Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])[S:7]1(=[O:24])=[O:23].[CH3:29][NH2:30].[ClH:31]>>[ClH:31].[F:22][C:16]1[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:15]=1[N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([CH2:5][C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]=2[CH2:2][NH:30][CH3:29])[S:7]1(=[O:24])=[O:23]
Reactant: O=S1(=O)N(Cc2ccccc2CBr)c2ccccc2N1c1cccc(F)c1F
Reactant: CN
Agent: Cl
Product: CNCc1ccccc1CN1c2ccccc2N(c2cccc(F)c2F)S1(=O)=O
Yield: 48 %

Procedure:
In an analogous manner to general procedure V, 1-[2-(bromomethyl)benzyl]-3-(2,3-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (38 mg, 0.082 mmol) was treated with methyl amine to give 1-(2-{[3-(2,3-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]methyl}phenyl)-N-methylmethanamine hydrochloride (18 mg, 48%) after treatment with HCl.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][N:5]=1)([O-])=O>[Pd]>[N:10]1([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[N:5][CH:6]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(N2CCCC2)cn1
Agent: [Pd]
Product: Nc1ccc(N2CCCC2)cn1
Yield: 92.8 %

Procedure:
410 mg (2.12 mmol) of the product obtained in step 25.1 are hydrogenated in the presence of 10% Pd/C at atmospheric pressure at 35° C. The solution obtained is evaporated under reduced pressure to give 321 mg of 5-pyrrolidin-1-ylpyridin-2-ylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[CH2:13][CH2:12]2)[C:8]([NH:24][C:25]([C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)=[O:26])=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C)C=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:70][N:71]([CH2:73][C:74]1[CH:75]=[C:76]([CH:79]=[CH:80][CH:81]=1)[CH2:77][NH2:78])[CH3:72]>O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:4](=[O:5])[NH:78][CH2:77][C:76]2[CH:79]=[CH:80][CH:81]=[C:74]([CH2:73][N:71]([CH3:72])[CH3:70])[CH:75]=2)=[CH:7][C:8]([NH:24][C:25]([C:27]2[O:28][CH:29]=[CH:30][CH:31]=2)=[O:26])=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])[CH2:13][CH2:12]2)[CH:10]=1
Reactant: Cc1ccccc1N1CCN(c2cc(Cl)c(C(=O)O)cc2NC(=O)c2ccco2)CC1
Reactant: CN(C)Cc1cccc(CN)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1N1CCN(c2cc(Cl)c(C(=O)NCc3cccc(CN(C)C)c3)cc2NC(=O)c2ccco2)CC1
Temperature: 25 °C
Yield: 19.4 %

Procedure:
In a 40 ml scintillation vial equipped with a magnetic stir bar and fitted with a nitrogen inlet, the 2-chloro-5-[(furan-2-carbonyl)-amino]-4-(4-o-tolyl-piperazin-1-yl)-benzoic acid 14b (135.70 mg, 0.31 mmol) was taken up in clean, dry N,N-dimethylformamide (4.00 ml, 51.66 mmol) and the mixture was stirred at room temperature under nitrogen until all solids were in solution. To this was added first the HATU (140.80 mg, 0.37 mmol) followed by the N,N-diisopropylethylamine (0.16 ml, 0.92 mmol) and the mixture was once again stirred until all solids were in solution. The 3-dimethylaminomethyl-benzylamine (76.00 mg, 0.46 mmol) was added and the reaction stirred at room temperature overnight. The reaction was diluted with 10 ml of water and 10 ml of ethyl acetate. The layers were separated and the product was extracted from the aqueous using ethyl acetate (3×15 ml). The organic phases were combined, washed with brine (1×25 ml) and saturated aqueous lithium chloride solution (2×25 ml). The product solution was dried over Na2SO4; the solution was then decanted and the solvent was removed under reduced pressure. The product was isolated using silica gel column chromatography, eluting a gradient of 100% dichloromethane to 10% MeOH in dichloromethane. A secondary purification was required, using reverse-phase prep HPLC, eluting a gradient of 30% MeOH in water to 100% MeOH over a 5 min period. The product, furan-2-carboxylic acid [4-chloro-5-(3-dimethylaminomethyl-benzylcarbamoyl)-2-(4-o-tolyl-piperazin-1-yl)-phenyl]-amide 14c (37.30 mg, 0.06 mmol), was isolated as an off-white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]2[N:17]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:18]=[CH:19][C:3]=12.[CH:25]12[O:33][CH:29]([CH2:30][NH:31][CH2:32]1)[CH2:28][N:27]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:26]2.C(N(CC)CC)C>C(O)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]3[N:17]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:18]=[CH:19][C:3]3=[C:2]([N:31]3[CH2:32][CH:25]4[O:33][CH:29]([CH2:28][N:27]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:26]4)[CH2:30]3)[N:7]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)c3cnn(CC(F)(F)F)c3n2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CN(c3nc(-c4ccc([N+](=O)[O-])cc4)nc4c3cnn4CC(F)(F)F)CC(C1)O2
Temperature: 150 °C
Yield: 70.2 %

