Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([NH:11][CH3:12])[C@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([CH2:42][C:43](OCC)=[O:44])[N:21]=[C:22]([C:23]3[CH:28]=[CH:27][C:26]([NH:29][S:30]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=4[Cl:40])(=[O:32])=[O:31])=[C:25]([F:41])[CH:24]=3)[C:15]=12>>[OH:10][C@@H:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C@@H:2]([N:11]([CH3:12])[C:43](=[O:44])[CH2:42][N:20]1[C:16]2=[N:17][CH:18]=[N:19][C:14]([NH2:13])=[C:15]2[C:22]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][S:30]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=3[Cl:40])(=[O:32])=[O:31])=[C:25]([F:41])[CH:24]=2)=[N:21]1)[CH3:1]
Reactant: CN[C@H](C)[C@H](O)c1ccccc1
Reactant: CCOC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21
Product: C[C@@H]([C@@H](O)c1ccccc1)N(C)C(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21
Yield: 15 %

Procedure:
Using a procedure similar to that above, (+)-ephedrine hydrochloride (0.061 g, 0.302 mmol) and ethyl 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetate (0.054 g, 0.10 mmol) were combined. Purification by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 11.4-11.9 min) afforded N1-[(1S,2S)-2-hydroxy-1-methyl-2-phenylethyl]-N1-methyl-2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetamide as an off-white solid (0.010 g, 0.015 mmol): RP-HPLC (25 to 100% CH3CN in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) Rt 9.36 min; MS: (M−H)− 656.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:4][CH:3]=1.[K+].[N+:17]([O-])([OH:19])=[O:18]>C(OCC)C>[Br:1][C:2]1[C:11]2[C:6](=[C:7]([N+:17]([O-:19])=[O:18])[CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=S(=O)([O-])c1ccc(Br)c2ccccc12
Agent: [K+]
Solvent: CCOCC
Product: O=[N+]([O-])c1cccc2c(Br)ccc(S(=O)(=O)O)c12
Temperature: -15 °C
Reaction time: 1.5 h

Procedure:
Potassium 4-bromo-naphthalene-1-sulfonate (1.38 g, 4.24 mmol) was added portionwise over 20 minutes to 90% nitric acid (2 mL), which was cooled in a methanol/ice bath to approximately −15° C. After 1.5 hours, the mixture was placed in a refrigerator for 20 hours. Diethyl ether (20 mL) was added and the precipitated solid was filtered, washed with ether (100 mL) and isopropanol (20 mL), and dried under a stream of nitrogen to give the title compound as an approximately 4:1 mixture of the 5- and 8-nitro isomers (1.25 g).
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]1[CH2:39][CH:38]([OH:40])[CH:37]([OH:41])[CH2:36]1>>[F:25][C:18]1[CH:19]=[C:20]([CH3:24])[C:21]([F:23])=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]2[CH2:39][CH:38]([OH:40])[CH:37]([OH:41])[CH2:36]2)=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)cc1F
Reactant: NCCCCN1CC(O)C(O)C1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN3CC(O)C(O)C3)c2C(N)=O)cc1F

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,5-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 1-(4-amino-butyl)-pyrrolidine-3,4-diol by the procedure analogous to Example 8. HPLC ret. time: minutes. 1H NMR (400 MHz, CD3OD) δ 7.20 (dd, 1H, J=6.0, 9.2 Hz), 7.04 (dd, 1H, J=6.8, 9.6 Hz), 5.45 (s, 2H), 3.63 (t, 4H, J=5.6 Hz), 3.28 (m), 2.74 (m, 4H), 2.68 (m, 2H), 2.25 (d, 3H, J=2.0 Hz), 1.56 (m, 4H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:42][C:39]3[C:40]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:41][C:36]([O:35][C:34]([F:45])([F:44])[F:33])=[CH:37][CH:38]=3)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Cl)cc3)CC2)c1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(Cl)cc4)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 598.2 (M+H)+.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([SH:10])[CH2:6][CH2:5]1)[CH2:2][CH3:3].[OH-:11].[Na+].ClCCl.[CH2:16]([OH:18])C>>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([S:10][O:11][CH2:16][O:18][S:10][CH:7]2[CH2:8][CH2:9][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC1CCC(S)CC1
Reactant: CCO
Reactant: [OH-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCC1CCC(SOCOSC2CCC(CCC)CC2)CC1
Yield: 103.9 %

