Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:11]N1C(=O)CCC1=O.CO>CN(C=O)C>[Br:11][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CO
Product: Clc1ncnc2[nH]cc(Br)c12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (4-1) (1.53 g, 10.0 mmol) in DMF (20 mL) was added N-bromosuccinimide (1.78 g, 10.0 mmol) in DMF (10 mL) dropwise at 0° C. The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 1 h. Methanol (25 mL) was added, and the reaction mixture was stirred for an additional 1 h. The solvent was evaporated and the residue was crystallized from methanol to give the title compound as white solid.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][C@@H:8]([S:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][N:6]1[S:30]([C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=1)(=[O:32])=[O:31])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O.CCOC(C)=O>[CH:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:41]=[CH:42][C:33]=1[S:30]([N:6]1[CH2:7][C@H:8]([S:10][C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9][C@H:5]1[CH2:4][NH2:1])(=[O:32])=[O:31]
Reactant: [N-]=[N+]=NC[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: NC[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Yield: 97.7 %

Procedure:
1.7 g (2.9 mmol) (2S,4R)-2-Azidomethyl-1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine were treated with 2.3 g (8.8 mmol, 3 eq) of triphenyl phosphine in 12 ml THF and 0.5 ml H2O for 2 days at RT. The solution was diluted with EtOAc, extracted with H2O and aqueous saturated NaHCO3 solution, washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography on silica gel with CH2Cl2/MeOH 95:5 yielded 1.6 g (99%) (2S,4R)-C-[1-(naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidin-2-yl]-methylamine as white foam, MS: 565 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22](Cl)=[N:21][CH:20]=[N:19][C:18]=3[N:17]([CH:25]3[CH2:34][CH2:33][C:28]4([O:32][CH2:31][CH2:30][O:29]4)[CH2:27][CH2:26]3)[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:36].C(OCC)(=O)C.[Cl-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:36])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([CH:25]3[CH2:34][CH2:33][C:28]4([O:32][CH2:31][CH2:30][O:29]4)[CH2:27][CH2:26]3)[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: Clc1ncnc2c1c(-c1ccc(OCc3ccccc3)cc1)cn2C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1ncnc2c1c(-c1ccc(OCc3ccccc3)cc1)cn2C1CCC2(CC1)OCCO2
Temperature: 120 °C
Yield: 81 %

Procedure:
A mixture of 5-[4-(benzyloxy)phenyl]-4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidine (1.925 g, 4.01 mmol) and concentrated ammonium hydroxide (50 ml) in dioxane (50 mL) was heated at 120° C. in a pressure vessel for 20 hours. The reaction mixture was allowed to cool to room temperature. Ethyl acetate (300 mL) and saturated sodium chloride aqueous solution (300 mL) were added. The layers were partitioned and the aqueous layer was extracted with ethyl acetate (700 mL). The organic layers were combined, washed with water, dried over magnesium sulfate, and the solvent removed under reduced pressure. The compound was purified by flash chromatography on silica using 5% methanol in dichloromethane to give 1.457 g (81%) of 5-[4-(benzyloxy)phenyl]-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine. 1H NMR (DMSO-d6, 400 MHz) δ 8.13(s, 1H), 7.49-7.31(m, 8H), 7.121-7.100(d, 2H, J=8 Hz), 6.02(br s, 2H), 5.149(s, 2H), 4.681-4.620 (m, 1H), 3.94-3.88(m, 4H), 2.12-2.03(m, 2H), 1.93-1.90(m, 2H), 1.82-1.71(m, 4H); Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 6.924 min.
Reaction SMILES: S(Cl)([Cl:3])=O.[ClH:5].Cl.[NH2:7][CH:8]([CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([NH2:23])=[N:18][CH:17]=[CH:16]2)[C:9]([OH:11])=[O:10].[CH3:24]O>>[ClH:3].[ClH:5].[CH3:24][O:10][C:9](=[O:11])[CH:8]([NH2:7])[CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([NH2:23])=[N:18][CH:17]=[CH:16]2
Reactant: CO
Reactant: Nc1nccc2cc(CC(N)C(=O)O)ccc12
Reactant: O=S(Cl)Cl
Agent: Cl
Product: COC(=O)C(N)Cc1ccc2c(N)nccc2c1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
1.1 mL of thionyl chloride was added to a cooled solution (ice bath) of 65 mg of amino acid 1i in 4 mL of methanol. After stirring at 50° C. for 3 hours the mixture was concentrated under reduced pressure to give 66 mg of methyl ester 1j. The crude product was used without further purification. 1H-NMR 200 MHz (CD3OD) δ: 3.36-3.59 (2H, m), 3.81 (3H, s), 4.53 (1H, t, J=7 Hz), 7.23 (1H, d, J=7 Hz), 7.60 (1H, d, J=7 Hz), 7.73 (1H, dd, J=9 Hz and J=2 Hz) 7.87 (1H, d, J=2 Hz), 8.47 (1H, d, J=9 Hz),
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=O)/[C:7](=[CH:12]/N(C)C)/[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[CH3:19][C:20]1[C:25]([NH:26][C:27]([NH2:29])=[NH:28])=[CH:24][CH:23]=[C:22]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)[N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CCO>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:29]=[C:27]([NH:26][C:25]4[C:20]([CH3:19])=[N:21][C:22]([NH:30][CH:31]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]5)=[CH:23][CH:24]=4)[N:28]=[CH:12][C:7]=3[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: Cc1nc(NC2CCN(C)CC2)ccc1NC(=N)N
Reactant: CN(C)/C=C1\CC(=O)Nc2cc(Cl)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1nc(NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)-c1ccc(Cl)cc1NC(=O)C2
Temperature: 70 °C
Reaction time: 48 h
Yield: 93 %

