Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][NH:23][C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C1C2C(=CC=CC=2)C=CC=1S(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][N:23]([CH2:41][C:42]([F:45])([F:44])[F:43])[C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(OCC(F)(F)F)c1ccc2ccccc2c1
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N2CCN(c3ccc(-n4cnn(CC(F)(F)F)c4=O)cc3)CC2)cc1
Yield: 42.4 %

Procedure:
A mixture of 17.5 parts of 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]-phenyl]-3H-1,2,4-triazol-3-one prepared as described in example XVII of U.S. Pat. No. 4,267,179, 19.5 parts of 2,2,2-trifluoroethyl 2-naphthalenesulfonate, 10.0 parts of potassium carbonate and 135 parts of N,N-dimethylformamide was stirred overnight at 145° C. After cooling, water was added. The crystallized product was filtered off under pressure and dissolved in dichloromethane. The organic layer was dried, filtered and evaporated in vacuo. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-butanone. The product was filtered off and dried, yielding 9.2 parts (42.4%) of 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2-(2,2,2-trifluoroethyl)-3H-1,2,4-triazol-3-one; mp. 208.0° C. (int. 37).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]([Cl:11])=[C:5]2[C:9]([N:10]=1)=[N:8][CH:7]=[N:6]2.[H-].[Na+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([Cl:11])[N:3]=1
Reactant: CCOC(=O)CBr
Reactant: Clc1nc2ncnc-2c(Cl)[nH]1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1cnc2c(Cl)nc(Cl)nc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
An ice-cold solution of 2,6-dichloro-1H-purine (1.89 g, 10 mmol) in THF (10 mL) was treated with NaH (60% in oil, 440 mg, 11 mmol), stirred at 0° C. for 30 min, treated with ethyl bromoacetate (1.22 mL, 11 mmol), stirred at room temperature for 2 h, poured into sat. NaHCO3, extracted with EtOAc and the combined organic phase dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; Heptane:EtOAc (2:1)] to give the title compound (1.46 g, 53%) as a white solid: IR νmax (Nujol)/cm−1 3106, 2985, 2955, 2924, 2854, 1734, 1598, 1557, 1374, 1341, 1298, 1156 and 884; NMR δH (400 MHz, CDCl3) 1.31 (3H, t, J7.0 Hz), 4.29 (2H, q, J7.0 Hz), 5.01 (2H, s), 8.17 (1H, s).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]([F:37])([F:36])[CH2:27][C:28]1[S:29][CH:30]=[C:31]([C:33]([OH:35])=O)[N:32]=1.[O:38]1[C:43]2([CH2:48][CH2:47][N:46]([CH2:49][C:50]3[C:51]([F:59])=[C:52]([CH2:56][CH2:57][OH:58])[CH:53]=[CH:54][CH:55]=3)[CH2:45][CH2:44]2)[CH2:42][NH:41][CH2:40][CH2:39]1.C(N(CC)CC)C>CN(C=O)C>[F:59][C:51]1[C:52]([CH2:56][CH2:57][OH:58])=[CH:53][CH:54]=[CH:55][C:50]=1[CH2:49][N:46]1[CH2:47][CH2:48][C:43]2([O:38][CH2:39][CH2:40][N:41]([C:33]([C:31]3[N:32]=[C:28]([CH2:27][C:26]([F:25])([F:37])[F:36])[S:29][CH:30]=3)=[O:35])[CH2:42]2)[CH2:44][CH2:45]1
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Reactant: O=C(O)c1csc(CC(F)(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1csc(CC(F)(F)F)n1)N1CCOC2(CCN(Cc3cccc(CCO)c3F)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU (0.181 g) was added in one portion to a stirred solution at 0° C. of 2-(2,2,2-trifluoroethyl)thiazole-4-carboxylic acid (example 67, step d) (0.077 g) and 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol (example 67, step f) (0.113 g) and triethylamine (0.153 mL) in DMF (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.180 g.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:30]=[CH:29][CH:28]=[CH:27][C:15]=2[C:16]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)=[O:17])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O>C(O)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:30]=[CH:29][CH:28]=[CH:27][C:15]=2[C:16]([NH:18][CH2:19][CH2:20][CH2:21][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)=[O:17])(=[O:12])=[O:11])=[CH:8][CH:9]=1
Reactant: O=C(NCCCn1ccnc1)c1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc(S(=O)(=O)Nc2ccccc2C(=O)NCCCn2ccnc2)cc1
Reaction time: 4 h
Yield: 74.8 %