Procedure:
Synthesis was conducted as in Synthesis Example 2 using 38.1 g (0.22 mol) of the 4-n-propylcyclohexylmercaptan prepared above, 9.4 g (0.23 mol) of sodium hydroxide, 77 g of ethanol and 14.3 g (0.17 mol) of dichloromethane. There was obtained 41.2 g of the desired formaldehyde bis(4-n-propylcyclohexylthio)acetal.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1([OH:21])C2C(=CC=CC=2)C=CC=1>>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][C:8]=1[OH:21]
Reactant: c1ccc2ccccc2c1
Reactant: Oc1cccc2ccccc12
Product: Oc1ccc2ccccc2c1

Procedure:
A further selective hydroxylation reaction was carried out with the sol-gel-embedded CYP BM-3 on the substrate naphthalene. 77% of the precursor were hydroxylated. The main product obtained was 1-naphthol (85%), and 2-naphthol was obtained as by-product (15%) (detected by gas chromatography).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[CH:16]=1)[CH3:11].C(NC(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[CH2:10]([O:12][C:13](=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:7]([C:5]2[O:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])[CH:16]=1)[CH3:11]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCOC(=O)Cc1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
To a solution of 5-bromo-2-furoic acid (1.14 g) and 3-aminophenylacetic acid ethyl ester (1.06 g) in anhydrous DMF (15 ml) was added diisopropylamine (2.1 ml) and then O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (2.25 g). The solution was stirred at room temperature for 16 hours then partitioned between ethyl acetate and water. The organic layer was separated, washed twice with 1M hydrochloric acid, water, aqueous sodium carbonate solution, brine, dried over sodium sulphate and evaporated in vacuo. Compound 11 (1.8 g) was obtained following silica gel column chromatography of the residue in 2:1 ethyl acetate:petroleum ether.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][F:16])[CH:8]=[CH:7][N:6]=1)=[O:4].Cl>CO.O.[Pt]=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][F:16])[CH2:8][CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)c1cc(CCCCCF)ccn1
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)C1CC(CCCCCF)CCN1
Reaction time: 8 h

Procedure:
To a mixture of 4-(5-fluoro-pentyl)-pyridine-2-carboxylic acid methyl ester (254 mg, 1.13 mmol) in MeOH (5 mL) and water (5 mL) were added conc. HCl (0.28 mL, 3.39 mmol, 3 equiv) and platinum oxide (130 mg). The mixture was purged and charged with hydrogen (1 atm) and stirred overnight. The platinum oxide was removed by filtration and the filtrate was evaporated to give 4-(5-fluoro-pentyl)-piperidine-2-carboxylic acid 2-methyl ester.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]([C:14]1([OH:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:6]1[CH:7]=[CH:8][C:9]([O:12]C)=[CH:10][CH:11]=1)[CH3:3].OC1C=C2C(NC=C2CCN)=CC=1.C1C([C@@H](O)CN)=CC(O)=C(O)C=1>>[CH3:3][N:2]([CH3:1])[CH2:4][CH:5]([C:14]1([OH:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: COc1ccc(C(CN(C)C)C2(O)CCCCC2)cc1
Agent: NCCc1c[nH]c2ccc(O)cc12
Agent: NC[C@H](O)c1ccc(O)c(O)c1
Product: CN(C)CC(c1ccc(O)cc1)C1(O)CCCCC1