Procedure:
To a Smith process vial containing a suspension of 4-chloro-6-(4-nitro-phenyl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidine (0.50 g, 1.4 mmol) and tert-butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (0.34 g, 1.5 mmol) in ethanol (10 mL) was added triethylamine (0.55 mL, 4.2 mmol). The mixture was heated in the microwave reactor for 12 minutes at 150° C. The precipitate was collected by Buchner filtration, washed with methanol, and dried under house vacuum to provide tert-butyl 7-(6-(4-nitrophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate as a pale yellow solid (0.54 g, 70%). MS (ES+): 550.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:19][CH:18]3[CH:14]([N:15](C(OCC4C5C=CC=CC=5C5C4=CC=CC=5)=O)[CH2:16][CH2:17]3)[CH2:13]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1.N1CCCCC1>C(Cl)Cl>[Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:19][CH:18]3[CH:14]([NH:15][CH2:16][CH2:17]3)[CH2:13]2)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[CH:3]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC2CN(c3nc(Cl)cc4nccnc34)CC21
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Clc1cc2nccnc2c(N2CC3CCNC3C2)n1

Procedure:
A solution of (9H-fluoren-9-yl)methyl 5-(7-chloropyrido[4,3-b]pyrazin-5-yl)hexahydropyrrolo[3,4-b]pyrrole-1 (2H)-carboxylate (140 mg) and piperidine (2 mL) in CH2Cl2 (8 mL) was stirred at room temperature for 3 hours. The volatiles were removed under reduced pressure. The residue was treated with EtOAc/H2O, separated, and the aqueous solution was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography to afford the title compound. MS (m/z): 276 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1([CH3:18])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12](O)([CH3:16])[C:13]([OH:15])=[O:14])[CH:9]=2)[CH2:4]1)[CH3:2].C1([NH3+])CCCCC1>>[CH2:1]([C:3]1([CH3:18])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:9]=2)[CH2:4]1)[CH3:2]
Reactant: CCC1(C)Cc2ccc(C(C)(O)C(=O)O)cc2C1
Agent: [NH3+]C1CCCCC1
Product: CCC1(C)Cc2ccc(C(C)C(=O)O)cc2C1

Procedure:
2-ethyl-α-hydroxy-2,α-dimethyl-5-indanacetic acid is hydrogenated in a manner analogous to that described in Example 1. The cyclohexyl-ammonium salt of the title compound has a M.P. of 165°-167° (from ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:50])[C:30]([CH3:49])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][CH3:48])=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:50])[C:30]([CH3:49])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][CH3:48])=[C:42]([CH:46]=2)[C:43]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.4 %

Procedure:
p-Methoxyaniline (0.043 g, 0.347 mmol), triethylamine (0.035 g, 0.347 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.059 g, 0.347 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-methoxybenzoic acid (0.060 g, 0.173 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate) to obtain the titled compound (0.044 g, 0.0975 mmol, 56%).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7]>C1COCC1>[N:22]1[CH:23]=[CH:24][C:19]([C:16]2[N:15]=[C:14]([C@H:11]3[CH2:10][CH2:9][C@H:8]([C:6]([OH:7])=[O:5])[CH2:13][CH2:12]3)[O:18][N:17]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)C1CCC(c2nc(-c3ccncc3)no2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CC[C@H](c2nc(-c3ccncc3)no2)CC1
Temperature: 60 °C

