Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][NH:9][C:8]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.[H-].[Na+].[C:25]1(C)[CH:30]=CC(S(OC(C)C)(=O)=O)=C[CH:26]=1>O>[C:1]1([N:7]2[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][N:9]([CH:25]([CH3:30])[CH3:26])[C:8]2=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NCc2cccnc2N1c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OC(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1Cc2cccnc2N(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 256.8 %

Procedure:
To a solution of 4.5 g of 1-phenyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine and 50 ml of dry dimethylformamide was added 1.2 g of 50% sodium hydride and the mixture was stirred for 30 minutes at room temperature, and then heated to a temperature of 90° - 100° C. To this was gradually added 1.28 g of isopropyl p-toluenesulfonate and the whole was reacted for 1 hour. After the reaction was complete, the solvent was distilled off from the mixture under reduced pressure. The residue obtained was diluted with water to produce a crude precipitate, which was collected by filtration and then dissolved in ethyl ether. Separation and purification were accomplished by applying the solution on a column of alumina, and the eluate was concentrated to give 4.1 g of 1-phenyl-3-isopropyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as colorless prisms, melting at 164° - 165° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[CH:13][N:14]=[C:7]3[C:6]=2[CH:15]=1.[F:16][C:17]1[C:22](B(O)O)=[CH:21][CH:20]=[CH:19][N:18]=1.C([O-])(=O)C.[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:16][C:17]1[C:22]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[CH:13][N:14]=[C:7]4[C:6]=3[CH:15]=2)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: OB(O)c1cccnc1F
Reactant: Brc1ccc2c(c1)-c1nccn1CCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ncccc1-c1ccc2c(c1)-c1nccn1CCO2
Temperature: 100 °C

Procedure:
To 10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (140 mg, 0.53 mmol) in DMF (20 mL) and water (2 mL) was added 2-Fluoropyridine-3-boronic acid (89 mg, 0.632 mml), Potassium acetate (207 mg, 2.11 mmol) and Tetrakis(triphenylphosphine)palladium (30 mg, 0.0264 mmol). The reaction mixture was degassed for 5 minutes, and heated at 100° C. overnight. LCMS showed desired product peak. The reaction was allowed to cool to room temperature, diluted with EtOAc, and filtered through a thin pad of celite. The filtrate was washed with water followed by brine, dried over MgSO4 and concentrated. The crude residue was purified by Prep HPLC to provide 10-(2-fluoropyridin-3-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine. LC/MS (ESI+): m/z 282 (M+H)
Reaction SMILES: [CH:1]1(O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1.C1C=CC=CC=1>O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:17])=[CH:13][CH:14]=1
Reactant: OC1CCCCC1
Reactant: O=C(O)Cc1ccc(O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C(Cc1ccc(O)cc1)OC1CCCCC1
Yield: 104.6 %

Procedure:
Cyclohexyl alcohol (6 g), 4-hydroxyphenylacetic acid (7.6 g) p-toluenesulfonic acid (1 g) and benzene (300 mL) were refluxed with continuous water separation for 8 hours. The mixture was cooled and washed with a 10% Na2CO3 solution, then with water. Drying over MgSO4 and evaporation of the solvent in vacuo gave 12.24 g of cyclohexyl 4-hydroxyphenylacetate. That compound can be represented by the formula: ##STR24##
Reaction SMILES: [C:1]1(=[O:18])[N:5]([CH:6]2[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]2)[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12.[NH:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)N>C(O)(=O)C>[C:25]([C:24]1[CH:23]=[C:22]2[C:21](=[CH:29][CH:28]=1)[NH:19][C:9]1[CH2:10][CH2:11][CH:6]([N:5]3[C:4](=[O:13])[C:3]4=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]4[C:1]3=[O:18])[CH2:7][C:8]2=1)([OH:27])=[O:26]
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Solvent: CC(=O)O
Product: O=C(O)c1ccc2[nH]c3c(c2c1)CC(N1C(=O)c2ccccc2C1=O)CC3
Reaction time: 12 h
Yield: 41.7 %

