Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([SH:12])[N:11]=[C:4]2[N:3]=1.Br[CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([O:16][CH2:15][CH2:14][S:12][C:10]2[N:11]=[C:4]3[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]3[N:9]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: BrCCOC1CCCCC1
Reactant: Cc1cc(C)n2nc(S)nc2n1
Product: Cc1cc(C)n2nc(SCCOC3CCCCC3)nc2n1
Yield: 78 %

Procedure:
The title compound was prepared according to the experimentals described for Example 1 above from 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol and 2-bromoethoxy cyclohexane in 78% yield; EM (calc.): 306.2; MS (ESI) m/e: 307.2 (M+H)+.
Reaction SMILES: C(O[C:4](=[O:11])[C:5]([C:9]#[N:10])=[C:6]([OH:8])[CH3:7])C.[F:12][C:13]([F:22])([F:21])[C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>C1(C)C(C)=CC=CC=1>[CH3:7]/[C:6](/[OH:8])=[C:5](/[C:4]([NH:18][C:17]1[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:21])[F:22])=[CH:20][CH:19]=1)=[O:11])\[C:9]#[N:10]
Reactant: CCOC(=O)C(C#N)=C(C)O
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1C
Product: C/C(O)=C(\C#N)C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 71.2 %

Procedure:
Ethyl 2-cyano-3-hydroxybut-2-enoate (III) (50 g) and 4-(trifluoromethyl) aniline (51.9 g) in xylene (1000 ml) was refluxed for 48 hours. The reaction mixture was allowed to cool at room temperature. Separated solid was filtered and washed with xylene (2×100 ml). Solid was dried under vacuum at 70° C. to yield (62 g) of Teriflunomide.
Reaction SMILES: C([BH-](CC)CC)C.[Li+].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]([N:18]2[CH2:23][CH2:22][C@:21]([CH2:30][C:31]3([CH3:34])[CH2:33][O:32]3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:20][C:19]2=[O:35])[CH3:17])=[C:12]([CH3:36])[CH:11]=1>O1CCCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]([N:18]2[CH2:23][CH2:22][C@:21]([CH2:30][C:31]([OH:32])([CH3:34])[CH3:33])([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:20][C:19]2=[O:35])[CH3:17])=[C:12]([CH3:36])[CH:11]=1
Reactant: Cc1cc(Br)ccc1[C@H](C)N1CC[C@](CC2(C)CO2)(c2ccccc2)OC1=O
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1[C@H](C)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium triethylborohydride (1 mol/L in tetrahydrofuran, 4.2 mL) was added to an ice-cold solution of 3-[(S)-1-(4-bromo-2-methyl-phenyl)-ethyl]-(S)-6-(2-methyl-oxiranylmethyl)-6-phenyl-[1,3]oxazinan-2-one (1.55 g, ca. 85-90% pure) in tetrahydrofuran (15 mL) at such a rate that the solution temperature remained below 10° C. The resulting solution was stirred in the cooling bath for one more hour and at room temperature for another 2 h. Then, the solution was cooled in an ice bath and the reaction was quenched by the careful addition of water (7 mL). After the addition of aqueous hydrochloric acid and ethyl acetate (80 ml), the organic phase was separated, washed with brine, and dried (MgSO4). The solvent was evaporated to afford the title compound. Yield: 1.48 g (95% of theory); LC-MS (Method 4): tR=4.00 min; Mass spectrum (ESI+): m/z=446/448 (Br) [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5](B2OC(C)(C)C(C)(C)O2)[C:4]([CH3:17])=[N:3]1.Br[C:19]1[C:20]([Cl:35])=[C:21]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:22]=[C:23]([C:25]#[N:26])[CH:24]=1.P(=O)(O)(O)O.[K]>C(OCC)(=O)C.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].O1CCOCC1>[Cl:35][C:20]1[C:19]([C:5]2[C:4]([CH3:17])=[N:3][N:2]([CH3:1])[C:6]=2[CH3:7])=[CH:24][C:23]([C:25]#[N:26])=[CH:22][C:21]=1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(Br)c1Cl
Reactant: Cc1nn(C)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=P(O)(O)O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1nn(C)c(C)c1-c1cc(C#N)cc(NC(=O)OC(C)(C)C)c1Cl
Temperature: 85 °C
Yield: 50.7 %