Procedure:
2-(4-Nitrobenzenesulphonamido)-N-(3-imidazol-1-ylpropyl)benzamide (38.4 g) was dissolved in glacial acetic acid (30 ml) and 5% w/w palladium-on-charcoal (8.0 g) was added. The mixture was stirred under an atmosphere of hydrogen for 4 hours, filtered free of catalyst and evaporated. The solid residue was dissolved in water and the solution was adjusted to pH 9 by the addition of aqueous ammonia. The solid which had precipitated was collected and recrystallised from ethanol to give 2-(4-aminobenzenesulphonamido)-N-(3-imidazol-1-ylpropyl)benzamide (26.7 g) in the form of a white solid, m.p. 171°-175° C.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.O.[OH:19][N:20]=[C:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([OH:24])=[O:23].C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:19][N:20]=[C:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([OH:24])=[O:23]
Reactant: CC(C)CC(=NO)C(=O)O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)CC(=NOC1CCCCO1)C(=O)O
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 87 %

Procedure:
9.6 Milliliters of 3,4-dihydro-2H-pyran and 0.29 g of p-TsOH.H2O were added to 50 ml of a solution of 4.35 g of α-hydroxyimino-isocaproic acid dissolved in dry CH2Cl2. The mixture was stirred for 100 minutes at room temperature. The reaction mixture was added to an aqueous solution saturated with NaHCO3 with ice cooling, and subjected to phase separation. An aqueous solution saturated with NaHCO3 was covered with ethyl acetate, then concentrated hydrochloric acid was added thereto, with stirring under ice cooling, to make the reaction mixture weakly acidic. The ethyl acetate layer was separated, washed with an aqueous selection saturated with NaCl, and dried over magnesium sulfate to obtain 6.00 g (87%) of the title compound as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=1)=[O:10].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[O:10])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccc(Cl)nc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccc(Cl)nc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(6-chloro-pyridin-3-yl)-methanone and 4-tert-butyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR: δ 1.21 (s, 9H), 7.30 (d, J=2.4 Hz, 1H), 7.33 (d, J=6.6 Hz, 2H), 7.43 (d, J=8.0 Hz, 1 H), 7.52 & 7.55 (dd, J=8.8 Hz, 2.8 Hz, 1H), 7.60 (d, J=7.0 Hz, 1 H), 7.79 (m, 3 H), 8.27 (d, J=2.0 Hz, 1H), 9.73 (s, 1H). MS: M/z 463.0 (M++1).
Reaction SMILES: [CH2:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:18][N:17]([C:19]([C:21]4[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][N:22]=4)=[O:20])[CH2:16]3)=[CH:11][C:10]=2[O:28][CH3:29])=[CH:5][CH:4]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:39][CH2:40][OH:41].O>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:18][N:17]([C:19]([C:21]4[CH:26]=[C:25]([O:27][CH2:39][CH2:40][OH:41])[CH:24]=[CH:23][N:22]=4)=[O:20])[CH2:16]3)=[CH:11][C:10]=2[O:28][CH3:29])=[CH:30][CH:31]=1)[CH3:2]
Reactant: OCCBr
Reactant: CCc1ccc(COc2ccc(C3CN(C(=O)c4cc(O)ccn4)C3)cc2OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(COc2ccc(C3CN(C(=O)c4cc(OCCO)ccn4)C3)cc2OC)cc1
Temperature: 80 °C
Reaction time: 11 h
Yield: 80 %

