Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].C=O.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19](S(O)(=O)=O)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]=1[CH2:7][C:6]1[CH2:26][C:16]2[C:21]([C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1C=Cc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: Cc1ccccc1
Product: CC(C)(C)C1=C(CC2=C(C(C)(C)C)c3ccccc3C2)Cc2ccccc21
Temperature: 80 °C
Reaction time: 6 h
Yield: 216.4 %

Procedure:
In a 500 mL flask equipped with magnetic stirring bar were introduced 12.35 g (0.072 moles) of 1-t-butyl-indene, 1.43 g (0.048 moles) of para-formaldehyde and 2.73 g (0.014 moles) of para-toluenesulphonic acid in 200 ml of toluene; the mixture was heated to 80° C. and was maintained under stirring for 6 hours at 80° C. Then the reaction was quenched with water/NaHCO3; the conversion, measured by gas chromatographic analysis, was 79.5%. The organic layer was separated, washed with water and brought to dryness under reduced pressure. The crude product crystallized upon standing at room temperature, and then was further purified by washing with MeOH, thus isolating 10.8 g bis(3-t-butyl-2-indenyl)methane (purity of 90.9 by G.C.; yield=76.81%).
Reaction SMILES: C(C1SCCCS1)C.C([Li])CCC.[CH3:14][N:15]1[C:19]([S:20][CH2:21][CH2:22][CH2:23]Cl)=[N:18][N:17]=[N:16]1.[O:25]1C[CH2:28][CH2:27][CH2:26]1>CCCCCC>[CH3:14][N:15]1[C:19]([S:20][CH2:21][CH2:22][CH2:23][C:26](=[O:25])[CH2:27][CH3:28])=[N:18][N:17]=[N:16]1
Reactant: Cn1nnnc1SCCCCl
Reactant: C1CCOC1
Agent: CCC1SCCCS1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCC(=O)CCCSc1nnnn1C
Temperature: -78 °C

Procedure:
2-Ethyl-1,3,-dithian (1,5 g) is dissolved in dried tetrahydrofuran (20 ml) and cooled to -78° C. To the mixture is added dropwise 1.6 N solution of n-butyllithium in n-hexane (6.5 ml) with stirring in argon gas flow. The mixture is stirred at -78° C. for 30 minutes. To the mixture is added dropwise a solution of 1-methyl-5-(3-chloropropyl)thio-1,2,3,4-tetrazole (1.9 g) in dried tetrahydrofuran (5 ml). After stirring at -78° C. for 1 hour, the mixture is stirred 4 hours while it is heated slowly to 0° C. The reaction mixture is poured into ice-water and extracted with ether. The ether solution is washed with water and saturated aqueous sodium chloride and dried over magnesium sulfate. After ether is distilled off, the residue is dissolved in acetonitrile (20 ml). Silver nitrate (7 g) and N-chlorosuccinimide (4.9 g) are dissolved in a mixture of water (40 ml) and acetonitrile (100 ml). To the mixture is added dropwise the dithian solution as above-mentioned with stirring at 0° C. in nitrogen gas flow. After stirring at 0° C. for 30 minutes, the mixture is heated to room temperature and further stirred for 30 minutes. The reaction mixture is diluted with water and extracted with chloroform. The chloroform solution is washed with water and saturated aqueous sodium chloride and dried over magnesium sulfate. After chloroform is distilled off, the residue is purified by column chromatography (Kieselgel 60) and eluted with benzene-ether (10:1) to give 1-methyl-5-(3-propionylpropyl)thio-1,2,3,4-tetrazole (0.3 g) as colorless liquid, nD25 =1.5042
Reaction SMILES: C(OC([N:6]1[CH2:9][C:8]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][NH:19][S:20]([CH2:23][CH:24]3[CH2:26][CH2:25]3)(=[O:22])=[O:21])[CH:11]=2)[CH2:7]1)=O)C.[OH-].[Na+].CCO>[Cl-].[Na+].O>[CH2:27]([C:8]1([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[O:16][CH2:17][CH2:18][NH:19][S:20]([CH2:23][CH:24]2[CH2:25][CH2:26]2)(=[O:22])=[O:21])[CH2:7][NH:6][CH2:9]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)N1CC(Cc2ccccc2)(c2cccc(OCCNS(=O)(=O)CC3CC3)c2)C1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=S(=O)(CC1CC1)NCCOc1cccc(C2(Cc3ccccc3)CNC2)c1