Procedure:
A vial was charged with 1,3,5-trimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.117 g, 0.498 mmol), tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate (0.15 g, 0.452 mmol), PdCl2(DPPF) (0.033 g, 0.045 mmol) and dioxane (3.62 ml). The slurry was evacuated and backfilled with nitrogen (4×). Phosphoric acid, potassium salt (0.588 ml, 1.176 mmol) was added and the vial was capped and warmed to 85° C. 2 h. The reaction mixture was diluted with ethyl acetate and vacuum filtered through a pad of Celite. The filtrate was concentrated and the crude residue purified by column chromatography on the ISCO system (12 g, 0-70% EtOAc/Hex) to provide tert-butyl (2-chloro-5-cyano-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenyl)carbamate (82.7 mg) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[C:3]=1[C:17](=[O:19])[NH2:18].[OH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>CCO.N1CCCCC1>[C:17]([C:3]1[C:4]([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[N:5][NH:6][C:2]=1[N:1]=[CH:25][C:24]1[CH:27]=[CH:28][C:21]([OH:20])=[CH:22][CH:23]=1)(=[O:19])[NH2:18]
Reactant: NC(=O)c1c(Nc2ccc(C(=O)O)cc2)n[nH]c1N
Reactant: O=Cc1ccc(O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2ccc(C(=O)O)cc2)n[nH]c1N=Cc1ccc(O)cc1

Procedure:
4-((5-amino-4-carbamoyl-1H-pyrazol-3-yl)amino)benzoic acid was then suspended in 8 mL EtOH and 4-hydroxybenzaldehyde (325 mg, 1 eq.) and piperidine (4 drops) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 4-((4-carbamoyl-5-((4-hydroxybenzylidene)amino)-1H-pyrazol-3-yl)amino)benzoic acid as a yellow powder. Powder was washed with EtOH to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)[N:20]=3)[CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:28][C:25]([F:26])([F:27])[C:23]1[CH:22]=[C:21]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:31][CH:30]=2)[N:20]=[C:19]([N:17]2[CH:18]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[N:15]=[CH:16]2)[N:24]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 16 %

Procedure:
To a cooled and stirred solution of 5-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.43 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by flash chromatography (heptane/ethyl acetate) and crystallization (dichloromethane/MeOH/hexane) to yield the title compound as a white solid (0.062 g, 8%). MS (ISN) 518.3 [(M−H)−]; mp 281° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH2:15])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3.C(N(CC)CC)C.[C:25](Cl)(=[O:28])[CH2:26][CH3:27]>C(Cl)Cl>[CH3:1][C:2]1([CH3:17])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:25](=[O:28])[CH2:26][CH3:27])[CH:3]1[OH:16])=[N:10][O:11][N:12]=3
Reactant: CCC(=O)Cl
Reactant: CC1(C)Oc2cc3nonc3cc2C(N)C1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NC1c2cc3nonc3cc2OC(C)(C)C1O
Temperature: 25 °C
Yield: 31 %

Procedure:
To a mixture of 200 mg (0.85 m mol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-amino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole, 130 ml (0.935 m mol) of triethylamine and 20 ml of methylene chloride were added 81 μl (0.935 m mol) of propionyl chloride with stirring at the room temperature, followed by further stirring for 6 hours. After the completion of the reaction, the mixture solution was washed thrice with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was recrystallized from ethanol to obtain 77 mg (yield: 31%) of the pure intended compound.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3](=[O:15])[C@H:4]([CH:12]([CH3:14])[CH3:13])[NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:17][C:18]([F:39])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:39][C:18]([F:17])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25](/[CH:28]=[C:10]2/[C:6]([NH:5][C@H:4]([C:3]([N:2]([CH3:1])[CH3:16])=[O:15])[CH:12]([CH3:14])[CH3:13])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:24][CH2:23]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CC(C)[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CC(C)[C@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 42.5 %