Procedure:
To a suspension of {3-[4-(4-ethylbenzyloxy)-3-methoxyphenyl]azetidin-1-yl}-(4-hydroxypyridin-2-yl)-methanone (9.6 g) prepared in Example 4 (4) and K2CO3 (40 g) in DMF (90 mL) was added 2-bromoethanol (9.6 mL). The reaction mixture was stirred at 80° C. for 11 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4. The solvent was removed under reduced pressure. Diisopropyl ether was added to the residue. The precipitated solid was collected on a filter and dried to give the title compound (8.4 g, 80%).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([S:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]2C(=O)C3=CC=CC=C3C2=O)=[CH:8][CH:7]=1)=[O:4].CN>C(O)C>[CH3:27][N:2]([CH3:1])[C:3]([S:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[CH:8][CH:7]=1)=[O:4]
Reactant: CN(C)C(=O)Sc1ccc(CCCCN2C(=O)c3ccccc3C2=O)cc1
Agent: CN
Solvent: CCO
Product: CN(C)C(=O)Sc1ccc(CCCCN)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
Phthalimide 35 (1.1 g, 2.8 mmol) was dissolved in a solution containing 6.6% methylamine in ethanol (100 mL) and allowed to stir at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by flash chromatotography (silica gel, chloroform/methanol/ammonium hydroxide, 10:1:0.1, v/v) to afford the free amine 36 (0.31 g, 42%) as a white powder. 1H NMR (300 MHz, CD3OD) δ 1.51 (m, 2H), 1.65 (m, 2H), 2.66 (m, 4H), 3.02 (m, 6H), 7.23 (d, 2H), 7.35 (d, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][CH2:16][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1.[F:18][C:19]1[CH:20]=[C:21]([C:27]2([CH3:30])[CH2:29][O:28]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>CN(C=O)C>[CH3:3][N:4]1[CH2:17][CH2:16][C:7]2[N:8]([CH2:30][C:27]([C:21]3[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:19]([F:18])[CH:20]=3)([OH:28])[CH3:29])[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: COc1ccc(C2(C)CO2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A flask was charged with sodium hydride 60% (461 mg, 1.15 mmol) in DMF and stirred at RT for 10 min. 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.76 g, 3.8 mmol) was added and the mixture stirred at RT for 1 h. 2-(3-Fluoro-4-methoxyphenyl)-2-methyloxirane (1 g, 5.4 mmol) was added and the mixture stirred at RT overnight. Ice water was added and the mixture extracted with EtOAc (3×). The combined organic layers were washed with water (4×) and concentrated, followed by purification of the product on silica gel (#100-200 mesh) using 0-5% MeOH:DCM as eluent. 1HNMR (DMSO, Oxalate salt) d (ppm): 7.30 (m, 3H), 7.18 (s, 1H), 7.10 (d, 1H), 6.90 (d, 1H), 4.30 (m, 2H), 4.18 (d, 1H), 4.05 (d, 1H), 3.80 (s, 3H), 3.60 (m, 2H), 3.0 (m, 2H), 2.80 (s, 3H), 2.35 (s, 3H), 1.70 (m, 1H), 1.40 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].Cl[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]>[OH-].[Na+]>[NH:1]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCNC(=O)OCc1ccccc1
Reaction time: 1.5 h
Yield: 92 %

Procedure:
A stirred solution of β-alanine (50.10 g, 0.562 mol) in 2M NaOH (281 mL) at 0° C. was treated with benzyl chloroformate (88 mL, 1.1 equiv), dropwise over 1 h. Stirring was continued for 1.5 h at 0° C., followed by 1.5 h at rt. The resulting mixture was extracted with ether (4×500 mL). The aqueous phase was acidified with 5M HCl (120 mL). The resulting white precipitate was collected by filtration, washed with water and dissolved in methylene chloride. The solution was dried over sodium sulfate and concentrated in vacuo to give a white solid (114.95 g, 92%). 1H-NMR (CDCl3) 6 2.61 (t, 2H), 3.48 (q, 2H), 5.12 (s, 2H), 5.29 (br, 1H), 7.37 (s, 5H). MS (DCl) 224 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=1.[Cl:23][C:24]1[N:29]=[CH:28][C:27]([C:30]([C:32]2[N:33]([CH3:37])[CH:34]=[N:35][CH:36]=2)=[O:31])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[N:29]=[CH:28][C:27]([C:30]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]3[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)([C:32]2[N:33]([CH3:37])[CH:34]=[N:35][CH:36]=2)[OH:31])=[CH:26][CH:25]=1
Reactant: CCOc1cccc(-c2cc(OC)nc3ccc(Br)cc23)c1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)nc1
Product: CCOc1cccc(-c2cc(OC)nc3ccc(C(O)(c4ccc(Cl)nc4)c4cncn4C)cc23)c1
Yield: 52.1 %