Procedure:
To 3-benzyl-3-[3-(2-cyclopropylmethanesulfonylamino-ethoxy)-phenyl]-azetidine-1-carboxylic acid ethyl ester (50 mg, 0.11 mmol) was added 4 ml 2N NaOH/EtOH. The mixture was heated for 1 hour in a microwave. After cooling to room temperature 50% brine was added and the mixture extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium bicarbonate, filtered and the solvent evaporated. The residue was purified on 4 g SiO2 using 10% methanol in dichloromethane affording the desired product as a clear oil. m=15.5 mg
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH2:13][CH3:14])[N:5]=[C:4]2[N:15]([CH2:18][CH3:19])[N:16]=[CH:17][C:3]=12.C(N(C(C)C)CC)(C)C.[O:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1.O>CN1CCCC1>[CH2:18]([N:15]1[C:4]2=[N:5][C:6]([CH2:13][CH3:14])=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]([NH:35][CH:32]3[CH2:33][CH2:34][O:29][CH2:30][CH2:31]3)=[C:3]2[CH:17]=[N:16]1)[CH3:19]
Reactant: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1Cl
Reactant: NC1CCOCC1
Agent: CN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1NC1CCOCC1
Yield: 111.3 %

Procedure:
To a solution of ethyl 4-chloro-1,6-diethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (380 g) in 1-methylpyrrolidine (3,166 mL) was added diisopropylethylamine (469.8 mL) and tetrahydro-2H-pyran-4-ylamine (163 g) and the mixture was heated at reflux for 16 h. The cooled mixture was treated with water (12 L) and extracted with ethyl acetate (6×1250 mL). The combined organics were washed with brine, dried over magnesium sulphate, filtered and concentrated to dryness to afford 520 g of a dark brown oil. The product was purified by flash chromatography on silica using ethyl acetate/cyclohexane @ 1:4-1:2 as eluant to afford 336 g of the title compound. LC-MS m/z 347 (M+H)+, 3.02 min (ret time).
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][NH:11]C(=O)OC(C)(C)C)[CH2:6][CH2:5]1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[NH2:11][CH2:10][C@H:7]1[CH2:8][CH2:9][C@H:4]([CH2:3][C:1]#[N:2])[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CC#N)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC[C@H]1CC[C@H](CN)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (trans-4-(cyanomethyl)cyclohexyl)methylcarbamate (500 mg) in dichloromethane (5 mL) was slowly added trifluoroacetic acid (3 mL) at 0° C. The mixture was warmed to room temperature, stirred for 1 hour. The title compound was obtained by concentration.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([S:23][CH3:24])[C:4]=1[C:5]([NH:7][CH:8]1[C:13](=O)[CH2:12][CH2:11][O:10][CH2:9]1)=[O:6].C(O)(=O)C.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:18]=[C:17]([C:19]([F:20])([F:22])[F:21])[CH:16]=[C:15]([S:23][CH3:24])[C:4]=1[C:5]([NH:7][C@H:8]1[C@@H:13]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:12][CH2:11][O:10][CH2:9]1)=[O:6]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1COCCC1=O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)N[C@@H]1COCC[C@@H]1N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
2-Methoxy-6-methylsulfanyl-N-(4-oxo-tetrahydro-pyran-3-yl)-4-trifluoromethyl-benzamide (intermediate C, 300 mg, 0.83 mmol) was dissolved in 5 mL tetrahydrofurane. Acetic acid (86 mg, 1.4 mmol) and pyrrolidine (70 mg, 0.99 mmol) were added and the reaction mixture was stirred 1 h at room temperature. Sodium triacetoxyborohydride (209 mg, 0.99 mmol) was added and stirring was continued at room temperature overnight. The mixture was extracted with 2N sodium carbonate solution and ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (dichloromethane/methanol/ammonia 100:0:0→140:10:1) yielded cis-2-methoxy-6-methylsulfanyl-N-((3RS,4RS)-4-pyrrolidin-1-yl-tetrahydro-pyran-3-yl)-4-trifluoromethyl-benzamide as a light brown solid (80 mg, 40%), MS: m/e=419.1 [(M+H)] and trans-2-methoxy-6-methylsulfanyl-N-((3RS,4SR)-4-pyrrolidin-1-yl-tetrahydro-pyran-3-yl)-4-trifluoromethyl-benzamide as a light brown solid (25 mg, 12%), MS: m/e=419.1 [(M+H)+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:20](O)=[O:21])[CH2:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([C:20]([N:1]3[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][OH:8])[CH2:2]3)=[O:21])[CH2:19][CH2:18][CH2:17]2)=[CH:14][CH:15]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Reactant: OCC1CCCNC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCCC(CO)C1)C1(c2ccc(Cl)cc2)CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 43.4 %

