Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([O:5][C:6]1([C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[CH2:11][CH2:10][N:9](CC2C=CC=CC=2)[CH2:8][CH2:7]1)(=[O:4])[CH3:3].Cl>>[C:2]([O:5][C:6]1([C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][CH2:6][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][CH2:7]1)(=[O:4])[CH3:3]
Reactant: CC(=O)OC1(c2ccc3c(c2)OCO3)CCN(Cc2ccccc2)CC1
Agent: Cl
Product: CC(=O)OC1(c2ccc3c(c2)OCO3)CCN(CCCc2ccccc2)CC1

Procedure:
4-Acetoxy-4-(3.4-methylene dioxy phenyl)-piperidine hydrochloride (M.P. 167° - 168°C) is obtained in analogous manner to that described in Example 1d from 4-Acetoxy-1-benzyl-4-(3.4-methylene dioxy phenyl)-piperidine hydrochloride with no free hydrochloric acid and at a temperature of 40° - 50°C.
Reaction SMILES: [N+]([C:4]1[C:5]([N+]([O-])=O)=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[N+:14]([O-:17])(O)=[O:15].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[N+:14]([C:9]1[CH:8]=[CH:7][C:6]([CH3:10])=[CH:5][CH:4]=1)([O-:17])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])cc1

Procedure:
The process according to the invention is preferably used for the production of dinitrotoluene by the two-stage reaction of toluene with nitric acid in the presence of sulphuric acid, wherein in the first stage toluene is nitrated to form mononitrotoluene (MNT) using waste acids from the second stage, in which mononitrotoluene is nitrated to form dinitrotoluene (DNT) using concentrated waste acid from the first stage.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1>CO.[Pd]>[ClH:1].[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([N:3]([CH3:2])[C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[CH:19][CH:20]=2)=[O:14])=[CH:6][CH:7]=1
Reactant: CN(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccc(Nc2ccncc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C(=O)c1ccc(N)cc1)c1ccc(Nc2ccncc2)cc1
Reaction time: 16 h

Procedure:
To a solution of amide 3 (3.46 g, 8.99 mmol) in MeOH (˜40 mL) was added a spatula tipful of 10% Pd/C, and the resulting suspension hydrogenated at 40 psi for 16 h. After this time, the reaction mixture was filtered through a pad of Celite, and solvent removed under reduced pressure. The residue was reprecipated from MeOH-EtOAc to give amine 4 as an amorphous cream solid (0.25 g, 15% from 1); mp 235-238° C. (powder -tar), 245-249° C. (gas evolved); 1H NMR: 13.85 (v br s, 1H, pyridine-N+—H), 10.75 (s, 1H, ArNHAr), 8.28 (d, J=7.23 Hz, 2H, ArH), 7.25 (s, 4H, ArH), 7.16 (d, J=8.44 Hz, 2H, ArH), 7.07 (d, J=7.03 Hz, 2H, ArH), 6.73 (d, J=7.79 Hz, 2H, ArH), 3.36 (s, ArC(O)N(CH3)Ar) [ArN+H3 not visible]; HRMS (EI) calc. for C19H18N4O m/z 318.1481, found 318.1481.
Reaction SMILES: C[O-].[Na+:3].[Cl:4][C:5]1[CH:6]=[C:7]([CH3:27])[C:8]([OH:26])=[C:9]([C:11](=[N:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:10]=1>CO>[Cl:4][C:5]1[CH:6]=[C:7]([CH3:27])[C:8]([OH:26])=[C:9]([C:11](=[N:19][CH2:20][CH2:21][CH2:22][C:23]([O-:25])=[O:24])[C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH:10]=1.[Na+:3]
Reactant: Cc1cc(Cl)cc(C(=NCCCC(=O)O)c2ccc(Cl)cc2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Cl)cc(C(=NCCCC(=O)[O-])c2ccc(Cl)cc2)c1O