Procedure:
It is reported that venlafaxine of formula (II), 1-[2-dimethylamino-1-(4-methoxylphenyl)ethyl]cyclohexanol, is a reuptake inhibitor of 5-hydroxytryptamine (5-HT) and norepinephrine (NA), and is widely used for inhibiting reuptake of 5-hydroxytryptamine (5-HT) and norepinephrine (NA) and treating or adjuvantly treating central nervous system diseases such as depression. Venlafaxine is metabolized in liver to form a strongly active metabolite of formula (III), 1-[2-dimethylamino-1-(4-hydroxyphenyl)ethyl]cyclohexanol, a weakly active metabolite of formula (IV), 1-[2-dimethylamino-1-(4-methoxyphenyl)ethyl]cyclohexanol, and a metabolite of formula (V), 1-[2-methylamino-1-(4-hydroxyphenyl)ethyl]cyclohexanol, in which the metabolite (III) and venlafaxine have the same therapeutic effects (see U.S. Pat. No. 4,535,186A, US20040176468A1, US20040147601A1, US20030191347A1). Moreover, the direct uptake of the metabolite (III) for treating central nervous system diseases, especially, depression, has the advantages of using a single active compound, facilitates the adjustment of dosage and therapeutic effects, alleviates side-effects, and reduces the risk of interaction with other drugs (see U.S. Pat. No. 6,673,838B2). However, because of the presence of more hydroxyl groups, the metabolite (III) has increased hydrophilicity, thus decreasing absorption rate via oral or transdermal routes of administration and possibly increasing pre-system side effects of unabsorbed drugs. In order to overcome the above defects of the metabolite (III), a series of derivatives represented by formula (VI) were synthesized. These compounds of formula (VI), which are prodrugs of the metabolite (III), were shown to have metabolized in vivo to produce the metabolite (III), thereby exhibiting therapeutic effects (see Chinese Patent No. CN1955159A, CN1706813A). Chinese Patent No. CN1955159A discloses a compound of formula (I), 4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenyl 4-methylbenzoate hydrochloride, and a method for preparing the same. The compound of formula (I), as described in CN1955159A, is a white crystalline solid with a melting point of 203.2° C.-206.5° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C([O:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)=[CH2:13])C>C1COCC1.O.CCOC(C)=O>[Br:1][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)=[O:13]
Reactant: C=C(OCC)c1ccc(F)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CBr)c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-Bromosuccinimide (200 mg, 1 mmol) was added to a mixture of 2-(1-ethoxyvinyl)-5-fluoropyridine (200 mg, 1 mmol) in THF (6 mL) and water (2 mL). The reaction mixture was stirred at room temperature for 15 min., diluted with EtOAc and washed with brine. The combined organic layer was dried with MgSO4, filtered and concentrated to give 2-bromo-1-(5-fluoropyridin-2-yl)ethanone as a clear oil, which was used in the next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:18][CH:19]1[CH2:22][NH:21][CH2:20]1>CN(C=O)C.CCOC(C)=O>[F:18][CH:19]1[CH2:22][N:21]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=2)[CH2:20]1
Reactant: FC1CNC1
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(N2CC(F)C2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 98 %

Procedure:
To a solution of 6-chloro-2-methyl-3-nitropyridine (0.5 g, 2.9 mmol) in DMF (5 mL) was added Cs2CO3 (1.9 g, 5.8 mmol) followed 3-fluoroazetidine (0.64 g, 5.8 mmol) and the reaction mixture was heated for 2 h at 80° C. The reaction mixture was then diluted with EtOAc and the organic layer was washed with saturated aqueous sodium bicarbonate solution. The organic layer was then dried over sodium sulphate and concentrated. The crude material obtained was purified by column chromatography (silica: 100-200 mesh, MeOH:DCM 2-3%) to afford the title compound (0.6 g, 92%). LCMS (ES+) 211.95 (M+H)+, RT 2.33 minutes (method 1).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1.I[CH2:15][CH2:16][CH3:17].CN(C)C=O>O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]([N:10]([CH2:15][CH2:16][CH3:17])[C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)Nc1cccc(Br)c1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCN(C(C)=O)c1cccc(Br)c1

