Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][O:5][C:6]1[N:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([N:16]3[CH:24]([CH2:25][C:26](=O)[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:33])=[N:13]2)=[CH:8][CH:7]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:3][N:2]=[C:26]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:25][CH:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:33])[N:16]1[C:12]1[CH:11]=[CH:10][C:9]2[C:14](=[N:15][C:6]([O:5][CH3:4])=[CH:7][CH:8]=2)[N:13]=1
Reactant: NO
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(=O)CCC(C)C)nc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3CC(CCC(C)C)=NO)nc2n1
Yield: 22.4 %

Procedure:
Hydroxylamine hydrochloride (0.9 g) is added to a suspension, maintained at 0° C. with a bath of ice-cold water, of 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)-1-isoindolinone (4.3 g) in a mixture (100 cc) of water and ethanol (50:50 by volume). The suspension obtained is allowed to return to a temperature in the region of 20° C. and a solution of sodium carbonate (0.7 g) in distilled water (10 cc) is added. The suspension obtained is heated to reflux for 22 hours. During this period, ethanol (80 cc) is added in two portions. Refluxing is maintained for 12 hours, adding in three portions further hydroxylamine hydrochloride (1.35 g) and sodium carbonate (1.05 g). The reaction mixture is then poured into water (1 litre). The aqueous phase is extracted with methylene chloride (3×300 cc). The organic phases are combined, washed with distilled water (2×100 cc), dried over magnesium sulphate, filtered and concentrated to dryness. After recrystallization in 2-propanol, 3-(2-hydroxyimino-5-methylhexyl)-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (1 g), m.p. 200° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH:12]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:11][CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:23][CH:24]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COc1c(N)ccc2c1CCCC(N1CCOCC1)C2
Product: COc1c(Nc2ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n2)ccc2c1CCCC(N1CCOCC1)C2

Procedure:
The title compound was prepared from 1-methoxy-6-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (149 mg, 0.54 mmol) and N-[(1R,2R)-2-(2,5-dichloropyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (204 mg, 0.60 mmol) in an analogous manner to Example 946 to afford a white foam (227 mg, 73%). Mp: 110-12° C. LCMS (m/e) 579 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.96 (m, 2H), 7.31 (d, J=9 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 5.47-5.27 (m, 2H), 3.91 (m, 1H), 3.73 (m, 7H), 3.26 (m, 2H), 2.88 (m, 2H), 2.81 (s, 3H), 2.70 (m, 2H), 2.60 (m, 2H), 2.39 (m, 2H), 2.23 (m, 2H), 2.15 (m, 2H), 1.85 (m, 3H), 1.63 (br s, 1H), 1.42 (m, 4H).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O>>[CH3:19][O:18][C:11]1[C:10]([CH:2]2[N:1]([CH2:28][C:27]3[CH:30]=[CH:31][CH:32]=[C:25]([C:21]4[S:20][CH:24]=[CH:23][N:22]=4)[CH:26]=3)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]2)=[C:15]([O:16][CH3:17])[CH:14]=[CH:13][N:12]=1
Reactant: COC(=O)CCCC(N)c1c(OC)ccnc1OC
Reactant: O=Cc1cccc(-c2nccs2)c1
Product: COc1ccnc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2nccs2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,4-dimethoxypyridin-3-yl)pentanoate with commercially available 3-(thiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.68 min.; [M+H]+: 409.86 g/mol.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9]C)=[CH:7][C:5]([NH2:6])=[C:4]([O:11][CH3:12])[CH:3]=1.C[O:14][C:15]1[CH:23]=[CH:22][C:18](C(Cl)=O)=[CH:17][CH:16]=1>>[Cl:1][C:2]1[C:8]([OH:9])=[CH:7][C:5]2[N:6]=[C:12]([C:18]3[CH:22]=[CH:23][C:15]([OH:14])=[CH:16][CH:17]=3)[O:11][C:4]=2[CH:3]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1cc(Cl)c(OC)cc1N
Product: Oc1ccc(-c2nc3cc(O)c(Cl)cc3o2)cc1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 16, from 4-chloro-2,5-dimethoxyaniline, and 4-methoxybenzoyl chloride and was obtained as an off-white solid, m.p. 260-262° C.; MS m/e 260 (M−H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.NC(N)=[S:14].[OH-].[K+]>C(O)C>[SH:14][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1
Reactant: NC(N)=S
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: FC(F)(F)c1ccc(S)nc1
Temperature: 25 °C
Yield: 38 %