Procedure:
Water (0.5 ml) and lithium hydroxide (9.2 mg, 0.22 mmol) were added to a stirred solution of 4-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)cyclohexanecarboxylic acid methyl ester (Preparation 3, 30 mg, 104 μmol) in THF (1.5 ml). The mixture was heated at 60° C. for 1.5 h, cooled and the THF removed in vacuo. Water (5 ml) was added, the aqueous washed with EtOAc (5 ml) and carefully acidified with 1M HCl to pH 4. The resulting precipitate was extracted into 3% MeOH in EtOAc (2×15 ml) and the combined organic phases dried (MgSO4) and evaporated to afford the title compound: RT=2.74 min, m/z (ES+)=274.2 [M+H]+.
Reaction SMILES: C(=O)([O-])O.[Na+].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[OH:16].[Cl:17][CH2:18][C:19](Cl)=[O:20].[Cl-].[NH4+]>C(OCC)(=O)C.O>[Cl:17][CH2:18][C:19]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[OH:16])=[O:20]
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc([N+](=O)[O-])c1O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCl)Nc1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium hydrogen carbonate (6.30 g, 75.0 mmol) and water (75 mL) were added to a solution of 2-amino-6-nitrophenol obtained (5.77 g, 37.5 mmol) in ethyl acetate (75 mL) while cooling in ice, and chloroacetic acid chloride (3.58 mL, 45.0 mmol) was added dropwise thereto. After stirring at room temperature for 1.5 hr, the reaction mixture was cooled in ice, saturated aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→1:1) to afford 2-chloro-N-(2-hydroxy-3-nitrophenyl)acetamide as a pale yellow powder (5.70 g).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([C:32]2[N:36]([CH3:37])[N:35]=[N:34][CH:33]=2)[OH:31])=[CH:26][CH:25]=1>C(Cl)Cl>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([C:32]2[N:36]([CH3:37])[N:35]=[N:34][CH:33]=2)=[O:31])=[CH:26][CH:25]=1
Reactant: Cn1nncc1C(O)c1ccc(Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cn1nncc1C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Similar to the procedure described in J. Am. Chem. Soc. 1991, 7277, a flask containing Dess-Martin reagent (1.50 g, 3.54 mmol) in DCM (30 mL) was cooled to 0° C. and then a solution of (4-chlorophenyl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol (500 mg, 2.24 mmol, Intermediate 42, step b) in 10 mL of DCM was added. After 5 min, the ice bath was removed and the mixture was allowed to stir at room temperature for 45 min, at which time TLC (20% EtOAc-DCM) indicated the reaction was complete. The mixture was quenched with a saturated NaHCO3 solution and 2 mL of 1 N NaOH and the aqueous portion (pH ˜9) was extracted with DCM (3×75 mL). The combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give a light amber solid. Flash chromatography on silica gel (10% EtOAc-DCM) afforded the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:34]=[CH:33][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[C:22]([CH2:31][OH:32])=[CH:21]2)=[CH:17][CH:16]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[C:22]([CH:31]=[O:32])=[CH:21]2)=[CH:33][CH:34]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CO)c(-c3ccccn3)c2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(C=O)c(-c3ccccn3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A mixture of [1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-(2-pyridyl)-3-pyrrolyl]methanol (2.01 g), activated manganese dioxide (5.09 g), and tetrahydrofuran (50 ml) was stirred at room temperature overnight. After the manganese dioxide was removed by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-(2-pyridyl)pyrrole-3-carbaldehyde (1.71 g, yield: 85%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)[CH3:35]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:33]=[C:34]([C:36]1[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=1)[CH3:35])[C:6]1[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:5]2=1
Reactant: CN1CCc2c([nH]c3ccc(Cl)cc23)C1
Reactant: COc1ccc(C(C)=CBr)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: COc1ccc(C(C)=Cn2c3c(c4cc(Cl)ccc42)CCN(C)C3)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (80 mg, 0.36 mmol) was dissolved in DMF (6 mL). To this solution was added CuI (7 mg, 0.036 mmol), L-proline (8 mg, 0.073 mmol), K3PO4 (156 mg, 0.734 mmol). The reaction mixture was stirred for 10 min at room temperature followed by addition of 1-(1-bromoprop-1-en-2-yl)-4-methoxybenzene (100 mg, 0.44 mmol). The reaction mixture was heated at 80° C. for 18 h. Solvent was evaporated under reduced pressure, the residue was diluted with brine and extracted with ethyl acetate. Organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain 67 mg of 6-chloro-9-(2-(4-methoxyphenyl)prop-1-enyl)-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. 1H NMR (DMSO) OXALATE SALT 7.60 (m, 3H), 7.25 (d, 1H), 7.18 (d, 1H), 7.0 (m, 3H), 4.20 (m, 2H), 3.80 (s, 3H), 3.38 (m, 2H), 2.95 (m, 2H), 2.80 (s, 3H), 1.82 (s, 3H).
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH:17][CH:18]([CH2:22][CH2:23][CH2:24][CH3:25])[C:19]([OH:21])=[O:20]>C(OCC)(=O)C>[OH:17][CH:18]([CH2:22][CH2:23][CH2:24][CH3:25])[C:19]([O:21][CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:20]
Reactant: CCCCC(O)C(=O)O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCC(O)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 90 ml of ethyl acetate, the 2-hydroxy-L-hexanoic acid (H-L-norLEUA-OH) was dissolved. A solution (15.1 g/30 ml) of diphenyldiazomethane in ethyl acetate was added dropwise to the resulting solution, followed by stirring overnight at room temperature. The reaction mixture was adjusted to pH 2 with 2N--HCl, followed by washing thrice with 200 ml portions of a saturated aqueous solution of sodium bicarbonate. The organic layer so obtained was dried over anhydrous magnesium sulfate and then filtered. The filtrate was thereafter concentrated under reduced pressure. The residue obtained was then purified by subjecting to chromatography on a silica gel column (toluene:ethyl acetate=20:1), whereby 11.35 g of the title compound were obtained as pale yellow crystals (yield: 54.7%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([CH3:22])=[CH:17][C:16]=2[NH2:23])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:24]([O-])([O-])OC>C(O)=O>[F:21][C:19]1[C:18]([CH3:22])=[CH:17][C:16]2[N:23]=[CH:24][N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:15]=2[CH:20]=1
Reactant: COC([O-])[O-]
Reactant: Cc1cc(N)c(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Solvent: O=CO
Product: Cc1cc2ncn(C3CCNCC3)c2cc1F
Temperature: 60 °C
Yield: 99 %