Procedure:
Following the same procedure as that described in example 1E, 6-bromo-4-(3-ethoxy-phenyl)-2-methoxy-quinoline (2 g, 5.59 mmol) and (6-chloro-pyridin-3-yl)-(3-methyl-3H-imidazol-4-yl)-methanone (1.48 g, 6.70 mmol) generated the title compound of 26A (1.458 g, 52% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[S:10](=[O:12])(=[O:11])[NH:9][C:8](=[O:13])[CH2:7]1.[C:17](OC(=O)C)(=[O:19])[CH3:18].O>C(O)(=O)C>[O:11]=[S:10]1(=[O:12])[NH:9][C:8](=[O:13])[CH2:7][N:6]1[CH2:5][C:4]1[CH:3]=[C:2]([NH:1][C:17](=[O:19])[CH3:18])[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cccc(CN2CC(=O)NS2(=O)=O)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(CN2CC(=O)NS2(=O)=O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of the title compound of Example 6, 5-(3-aminobenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (10 mg, 0.041 mmol) in acetic acid (AcOH, 5 mL) is treated with acetic anhydride (85 mg, 0.83 mmol) and stirred at RT for 72 h. The mixture is stirred with water for 2 h, then concentrated to dryness. The crude mixture is purified by LC/MS to afford N-[3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)phenyl]acetamide: [M−1]−=282.
Reaction SMILES: [OH:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([CH3:15])=[CH:8][C:3]=1[C:4](OC)=[O:5].[CH3:16][NH:17][CH3:18]>C(O)C>[CH3:16][N:17]([CH3:18])[C:4](=[O:5])[C:3]1[CH:8]=[C:9]([CH3:15])[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:2]=1[OH:1]
Reactant: CNC
Reactant: COC(=O)c1cc(C)cc([N+](=O)[O-])c1O
Solvent: CCO
Product: Cc1cc(C(=O)N(C)C)c(O)c([N+](=O)[O-])c1
Temperature: 100 °C

Procedure:
Methyl 2-hydroxy-5-methyl-3-nitrobenzoate (5.0 g) was dissolved in a solution of dimethylamine in ethanol (33% w/v; 50 ml) and the solution was heated at 100° C. in a sealed pressure vessel for 20 hours. The solvent was removed in vacuo and the residue was triturated with hydrochloric acid (2 N; 50 ml), and washed with water. Recrystallisation from methanol gave N,N-dimethyl-2-hydroxy-5-methyl-3-nitrobenzamide (3.0 g), m.p. 160°-162° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[CH:14][CH:13]=1)(=O)=O.O>CN(C)C=O>[O:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH:21]1[O:20][CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][N:1]=[N+:2]=[N-:3])=[CH:13][CH:14]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCc1ccc(CCOC2CCCCO2)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCc1ccc(CCOC2CCCCO2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
Sodium azide (1.73 g, 26.61 mmol) was added to a solution of 4-(2-(tetrahydropyran-2-yloxy)ethyl)phenethyl methanesulfonate (5.24 g, 15.95 mmol) in N,N-dimethylformamide (50 ml). The mixture was stirred at 100° C. for 1 hour. Water (40 ml) was added to the reaction mixture. The mixture was extracted with ethyl ether and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=20/1) to give the desired 4-(2-(tetrahydropyran-2-yloxy)ethyl)-1-(2-azidoethyl)benzene (4.30 g, 98%).
Reaction SMILES: C(OC([N:6]1[CH:14]2[CH:9]([CH:10]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]1)=O)C.[OH-:23].[Na+]>CO>[Cl:22][C:17]1[CH:16]=[C:15]([C:10]2([OH:23])[CH2:11][CH2:12][CH2:13][CH:14]3[CH:9]2[CH2:8][CH2:7][NH:6]3)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: CCOC(=O)N1CCC2C(c3ccc(Cl)c(Cl)c3)CCCC21
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: OC1(c2ccc(Cl)c(Cl)c2)CCCC2NCCC21