Procedure:
To a solution of 3-piperidinemethanol (5.0 g, 43.4 mmol), 1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid (9.14 g, 43.4 mmol), and diisopropylethylamine (11.22 g, 86.8 mmol) in dichloromethane (100 mL) at 0° C. was added PyBroP® (22.26 g, 47.8 mmol). The reaction was stirred at 0° C. for 1 h and then at room temperature for 4 h. The reaction mixture was washed successively with water, 1 N HCl, water, sat. sodium bicarbonate solution, and water (100 mL each). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by chromatography on silica gel, eluting with dichloromethane/methanol (96:4) to give 5.8 g of the amide 1 as a thick gum.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:5]=[N:4][N:3]=[N:2]1.S(Cl)([Cl:15])=O>C1C=CC=CC=1.CN(C=O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([Cl:15])=[O:12])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=C(O)CCCCn1cnnn1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)CCCCn1cnnn1

Procedure:
1 g of 5-(tetrazol-1-yl)-valeric acid is heated for 20 minutes at reflux temperature in 12 ml of absolute benzene with 0.6 ml of thionyl chloride and 2 drops of DMF. After concentration by evaporation under reduced pressure, the title compound is obtained.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccc(I)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Ic1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A reaction mixture composed of 21.40 g (95.3 mmol) of 98% 4-iodophenol, 12.19 g (95.3 mmol) of 99% benzyl chloride, 20.73 g (150 mmol) of potassium carbonate and 250 ml of acetone was heated to reflux temperature and heated to boiling for 30 hours. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated and then cooled in an ice bath, in the course of which a solid precipitated out. This was removed by means of a blue-band filter and then dried. The crude product (23.22 g) was recrystallized from 70 ml of ethanol. 17.20 g (58% of theory) of colorless microcrystals having an m.p. of 61-62° C. (lit. 62° C.) were obtained.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH3:13].[CH3:14][N:15]1[CH2:21][C:20]2[CH:22]=[C:23]([CH:26]=[CH:27][C:28](O)=[O:29])[CH:24]=[N:25][C:19]=2[NH:18][C:17](=[O:31])[CH2:16]1>>[CH3:1][N:2]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH3:13])[C:28](=[O:29])/[CH:27]=[CH:26]/[C:23]1[CH:24]=[N:25][C:19]2[NH:18][C:17](=[O:31])[CH2:16][N:15]([CH3:14])[CH2:21][C:20]=2[CH:22]=1
Reactant: CN1CC(=O)Nc2ncc(C=CC(=O)O)cc2C1
Reactant: CNCc1c(C)[nH]c2ccccc12
Product: Cc1[nH]c2ccccc2c1CN(C)C(=O)/C=C/c1cnc2c(c1)CN(C)CC(=O)N2
Yield: 9.9 %