Procedure:
2-chloro-5-trifluoromethylpyridine (13.7 g) was dissolved in ethanol (96 ml), thiourea (5.7 g) was added to the mixture, and the mixture was heated to reflux for 3 hours. After allowing the mixture to be cooled to room temperature, an aqueous solution (19.2 ml) of potassium hydroxide (6.4 g) was added to the mixture, and the mixture was heated to reflux for 1 hour. After allowing the mixture to be cooled to room temperature, diluted aqueous solution of potassium hydroxide (20 ml) was added to the mixture, and the mixture was washed with methylene chloride. With acetic acid, pH of the mixture was adjusted to about 6, and the mixture was extracted with methylene chloride. The mixture was washed with water, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was washed with hexane/ethyl acetate, to give 2-mercapto-5-trifluoromethylpyridine (5.1 g).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:22])[C@H:11]([NH2:21])[CH2:12][C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[O:30]([C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[CH2:2]([O:9][C:10](=[O:22])[C@H:11]([NH:21][S:43]([C:40]1[CH:39]=[CH:38][C:37]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:42][CH:41]=1)(=[O:45])=[O:44])[CH2:12][C:13]([N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)=[O:14])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: N[C@H](CC(=O)N1CCOCC1)C(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H](CC(=O)N1CCOCC1)NS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Reaction time: 16 h
Yield: 64 %

Procedure:
A solution of the title B compound, (2R)-amino-4-morpholin-4-yl-4-oxobutyric acid benzyl ester hydrochloride (420 mg, 1.28 mmol) in 5 mL of dichloromethane is treated with triethylamine (345 mg, 2.82 mmol) followed by a solution of 4-phenoxybenzenesulfonyl chloride (345 mg, 1.28 mmol) in 2 mL of dichloromethane. The reaction is stirred for 16 h, then partitioned between dichloromethane and water. The organic solution is washed with brine, dried over anhydrous MgSO4 and concentrated. Chomatography on silica gel (eluant; 3% MeOH in dichloromethane) affords 430 mg (64%) of (2R)-(4-phenyloxybenzenesulfonylamino)-4-morpholin-4-yl-4-oxobutyric acid benzyl ester as a white foam.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])[CH2:2]C(C)=O.[N:14]([O-])=[O:15].[Na+].S(=O)(=O)(O)O>[OH-].[Na+]>[OH:15][N:14]=[CH:2][C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: O=N[O-]
Reactant: CC(=O)CC(=O)Nc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(C=NO)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
Acetoacetanilide (25.0 g, 0.14 mol) and sodium nitrite (12.65 g, 0.18 mol) were dissolved in aqueous sodium hydroxide solution (140 ml, 1 N) and the resulting solution was added dropwise over 20 min to an aqueous solution of sulfuric acid (120 ml conc. H2SO4 in 950 ml water) cooled in an ice bath. The reaction mixture was stirred at 0° C. for 30 min, then the precipitate was filtered and washed with water to yield 2-hydroxyiminoacetanilide (22.64 g, 78% yield) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[CH2:10][CH:9]([CH3:11])[O:8][CH:7]([CH2:12][N:13]2C(=O)C3=CC=CC=[C:15]3[C:14]2=[O:23])[CH2:6]1.O.NN>C(O)C>[C:14]([NH:13][CH2:12][CH:7]1[O:8][CH:9]([CH3:11])[CH2:10][N:5]([CH2:4][C:3]2[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=2[Cl:1])[CH2:6]1)(=[O:23])[CH3:15]
Reactant: CC1CN(Cc2ccccc2Cl)CC(CN2C(=O)c3ccccc3C2=O)O1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(=O)NCC1CN(Cc2ccccc2Cl)CC(C)O1
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
A mixture of N-[[4-(2-chlorobenzyl)-6-methyl-2-morpholinyl]methyl]phthalimide (26 g), 100% hydrazine hydrate (4.2 g), and ethanol (20 ml) is refluxed with stirring for 15 minutes. After the insoluble materials are filtered off, the filtrate is diluted with water and extracted with chloroform. The organic layer is washed successively with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and filtered. Acetic anhydride (14.7 g) is added to the filtrate, and the mixture is stirred at 25° C. for 2 hours. The reaction mixture is washed successively with aqueous sodium hydroxide solution, water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. After removal of the solvent under reduced pressure, the residue is chromatographed on silica gel with ethyl acetate to give the title compound (15 g) as an oil.
Reaction SMILES: [CH:1]12[CH2:11][CH:4]([CH:5]3[C:10]1=[CH:9][CH2:8][CH2:7][CH2:6]3)[CH2:3][CH2:2]2.[H][H]>[Pd].CO>[CH:4]12[CH2:11][CH:1]([CH:10]3[CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9]3)[CH2:2][CH2:3]2
Reactant: [H][H]
Reactant: C1=C2C3CCC(C3)C2CCC1
Agent: [Pd]
Solvent: CO
Product: C1CCC2C3CCC(C3)C2C1
Reaction time: 0.75 h
Yield: 257.6 %

