc([N+](=O)[O-])c2n1C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cc2cc(COC(C)=O)cc([N+](=O)[O-])c2[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.8 %

Procedure:
1-BOC-5-acetoxymethyl-7-nitro-indole-2-carboxylic acid methyl ester (4.7 g, 12.0 mmol) prepared in Step A was dissolved in dichloromethane (50 mL). 2N hydrochloric acid solution (30 mL, 60 mmol) was added thereto, and the mixture was stirred for 12 h at room temperature. The reaction mixture was distilled under reduced pressure to give the solid title compound (3.5 g, Yield 100%).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([CH2:13][CH2:14][S:15]([O-:18])(=O)=[O:16])[CH:9]=[CH:10][C:11]=1[Cl:12].[Na+].C1C=CC=CC=1>CN(C)C=O>[Cl:5][C:6]1[CH:7]=[C:8]([CH2:13][CH2:14][S:15]([Cl:3])(=[O:18])=[O:16])[CH:9]=[CH:10][C:11]=1[Cl:12]
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])CCc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)CCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
Thionyl chloride (1.15 mL, 15.83 mmol) was added dropwise to a suspension of sodium 2-(3,4-dichloro-phenyl)-ethanesulfonate (3.17 g, 11.47 mmol) in a mixture of anhydrous benzene (50 mL) and anhydrous N,N-dimethylformamide (1 mL) at 0° C. The reaction mixture was allowed to warm slowly to room temperature and was then heated at 80° C. for 18 hours. The reaction mixture was cooled to room temperature and filtered through a pad of Celite. The solids were washed with benzene and the combined filtrates were concentrated in vacuo. The residue was taken up in hexane and the resulting suspension was heated at 50° C. for 30 min. After cooling to room temperature, a solid was collected by filtration to give 2.20 g (70% yield) of the title compound.
Reaction SMILES: [F:1][CH:2]([F:34])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]([CH3:21])[CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:11]=[C:10]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:9]=2)[C:6]2[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:5]=2[N:4]=1.CCN(CC)CC.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C1COCC1.O>[F:34][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]([CH3:21])[CH:15]3[CH2:20][CH2:19][N:18]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:17][CH2:16]3)[CH:11]=[C:10]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:9]=2)[C:6]2[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:5]=2[N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)cc(N(C)C2CCNCC2)n1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)cc(N(C)C2CCN(S(C)(=O)=O)CC2)n1
Temperature: 0 °C
Yield: 8.9 %

Procedure:
A mixture of 95 mg (2 mmol) of 2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-6-(4-morpholinyl)-N-(4-piperidinyl)-4-pyrimidinamine and 61 mg (6 mmol) of Et3N in 15 mL THF was cooled to 0° C. and 46 mg (4 mmol) of methanesulphonyl chloride was added. The stirred mixture was allowed to warm to room temperature, and after 2 hrs it was diluted with water to give a precipitate of 98 mg (89% yield) of 2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-methyl-N-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-4-pyrimidinamine: mp (MeOH) 191-193° C.; 1H NMR (CDCl3) δ 7.77 (dd, J=8.4. 0.6 Hz, 1H), 7.37 (t, JHF=53.4 Hz, 1H), 7.31 (t, J=8.2 Hz, 1H), 6.79 (d, J=7.6 Hz, 1H), 5.40 (s, 1H), 4.96 (m, 1H), 4.05 (s, 3H), 3.99-3.93 (m, 2H), 3.83 (m, 4H), 3.64 (m, 4H), 2.90 (s, 3H), 2.82 (s, 3H), 2.81 (dt, J=12.0, 2.4 Hz, 2H), 1.91 (dq J=12.3, 4.3 Hz, 2H), 1.85-1.76 (m, 2H); Anal. Calcd. for C24H31F2N7O4S: C, 52.3; H, 5.7; N, 17.8. Found: C, 52.5; H, 5.7; N, 17.9%.