Procedure:
To a solution of 4-(2-amino-5-fluoro-4-methyl-phenylamino)piperidine-1-carboxylic acid tert-butyl ester (250 mg, 0.309 mmol) in formic acid (3 mL) was added methyl orthoformate (0.5 mL). After heating for 3 hours at 60° C., the volatiles was removed under reduced pressure to afford crude product 6-fluoro-5-methyl-1-piperidin-4-yl-1H-benzoimidazole (180 mg, 99%) as a brown solid.
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]2[CH2:25][NH:24][CH2:23][CH:22]2[CH:26]([O:28][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][N:30]=2)[CH3:27])[CH:17]=[CH:18][C:19]=1[Cl:20].N1C=CC=CC=1.CCOC(C)=O>C(Cl)Cl>[C:33]([C:32]1[CH:35]=[CH:36][C:29]([O:28][CH:26]([CH:22]2[CH:21]([C:16]3[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=3)[CH2:25][N:24]([C:7]([Cl:10])=[O:6])[CH2:23]2)[CH3:27])=[N:30][CH:31]=1)#[N:34]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(Oc1ccc(C#N)cn1)C1CNCC1c1ccc(Cl)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 154.1 %

Procedure:
To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (67 mg, 0.22 mmol) in CH2Cl2 (14 ml) at −78° C., was added a solution of 6-{(SR)-1-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-nicotinonitrile (intermediate XV-B-4) (210 mg, 0.56 mmol) and pyridine (0.10 ml, 1.23 mmol) in CH2Cl2 (7 mL) over 30 minutes. The temperature was raised to RT, and stirring was continued over night. The organic phase was washed with H2O, dried over Na2SO4. Concentration under vacuo yielded and column chromatography (SiO2, EtOAc/H, 1:1) yielded 144 mg (57%) of the title compound as a viscous colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:25])=[C:12]([O:14]C(=O)C2C=CC(F)=C(Cl)C=2)[CH:13]=1)=[O:6].[OH-].[Na+]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:25])=[C:12]([OH:14])[CH:13]=1)=[O:6]
Reactant: Cc1ccc(NC(=O)c2ccc(F)c(Cl)c2)cc1OC(=O)c1ccc(F)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(NC(=O)c2ccc(F)c(Cl)c2)cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Chloro-4-fluoro-benzoic acid 5-(3-chloro-4-fluoro-benzoylamino)-2-methyl-phenyl ester (3.93 g, 9 mmol) was dissolved in a mixture of tetrahydrofuran (25 mL), methanol (50 mL) and aqueous 1N sodium hydroxide (9 mL, 9 mmol). The mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure to remove most of the organic solvent. The resulting suspension was diluted with water (45 mL) and saturated aqueous sodium bicarbonate solution (5 mL). After standing for 30 minutes, the precipitate was collected and washed with water and dried to give crude 3-chloro-4-fluoro-N-(3-hydroxy-4-methyl-phenyl)-benzamide as a white powder. (Yield 2.59 g, 103%).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([CH2:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1)=[O:8].N>[Ni]>[CH3:18][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([CH2:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1)=[O:8]
Reactant: CN(C)CCCNC(=O)Cc1ccc(C#N)cc1
Agent: [Ni]
Agent: N
Product: CN(C)CCCNC(=O)Cc1ccc(CN)cc1

