Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([Br:17])[CH:12]=2)=[C:6]([NH2:18])[CH:5]=1.[CH:20](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([Br:17])[CH:12]=3)[CH:20]=[N:18][C:6]=2[CH:5]=1)=[O:19]
Reactant: COC(OC)OC
Reactant: COC(=O)c1ccc(Nc2ccnc(Br)c2)c(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)ncn2-c1ccnc(Br)c1
Temperature: 60 °C

Procedure:
3-Amino-4-(2-bromo-pyridin-4-ylamino)-benzoic acid methyl ester 4 (3 g; 9.3 mmol) was dissolved in 50 ml dry THF and added trimethyl orthoformate (1.4 ml; 13.9 mmol) and p-toluenesulphonic acid (1 g), the reaction mixture was heated to 60° C. for 6 h. LCMS showed almost complete conversion and the reaction was quenched with sodium bicarbonate and extracted with EtOAc (500 ml*3). The organic layer was washed with water and brine. Finally it was dried over sodium sulphate and concentrated in vacuo to give the expected product 5. The compound was pure enough for progress into the next step as seen by NMR and HPLC.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]1[CH2:8][CH:7]2[O:9][CH:6]2[CH2:5][CH2:4]1.O.S(=O)(=O)(O)[OH:12]>CC(C)=O>[OH:9][CH:6]1[CH2:5][CH2:4][CH:3]([CH:2]=[CH2:1])[CH2:8][CH:7]1[OH:12]
Reactant: O=S(=O)(O)O
Reactant: C=CC1CCC2OC2C1
Solvent: O
Solvent: CC(C)=O
Product: C=CC1CCC(O)C(O)C1

Procedure:
Into a two-neck flask (100 ml) were fed 15.9 g (128 mmol) of 4-vinylcyclohexene-1,2-epoxide, 40 ml of water, 20 ml of acetone, and 40 μl of sulfuric acid, and the reaction mixture was refluxed at 75° C. for 4 hours. After complete reaction, an object compound was extracted with each 60 ml of diethylether four times, and was washed with saturated salt solution, and then was dried with sodium sulfate. The solvent was evaporated to obtain 1,2-dihydroxy-4-vinylcyclohexane.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.Cl.[NH2:13][OH:14].O>CO>[OH:14][N:13]=[CH:7][C:6]1[CH:1]=[CH:2][C:3]2[O:11][CH2:10][O:9][C:4]=2[CH:5]=1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CO
Product: ON=Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
Piperonal(15.0 g, 0.10 mol) was dissolved in methanol(150 ml), and hydroxylamine hydrochloride(10.5 g, 0.15 mol) and water(15 ml) were added thereto. The mixture was stirred for 1 hour at room temperature, then excess water was added, and the resulting mixture was stirred for further 1 hour. The white solid thus obtained was washed with water under reduced pressure, filtered, and dried to give (hydroxyimino)-(benzo[3,4-d]1,3-dioxolan-5-yl)methane(15.7 g, Yield 95%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C:8](=[N:21][S:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])[C:9]([F:20])([F:19])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:7]=1.[CH3:29][Mg+].[Br-]>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C:8]([NH:21][S:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])([C:9]([F:20])([F:19])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:14])[CH3:13])[CH3:29])[CH:7]=1
Reactant: C[Mg+]
Reactant: CC(C)(C)S(=O)N=C(c1cc(Br)ccc1F)C(F)(F)CO[Si](C)(C)C(C)(C)C
Agent: [Br-]
Solvent: CCOCC
Product: CC(C)(C)S(=O)NC(C)(c1cc(Br)ccc1F)C(F)(F)CO[Si](C)(C)C(C)(C)C
Temperature: -35 °C

Procedure:
To a solution of N-(1-(5-bromo-2-fluorophenyl)-3-(tert-butyldimethylsilyloxy)-2,2-difluoro-propylidene)-2-methylpropane-2-sulfinamide (12 g, 24.04 mmol) in diethyl ether (120 mL) was added CH3MgBr (3M in Diethyl ether) (41 mL, 120 mmol) at −25° C. The reaction mixture was brought to 0° C. and maintained for 30 min. Reaction mixture was again cooled to −35° C. and quenched by drop wise addition of saturated ammonium chloride solution. Organic layer was separated and washed with brine and dried over anhydrous sodium sulphate. Crude compound was purified by column chromatography on silica gel with 8% ethyl acetate in Hexane to furnish title compound as a colorless liquid. Yield=8.8 g (71%). TLC (20% ethyl acetate in Hexane): Rf=0.33),
Reaction SMILES: C(OC([NH:8][C@H:9]([C:36]([O:38][CH3:39])=[O:37])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:35])[CH2:19][NH:20][C:21](=[O:34])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[C:31](=[O:32])[CH:30]=[CH:29][C:28]2=[O:33])=[CH:13][CH:12]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[O:33]=[C:28]1[CH:29]=[CH:30][C:31](=[O:32])[N:27]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:21]([NH:20][CH2:19][C:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C@@H:9]([C:36]([O:38][CH3:39])=[O:37])[NH2:8])=[CH:12][CH:13]=1)=[O:35])=[O:34]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)CNC(=O)CCCCCN2C(=O)C=CC2=O)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)Cc1ccc(NC(=O)CNC(=O)CCCCCN2C(=O)C=CC2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 122.4 %