Procedure:
To (4E)-8-chloro-4-[(dimethylamino)methylene]-3,4-dihydro-1H-1-benzazepine-2,5-dione (3.25 g. 12.3 mmol) in EtOH (50 mL) were added N-{2-methyl-6-[(1-methylpiperidin-4-yl)amino]pyridin-3-yl}guanidine *xHCl (6.5 g, 14 mmol) and potassium carbonate (13.6 g, 98.3 mmol). The reaction mixture was allowed to stir for 2 days at 70° C. and then allowed to cool to room temperature. The solids were filtered and the filtrate was concentrated to give a thick red oil. Water was added to the residue and the aqueous solution was extracted with EtOAc. The organic solutions were combined, dried, filtered and concentrated to give 9-chloro-2-({2-methyl-6-[(1-methylpiperidin-4-yl)amino]pyridin-3-yl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (5.3 g, 93%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[C:16]([CH3:19])=[C:15]([CH3:20])[C:14]1=[O:21].[H][H]>C(OCC)(=O)C.[Pt]=O>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:11])[CH3:12])=[CH:4][C:3]=1[N:13]1[C:17](=[O:18])[C@H:16]([CH3:19])[C@H:15]([CH3:20])[C:14]1=[O:21]
Reactant: CC1=C(C)C(=O)N(c2cc(OC(C)C)c(Cl)cc2F)C1=O
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(N2C(=O)[C@@H](C)[C@@H](C)C2=O)c(F)cc1Cl
Reaction time: 5 h