Procedure:
A solution of sodium methoxide (11.68 ml; 0.748 N, 0.0087 mol) is added to a solution of the acid product of Example 4 (3.2 g; 0.0087 mol) in methanol (200 ml). The mixture is evaporated to dryness in vacuo at 30° C., 150 ml of diethyl ether are added and the mixture is evaporated to dryness again. The residue is taken up in diethyl ether and filtered off. The yellow solid is dried in a vacuum desiccator in the presence of P2O5.
Reaction SMILES: C([S:4][CH2:5][C:6]([N:8]1[CH2:15][C@@H:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])(=O)C.N>>[SH:4][CH2:5][C:6]([N:8]1[CH2:15][C@@H:14]([O:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7]
Reactant: COc1ccc(O[C@H]2C[C@@H](C(=O)O)N(C(=O)CSC(C)=O)C2)cc1
Agent: N
Product: COc1ccc(O[C@H]2C[C@@H](C(=O)O)N(C(=O)CS)C2)cc1

Procedure:
Hydrolysis of 1-[2-(acetylthio)-1-oxoethyl]-cis-4-(4-methoxyphenoxy)-L-proline with an aqueous ammonia solution according to the procedure of Example 2 yields 1-(2-mercapto-1-oxoethyl)-cis-4-(4-methoxyphenoxy)-L-proline.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5](/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]([NH:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH2:21][CH2:20]2)=[O:15])=[CH:4][C:3]=1[O:34][CH3:35].C(N(CC)CC)C.CN(C)C=O.[C:48](Cl)(=[O:50])[CH3:49]>C(Cl)Cl.O>[C:48]([O:1][C:2]1[C:3]([O:34][CH3:35])=[CH:4][C:5](/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]([NH:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)[CH2:21][CH2:20]2)=[O:15])=[CH:6][C:7]=1[O:8][CH3:9])(=[O:50])[CH3:49]
Reactant: CC(=O)Cl
Reactant: COc1cc(/C=C/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)cc(OC)c1O
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COc1cc(/C=C/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)cc(OC)c1OC(C)=O
Reaction time: 1 h
Yield: 62 %

Procedure:
To a mixture of 1-[2-{5-(4-hydroxy-3,5-dimethoxyphenyl)-(2E,4E)-2,4-pentadienoylamino}ethyl]-4-(3-indolyl)piperidine (2.0 g), triethylamine (2.9 ml) and dry N,N-dimethylformamide (20 ml) was added slowly a solution of acetylchloride (0.5 g) in methylene chloride (1.0 ml) at 0° to 5° C. After 1 hour, the reaction mixture was poured into water (200 ml) and stirred for 1 hour. The resulting precipitate was collected, washed with water and air-dried at ambient temperature. The precipitate was subjected to column chromatography on silica gel (60 g) and eluted with a mixture of chloroform and methanol (20:1 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give pale yellow crystals of 1-[2-{5-(4-acetoxy-3,5-dimethoxyphenyl)-(2E,4E)-2,4-pentadienoylamino}ethyl]-4-(3-indolyl)piperidine (1.35 g).
Reaction SMILES: C1(NC2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C.N([O-])=O.[Na+].[OH-].[Na+].[NH2+]([O-])(=O)C(N)=S.[N:30]([N:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=O>O.CO>[C:33]1([N:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[NH2:30])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=NN(c1ccccc1)c1ccccc1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: NN(c1ccccc1)c1ccccc1