Procedure:
A 400 ml autoclave was charged with octahydro-1,4-methanonaphthalene (122 g, prepared as described above), methanol (100 ml, Burdick & Jackson, HPLC grade), and palladium on activated carbon (1.5 g containing 10% Pd, Alfa products, powder). The autoclave was closed and sealed, then shaken under 50 psig hydrogen pressure for 20 minutes at room temperature. The hydrogen pressure was increased to 200 psig for 10 minutes at room temperature followed by 600 psig at 70° C. for 45 minutes. The reaction mixtures from three identical reactions were combined and filtered to remove the catalyst. The filtrate separated into two layers. The MeOH layer (top layer) was isolated and concentrated to give a residue, which was combined with product layer (the bottom layer). The combined crude product was distilled at reduced pressure to give decahydro-1,4-methanonaphthalene (318.6 g, bp 71–73° C./0.2 Torr, yield 86%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]([F:25])([F:24])[C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[C:16]([F:15])([F:24])[F:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccccc1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C(F)(F)F)CC1
Reaction time: 14 h
Yield: 307.8 %

Procedure:
To a stirred solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.20 g, 0.0001 mole) in dry 1,2-dichloroethane (7 mL) under an atmosphere of nitrogen for 10 minutes, was added 2-trifluoromethylaniline (0.161 g, 0.0001 mole), acetic acid (0.06 g, 0.0001 mole) and sodium triacetoxyborohydride (1.05 g, 0.0005 mole). The stirring was continued at ambient temperature for 14 hours. The reaction mixture was then quenched in cold aqueous 1N NaOH solution and the product extracted with ether. The ether layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to get the crude product as transparent viscous liquid. Purification by column chromatography using silica gel 60-120 mesh (2% ethyl acetate in hexane) afforded 0.106 g (31%) of 4-(2-trifluoromethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (DMSO-d6): δ 7.4 (t, 2H), 7.0 (d, 1H), 6.7 (t, 1H), 3.9 (m, 2H), 2.9 (m, 2H), 1.9 (m, 2H), 1.4 (s, 9H). To a solution of 4-(2-trifluoromethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.106 g, 0.000307 mole) in dioxane (0.5 mL) which was cooled to 0° C., was added, dioxane.HCl (2.5 mL) and the mixture was stirred at the same temperature for 10 minutes. The reaction mixture was gradually brought to ambient temperature and stirring was continued for 15 minutes. The reaction mixture was evaporated under reduced pressure and the resulting residue was washed with dry ether to afford 0.04 g (41%) of piperidin-4-yl-(2-trifluoromethyl-phenyl)-amine dihydrochloride. 1H NMR (DMSO-d6): δ 7.41 (t, 2H), 7.0 (d, 2H), 6.75 (t, 1H), 4.8 (d, 1H), 3.7 (bs, 1H), 3.3 (bs, 1H), 3.0 (m, 2H), 2.1 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17](=[O:20])[CH2:18][CH3:19])=[C:14]([CH3:21])[C:13]=2[CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1.CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([OH:20])[CH2:18][CH3:19])=[C:14]([CH3:21])[C:13]=2[CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)c1oc2ccc(OCc3ccccc3)cc2c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)c1oc2ccc(OCc3ccccc3)cc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
1-[5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl]propan-1-one (0.88 g) synthesized in the above-mentioned (1) was dissolved in tetrahydrofuran (15 mL) and methanol (1 mL), and sodium borohydride (90%, 0.25 g) was added to the solution under ice-cooling. The ice bath was removed, and the reaction mixture was stirred at room temperature for 1 hr then ice-cooled again, and water (2 mL) and 1N hydrochloric acid (5 mL) were carefully added to the mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a crude product (0.85 g, quantitative) of the title object compound as a pale-yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][N:9]2[C:15](=[O:16])[C@H:14]3[CH2:17][CH2:18][CH2:19][C@H:13]3[NH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:26][CH2:27][C:28](Br)=[O:29]>C(OCC)(=O)C.CCCCCC>[Br:26][CH2:27][C:28]([N:12]1[C@@H:13]2[CH2:19][CH2:18][CH2:17][C@@H:14]2[C:15](=[O:16])[N:9]([CH2:8][C:7]2[CH:24]=[CH:25][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:10]2[CH:23]=[CH:22][CH:21]=[CH:20][C:11]1=2)=[O:29]
Reactant: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Br)CBr
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1[C@H]2CCC[C@H]2N(C(=O)CBr)c2ccccc2N1Cc1ccc([N+](=O)[O-])cc1
Yield: 37 %