Procedure:
Prepared analogously to Example 6c) from 4-[[[[3-(dimethylamino)propyl]amino]carbonyl]methyl]benzonitrile by catalytic hydrogenation in the presence of Raney nickel and ammonia in a quantitative yield. Colourless, highly viscous oil, which was used in the next step without purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[K].[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(S)C=CC=CC=1.[OH-].[K+].C>CO.CN(C)C=O>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([NH2:10])=[CH:3][C:2]=1[S:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:9]
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: Sc1ccccc1
Agent: C
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: CO
Product: N#Cc1ccc(N)cc1Sc1ccccc1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
3-Chloro-4-cyanobenzenamine (20.0 g, 13.1 mmol) was added to a N,N-dimethylformamide (115 mL) solution of thiophenol potassium salt [prepared by adding thiophenol (13.5 mL, 13.1 mmol) to a solution of potassium hydroxide (7.35 g, 13.1 mmol) in methanol followed by removal of the methanol in vacuo] and washed in with an additional 15 ml of N,N-dimethylformamide. After stirring at 140° C. for 16 hours the mixture was poured into water, extracted with ethyl ether (3×150 mL) and the solvent removed in vacuo to yield a red oil. The oil was chromatographed on silica gel using methylene chloride as eluent. The fractions containing product (TLC-silica gel, 2% methanol/chloroform) were combined, the solvent removed and the material rechromatographed using 2:1 methylene chloride/hexane as eluent. The proper fractions were combined, concentrated to a low volume, treated with hexane and cooled (dry ice) and scratched as crystals formed. The white solid weighed 8.29 g (30%); mp 69°--71° C. 1H--NMR (250 MHz, CDCl3): 4.07 (s, 2H, NH2), 6.29 (d,1H, J=2.2 Hz, aromatic), 6.46 (dd 1H, J=2.2 Hz, aromatic), 7.36-7.50 (m, 6H, aromatic). MS (CI, CH4): 227(M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][O:22][C:23]3[CH:36]=[CH:35][C:26]([CH:27]=[C:28]4[S:32][C:31](=[O:33])[NH:30][C:29]4=[O:34])=[CH:25][CH:24]=3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(OC(C1CC(C(OCC)=O)=C(C)NC=1C)=O)C>>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][O:22][C:23]3[CH:36]=[CH:35][C:26]([CH2:27][CH:28]4[S:32][C:31](=[O:33])[NH:30][C:29]4=[O:34])=[CH:25][CH:24]=3)=[CH:16][CH:15]=2)(=[O:11])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1NC(=O)C(=Cc2ccc(OCCc3ccc(OS(=O)(=O)c4cccc([N+](=O)[O-])c4)cc3)cc2)S1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Product: O=C1NC(=O)C(Cc2ccc(OCCc3ccc(OS(=O)(=O)c4cccc([N+](=O)[O-])c4)cc3)cc2)S1
Temperature: 145 °C
Yield: 41.2 %

Procedure:
2,4 g (4.6 mmole) 5-(4-[2-(4-(3-nitrophenylsulfonyloxy)phenyl)ethoxy]benzylidene)thiazolidine-2,4-dione and 3.5 g (14 mmole) diethyl-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate were mixed and heated to 145° C. under vacuum and after 1-2 hours the heat was removed. The solid material was dissolved in toluene, evaporated in vacuo and purified by chromatography on silica gel twice with ethyl acetate:petroleum ether (1:1) as eluents to give 1.002 g (yield 41%) of the desired product.