Procedure:
To a solution of N,N-dimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-L-valinamide (973 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1764 mg) in 2-propanol (10 mL) was added piperidinium acetate (755 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (960 mg)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][O:9][C:10](=[O:27])[C:11]1[C:12](=[C:17]([NH:21]CCCCC)[CH:18]=[CH:19][CH:20]=1)[C:13]([O:15][CH3:16])=[O:14]>>[CH3:8][O:9][C:10](=[O:27])[C:11]1[C:12](=[C:17]([NH:21][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:18]=[CH:19][CH:20]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: CCCCCNc1cccc(C(=O)OC)c1C(=O)OC
Reactant: O=Cc1cccs1
Product: COC(=O)c1cccc(NCc2cccs2)c1C(=O)OC
Yield: 58 %

Procedure:
2-Thiophenecarboxaldehyde (1.12 g, 10 mmol) was treated in the same manner as described above for the synthesis of 3-pentylamino-phthalic acid dimethyl ester. The residue (oil) was purified by preparative HPLC (Symmetry C18, isocratic, 45% acetonitrile/water) to give 0.88 g (58%) of yellow oil: 1H NMR (CDCl3) δ 7.38-7.15 (m, 3H), 7.00-6.93 (m, 2H), 6.87-6.82 (m, 2H), 4.58 (d, J=5.3 Hz, 2H), 3.86 (s, 3H), 3.83 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([N:12]3[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]3[CH3:18])=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[Br:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:23]([NH2:24])=[C:22]([O:28][CH3:29])[CH:21]=1.C(=O)([O-])O.[Na+]>>[Br:19][C:20]1[CH:26]=[C:25]([CH3:27])[C:23]([NH:24][C:2]2[N:6]([CH3:7])[C:5]3[C:8]([N:12]4[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]4[CH3:18])=[CH:9][CH:10]=[CH:11][C:4]=3[N:3]=2)=[C:22]([O:28][CH3:29])[CH:21]=1
Reactant: Cc1ccc(C)n1-c1cccc2nc(Cl)n(C)c12
Reactant: COc1cc(Br)cc(C)c1N
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(Br)cc(C)c1Nc1nc2cccc(-n3c(C)ccc3C)c2n1C
Temperature: 110 °C
Reaction time: 15 h
Yield: 35 %

Procedure:
A mixture of 90 mg (0.347 mmol) of 2-chloro-7-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-benzimidazole and 225 mg (1.04 mmol) of 4-bromo-2-methoxy-6-methylaniline was stirred at 110° C. for 15 hours. After cooling, the reaction mixture was neutralized by saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (X2). The combined organic layer was washed with brine (X1), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 60-90% ethylacetate/n-hexane gradient mixture. The desired fractions were collected and evaporated in vacuo, the residual solids were washed with diethyl ether to give 53.4 mg (35%) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11]C)=O)=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:6]=[C:5]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31]C(OC(C)(C)C)=O)[N:4]=1.[OH-].[NH4+:40].[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42].C(Cl)Cl>C1COCC1>[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42].[NH2:31][C@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[NH:24][C:5]1[N:6]=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:21])[F:23])[CH:15]=2)[C:8]2[C:9](=[O:11])[NH:40][CH2:2][C:3]=2[N:4]=1
Reactant: COC(=O)c1c(CBr)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(C(F)(F)F)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: N[C@H]1CCCC[C@H]1Nc1nc2c(c(Nc3cccc(C(F)(F)F)c3)n1)C(=O)NC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 3 %

Procedure:
A mixture of methyl 4-(bromomethyl)-2-((1R,2S)-2-(tert-butoxycarbonyl-amino)cyclohexylamino)-6-(3-(trifluoromethyl)phenylamino)pyrimidine-5-carboxylate (120 mg, 0.199 mmol) in THF was treated with ammonium hydroxide. The reaction mixture was stirred at RT overnight, and subsequently worked up and purified by reverse phase preparative HPLC. The fractions were collected and concentrated under reduced pressure to give a residue, which was treated with TFA/DCM. The final product was purified again by preparative HPLC. Lyophilization gave a TFA salt of the title compound as a white solid (2.6 mg, 3%). [M+H] calc'd for C19H21F3N6O, 407; found, 407.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].N1C=CC=CC=1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCOCC>[C:12]([O:5][CH2:4][CH:2]1[O:3][CH2:1]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OCC1CO1
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(OCC1CO1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
A mixture containing 14.8 g (0.2 mole) of glycidol, 150 ml of anhydrous ether, 16 g (0.4 mole) of pyridine and 28 g (0.2 mole) of benzoyl chloride was stirred at room temperature for 2 hours. The mixture was filtered and the ether was evaporated to leave an oil. This oil was distilled to give 21 g (60%) of colorless oil: b.p. 92° C./0.5 mm Hg. The NMR and IR spectra were consistent with the assigned structure.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[C:18](OCC)=O.[OH-].[NH4+]>O>[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=1[C:18]1[NH:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:8][C:9]=2[N:14]=1
Reactant: CCOC(=O)c1ccccc1Cl
Reactant: Nc1ccc(Cn2ccnc2)cc1N
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Clc1ccccc1-c1nc2cc(Cn3ccnc3)ccc2[nH]1
Temperature: 140 °C
Reaction time: 4 h
Yield: 26 %