Procedure:
A mixture of 9.4 g (0.03 mol) of N-(2-fluoro-4-chloro-5-isopropoxyphenyl)-2,3-dimethylmaleic acid imide and 500 mg of platinum oxide (PtO2) in 100 ml of ethyl acetate is hydrogenated with hydrogen at room temperature under normal pressure. After about 5 hours, when the absorption of hydrogen has ceased, the catalyst is filtered off and the filtrate is concentrated to dryness. 7.9 g (85% of the theoretical yield) of an almost colourless oil which is uniform in a thin-layer chromatogram are obtained as residue and crystallised from isopropyl ether. The cis-N-(2-fluoro-4-chloro-5-isopropoxyphenyl)-2,3-dimethyl-succinimide so obtained has a melting point of 101°-102°.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:22][N:23](C)[C:24](=O)[O:25][C:26]([CH3:29])(C)C)[CH:9]=2)=[CH:6][CH:5]=[C:4]([CH3:32])[N:3]=1.[C:33]([O:36]CC)(=[O:35])[CH3:34].Cl.C[OH:41]>>[C:26]([OH:25])(=[O:41])/[CH:29]=[CH:34]/[C:33]([OH:36])=[O:35].[F:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)(=[O:14])=[O:15])[CH:11]=[C:10]([CH2:22][NH:23][CH3:24])[CH:9]=2)=[CH:6][CH:5]=[C:4]([CH3:32])[N:3]=1
Reactant: CO
Reactant: Cc1ccc(-c2cc(CN(C)C(=O)OC(C)(C)C)cn2S(=O)(=O)c2cccnc2)c(F)n1
Reactant: CCOC(C)=O
Agent: Cl
Product: CNCc1cc(-c2ccc(C)nc2F)n(S(=O)(=O)c2cccnc2)c1
Product: O=C(O)/C=C/C(=O)O
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
tert-Butyl {[5-(2-fluoro-6-methylpyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (400 mg) was dissolved in methanol (20 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added, and the mixture was stirred at 60° C. for 10 min. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from a mixed solution of fumaric acid (101 mg), methanol (3 mL) and ethyl acetate (12 mL) to give the title compound as colorless crystals (yield 264 mg, 64%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH2:19]([CH2:21][NH2:22])[OH:20]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:22][CH2:21][CH2:19][OH:20])=[O:14]
Reactant: NCCO
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NCCO)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-(2-Fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethyl)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.39 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.50 mmol of ethanolamine. LC/MS [3.42 min; 402 (M+1)]
Reaction SMILES: [Br-].[CH3:2][N+:3]([CH3:10])([CH3:9])[CH2:4][CH2:5][CH2:6][NH:7][CH3:8].[I:11][CH2:12][CH2:13][CH2:14][Cl:15]>C(#N)C>[I-:11].[Cl:15][CH2:14][CH2:13][CH2:12][N:7]([CH2:6][CH2:5][CH2:4][N+:3]([CH3:10])([CH3:9])[CH3:2])[CH3:8]
Reactant: CNCCC[N+](C)(C)C
Reactant: ClCCCI
Agent: [Br-]
Solvent: CC#N
Product: CN(CCCCl)CCC[N+](C)(C)C
Product: [I-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 216.2 mg. (1 mmole) of N,N,N-trimethyl-[3-(methylamino)]-1-propanaminium bromide in 1.5 ml. of acetonitrile is added a solution of 205 mg. (1 mmole) of 3-iodo-1-chloropropane in 0.5 ml. of acetonitrile. The mixture is stirred at room temperature for 2.0 hours and the insoluble N,N,N-trimethyl-[3-(methylamino)]-1-propanaminium bromide hydrobromide is removed by filtration. The filtrate is evaporated and the solid residue obtained is extracted with methylene chloride. The methylene chloride extract is evaporated to give the oily product which is recrystallized from isopropanol-ether to afford 90 mg. (52%) of product; m.p. 93° (dec.); NMR δ: 2.2 (3H, S, --NCH3); 3.46 (9H, S, --N+Me3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[NH2:33][C@@H:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][C@@H:35]1[OH:43]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:33][C@@H:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][C@@H:35]1[OH:43])=[O:31]
Reactant: O=C(Br)CBr
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)c(OC)c32)cc1OC
Product: COc1ccc(CC2c3c(cc(OC)c(OC)c3OC)CCN2CC(=O)N[C@@H]2c3ccccc3C[C@@H]2O)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with (1R,2S)-1-amino-2-indanol
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[Cl:28][C:29]1[CH:30]=[C:31]([N:37]([CH:39]2[CH2:41][CH2:40]2)[CH3:38])[C:32]([NH2:36])=[CH:33][C:34]=1[F:35]>CCCCCCC.C(OCC)(=O)C>[Cl:28][C:29]1[C:34]([F:35])=[CH:33][C:32]([NH:36][C:11](=[O:12])[C:6]2[C:5]([O:4][C:3]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=3[Cl:1])=[CH:10][CH:9]=[N:8][CH:7]=2)=[C:31]([N:37]([CH:39]2[CH2:40][CH2:41]2)[CH3:38])[CH:30]=1
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Reactant: CN(c1cc(Cl)c(F)cc1N)C1CC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CN(c1cc(Cl)c(F)cc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl)C1CC1