Procedure:
A mixture of 4-phthalimidocyclohexanone (2.43 g) and 4-hydrazinobenzoic acid (1.52 g) were combined in acetic acid and boiled for 12 hours. The precipitate was filtered and washed with acetic acid (3×10 ml) and diethyl ether (3×10 ml) to give 6-carboxy-3-phthalimido-1,2,3,4-tetrahydrocarbazole (1.50 g) m.p. 345°-348° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: O=C1CNCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCNC(=O)C2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
The mixture of piperazin-2-one (1.11 g, 11.1 mmol, Aldrich), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.43 g, 12.21 mmol, Aldrich) and sodium triacetoxyborohydride (2.59 g, 12.21 mmol, Aldrich) in dichloromethane (50 mL) was stirred at ambient temperature for 2 h. After the aqueous work up, the crude residue was purified by flash column chromatography (silica gel, Isco system, eluting with ethyl acetate and hexane) to give 4-(3-oxo-piperazin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.78 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:35][C@@H:34]4[C@@H:30]([CH2:31][NH:32][CH2:33]4)[CH2:29]3)=[O:27])[N:9]=2)[CH:7]=1.[CH:40]1([CH:43]=O)[CH2:42][CH2:41]1.[BH4-].[Na+].CO>FC(F)(F)CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:29][C@@H:30]4[C@@H:34]([CH2:33][N:32]([CH2:43][CH:40]5[CH2:42][CH2:41]5)[CH2:31]4)[CH2:35]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=CC1CC1
Reactant: O=C(Nc1cn(CC(=O)N2C[C@H]3CNC[C@H]3C2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: OCC(F)(F)F
Product: O=C(Nc1cn(CC(=O)N2C[C@H]3CN(CC4CC4)C[C@H]3C2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of cis-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid {3-(5-chloro-2-difluoromethoxyphenyl)-1-[2-(hexahydropyrrolo[3,4-c]pyrrol-2-yl)-2-oxoethyl]-1H-pyrazol-4-yl}amide (100 mg, 0.18 mmol) in 2,2,2-trifluoroethanol (3 mL) was added cyclopropanecarbaldehyde (67 μL, 0.90 mmol). After stirring at room temperature for 15 minutes, sodium borohydride (21 mg, 0.54 mmol) was added and the reaction was heated at 90° C. for 2 hours. MeOH was added to quench the reaction and the mixture was loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. Evaporation gave a crude product which was purified by HPLC (Method 1). The pure fractions loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. Evaporation gave the title compound as a free base which was crystallised from MeOH/Et2O and obtained as a yellow solid (55 mg, 50%). LCMS (Method 5) [M+H]+=611.1, RT=3.02 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 10.94-10.88 (m, 1H), 9.57-9.55 (m, 1H), 8.95-8.92 (m, 1H), 8.38-8.35 (m, 1H), 8.29-8.28 (m, 1H), 7.65-7.61 (m, 1H), 7.56-7.54 (m, 1H), 7.47 (d, 1H, J=8.9 Hz), 7.45-7.07 (m, 1H), 7.08 (d, 1H, J=1.9 Hz), 7.02-6.99 (m, 1H), 5.24-5.07 (m, 2H), 3.86-3.52 (m, 5H), 3.52-3.22 (m, 2H), 3.17-3.11 (m, 1H), 3.07-3.00 (m, 2H), 3.00-2.79 (m, 1H), 1.27-1.01 (m, 1H), 0.63-0.56 (m, 2H), 0.42-0.34 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:26])(=[O:25])[NH:23][CH3:24])[CH:17]=1.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][C:2]1([CH3:27])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:26])(=[O:25])[NH:23][CH3:24])[CH:17]=1
Reactant: CNS(=O)(=O)c1cccc(C2Nc3ccc(C(=O)OC)cc3CC2(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CNS(=O)(=O)c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Reaction time: 1.5 h
Yield: 79.7 %