Procedure:
Into a 500 ml four-neck flask were added 16.9 g (100 mmol) of diphenylamine, 15.1 g (251 mmol) of acetic acid, and 207 g of methanol and the whole was dissolved under stirring. Thereto was added 13.8 g (200 mmol) of sodium nitrite dissolved in 57 g of water, followed by stirring at 15 to 20° C. for 3 hours. After the disappearance of diphenylamine was confirmed by high-performance liquid chromatography, 26.1 g (653 mmol) of sodium hydroxide dissolved in 119 g of water and 259 g (240 mmol) of thiourea dioxide were added, followed by stirring at 38 to 43° C. for 3 hours. After the disappearance of N-nitrosodiphenylamine was confirmed by high-performance liquid chromatography, methanol was removed by distillation under reduced pressure, followed by extraction with 120 g of toluene to obtain a toluene solution of 1,1-diphenylhydrazine. The compositional ratio excluding toluene determined by high-performance liquid chromatography was 88.9% of 1,1-diphenylhydrazine and 10.2% of diphenylamine.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@H:21]([C@@:39]([OH:51])([CH2:47][C:48]([O-])=[O:49])[C:40]([O:42]C(C)(C)C)=[O:41])/[CH:22]=[CH:23]/[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[Cl-].[NH4+].CC[N:56]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:22]=[CH:23]/[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C@:39]([CH2:47][C:48](=[O:49])[NH2:56])([OH:51])[C:40]([OH:42])=[O:41])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CC(=O)[O-])C(=O)OC(C)(C)C)C(=O)OC)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CC(N)=O)C(=O)O)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
No. 5317776, 1-tert-butyl (S)-2-{(E)-(S)-1-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-10-oxo-heptadec-2-enyl}-2-hydroxy-succinate (40.6 mg, 56.9 nmol) was dissolved in DMF (1.0 mL), and ammonium chloride (9.13 mg, 170.6 nmol), WSC (16.4 mg, 85.3 nmol), HOBt (11.5 mg, 85.3 nmol), N,N-diisopropylethylamine (59.4 mL, 341.2 nmol) were added. The mixture was stirred at room temperature for 20 hours. To the reaction solution was added water. The mixture was extracted with ethyl acetate, washed with 1 M hydrochloric acid, an aqueous solution of sodium bicarbonate, and a saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[C:9]1([C:3]2[N:4]=[C:5]([NH2:8])[N:6]=[N:7][C:2]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C1CCNCC1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(N2CCCCC2)c(-c2ccccc2)n1
Yield: 8.8 %

Procedure:
5-Phenyl-6-(piperidin-1-yl)-1,2,4-triazin-3-amine (18 mg, 18%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.21 g, 0.80 mmol) and piperidine (0.14 g, 1.60 mmol) according to the general procedure of Example 2.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][O:12][C:13](=[O:25])[CH2:14][C@H:15]([OH:24])[C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17].[CH2:26](Br)[CH:27]=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OCC)(=O)C>C1COCC1.C(Cl)Cl>[CH3:11][O:12][C:13](=[O:25])[C@@H:14]([C@H:15]([OH:24])[C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])[CH2:26]/[CH:27]=[CH:28]/[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)C[C@H](O)C(=O)N1CCOCC1
Reactant: BrCC=Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)[C@H](C/C=C/c1ccccc1)[C@H](O)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Lithium hexamethyldisilazide (1M in THF, 14.5 ml, 14.5 mmol) was added to a solution of (S)-3-Hydroxy-4-morpholin-4-yl-4-oxo-butyric acid methyl ester (1.5 g, 6.9 mmol) in dry THF (15 ml) at −78° C. under N2 and stirred for 30 min. Cinnamyl bromide (1.6 g, 7.32 mmol) was then added, the reaction mixture stirred at −78° C. for 2 hrs, warmed up to room temperature and stirred overnight at room temperature. The reaction was quenched with saturated ammonium chloride solution, adjusted the pH to 6 with 1N HCl and extracted with ethyl acetate. Combined ethyl acetate extracts were dried over MgSO4 and concentrated under reduced pressure to give pale brown solid. Column chromatography on silica eluting with a mixture of ethyl acetate and methylene chloride gave the title compound as pale, yellow solid (1.15 g).
Reaction SMILES: P([O-])([O-])([O-])=O.[O:6]=[C:7]1[CH2:12][CH2:11][CH:10]2[CH:8]1[CH:9]2[C:13]([O:15]CC)=[O:14]>CCCCCC>[O:6]=[C:7]1[CH2:12][CH2:11][C@H:10]2[C@@H:8]1[C@@H:9]2[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)C1C2CCC(=O)C21
Agent: O=P([O-])([O-])[O-]
Solvent: CCCCCC
Product: O=C(O)[C@@H]1[C@H]2CCC(=O)[C@H]21
Temperature: 40 °C