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 4-chloro-N2-cyclopropyl-5-fluoro-N2-methyl-benzene-1,2-diamine and using a gradient of n-heptane:ethyl acetate (100:0 to 30:70) for the chromatographic purification. Colorless solid (70%). MS (ESI): m/z=446.083 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16]C(OC(C)(C)C)=O)=[CH:11][C:10]=1[P:24]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[O:25])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([O:3][P:4]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][C:10]=1[P:24]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])=[O:25])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)c1ccc(CNC(=O)OC(C)(C)C)cc1P(=O)(OCC)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOP(=O)(OCC)c1ccc(CN)cc1P(=O)(OCC)OCC
Reaction time: 3 h

Procedure:
[4-(tert-Butoxycarbonylamino-methyl)-2-(diethoxy-phosphoryl)-phenyl]-phosphonic acid diethyl ester (2.0 g, 4.2 mmol) was dissolved in TFA/CH2Cl2 (25%, 20 mL) and stirred for 3 h. The mixture was evaporated under a stream of N2, dissolved in EtOAc and washed with sat'd NaHCO3. The organic layer was dried over magnesium sulfate, and concentrated to a brown oil (0.9 g, 2.3 mmol) which was used without purification in the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11](CC([O-])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:18].[Na+].O.C1(C)C=CC=CC=1>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([OH:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])C[C@H]1CC[C@H](c2ccc(Br)cc2)CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: O[C@H]1CC[C@H](c2ccc(Br)cc2)CC1

Procedure:
The mixture (208.5 g) of the compound (X1) and the compound (X11) obtained in Step E was dissolved in ethanol (460 ml), and a solution of NaOH (28 g) and water (30 ml) was added and the mixture was heated, followed by reflux for one hour. After cooling, toluene (500 ml) and water (500 ml) were added, and the resulting toluene layer was washed with 2 N--NaOH aqueous solution and further with water till the layer became neutral. After removing toluene by concentration of the layer, the resulting raw crystals were recrystallized from ethyl acetate (130 ml) to obtain trans-4-(p-bromophenyl)-cyclohexanol (X11) (130 g) having a melting point of 109.5°~111.0° C.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3](Cl)=[O:4].[CH3:16][NH:17][C@@H:18]1[C@@H:24]([OH:25])[C@H:23]([O:26][C@@H:27]2[O:35][C@H:34]([CH2:36][OH:37])[C@H:32]([OH:33])[C@H:30]([OH:31])[C@H:28]2[OH:29])[C@@H:22]([CH2:38][OH:39])[O:21][CH:19]1[OH:20].C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[Br:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([C:19]1([O:21][C@H:22]([CH2:38][OH:39])[C@@H:23]([O:26][C@@H:27]2[O:35][C@H:34]([CH2:36][OH:37])[C@H:32]([OH:33])[C@H:30]([OH:31])[C@H:28]2[OH:29])[C@H:24]([OH:25])[C@H:18]1[NH:17][CH3:16])[OH:20])=[O:4]
Reactant: CCCCCCCCCCC(Br)C(=O)Cl
Reactant: CN[C@H]1C(O)O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CCCCCCCCCCC(Br)C(=O)C1(O)O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1NC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Alpha-bromolauroyl chloride (2.4 g) was added drop-wise to a 30% aqueous solution of N-methyl-lactosamine (3.5 g) at zero degrees centigrade. The pH of the solution was maintained above 9 by the addition of a saturated aqueous sodium carbonate solution. The reaction was stirred overnight at room temperature. It was then heated up to 36° C. for an additional hour. The final product was obtained by extraction two times with n-butanol. The organic layer was dried with sodium sulfate and then rotevaporated under vacuum. The final product was taken for NMR analysis. The result confirmed that the solid material is the expected product. The yield of reaction was 80%.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([C:7]([OH:9])=[O:8])=[CH:3][CH:2]=1.[Si](Cl)(Cl)(Cl)Cl.Cl.[CH:17]1C=CC=CC=1>>[CH3:17][C:5]1[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=1[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: c1ccccc1
Agent: Cl
Agent: Cl[Si](Cl)(Cl)Cl
Product: Cc1ccccc1C(=O)O
Temperature: 25 °C