Procedure:
To a stirred solution of methyl 3,3-dimethyl-2-(3-(N-methylsulfamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (75 mg, 0.19 mmol) in tetrahydrofuran/methanol (2.5 mL/2.5 mL) was added 1M sodium hydroxide aqueous solution (2.89 mL, 2.89 mmol). The mixture was heated to reflux and stirred for 1.5 h. LC-MS indicated that 2005467-012-01 was consumed. The mixture was concentrated and the residue was dissolved in water. The aqueous layer was basified to pH=4 by 1M hydrochloric acid solution. The precipitated solid was filtered, and dried to give 56.7 mg of 3,3-dimethyl-2-(3-(N-methylsulfamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid. Yield: 78.5%.MS (ESI+APCI) M+1=375.2.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:14][S:15](Cl)(=[O:17])=[O:16])[CH2:9]1)=O)(C)(C)C.[CH3:30][NH2:31].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[CH3:30][NH:31][S:15]([CH2:14][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)(=[O:17])=[O:16].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]([C@@H](CS(=O)(=O)Cl)Oc2ccc(C(F)(F)F)cc2)C1
Reactant: CN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNS(=O)(=O)C[C@@H](Oc1ccc(C(F)(F)F)cc1)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-3-[(S)-2-Chlorosulfonyl-1-(4-trifluoromethylphenoxy)ethyl]pyrrolidine-1-carboxylic acid t-butyl ester (50 mg, 109 μmol, 1.0 eq.) in DCM (1.0 mL) was combined with a solution of methylamine (2M in THF; 4.0 eq) and the resulting mixture was stirred at room temperature for 2 hours. TFA (1.0 mL) was added and stirred for 1 minute. The mixture was then concentrated and purified by preparative HPLC to yield the title compound as a TFA salt (8.7 mg). MS m/z: [M+H]+ calcd for C14H19F3N2O3S, 353.11. found 353.0.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])=[N:7][C:6]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=O)[O:26]C4C=CC=CC=4)=[CH:20][CH:19]=3)=[N:5][C:4]=2[CH2:3]1.[F:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1>>[F:34][C:35]1[CH:41]=[CH:40][C:38]([NH:39][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([C:6]3[N:7]=[C:8]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]4[CH3:17])[C:9]4[CH2:10][N:2]([CH3:1])[CH2:3][C:4]=4[N:5]=3)=[CH:19][CH:20]=2)=[O:26])=[CH:37][CH:36]=1
Reactant: Nc1ccc(F)cc1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc2c1CN(C)C2
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Nc3ccc(F)cc3)cc2)nc2c1CN(C)C2

Procedure:
Method as described for example 51 using intermediate 10 and 4-fluoroaniline as starting materials. Purified by prep. LCMS (high pH).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1.[C:20]1(=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[CH:20]1([NH:8][C:6]2[CH:5]=[CH:4][C:3]([CH2:9][C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=4)[NH:12][CH:11]=3)=[C:2]([F:1])[N:7]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1CCCCC1
Reactant: Cc1cnc2[nH]cc(Cc3ccc(N)nc3F)c2c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1cnc2[nH]cc(Cc3ccc(NC4CCCCC4)nc3F)c2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To 6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (49, 100 mg, 0.39 mmol) and cyclohexanone (67, 0.0465 mL, 0.449 mmol) in 3.00 mL of acetonitrile, triethylsilane (0.400 mL, 2.50 mmol) and trifluoroacetic acid (0.300 mL, 3.89 mmol) were added. The reaction was stirred at 80° C. overnight, then extracting with ethyl acetate and 1N aqueous sodium bicarbonate. The organic layer was washed with brine, dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 0-60% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (P-3008, 115 mg). MS (ESI) [M+H+]+=339.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:34])=[C:11]([CH2:13][N:14]3[C:22]4[C:17](=[CH:18][C:19]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:20][CH:21]=4)[CH:16]=[C:15]3[CH3:33])[N:12]=2)[CH:5]=[CH:6][CH:7]=1.CN([CH:38]=[O:39])C.O=P(Cl)(Cl)Cl>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:34])=[C:11]([CH2:13][N:14]3[C:22]4[C:17](=[CH:18][C:19]([C:23]([OH:32])([C:24]([F:26])([F:27])[F:25])[C:28]([F:29])([F:30])[F:31])=[CH:20][CH:21]=4)[C:16]([CH:38]=[O:39])=[C:15]3[CH3:33])[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Cc1oc(-c2cccc(Cl)c2)nc1Cn1c(C)cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1oc(-c2cccc(Cl)c2)nc1Cn1c(C)c(C=O)c2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Temperature: 0 °C
Yield: 51.8 %