Procedure:
As the present enzyme, each of the various commercial enzymes shown in Table 1 was added in an amount shown in Table 2 to 1 ml of 100 mM phosphate buffer (pH 7.0) and dissolved therein. 10 mg of racemic ethyl (1SR,5RS,6SR)-2-oxobicyclo[3.1.0]hexane-6-carboxylate was dissolved in 1 ml n-hexane, then added to the enzyme solution, and heated to 40° C. and the mixture was stirred. After the time shown as the reaction time in Table 2 elapsed, an aliquot of the reaction solution was removed and analyzed by HPLC [column: Sumichiral OA-5000, 4.6 mmφ×15 cm (Shumika Bunseki Center)], and the optical purity and reaction yield of the formed 2-oxobicyclo [3.1.0]hexane-6-carboxylic acid were determined. (−)-(1R,5S,6R)-2-oxobicyclo [3.1.0]hexane6-carboxylic acid was obtained in excess. The results are shown in Table 2.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[C:32]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)#[N:33].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:38]3[CH:39]=[C:34]([CH:35]=[CH:36][CH:37]=3)[C:32]#[N:33])[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1cccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)c1
Yield: 20 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 3-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (20%).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][OH:22])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28]>N1C=CC=CC=1.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][O:22][C:27]([N:26]([CH3:30])[CH3:25])=[O:28])=[O:11])=[CH:23][CH:24]=1)([O-:3])=[O:2]
Reactant: CC(=O)S[C@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)S[C@H]1C[C@@H](COC(=O)N(C)C)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 20 h

Procedure:
(2S,4S)-1-(p-Nitrobenzyloxycarbonyl)-2-hydroxymethyl-4-acetylthiopyrrolidine (78 mg) was dissolved in 1 ml of dry pyridine, and 135 mg of 4-N,N-dimethylaminopyridine and 119 mg of dimethylaminocarbonyl chloride were added successively thereto, followed by stirring at 90° to 100° C. for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed successively with water, dilute hydrochloric acid, water, a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and distilled to obtain (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-dimethylaminocarbonyloxymethyl-4-acetylthiopyrrolidine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:28]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][C:36]1=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1COCC1.C([BH3-])#N.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][CH:36]4[CH2:37][CH2:38][CH2:39][CH2:40][CH:35]4[CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1CCCCC1Cc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC4CCCCC4Cc4ccccc4)cc3)cc2)CC1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
1-[4′-(4-Amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.200 g, 0.55 mmol) and 2-benzylcyclohexanone (0.156 g, 0.83 mmol) were combined in toluene and stirred at 110° C. for 1 hour. After cooling to room temperature, THF was added, followed by sodium cyanoborohydride (0.086 g, 1.37 mmol), and the reaction was stirred at room temperature for 2 hours. The mixture was adsorbed onto silica gel and purified by silica gel chromatography to give the title compound.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:24]/[C:23](=[N:25]\[C:26](=[O:34])[C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)/[N:22]([C@@H:35]4[CH2:40][CH2:39][C@H:38]([C:41](O)=[O:42])[CH2:37][CH2:36]4)[C:21]=3[CH:44]=2)[CH2:12][CH2:11]1)=O)(C)(C)C.S(Cl)(Cl)=O.[CH:49]([NH2:52])([CH3:51])[CH3:50].Cl>C1COCC1>[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[NH:24]/[C:23](=[N:25]\[C:26](=[O:34])[C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)/[N:22]([C@H:35]4[CH2:36][CH2:37][C@@H:38]([C:41](=[O:42])[NH:52][CH:49]([CH3:51])[CH3:50])[CH2:39][CH2:40]4)[C:21]=3[CH:44]=2)[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(Cc2ccc3[nH]/c(=N\C(=O)c4ccc(F)cc4)n([C@H]4CC[C@@H](C(=O)O)CC4)c3c2)CC1
Reactant: CC(C)N
Agent: Cl
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCC(CN)CC4)cc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
A suspension of cis-4-((E)-6-((4-((tert-butoxycarbonylamino)methyl)piperidin-1-yl)methyl)-2-(4-fluorobenzoylimino)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylic acid (0.57 g, 0.94 mmol) in thionyl chloride (6.85 mL, 94 mmol) under nitrogen atmosphere was stirred for 30 minutes at RT and then concentrated to dryness. The residue was suspended in THF (9.4 mL) and cooled in an ice bath under nitrogen atmosphere. To the resulting mixture was added isopropylamine (0.804 mL, 9.38 mmol) as a solution in THF (1 mL). The ice bath was removed and the mixture was stirred for 1 hour at RT. The resulting mixture was diluted with water (10 mL) and the aqueous layer extracted with DCM (30 mL). The organic layer was dried over sodium sulfate and concentrated to dryness under high vacuum to afford a tan solid. The solid was suspended in HCl (4.0M in dioxanes) (23.45 mL, 94 mmol) and stirred for 16 hours. The mixture was concentrated, suspended in DCM and washed with aqueous NaHCO3 solution. The organic portion was collected, dried over sodium sulfate, and concentrated to dryness under high vacuum to afford a tan solid. The solid was purified by silica gel chromatography (1-10% MeOH/DCM (1% NH4OH)) to afford (E)-N-(6-((4-(aminomethyl)piperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide (0.3 g, 58.3% yield). MS m/z=549.2 [M+H]. Calc'd for C31H41FN6O2: 548.3.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:20])[N:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:28](=[O:29])[O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])[N:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc3ncccc3c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc3ncccc3c2)n1
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a cold solution (−10° C.) of 5-tert-butyl-2-quinolin-6-yl-2H-pyrazol-3-ylamine (8.00 g, 30 mmol) in 100 ml of CH2Cl2 was added pyridine (8.0 ml, 99 mmol) and DMAP (100 mg), followed by a solution of trichloroethyl chloroformate (8.9 ml, 42 mmol) in 30 ml of CH2Cl2 over a period of 20 minutes. After stirring for 1 hour, water (100 ml) was added, stirring continued for 10 more minutes and the organic layer separated. The organic layer was washed with brine, dried and the dark brown residue obtained after removal of the solvent crystallized from acetonitrile to furnish 2,2,2-trichloroethyl 3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-ylcarbamate as a white solid (8.23 g, 62% yield). 1H NMR (DMSO-d6) δ 10.15 (br s, 1H) 8.93 (m, 1H), 8.41 (d, J=8 Hz, 1H), 8.11 (m, 2H), 7.90 (dd, J=8, 2 Hz, 1H), 7.60 (dd, J=6.4, 4.2 Hz, 1H), 6.39 (s, 1H), 4.85 (s, 2H), 1.32 (s, 9H); MS (ESI) m/z: 442 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])=[CH:6][C:5]=1[F:18])([O-])=O.C(O)(=O)C>CCO.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])=[CH:6][C:5]=1[F:18]
Reactant: O=C(Nc1nccs1)c1ccc([N+](=O)[O-])c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(C(=O)Nc2nccs2)cc1F
Reaction time: 288 h