Procedure:
A mixture of 5 parts of 4-(1H-imidazol-1-ylmethyl)-1,2-benzenediamine, 5 parts of ethyl 2-chlorobenzoate and 30 parts of polyphosphoric acid was stirred for 4 hours at 140° C. The whole was poured into 200 parts of water and crushed ice. The mixture was treated with ammonium hydroxide. The product was extracted three times with 120 parts of trichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography (HPLC) over silica gel using a mixture of trichloromethane, methanol and ammonium hydroxide (90:10:0.05 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 1,1'-oxybisethane. The product was filtered off and dried in vacuo at 100° C., yielding 2.1 parts (26%) of 2-(2-chlorophenyl)-5-(1H-imidazol-1-ylmethyl)-1H-benzimidazole; mp. 115.2° C. (compound 88).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1[C:17]2[CH:16]=[C:15]([C:18]([OH:20])=O)[C:14]3[CH:21]=[CH:22][CH:23]=[CH:24][C:13]=3[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(CC)CC>CN(C)C=O.ClCCl>[CH:7]1[C:17]2[CH:16]=[C:15]([C:18]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:20])[C:14]3[CH:21]=[CH:22][CH:23]=[CH:24][C:13]=3[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)C1=Cc2ccccc2Oc2ccccc21
Reactant: C1CCNCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1=Cc2ccccc2Oc2ccccc21)N1CCCCC1
Reaction time: 4 h
Yield: 69 %

Procedure:
1.1 ml (12.59 mmol) of oxalyl chloride and 1 drop of dimethylformamide are added at room temperature to a solution of 3.0 g is (12.59 mmol) of dibenz[b,f]oxepine-10-carboxylic acid in 20 ml of dichloromethane and the mixture is stirred for 4 hours. 1.86 ml (18.88 mmol) of piperidine and 2.62 ml (18.88 mmol) of Et3N are then added and the mixture is stirred at room temperature overnight. The reaction mixture is washed 1× with hydrochloric acid and brine, and the organic phase is dried, concentrated, subjected to column chromatography and crystallised from tert-butyl methyl ether. 2.64 g (8.6 mmol)=69% of dibenz[b,f]oxepin-10-yl-piperidin-1-yl-methanone are obtained in the form of light-yellow crystals; melting point: 127°-128° C.; 1H-NMR (CDCl3, 200 MHz): 1.30-1.50 (mbr, 2H); 1.50-1.70 (mbr, 4H); 3.30-3.45 (mbr, 2H); 363-3.78 (mbr 2H); 6.92 (s, 1H); 7.10-7.40 (m, 8H); MS: 305 (M+), 221, 193, 165; TLC (silica gel; ethyl acetate/hexane=1:1; UV): Rf =0.32.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[OH:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:36]2[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][OH:30])[CH2:34][CH2:35]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: OCCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCN(CCO)CC3)ccc21
Yield: 111.9 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.7 mg, 0.0504 mmol) was dissolved in acetonitrile (1 mL), and the solution was treated with 1-(2-hydroxyethyl)piperazine (28 mg, 0.22 mmol), acetic acid (0.232 mL, 4.05 mmol) and sodium triacetoxyborohydride (116 mg, 0.547 mmol). The reaction mixture was added with water and sodium carbonate, followed by extracting with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)piperazin-1-ylmethyl]indol-2-yl)isoindolinone (29.6 mg).
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:29]=[CH:28][C:7]([C:8]([NH:10][C@@H:11]([CH3:27])[C:12]([NH:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]([O:22]CCCC)=[O:21])=[O:13])=[O:9])=[CH:6][CH:5]=1.[ClH:30]>>[ClH:30].[NH2:1][N:2]=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C@@H:11]([CH3:27])[C:12]([NH:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]([OH:22])=[O:21])=[O:13])=[O:9])=[CH:28][CH:29]=1
Reactant: CCCCOC(=O)COCCCNC(=O)[C@H](C)NC(=O)c1ccc(C=NN)cc1
Agent: Cl
Product: C[C@H](NC(=O)c1ccc(C=NN)cc1)C(=O)NCCCOCC(=O)O