Procedure:
In a manner similar to that of Example (27b), by reaction of 820 mg (20.5 mmol, 1.1 eq) of 60% sodium hydride, 4.0 g (18.7 mmol, 1 eq) of N-(3-bromophenyl)acetamide (prepared in Example 27a) and 2.20 mL (22.4 mmol, 1.2 eq) of 1-iodopropane in 15 ml of tetrahydrofuran in the presence of 1.5 ml of dimethylformamide, N-(3-bromophenyl)-N-propylacetamide is obtained in oil form and is used in the following reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].F[C:17]1[CH:22]=[C:21]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])[C:20]([F:36])=[CH:19][C:18]=1[N+:37]([O-:39])=[O:38].Cl>CN(C)C=O>[F:36][C:20]1[C:21]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:32])([F:31])[F:33])[N:25]([CH3:34])[C:24]2=[O:35])=[CH:22][C:17]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[C:18]([N+:37]([O-:39])=[O:38])[CH:19]=1
Reactant: COc1cccc(O)c1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2[N+](=O)[O-])c1
Temperature: 65 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
The mixture of 3.53 g of 3-methoxyphenol, 5.12 g of anhydrous potassium carbonate, 10 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzen (described above, produced in Intermediate Production Example 4) and 40 ml of N,N-dimethylformamide was stirred at 60 to 70° C. for 2 hours. The reaction mixture was poured into the mixture of aqueous hydrochloric acid solution and ice water and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 4.17 g of 5-fluoro-2-(3-methoxyphenoxy)-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[CH2:6][NH:7][C:8]1[N:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1.C(N([CH2:29][CH3:30])CC)C.Cl[C:32](Cl)([O:34][C:35](=[O:41])OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1)[CH2:6][N:7]([C:8]1[N:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1)[C:35](=[O:41])[O:34][CH2:32][C:30]1[CH:29]=[CH:16][CH:17]=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1cc(CNc2ncc(Br)cn2)cc(C(F)(F)F)c1
Reactant: CCN(CC)CC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reaction time: 0.5 h

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-amine (10 g) and triethylamine (4.18 ml) are dissolved in methylene chloride (100 mL) and thereto is added triphosgene (2.97 g) under ice-cooling. The reaction solution is stirred at the same temperature for 30 minutes and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (100 mL) and thereto are added benzyl alcohol (3.88 ml) and triethylamine (10.45 ml) at room temperature and the mixture is stirred overnight. The reaction solution is diluted with ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution and a 1N-hydrochloric acid. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=97:3→9:1) to give benzyl (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-carbamate (11.58 g). MS (m/z): 534/536 [M+H]+
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=O.CO.Cl.[NH2:17][OH:18]>O>[CH3:1][NH:2][C:3](=[O:13])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=[N:17][OH:18]
Reactant: NO
Reactant: CNC(=O)C(=O)c1ccccc1C
Agent: Cl
Solvent: O
Solvent: CO
Product: CNC(=O)C(=NO)c1ccccc1C