Procedure:
4-Nitro-3-fluoro-N-thiazol-2-yl-benzamide (7.5 mmol) was suspended in EtOH (abs., 60 mL) and ethyl acetate (30 mL), glacial acetic acid (5 mL) and 10% Pd/C (300 mg) was added, and the mixture was hydrogenated for 12 days under 3 bar H2. The reaction mixture was filtered and evaporated, and re-dissolved in ethyl acetate (100 mL) and NaHCO3 (sat., 60 mL). The aqueous phase was adjusted to basic pH with NaOH (1M) and the phases were separated. The organic phase was washed with brine, dried over MgSO4, filtered and evaporated.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH2:1]([C:5]1[N:6]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Br:13])=[CH:15][CH:16]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(Br)cc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
In 200 ml of N,N-dimethylacetamide (DMAC) were dissolved 31.0 g (0.166 mol) of 2-n-butyl-4-chloro-5-formylimidazole and 41.5 g (0.166 mol) of p-bromobenzyl bromide. After this solution was cooled to -10° C., 23.7 g (0.168 mol) of potassium carbonate particles which had a specific surface area of 1.5 m2 /g and in which the content of particles each having a diameter of 74 μm or smaller was 30% by weight were added to the solution over 10 minutes while holding the solution at -10 to -5° C. The resultant mixture was stirred at -10° C. for 2 hours, subsequently heated to room temperature, and then stirred for 2 hours to complete the reaction (which was conducted in an air atmosphere). Thereafter, the reaction mixture was filtered and the filtrate was cooled to 0° C. Thereto was added 320 ml of 15° C. water. The crystals thus precipitated were taken out by filtration to obtain 55.8 g of 2-n-butyl-4-chloro-1-(4-bromobenzyl)-5-formylimidazole having a purity of 99.8% (yield, 98.0%).