Procedure:
To a solution of #251 (800 mg, 1.47 mmol, 1 eq.) in dichloromethane (16 mL) was added TFA (4.8 mL) at 0° C. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo. The residue was dissolved in water and filtered. The filtrate was lyophilized to afford #252 (800 mg, 97.5%) as a white solid. HPLC (Protocol Q3) [M+H+] 1445.4, retention time=0.90 min.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][N:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.Cl.[NH2:19][OH:20]>>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][N:11]1[CH2:16][CH2:15][C:14](=[N:19][OH:20])[CH2:13][CH2:12]1
Reactant: O=C1CCN(Cc2nc3ccccc3[nH]2)CC1
Reactant: NO
Agent: Cl
Product: ON=C1CCN(Cc2nc3ccccc3[nH]2)CC1

Procedure:
1-(2-Benzimidazolyl)methyl-4-piperidone oxime is prepared from 1-(2-benzimidazolyl)methyl-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[C:5]([O:9][C:10]([N:12]1[CH2:16][CH:15]([OH:17])[CH:14]([N:18]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O>O1CCCC1>[C:5]([O:9][C:10]([N:12]1[CH2:16][CH:15]([O:17][CH3:3])[CH:14]([N:18]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CC(O)C(N(Cc2ccccc2)Cc2ccccc2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC1CN(C(=O)OC(C)(C)C)CC1N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
0.19 g (0.0047 mole) of sodium hydride (as a 60% w/w dispersion in mineral oil) and 0.89 g (0.0063 mole) of methyl iodide were added, in that order, to a solution of 1.2 g (0.0031 mole) of 1-t-butoxycarbonyl-3-dibenzylamino-4-hydroxypyrrolidine [prepared as described in Step (1) above] dissolved in 10 ml of tetrahydrofuran. The mixture was then stirred at room temperature for 5 hours. At the end of this time, water was added to the reaction mixture, which was then extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel, eluted with a 5:95 by volume mixture of ethyl acetate and toluene, to give 0.99 g of 1-t-butoxycarbonyl-3-dibenzylamino-4-methoxypyrrolidine as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc(Cl)ccc1C(=O)Cl
Temperature: 80 °C

Procedure:
To a solution of 4-chloro-2-methoxybenzoic acid (1.0 g, 5.36 mmol) in toluene (10 ml) was added thionyl chloride (2.76 ml, 37.52 mmol) at room temperature under nitrogen atmosphere. The resulting reaction mixture was heated to 80° C. for 1 h. After the completion of the reaction (TLC monitoring), the solvent was evaporated under vacuum and was carried forward as such for the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].NC(N)=[S:32].NCCNCCNCCNCCN>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][SH:32])[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: NC(N)=S
Agent: NCCNCCNCCNCCN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCS)c1CCC(=O)OCC
Yield: 81.1 %

Procedure:
To a solution of 4-[3-(6-Bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (5g, 10.60 mmol) in THF (100 mL), thiourea (0.889 g, 11.68 mmol) was added and heated to reflux overnight. According to HPLC analysis, the starting material was completely consumed. Tetraethylenepentamine (4.02 g, 2.7 mL, 21.23 mmol) was added and the reaction mixture was heated to reflux overnight. At this time, the reaction mixture was diluted with EtOAc (500 mL), washed with 3N HCl (100 mL), water brine and dried over Na2SO4. The solvent was removed in vacuo to afford an oil. FCC (2% EtOAc/Hex) provided an oil (3.65 g, yield 81%). 1H NMR (CDCl3): □ 7.09 (t, 1H), 6.75 (d, 1H), 6.69 (d, 1H), 4.18-4.08 (m, 4H), 3.99 (t, 2H), 2.95 (t, 2H), 2.64-2.46 (m, 8H), 2.13 (m, 2H), 1.67-1.39 (m, 8H), 1.27 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[N:6][N:5]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)[C:4](=[O:27])[C:3]=1[C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29].[H][H]>[Pd].CO.C(OCC)(=O)C>[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][N:5]2[C:4](=[O:27])[C:3]([C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])=[C:2]([OH:1])[C:7]([CH:8]([CH3:10])[CH3:9])=[N:6]2)=[CH:23][CH:22]=1
Reactant: CC(C)c1nn(Cc2ccccc2-c2ccc([N+](=O)[O-])cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)c1nn(Cc2ccccc2-c2ccc(N)cc2)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 45.3 %