Procedure:
Using (3aR*,10aS*)-9-(4-nitrobenzyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]-diazepin-10(1H)-one and bromoacetyl bromide, the titled compound was synthesized in substantially the same manner as in Working Example 185 in a yield of 37%, m.p. 160.5°-161.5° C. (ethyl acetate-hexane).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][CH2:35][C:36]([NH:38][CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:37])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([NH:34][CH2:35][C:36]([NH:38][CH:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[O:37])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(NCC(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(NCC(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-cyclohexylaminocarbonylmethylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:13]([N:15]([CH2:22][CH3:23])[CH:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[NH2:21])[CH3:14].Cl>C(O)(C)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:21][CH:17]3[CH2:18][CH2:19][CH2:20][CH:16]3[N:15]([CH2:22][CH3:23])[CH2:13][CH3:14])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: CCN(CC)C1CCCC1N
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: Cl
Solvent: CC(C)O
Product: CCN(CC)C1CCCC1Nc1ccnc2cc(Cl)ccc12

Procedure:
8.16 g of base from 16 g of 4,7-dichloroquinoline and 12.7 g of 2-(diethylamino)cyclopentylamine (16 hours reaction duration at 140° C.). By addition of isopropanolic hydrochloric acid to a solution of the diamine in isopropanol were precipitated 7.84 g of dihydrochloride; colourless crystals from acetonitrile/ethanol, m.p.: 186°-190° C.
Reaction SMILES: [CH:1]1([N:6]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]2[CH:13]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.[NH2:17][NH2:18]>C(O)C>[CH:1]1([N:6]2[C:7]3=[CH:13][N:17]=[N:18][C:11]([NH2:12])=[C:8]3[CH:9]=[CH:10]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: N#Cc1ccn(C2CCCC2)c1C=O
Reactant: NN
Agent: Cl
Solvent: CCO
Product: Nc1nncc2c1ccn2C1CCCC1
Temperature: 25 °C

Procedure:
A mixture of 1-cyclopentyl-2-formyl-1H-3-pyrrolecarbonitrile (0.525 g, 2.79 mmol) and hydrazine dihydrochloride (0.35 g, 3.35 mmol) in ethanol (30 mL) was heated at reflux for 2.5 hours then cooled to ambient temperature and purified by preparative reverse phase HPLC to give the title compound as a hydroscopic glass contaminated with ammonium acetate (594 mg) (60% by weight as determined by 1H NMR, yield=337 mg; 1H NMR (DMSO-d6, 400 MHz) δ 8.83 (s, 1H), 7.55 (d, 1H), 6.71 (d, 1H), 6.10 (bs, 2H), 4.94 (m, 1H), 2.15 (m, 2H), 1.89 (m, 4H), 1.70 (m, 2H); 5%–100% acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr 19.46 min.; LC/MS: MH+ 203.0.
Reaction SMILES: [O-]CC.[Na+].[F:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[NH:9].Br/[C:16](=[C:20](/[Br:23])\[CH:21]=O)/[C:17]([OH:19])=[O:18]>C(O)C>[Br:23][C:20]1[C:16]([C:17]([OH:19])=[O:18])=[N:9][C:8]([C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[F:5])=[N:10][CH:21]=1
Reactant: O=C/C(Br)=C(\Br)C(=O)O
Reactant: N=C(N)c1ccccc1F
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1nc(-c2ccccc2F)ncc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium ethoxide (21 mass % in ethanol; 8.69 mL, 23.268 mmol) was added to an ice-bath cooled mixture of 2-fluorobenzamidine (2.71 g, 15.512 mmol) in ethanol (100 mL). The resulting mixture was allowed to warm to room temperature and stirred at rt (room temperature) under nitrogen for 30 min. To the reaction mixture was added a solution of (E)-2,3-dibromo-4-oxo-but-2-enoic acid (2.00 g, 7.7561 mmol) in ethanol (20 ml). The mixture was heated at 50° C. for 3 h. After cooling to RT, the reaction was concentrated in vacuo. Water and 1M NaOH (˜50 ml) were added and the aqueous mixture was extracted with EtOAc. The aqueous phase was acidified to pH4 with 1N HCl (about 30 ml), then extracted with EtOAc 3×. Combined organic extracts were dried over sodium sulfate, filtered and concentrated to gave 5-bromo-2-(2-fluorophenyl)pyrimidine-4-carboxylic acid, 770 mg.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[NH:5][C:4](=[O:28])[CH2:3]1.C([O-])(=O)C.[K+].Br[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[C:4](=[O:28])[CH2:3]1
Reactant: Brc1cccnc1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)Nc3ccccc32)C(C)C)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 49.4 %