Procedure:
416 mg of butyl (S)-[3-[2-[4-(aminoiminomethyl)benzoylamino]propionylamino]propoxy]acetate are stirred at 20° C. in 8.3 ml of 25 percent hydrochloric acid. The solution is evaporated and the residue is evaporated with water. From THF there are obtained 211 mg of (S)-[3-[2-[4-(aminoimino-methyl) benzoylamino]propionylamino]propoxy]acetic acid hydrochloride as the hydrate (1:1), m.p. 89°-90° C., [α]D20 =+23.4° (c=0.5 in methanol).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:19][C:20](=[O:33])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=2)=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][N:10](C(=O)C(F)(F)F)[CH2:9][CH2:8]2)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH2:1]([C:3]1[C:4]([NH:19][C:20](=[O:33])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([C:29]([F:30])([F:32])[F:31])[CH:22]=2)=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][NH:10][CH2:9][CH2:8]2)[CH3:2]
Reactant: CCc1c(NC(=O)c2ccc(OC)c(C(F)(F)F)c2)ccc2c1CN(C(=O)C(F)(F)F)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCc1c(NC(=O)c2ccc(OC)c(C(F)(F)F)c2)ccc2c1CNCC2
Reaction time: 8 h
Yield: 774.6 %

Procedure:
N-(8-Ethyl-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4methoxy-3-trifluoromethylbenzamide (0.157 g) was dissolved in methanol/water (5:1 6 ml), potassium carbonate (0.228 g) added and the mixture stirred overnight. The mixture was partitioned between dichloromethane and water the organic phase separated and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, ammonia/methanol/dichloromethane mixtures as eluant) to give the title compound (0.97 g)
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]1[CH2:22][S:21][CH2:20][C@@H:19]([CH:23]([CH3:25])[CH3:24])[N:18]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[C:17]1=[O:34])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@H:16]1[CH2:22][S:21][CH2:20][C@@H:19]([CH:23]([CH3:24])[CH3:25])[N:18]([CH2:26][C:27]([OH:29])=[O:28])[C:17]1=[O:34])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CSC[C@@H](C(C)C)N(CC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CSC[C@@H](C(C)C)N(CC(=O)O)C1=O
Yield: 91.7 %

Procedure:
0.32 g of t-butyl α-{6(R)-[1(S)-ethoxycarbonyl-3-phenylpropylamino]-3(R)-isopropyl-5-oxoperhydro-1,4-thiazepin-4-yl}acetate (isomer B) synthesized as described in Example 27 was subjected to de-t-butylation with trifluoroacetic acid in the same manner as described in Example 3, to give 260 mg of the title compound as an amorphous solid.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][C:11]1([CH3:31])[CH2:16][CH2:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)=[CH:13][CH2:12]1>C1COCC1>[CH3:10][C:11]1([CH3:31])[CH2:16][CH2:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]4=[N:30][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:26]4[CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)=[CH:13][CH2:12]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC1(C)CC=C(Oc2ccc(-c3cccnc3N)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CC=C(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)CC1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 382 mg) in THF (dry) (30 mL) was added 2-chloroethanesulfonyl chloride (0.402 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-((4,4-dimethylcyclohex-1-en-1-yl)oxy)phenyl)pyridin-2-amine (563 mg) in THF (dry) (30 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen for 3 hr. The mixture was quenched with water at 0° C. Water and EtOAc were added and the mixture was extracted. Silica-gel was added to the organic phase and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo to give the title compound (369 mg) as a pale yellow solid. A part of the product was crystallized from MeCN/IPE to give a pale yellow crystal.