Procedure:
According to the method of example 35g, methyl-(2-methyl-1H-indol-3-ylmethyl)amine (115 mg, 0.66 mmol) and 3-(4-Methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)-acrylic acid (192 mg, 0.6 mmol) were coupled to give crude product. Purification by column chromatography (silica gel, CH2Cl2/MeOH/NH3, 9:4.55:0.05) gave title compound (24 mg, 9%) as a white solid and as a mixture of amide rotomers. 1H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.95-8.01 (m, 2H), 7.56-7.60 (m, 2H), 7.47-7.50 (m, 1H), 7.16-7.26 (m, 2H), 6.92-7.05 (m, 2H), 3.90 (s, 2H), 3.56 (s, 2H), 3.02 (s, 2H), 2.93 (s, 3H), 2.83 (s, 3H), 2.46 (s, 3H); MS (EST) m/e 404 (C23H25N5O2+H)+.
Reaction SMILES: [N:1]#[C:2]Br.[NH2:4][C:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:6]=1OC.[OH-].[Na+]>CCO.O>[NH2:1][C:2]1[NH:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[N:11]=1
Reactant: N#CBr
Reactant: COc1cccc(N)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Cyanogen bromide (7.05 mmol, 0.74 g) was added to a solution of 2,3-diaminoanisole (4.7 mmol, 0.65 g) in EtOH (10 mL) and the reaction was stirred at room temperature for 14 h. The reaction was diluted with H2O and then basified (pH>12) using 4 M NaOH. The aqueous layer was extracted with CH2Cl2. The organic phase was then separated and washed with brine and then dried over MgSO4 and then concentrated to provide 2-aminobenzimidazole 37b.
Reaction SMILES: [O-]CC.[Na+].[CH3:5][C:6]([C:9]([NH2:11])=[NH:10])([CH3:8])[CH3:7].Cl.[C:13]([OH:21])(=[O:20])/[C:14](=[C:16](\[CH:18]=O)/[Br:17])/Br>C(O)C.Cl>[Br:17][C:16]1[C:14]([C:13]([OH:21])=[O:20])=[N:10][C:9]([C:6]([CH3:8])([CH3:7])[CH3:5])=[N:11][CH:18]=1
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Reactant: CC(C)(C)C(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1ncc(Br)c(C(=O)O)n1
Temperature: 50 °C
Yield: 76.6 %

Procedure:
A 22% solution of sodium ethoxide in ethanol (53 mL, 165 mmol) was added dropwise to a magnetically stirred suspension of tert-butylcarbamidine hydrochloride (20.0 g, 146 mmol) in ethanol (100 mL). When the addition was complete, the yellow suspension was warmed to 50° C., the heating mantle was removed, and a solution of mucobromic acid (15.7 g, 61 mmol) in ethanol (50 mL) was added dropwise at a rate which did not allow the temperature to exceed 55° C. When this addition was complete, a 22% solution of sodium ethoxide in ethanol (32 mL, 98 mmol) was added dropwise, then the mixture was allowed to cool to room temperature. The suspension was filtered, the solids were rinsed with ethanol (2×20 mL), and the combined filtrates were concentrated in-vacuo. The residue thus obtained was stirred in 2 N aqueous HCl (30 mL). The resulting solids were collected by filtration, rinsed with ice-cold water (2×20 mL), and air dried to yield 12.1 g of 5-Bromo-2-tert-butyl-pyrimidine-4-carboxylic acid as a beige powder. MS (ES+)=259, 261 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH2:16][CH:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH3:18])[N:12]3[N:25]=[CH:26][CH:27]=[C:11]3[N:10]=2)[CH:7]=1.P(Cl)(Cl)(Cl)=O.CN([CH:37]=[O:38])C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH2:16][CH:17]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[CH3:18])[N:12]3[N:25]=[CH:26][C:27]([CH:37]=[O:38])=[C:11]3[N:10]=2)[CH:7]=1
Reactant: CN(C)C=O
Reactant: CC(CNc1cc(Nc2cc(Cl)ccc2F)nc2ccnn12)N1CCOCC1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(CNc1cc(Nc2cc(Cl)ccc2F)nc2c(C=O)cnn12)N1CCOCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 41 %