Procedure:
A solution of 200 mg (0.4 mmol) of 2-{1-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-2-methyl-1H-indol-5-yl}-1,1,1,3,3,3-hexafluoro-propan-2-ol (example 12) in 2 mL of dichloroethane was treated with 0.06 mL (0.8 mmol) of DMF and cooled to 0° C. After addition of 0.04 mL (0.44 mmol) of POCl3 the mixture was allowed to reach RT and stirred for an additional hour. Distribution of the mixture between Et2O and H2O, drying of the combined organic phases over Na2SO4 and column chromatography on silica gel with n-heptane/EtOAc 1:2 yielded 110 mg (52%) of 1-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-1H-indole-3-carbaldehyde, light brown solid, MS: 531 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([N+:32]([O-])=O)[CH2:13][CH2:14][CH2:15][C:16]([C:30]#[N:31])([CH:27]([CH3:29])[CH3:28])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH2:32])[CH2:13][CH2:14][CH2:15][C:16]([C:30]#[N:31])([CH:27]([CH3:29])[CH3:28])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC(CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)[N+](=O)[O-])cc1OC
Solvent: CO
Product: COc1ccc(CC(N)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
A mixture of 1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane (10, 58.7 g, 0.125 mol) and methanol (950 mL) was added to a flask, and evacuated to remove oxygen. The catalyst, 5% Pd in carbon (50% water, 19 g, Engelhard Co.), was added under an N2 atmosphere. After stirring for 10 minutes at room temperature, solid HCO2NH4 (65 g, Aldrich) was added, and the resulting mixture stirred for 1 hour. The mixture was then slowly heated to 50° C. for 48 hours, then cooled to room temperature and filtered through Celite (50 g). The solids were washed with methanol (50 mL), the filtrates concentrated in vacuo, and the resulting solid dissolved in CH2Cl2. The solution was extracted with saturated aqueous NH4Cl (500 mL) and saturated aqueous NaHCO3 (300 mL), and the organic layer evaporated to yield 1-(3,4-dimethoxyphenyl)-2-amino-6-cyano- 6-(i-propyl)-6-(3,4-dimethoxyphenyl)hexane (11, 52.3 g, MS m/e 440(M+)) as a pale yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:26][P:27](=[O:30])([CH3:29])[CH3:28]>>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:26][P:27](=[O:30])([CH3:29])[CH3:28])[C:13](=[O:18])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(=O)n(-c2ccccc2)c2ncn(Cc3ccccc3)c12
Reactant: CP(C)(=O)CCl
Product: CP(C)(=O)Cn1c(=O)c2c(ncn2Cc2ccccc2)n(-c2ccccc2)c1=O

Procedure:
The title substance was prepared from 6.5 g (0.02 mol) of 7-benzyl-3-phenylxanthine and 3.1 g (0.0245 mol) of chloromethyldimethylphosphine oxide analogously to Example 67.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:5]2O.O([CH3:22])[Na]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:22])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:5]2
Reactant: O=c1[nH]c2ccc(Br)cc2c(O)c1-c1ccccc1
Reactant: CO[Na]
Solvent: CO
Product: COc1nc2ccc(Br)cc2cc1-c1ccccc1

Procedure:
In a 100-mL round-bottom flask was placed a mixture of 6-bromo-2-chloro-3-phenylquinoline (550 mg, 1.73 mmol, Intermediate 4, step b) and NaOCH3 (931 mg, 17.2 mmol) in methanol (50 mL). The resulting mixture was refluxed for 5 hours and concentrated under vacuum. The residue was purified by chromatography (silica gel column, 1:5 EtOAc/petroleum ether) to provide the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][NH:11][N:10]=1.N#N.[C:24](N1C=CN=C1)([N:26]1[CH:30]=CN=[CH:27]1)=[O:25].CNC>C1COCC1.C(O)C>[CH3:27][N:26]([CH3:30])[C:24]([N:11]1[N:10]=[C:9]([CH2:8][C:7]2[C:6]([Cl:21])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12]1)=[O:25]
Reactant: COc1ccc2c(c1)CNN=C2Cc1c(Cl)cncc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Agent: N#N
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(c1)CN(C(=O)N(C)C)N=C2Cc1c(Cl)cncc1Cl
Yield: 36.1 %