Procedure:
To a Parr shaker flask was added N-({5-hydroxy-6-(1-methylethyl)-2-[(4′-nitro-2-biphenylyl)methyl]-3-oxo-2,3-dihydro-4-pyridazinyl}carbonyl)glycine (example 89, 65 mg, 0.139 mmol) and palladium on carbon (7.41 mg, 0.070 mmol) in Methanol (10 ml) and Ethyl acetate (2.500 ml) under a nitrogen atmosphere. The mixture was placed on a Parr shaker under 50 psi Hydrogen for 1 hour. The reaction mixture was filtered to remove the palladium on carbon followed by removal of the solvent by rotary evaporation and purification by HPLC chromatography (ODS silica, gradient 10-85% acetonitrile/water (0.1% TFA)) to afford the title compound N-{[2-[(4′-amino-2-biphenylyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (29 mg, 0.063 mmol, 45.3% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.86 (s, 1H), 10.11 (t, J=5.56 Hz, 1H), 7.19-7.36 (m, 5 H), 7.05 (d, J=7.07 Hz, 1H), 6.93 (d, J=7.33 Hz, 2H), 5.25 (s, 2H), 4.08 (d, J=5.56 Hz, 2H), 3.16 (sept, J=6.82 Hz, 1H), 1.15 (d, J=6.82 Hz, 6H). MS (ES+) m/e 437 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[NH:13][C:12]4[N:20]=[CH:21][CH:22]=[CH:23][C:11]=4[N:10]3[CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:25]N1C(=O)CCC1=O>C1COCC1>[Br:25][C:24]1[N:10]2[C:11]3[CH:23]=[CH:22][CH:21]=[N:20][C:12]=3[NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:9]2=[N:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(-c2cn3c(n2)-c2ccccc2Nc2ncccc2-3)cc1
Solvent: C1CCOC1
Product: Brc1c(-c2ccccc2)nc2n1-c1cccnc1Nc1ccccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.7 g, 1 eq.) in THF (20 mL) was added N-bromosuccinimide (0.4 g, 1 eq.). The reaction was stirred at room temperature for 1 hour, poured onto water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic extracts were combined, washed with saturated sodium bicarbonate (1×100 mL), water (1×50 mL), brine (1×50 mL) and dried over sodium sulfate. After filtration and concentration under reduced pressure 3-bromo-2-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.85 g, 97%) was obtained which was used with no further purification. 1H NMR (DMSO-d6) 400 MHz δ 8.64 (s, 1H), 8.28 (dd, JA=4.8 Hz, JB=1.6 Hz, 1H), 8.05 (dd, JA=8 Hz, JB=1.6 Hz, 1H), 8.02-7.98 (m, 1H), 7.85 (dd, JA=8 Hz, JB=1.6 Hz, 1H), 7.53-7.48 (m, J=8 Hz, 2H), 7.42-7.34 (m, 2H), 7.30-7.22 (m, 2H), 7.14-7.09 (m, 1H); LCMS: 388 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[CH3:11])=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.Cl.[CH:18]1([NH:23][NH2:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:24]=[C:10]([CH3:11])[CH:9]=2)=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1
Reactant: NNC1CCCC1
Reactant: CC(=O)CC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(-c2ccc(Br)cc2[N+](=O)[O-])n(C2CCCC2)n1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
Under a nitrogen atmosphere, to a solution of 1.0 g of 1-(4-bromo-2-nitrophenyl)butane-1,3-dione in 10 ml of acetic acid was added 501 mg of cyclopentylhydrazine hydrochloride, followed by stirring at 100° C. for 1 hour and 30 minutes. The reaction mixture was concentrated, and to the obtained residue was added ethyl acetate. The solution was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 770 mg of 5-(4-bromo-2-nitrophenyl)-1-cyclopentyl-3-methyl-1H-pyrazole.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][CH:28]([O:31][CH2:32][CH3:33])[CH2:29][NH2:30])[CH3:26]>C1C=CC=CC=1>[CH2:25]([O:27][CH:28]([O:31][CH2:32][CH3:33])[CH2:29][N:30]=[CH:12][C:11]1[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[CH3:26]
Reactant: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: CCOC(CN)OCC
Solvent: c1ccccc1
Product: CCOC(CN=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)OCC