Procedure:
To a stirring solution of 26.6 g (69.7 mmol) 2-(2,4-Dioxo-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide, prepared as in Intermediate 46, in 1 L DMF is added 13.3 g (209 mmol, 3 equiv) of Cu powder, 13.7 g (139 mmol, 2 equiv) of potassium acetate and 13.4 mL (139 mmol, 2 equiv) of 3-bromopyridine. The reaction is heated to 120° C. After 5 h, an additional 13 g (133 mmol) of potassium acetate and 15 mL (156 mmol) of 3-bromopyridine were added, and the reaction is allowed to stir overnight. After ca. 18 h, an additional 15 g (236 mmol) Cu and 5 g (51 mmol) potassium acetate were added, and stirring is continued for an additional 24 h. The reaction is then allowed to cool, and is filtered through celite, rinsing with ethyl acetate. The organics were extracted with 10% NH4OH, the twice with water. The aqueous layer is extracted with EtOAc/ethyl ether. The combined organics were dried (MgSO4) filtered and concentrated in vacuo to afford an oil. This is purified by silica gel flash chromatography to afford 15.8 g of the title compound as a white powder as well as 1.5 g of recovered unreacted starting material: 1H NMR (CDCl3, 400 MHz) δ8.68 (s, br, 2H), 7.86 (d, 1H, J=7.8), 7.36 (d, 2H, J=7.6) 7.27-7.10 (m, 6H ) 6.95 (t, 2H, J=7.6) 6.84 (d, 1H, J=7.1) 4.95 (m, 1H), 4.23 (s, br, 2H) 3.82 (s, 3H) 3.53 (dd, 2H, J=12.2, 44) 1.04 (dd, 6H, J=2.4, 6.8); low resolution MS (FAB)m/e (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]([NH2:25])=[S:24])=[C:10]1[C:26]([O:28][CH2:29][CH3:30])=[O:27].Br[CH2:32][C:33](=O)[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]2[S:24][CH:32]=[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[N:25]=2)=[C:10]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCOC(=O)C1=C(COCC(N)=S)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Product: CCOC(=O)C1=C(COCc2nc(C(=O)OCC)cs2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl

Procedure:
2-{[4-(2,3-Dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}-4-ethoxycarbonylthiazole was prepared by the method of Example 44 but using 2-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}-thioacetamide and ethyl 3-bromopyruvate as starting materials.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([C:19](=[O:22])[CH2:20][CH3:21])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23]>O1CCOCC1.CCOCC>[ClH:23].[N:11]1([C:14]2[S:15][C:16]([C:19](=[O:22])[CH2:20][CH3:21])=[CH:17][N:18]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CCC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCC(=O)c1cnc(N2CCNCC2)s1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
To a solution of 0.58 mmol 4-(5-propionyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 6 ml dioxane was added dropwise 8.76 mmol hydrogen chloride solution (4 M in dioxane) and the mixture was stirred at 90° C. for 90 min. The reaction mixture was then cooled to 0° C. and diluted with ether. The resulting crystals were collected by filtration and washed with ether to afford the title compound as a white crystalline solid (yield 99%). MS (m/e): 226.4 (M+H+, 100%).