Procedure:
24.9 g (3aRS,4SR,7aRS)-4-(3,4-dichlorophenyl)hexahydro-1-indoline carboxylic acid ethyl ester in 240 ml methanol are treated with 240 ml 10N sodium hydroxide and refluxed for 15 hours. The cooled resulting mixture is repeatedly extracted with methylene chloride. The organic phase is extracted with 2N tartaric acid. The acidic phase is made alkaline and extracted with methylene chloride. The methylene chloride phases are dried over magnesium sulphate, and evaporated to give the title compound, in crude free base form, as an oil which is converted, by the addition of an equivalent amount of maleic acid, into the hydrogen maleate. M.Pt. 190°-191°.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][O:7][CH2:8][CH:9]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:38](O)[CH:39]([CH3:41])[CH3:40].CCN=C=NCCCN(C)C>C1COCC1.CN(C1C=CN=CC=1)C>[CH2:38]([O:27][C:26](=[O:28])[CH2:25][O:24][CH2:23][CH2:22][N:19]1[CH2:18][CH2:17][N:16]([CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][O:7][CH2:6][C:5]2[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=[C:3]([C:2]([F:1])([F:36])[F:37])[CH:4]=2)[CH2:21][CH2:20]1)[CH:39]([CH3:41])[CH3:40]
Reactant: CC(C)CO
Reactant: O=C(O)COCCN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)COC(=O)COCCN1CCN(C(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
In a round-bottomed flask fitted with a reflux condenser and a thermometer were introduced (2-{4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazin-1-yl}-ethoxy)-acetic acid (compound 235, 0.5 g, 0.84 mmoles) dissolved in THF (20 ml). To this solution cooled at 0° C. were successively added isobutanol (0.155 ml, 1.68 mmoles), DMAP (0.01 g, 0.084 mmoles) and EDCI (0.177 g, 0.93 mmoles). The reaction mixture was stirred for 2 hours at 0° C. and then allowed to reach room temperature and stirred overnight. The organic solution was washed with HCl 0.1N and water, dried over MgSO4 and concentrated. The resulting oil was purified by chromatography on silica gel (eluent: CH2Cl2/MeOH/NH3: 99.5/0.5/0.1 v/v/v) to yield (2-{4-[2-(3,5-Bis-trifluoromethyl-benzyloxy)-1-phenyl-ethyl]-piperazin-1-yl}-ethoxy)-acetic acid isobutyl ester (compound 287, 390 mg, 65%) which was converted into its dihydrochloride monohydrate salt by reaction with HCl in diethylether.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.[CH3:38][C:39]1[C:43]([C:44]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[O:45])=[C:42]([CH3:52])[O:41][N:40]=1>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C@H:11]2[C@@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:9]([C:27]([N:49]3[CH2:50][CH2:51][N:46]([C:44]([C:43]4[C:39]([CH3:38])=[N:40][O:41][C:42]=4[CH3:52])=[O:45])[CH2:47][CH2:48]3)=[O:28])[C:8]([C:6]3[C:5]([O:30][CH2:31][CH3:32])=[CH:4][C:3]([C:33]([CH3:34])([CH3:35])[C:36]#[N:37])=[C:2]([Cl:1])[CH:7]=3)=[N:12]2)=[CH:18][CH:17]=1
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: Cc1noc(C)c1C(=O)N1CCNCC1
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)c2c(C)noc2C)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(3,5-dimethyl-isoxazole-4-carbonyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-2-chloro-5-ethoxy-phenyl)-2-methyl-propionitrile was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and (3,5-dimethyl-isoxazol-4-yl)-piperazin-1-yl-methanone (example 13) in an analogous manner as described in example 25. LR-MS: 747.3 [(M+H)+]
Reaction SMILES: [F:1][C:2]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:3]=1[NH:4][C@@H:5]([CH3:9])[C:6]([OH:8])=[O:7].Cl.[CH3:17]O>>[F:1][C:2]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:3]=1[NH:4][C@@H:5]([CH3:9])[C:6]([O:8][CH3:17])=[O:7]
Reactant: CO
Reactant: C[C@H](Nc1ccc(F)c(F)c1F)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F

Procedure:
(2S)-2-(2,3,4-trifluoroanilino)propionic acid (1.1 g; 99% ee) was dissolved in methanol (10 ml) and hydrochloric acid (5 mol/l; 1 ml) was added thereto at room temperature. The liquid reaction mixture was heated under reflux for 6 hours and then the solvent was evaporated. To the obtained residue was added chloroform (10 ml). Next, the organic layer was washed with a saturated aqueous solution of sodium chloride and water and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography (ethyl acetate-normal hexane=1:4) to give the title compound (1.17 g) as an oily substance. The optical purity of the product was 99% ee. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 5.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)=[C:11]([F:28])[CH:10]=2)[CH2:4]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([O:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]3)=[C:11]([F:28])[CH:10]=2)[CH2:4]1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C[C@@H](CO)OC3=O)cc2F)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C[C@@H](COS(C)(=O)=O)OC3=O)cc2F)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
A solution of 2.88 g(7.28 mmol) of the alcohol 2 in 32 mL dichloromethane at 0° C. was treated with 1.29 g(1.77 mL, 12.7 mmol) of triethylamine followed by addition of 1.04 g(0.70 mL, 9.10 mmol) of methanesulfonylchloride. The solution was stirred at 0° C. for 15 min, followed by dilution with dichloromethane and extraction with water. The solution was dried (Na2SO4) and concentrated in vacuo to afford 3.4 g(98%) of the mesylate 3 as a light pink solid (high resolution mass spectrum: calcd for C20H28FN3O7S: 473.1632. found: 473.1631), sufficiently pure for use in the next step.