Procedure:
73 g (0.172 mol) of 3,4-bis(benzyloxy)benzaldehyde was dissolved in 500 ml of benzene, and 25 ml (0.23 mol) of aminoacetaldehyde diethylacetal was added thereto. The mixture was stirred under reflux for 5 hours to remove the resulting water. The reaction solution was concentrated under reduced pressure to obtain a residue of 2-(N-[3,4-bis(benzyloxy)benzyliden]amino)acetaldehyde diethylacetal. This residue was dissolved in 700 ml of methanol, and 6.0 g (0.16 mol) of sodium borohydride was added thereto at room temperature. The mixture was stirred for 15 minutes. The reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, then washed with a saturated a sodium chloride aqueous solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue of 2-{N-[3,4-bis(benzyloxy)benzyl]amino}acetaldehyde diethylacetal. This residue was dissolved in 600 ml of dry tetrahydrofuran, and 39.8 g (0.21 mol) of p-toluenesulfonyl chloride and 59 ml (0.42 mol) of triethylamine were added. The mixture was stirred at room temperature for 17.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (10% ethyl acetate/hexane), whereby 70 g (yield: 70.7%) of 2-{N-(P-tolylsulfonyl)-N-[3,4-bis(benzyloxy)benzyl]amino}acetaldehyde diethyl acetal was obtained.
Reaction SMILES: [CH:1]1([OH:8])[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[OH:7][CH:4]1[CH2:5][CH2:6][CH:1]([O:8][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[CH2:2][CH2:3]1
Reactant: OC1CCC(O)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OC2CCC(O)CC2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78.4 %

Procedure:
step 1—To a solution of 1,4-cyclohexanediol (20.0 g, 172 mmol) and pyridine (100 mL) cooled to 0° C. was added dropwise over 2 h a solution of 32.0 g (168 mmol)p-toluenesulfonyl chloride in CHCl3 (100 mL). After the addition was complete the reaction mixture was stirred at RT for 17 h. The solvent was evaporated in vacuo and the residue was taken up in refluxing toluene and petroleum ether was added until the solution became cloudy. The mixture was cooled and the supernatant was decanted. The remaining solid was dissolved in DCM and vacuum filtered through a pad of SiO2. The filter cake was washed with a mixture of DCM/MeOH (95:5). The dark golden oil was dried under vacuum to afford 35.6 g (78%) of toluene-4-sulfonic acid 4-hydroxy-cyclohexyl ester (76) contaminated with a small amount of bis-tosylate: 1H NMR (CDCl3, 300 MHz): δ 7.79 (dd, 2H), 7.73 (dd, 2H), 4.64-4.48 (m, 1H), 3.75-3.69 (m, 1H), 2.45 (s, 3H), 1.95-1.83 (m, 3H), 1.70-1.26 (m, 6H).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[CH3:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]=[C:20]([NH2:28])[N:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10]>C(O)=O>[CH3:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[N:21]=[C:20]([NH:28][CH:5]=[O:7])[N:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(N)n2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(NC=O)n2)cc1
Reaction time: 1 h

Procedure:
A mixture of formic acid (7 ml) and acetic anhydride (2 ml) was stirred at 20 C for 1 h. 4-[4-(Methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidin-2-amine (0.5 g, 1.576 mmol) was then added and stirring was continued at ambient temperature for 18 h. This gave the title compound as a colourless precipitate which was collected by filtration and dried (0.32 g).
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]2[CH2:18][NH:17][CH2:16][CH:15]2[N:19]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([F:32])[CH:23]=2)[CH3:20])[CH:10]=[CH:11][C:12]=1[Cl:13].C(N(CC)CC)C>C1COCC1>[Br:1][CH2:2][C:3]([N:17]1[CH2:16][CH:15]([N:19]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[C:24]([F:32])[CH:23]=2)[CH3:20])[CH:14]([C:9]2[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([Cl:6])[CH:8]=2)[CH2:18]1)=[O:4]
Reactant: O=C(Cl)CBr
Reactant: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CNCC1c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(C(=O)CBr)CC1c1ccc(Cl)c(Cl)c1
Yield: 70 %