Procedure:
A solution of 4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-1,2-dihydro-phthalazine (1 g, 3.1 mmoles), prepared as described in example 22, in dry THF (35 ml), under stirring and dry N2 at room temperature, was added with 1,1′-carbonyldiimidazole (0.6 g, 3.72 mmoles), then the mixture was refluxed for 3 hours, cooled, added with 5.6M dimethylamine in ethanol (5 ml) and refluxed again. After 44 hours the mixture was cooled, poured into water/ice and extracted more times with CH2Cl2. The organic phases were washed with 5% NaOH, then with water, anhydrified and concentrated. The residue was flash chromatographed (eluent: hexane/ethyl acetate 1:1), then crystallised from acetonitrile (30 ml) to give 0.44 g of the title compound (yield: 36.4%). m.p.: 160-162° C.
Reaction SMILES: Cl.N[C:3]1[O:4][C:5]2[C:21]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:20][C:19]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][C:6]=2[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1.C[OH:31]>O>[C:26]([C:19]1[CH:20]=[C:21]([C:22]([CH3:23])([CH3:24])[CH3:25])[C:5]2[O:4][C:3](=[O:31])[CH:7]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=3)[C:6]=2[CH:18]=1)([CH3:28])([CH3:27])[CH3:29]
Reactant: COc1ccc(-c2c(N)oc3c(C(C)(C)C)cc(C(C)(C)C)cc23)cc1OC
Reactant: CO
Agent: Cl
Solvent: O
Product: COc1ccc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.20 ml (0.40 mmol) of 2N HCl is added at room temperature to a solution of 50 mg (0.13 mmol) of 2-amino-5,7-di-tert-butyl-3-(3,4-dimethoxyphenyl)-benzofurane [compound (303), Table 3, prepared according to Example 3a] in 2 ml methanol and stirred at room temperature for one hour. The reaction mixture is diluted with water and extracted three times with ethyl acetate. The organic phases are combined, dried over sodium sulfate and concentrated using a vacuum rotary evaporator. The residue yields 41 mg (82%) of 5,7-di-tert-butyl-3-(3,4-dimethoxyphenyl-3H-benzofuran-2-one (compound (103), Table 1), viscous oil.
Reaction SMILES: [C:1]([N:8]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:9]1[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CI.[Li+].[CH3:21]C([N-]C(C)C)C>C1COCC1>[C:1]([N:8]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@@:9]1([CH3:21])[C:10]([O:12][CH3:13])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)[C@]1(C)C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of N-BOC-4(R)-hydroxyproline, methyl ester (Bachem, 17 g, 69 mmol) and MeI (276 mmol) in 250 mL of anhydrous THF at −30° C. was added LDA (Aldrich, 1.5 M in cyclohexane, 250 mmol). The reaction was allowed to warm up to rt over 4 h. The reaction was cooled to −30° C., and was quenched with saturated aqueous ammonium chloride (50 mL). The resulting mixture was partitioned between EtOAc and brine, and the product was extracted with EtOAc (3×100 mL). The combined extracts were dried over anhydrous MgSO4 and concentrated in vacuo. The solvent was removed in vacuo and the residue was purified by repeated flash column chromatography on silica gel eluted with 20:1 to 10:1 hexane/acetone to afford N-BOC-4(R)-hydroxy-2-methyl-(L)-proline, methyl ester (slower eluting and major isomer, 10 g, 58%). The stereochemistry was assigned by NMR comparisons with literature reports (Noe, C R et al Pharmazie 1996, 51, 800).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[Cl:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]2([CH2:16][CH3:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7]2=[O:15])[CH2:30][CH2:31]1
Reactant: Fc1ccc(N2CCNCC2)c(Cl)c1
Reactant: CCC1(CCCCCl)C(=O)Nc2ccccc21
Product: CCC1(CCCCN2CCN(c3ccc(F)cc3Cl)CC2)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 from 3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(2-chloro-4-fluorophenyl)-piperazine.