Procedure:
In a reaction flask, N5-(5-chloro-2-fluorophenyl)-N7-(2-morpholinopropyl)pyrazolo[1,5-a]pyrimidine-5,7-diamine (84 mg, 0.21 mmol) was dissolved in DMF (0.9 mL) then phosphorous oxychloride (58 uL, 0.62 mmol) was added slowly at room temperature. The reaction mixture was allowed to stir at room temperature for 2 days then quenched by addition to 6N NaOH solution. The pH of the mixture was adjusted with 6N HCl to pH=7-9. The solid was recovered by filtration and washed with water. The product, 5-(5-chloro-2-fluorophenylamino)-7-(2-morpholinopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde, was purified by preparative TLC (5% acetone/dichloromethane) to yield 37 mg of the desired product (41% yield). LCMS (M+1=433)
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:10][C:11]2[C:17]([CH3:18])=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=2[CH3:19])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:34](Cl)([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:35].C([O-])(O)=O.[Na+].[Na+].[Cl-]>ClCCl>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:10][C:11]2[C:12]([CH3:19])=[CH:13][C:14]([NH:15][C:34](=[O:35])[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:16][C:17]=2[CH3:18])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: COc1ccc(Cc2c(C)cc(N)cc2C)cc1Cc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1cc(C)c(Cc2ccc(OC)c(Cc3ccc(F)cc3)c2)c(C)c1
Reaction time: 4 h
Yield: 53.5 %

Procedure:
335 mg (0.96 mmol) of 4-[3-(4-fluorobenzyl)-4-methoxybenzyl]-3,5-dimethylaniline (Example X) and 107 mg (1.06 mmol) of triethylamine are introduced into ml of dichloromethane and, at 0° C., 177 mg (1.29 mmol) of ethoxalyl chloride are added dropwise. The mixture is stirred for 4 h. It is shaken with NaHCO3 solution and NaCl solution, and the organic phase is dried and concentrated in a rotary evaporator. Purification by chromatography (cyclohexane/ethyl acetate=7:1) affords 231 mg of ethyl ({4-[3-(4-fluorobenzyl)-4-methoxybenzyl]-3,5-dimethylphenyl}amino)(oxo)-acetate.
Reaction SMILES: [CH:1]12[CH2:8][CH:7]=[CH:6][CH:5]1[CH:4]1[C:9]([O:11][C:12](=[O:13])[CH:2]2[CH2:3]1)=O.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[N:29][CH:28]=[C:27]([Cl:31])[N:26]=2)[CH2:21][CH2:20]1>>[Cl:31][C:27]1[N:26]=[C:25]([N:22]2[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][CH2:15][N:14]3[C:9](=[O:11])[CH:4]4[CH2:3][CH:2]([CH:1]5[CH2:8][CH:7]=[CH:6][CH:5]54)[C:12]3=[O:13])[CH2:24][CH2:23]2)[CH:30]=[N:29][CH:28]=1
Reactant: NCCCCN1CCN(c2cncc(Cl)n2)CC1
Reactant: O=C1OC(=O)C2CC1C1C=CCC21
Product: O=C1C2CC(C(=O)N1CCCCN1CCN(c3cncc(Cl)n3)CC1)C1CC=CC21