Procedure:
To a stirred solution of bromo-acetyl chloride (0.146 ml, 1.75 mmol) in THF (15 ml) at RT was added over 1 hour a solution of [(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-(3-fluoro-4-trifluoromethyl-benzyl)-methyl-amine (Intermediate VIII-1, 0.70 g, 1.66 mmol) and triethyl amine (0.25 ml, 1.83 mmol) in THF (10 mL). The reaction was stirred over night, quenched by addition of an aqueous solution of NaHCO3, and the product extracted with EtOAC. Purification by flash chromatography (SiO2, EtOAc/Hx 1:1) yielded 0.63 g (70%) of the title compound as a white solid. ES-MS m/e: 542.6 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14](Br)=[C:13]([CH3:18])[CH:12]=2)=[CH:5][C:4]=1[N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+].[S:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1>O.COCCOC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([C:35]3[CH:36]=[CH:37][S:33][CH:34]=3)=[C:13]([CH3:18])[CH:12]=2)=[CH:5][C:4]=1[N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1
Reactant: COc1ccc(NC(=O)c2ccc(Br)c(C)c2)cc1N1CCN(C)CC1
Reactant: OB(O)c1ccsc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(NC(=O)c2ccc(-c3ccsc3)c(C)c2)cc1N1CCN(C)CC1
Yield: 68.3 %

Procedure:
N-(4Methoxy-3-(4-methyl-1-piperazinyl)phenyl)-4-bromo-3-methylbenzamide (0.35 g, 0.84 mmol), sodium carbonate (89 mg, 0.84 mmol), tetrakis (triphenylphosphine)palladium(0) (49 mg, 0.05 equiv), 3-thiophenyl boronic acid (115 mg, 0.84 mmol) in water (18 ml) and DME (18 ml) were heated at reflux under argon for 18 h. The solution was partitioned between saturated aqueous potassium carbonate solution (50 ml) and chloroform (50 ml), the organic extracts dried (sodium sulphate), filtered and evaporated to dryness under reduced pressure. The resulting oil was purified by column chromatography (silica, chloroform/methanol 5-30%) to afford the tide compound as an oil (242 mg, 63%) which was crystallised as an oxalate salt from methanol chloroform.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>C1COCC1>[Si:14]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
To a solution of 4-aminophenol (11 g, 100 mmol) and imidazole (10 g, 150 mmol) in THF (250 mL) was added tert-butyldimethylsilyl chloride (18 g, 120 mmol) and the reaction was stirred at room temperature for 18 h. The reaction mixture was poured into water and extracted with diethyl ether. The combined organic layers were dried over Na2SO4, filtered, concentrated and the residue was purified by column chromatography to afford the desired product (15 g, 67%): ESI MS m/z 224 [C12H21NOSi+H]+.
Reaction SMILES: [ClH:1].ClC1C=CC([NH:9][NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]3[N:19]=[N:18][N:17]([CH3:20])[C:16]=3[CH:21]=2)=CC=1.C(O)C.[OH-].[Na+].[OH:27][C@H:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:29]([OH:31])=[O:30]>O>[OH:27][C@H:28]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:29]([OH:31])=[O:30].[Cl:1][C:32]1[CH:37]=[CH:36][C:35]([CH:11]([NH:10][NH2:9])[C:12]2[CH:13]=[CH:14][C:15]3[N:19]=[N:18][N:17]([CH3:20])[C:16]=3[CH:21]=2)=[CH:34][CH:33]=1
Reactant: Cl
Reactant: Cn1nnc2ccc(CNNc3ccc(Cl)cc3)cc21
Agent: O=C(O)[C@H](O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1nnc2ccc(C(NN)c3ccc(Cl)cc3)cc21
Temperature: 14 °C
Reaction time: 0.17 h
Yield: 163.7 %

Procedure:
To a mixture of 200 g of intermediate 2-a and 479 ml of ethanol at 23° C. was added a solution of 23.94 g of sodium hydroxide in 180 ml of water. After stirring for 10 min. there were added 50.2 g of (-)-(R)α-hydroxybenzeneacetic acid. The whole was stirred for 30 min. at 60° C. and the product was crystallized by adding some product crystals obtained in a previous low-scale set-up. Then the whole was stirred for 2 hours at 50° C. and overnight at room temperature. The reaction mixture was cooled (temp.14° C.) and stirred for 1 hour. The product was filtered off, washed with ethanol and dried in vacuo, yielding 118.8 g (87%) of (±)-6-[(4-chlorophenyl)-hydrazinomethyl]-1-methyl-1H-benzotriazole (R)-α-hydroxybenzeneacetate (1:1) monohydrate (interm. 3-a); diastereomeric excess: 92.6%.