Procedure:
To N-methyl-2-(2-methylphenyl)-2-oxoacetamide (5.31 g, 0.03 mol), added were methanol (30 ml) and hydroxylamine hydrochloride (4.17 g, 0.06 ml), and the reaction mixture was heated under reflux for 5 hours. After completion of the reaction, water (150 ml) was added to the reaction mixture which was then extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give N-methyl-2-(2-methylphenyl)-2-hydroxyiminoacetamide in E-form (4.79 g; yield, 83.1%) and Z-form (0.50 g; yield, 8.7%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]=1[NH2:4].[Br:12][C:13]1[CH:17]=[C:16]([C:18](O)=[O:19])[N:15]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:14]=1.N1C=CC=C(C)C=1.CS(Cl)(=O)=O>CC#N>[Br:12][C:13]1[CH:17]=[C:16]([C:18]([NH:4][C:3]2[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:2]=2[CH3:1])=[O:19])[N:15]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:14]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: Cc1cccc([N+](=O)[O-])c1N
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: Cc1cccnc1
Product: Cc1cccc([N+](=O)[O-])c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
2-Methyl-6-nitroaniline (540 mg, 3.54 mmol), 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid (1 g, 3.54 mmol), CH3CN (0.3 M, 11.8 mL) and 3-picoline (0.69 mL, 7.08 mmol, 2.0 eq) were introduced to a 50 mL round flask and subjected to a reaction at room temperature. After 10 minutes, the reaction mixture thus obtained was added with methylsulfonylchloride (0.41 mL, 5.31 mmol, 1.5 eq.), subjected to a reaction at 30° C. for 24 hours, and followed by a further reaction at 40° C. for 24 hours. Upon completion of the reaction, CH3CN was removed from the reaction mixture under reduced pressure, and the residue was extracted with 1 M HCl (20 mL) and ethyl acetate (20 mL), and, then, extracted with NaHCO3 (20 mL) and ethyl acetate (20 mL), washed with brine (20 mL). The organic layer thus obtained was dried over MgSO4 and concentrated under reduced pressure. Subsequently, the residue was purified by silica gel column chromatography (MC:EA=9:1) to obtain the title compound (1.27 g, yield: 82%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]=2[C:14]=1[F:15].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([CH3:42])([CH3:41])[C:39]#[N:40])=[CH:34][CH:33]=1>C(Cl)Cl>[C:39]([C:38]([C:35]1[CH:34]=[CH:33][C:32]([CH2:31][NH:30][C:11](=[O:13])[CH2:10][N:7]2[C:6]3[C:14]([F:15])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[CH:37][CH:36]=1)([CH3:42])[CH3:41])#[N:40]
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Reactant: CC(C)(C#N)c1ccc(CN)cc1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(CNC(=O)Cn2cnc3ccc(F)c(F)c32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
(6,7-difluoro-1H-benzimidazol-1-yl)acetic acid (42 mg, 0.2 mmol) prepared according to scheme 2 is dissolved in CH2Cl2 (2 mL). Triethylamine (83 μL, 0.6 mmol) is added, followed by pivaloyl chloride (25 μL, 0.2 mmol). After 30 minutes, 2-[4-(aminomethyl)phenyl]-2-methylpropanenitrile (35 mg, 0.2 mmol) prepared according to scheme 18 is added dissolved in 1 mL of CH2Cl2. The mixture is stirred overnight at room temperature, concentrated under vacuo and purified on HPLCMS: Waters prep LCMS, 27 ml/min, Column: X-Bridge Prep C18 OBD, 30×50 mm, 5 μm particle size, Mobile phase: A=water (10 mM NH4CO3) B=MeCN, Gradient used 40% to 60% B in A, in 10 min. The fractions are combined and freeze dried to give the desired product (17 mg, 0.05 mmol, 25%). MS (ESI) (M+1) 383.3. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.65 (s, 6H) 2.30 (s, 3H) 4.29 (d, J=5.47 Hz, 2H) 5.09 (s, 2H) 7.19-7.31 (m, 3H) 7.32-7.35 (m, 1H) 7.47 (dd, J=8.98, 3.91 Hz, 1H) 8.22 (s, 1H) 8.66-8.74 (m, 1H).
Reaction SMILES: C(O)(=O)C.[CH:5]([OH:7])=O.C(OC(=O)C)(=O)C.[Cl:15][C:16]1[CH:38]=[CH:37][C:19]([C:20]([C:22]2[N:26]([CH3:27])[C:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][N:30]=3)=[CH:24][C:23]=2[CH3:36])=[O:21])=[CH:18][CH:17]=1>C1COCC1>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([C:22]2[N:26]([CH3:27])[C:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([NH:35][CH:5]=[O:7])=[CH:31][N:30]=3)=[CH:24][C:23]=2[CH3:36])=[O:21])=[CH:37][CH:38]=1
Reactant: O=CO
Reactant: Cc1cc(Cc2ccc(N)cn2)n(C)c1C(=O)c1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: Cc1cc(Cc2ccc(NC=O)cn2)n(C)c1C(=O)c1ccc(Cl)cc1
Temperature: 55 °C
Yield: 54 %

Procedure:
The mixed anhydride of formic and acetic acid was prepared by adding formic acid (1 ml, 98%) dropwise to acetic anhydride (2 ml) and heating the mixture at 55° C. for 2.5 h. This reagent (2.2 ml) was then added to a solution of N-{2-[5-(4-chlorobenzoyl)-1,4-di-methyl-1H-pyrrol-2-yl-methyl]-pyridin-5-yl}amine (0.3 g, 0.88 mmol) in THF (7 ml), and the reaction mixture was heated overnight at 60° C. The solvents were removed in vacuo and the residue was crystallized from chloroform-hexane to give N-{2-[5-(4-chloro-benzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]pyridin-5-yl}formamide (175 mg, 54%) as a solid, mp 166.6-167.7° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([NH2:32])=[CH:11][C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:13]=2[CH:31]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([NH:32][S:41]([C:38]2[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=2)(=[O:43])=[O:42])=[CH:11][C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:14]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[C:13]=2[CH:31]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)CCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccc(OC)cc1
Product: COC(=O)CCCCOc1cc2c(cc1NS(=O)(=O)c1ccc(Cl)cc1)nc(-c1ccccc1)n2-c1ccc(OC)cc1

Procedure:
5-[(5-Amino-1-(4-methoxyphenyl)-2-phenyl-1H-benzimidazol-6-yl)oxy]pentanoic acid methyl ester was reacted with 4-chlorobenzenesulfonic acid chloride according to general operating instructions 13.