Procedure:
The title compound was prepared from 2.1 g (12 mmoles) of bicyclo[3.3.0]oct-6-ene-2,4-dicarboxylic anhydride and 3.2 g (12 mmoles) of 1-(4-aminobutyl)-4-(6-chloro-2-pyrazinyl)piperazine following the procedure in Example 4. 620 mg of the hydrochloride salt was isolated as the hemihydrate, m.p. 222°-224° C., after two recrystallizations from isopropanol.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:25])[NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]3)[N:10]([CH2:26][C:27](=[O:36])[NH:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.[Li+].[BH4-].O>C1COCC1>[CH:22]([N:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:14]([C:11]2[N:10]([CH2:26][C:27](=[O:36])[NH:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=3)[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([CH2:3][OH:2])[C:13]=3[N:12]=2)=[O:25])[CH2:17][CH2:18]1)([CH3:24])[CH3:23]
Reactant: COC(=O)c1cccc2c1nc(C(=O)NC1CCN(C(C)C)CC1)n2CC(=O)Nc1ccc(Cl)cn1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N1CCC(NC(=O)c2nc3c(CO)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
85.0 mg (0.166 mmol) 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid methyl ester were dissolved in 3 mL abs. THF. Under argon 0.25 mL (0.497 mmol) of a 2 M LiBH4-solution in THF were added. After stirring for 1.5 h at room temperature 0.5 mL water were added and the reaction mixture was concentrated. The residue was purified by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) to give 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-hydroxymethyl-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide as a white amorphous solid. The title compound was obtained as its formiate. Yield: 20 mg MS (ES+): m/e=485, chloro pattern.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:24])[O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH:14]=1)[C:9]([OH:11])=O.[CH2:25]([O:27][C:28](=[O:37])[CH2:29][S:30][C:31]1[S:35][C:34]([NH2:36])=[N:33][CH:32]=1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:37])[CH2:29][S:30][C:31]1[S:35][C:34]([NH:36][C:9](=[O:11])[C:8]2[CH:12]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH:14]=[C:6]([O:5][C@@H:4]([CH3:24])[CH2:3][O:2][CH3:1])[CH:7]=2)=[N:33][CH:32]=1)[CH3:26]
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(OC)cc2)cc(C(=O)O)c1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(Oc3ccc(OC)cc3)cc(O[C@@H](C)COC)c2)s1

Procedure:
The title compound was prepared from {2-[3-((S)-2-methoxy-1-methyl-ethoxy)-5-(4-methoxy-phenoxy)-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[CH:14]=2)=[CH:9][CH:8]=1.[OH-].[Na+].CN(C)[CH:27]=[O:28]>>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[C:14]=2[CH:27]=[O:28])=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: Cn1cc(-c2ccc(F)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(C=O)c(-c2ccc(F)cc2)c2ccccc21
Temperature: 80 °C

Procedure:
78.5 ml. (0.84 mole) of phosphorus oxychloride is added dropwise over a 20 min. period to 213 ml. of dimethylformamide stirred at 0° C. under nitrogen, the temperature of the reaction mixture not being allowed to exceed 10° C. The reaction mixture is heated to 80° C., a solution of 163.5 g. (0.727 mole) of 3-(4'-fluorophenyl)-1-methylindole in 270 ml. of dimethylformamide is added at a rate such that the temperature of the reaction mixture is maintained at 81°-83° C., the reaction mixture is maintained at 80°-81° C. for 5 hours and cooled to 10° C., and 1 l. of 15% sodium hydroxide solution is added dropwise at a rate such that the temperature of the reaction mixture is maintained at 35°-40° C., the reaction mixture being stirred under nitrogen throughout. The reaction mixture is cooled to 25° C., and the solids are collected by filtration, washed three times with 500 ml. portions of water and dissolved in 500 ml. of methylene chloride. The methylene chloride solution is filtered through 500 ml. of silica gel (70-230 mesh A.S.T.M.) and the silica gel is carefully washed with 2 l. of methylene chloride. The methylene chloride solutions are combined and concentrated to a volume of 300 ml. at reduced pressure, 300 ml. of absolute ethanol is added, and the reaction mixture is distilled until the internal temperature reaches 78° C. The reaction mixture is cooled to 0° C. and the precipitated bright yellow product is collected by filtration and vacuum dried at room temperature (153.9 g. (84%)), m.p. 80.5°-81.5° C. A slightly less pure second crop may be obtained from the mother liquor.