Procedure:
To a reaction vessel was added 5 grams (0.037 moles) of para toluic acid suspended in about 100 ml of benzene. Then, 3.14 grams (0.0185 moles) of silicon tetrachloride were added and the reaction mixture stirred at room temperature. A small amount of HCl gas evolved during this stirring. Even though a small amount of material remained undissolved, the reaction mixture was distilled at 80° C. and atmospheric pressure. The overhead condensate contained only benzene and silicon tetrachloride. The pot residue was further heated until p-toluic acid sublimed. Analysis of the liquid remaining in the pot showed it to contain what is probably a silicon chloro toluate.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[OH-].[Na+]>ClCCl>[CH3:1][S:2]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: C1CNCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CS(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of methanesulfonyl chloride (1.85 ml, 24 mmol) and piperazine (2.06 g, 24 mmol) in dichloromethane (60 ml) was stirred at room temperature for 14 hours. The mixture was basified with aqueous sodium hydroxide and filtered. The filtrate was washed with water, dried (magnesium sulfate) and evaporated down to give the title sulfonamide. 1HNMR(CDCl3): 1.75 (br s, 1H), 2.78 (s, 3H), 2.97 (t, 4H, J =5.1 Hz) and 3.19 (t, 4H, J =7.5 Hz). LRMS (m/e, % abundance) 165[(M+H)+, 7), 164(M+, 5), 85(100) and 56(68).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:16]3[S:20][C:19]([NH2:21])=[N:18][C:17]=3[CH3:22])[CH:9]=[CH:10][C:11]=2[S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>>[Cl:23][CH2:24][C:25]([NH:21][C:19]1[S:20][C:16]([C:8]2[CH:9]=[CH:10][C:11]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:7]=2)=[C:17]([CH3:22])[N:18]=1)=[O:26]
Reactant: O=C(Cl)CCl
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(-n2ccnc2)c1
Product: Cc1nc(NC(=O)CCl)sc1-c1ccc(S(C)(=O)=O)c(-n2ccnc2)c1
Temperature: 25 °C

Procedure:
5-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 148) (0.537 g, 1.60 mmol) and chloroacetyl chloride (5 ml) are heated together for 2 hours. The reaction mixture is allowed to cool to room temperature and the solid filtered and washed with saturated sodium bicarbonate solution (3×100 ml) and water (2×50 ml) to yield the titled compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[F:27][C:28]([F:44])([F:43])[C:29](=[O:42])[CH2:30][C:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH3:41])([CH3:33])[CH3:32]>C(Cl)(Cl)(Cl)Cl>[F:27][C:28]([F:43])([F:44])[C:29](=[O:42])[CH2:30][C:31]([C:34]1[CH:39]=[C:38]([Br:1])[CH:37]=[CH:36][C:35]=1[O:40][CH3:41])([CH3:33])[CH3:32]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccccc1C(C)(C)CC(=O)C(F)(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)cc1C(C)(C)CC(=O)C(F)(F)F

Procedure:
A mixture of N-bromosuccinimide (6.84 g, 38.42 mmol), benzoylperoxide (catalytic amount) and 1,1,1-trifluoro-4-(2-methoxyphenyl)-4-methylpentan-2-one (10.0 g, 38.42 mmol) in carbon tetrachloride (120 mL) and was refluxed for two days. After cooling, the solution was washed with water (60 mL) and 1.0M NaOH (60 mL), dried over sodium sulfate (Na2SO4), and concentrated in vacuo giving 1,1,1-trifluoro-4-(5-bromo-2-methoxyphenyl)-4-methylpentan-2-one and the starting material as 3:1 mixture (13.0 g).
Reaction SMILES: C1(C)C=CC(S([Cl:10])(=O)=O)=CC=1.[NH2:12][C:13]1[C:14]([NH:18][C:19]([NH:21][C:22]2[C:26]([CH3:27])=[CH:25][S:24][C:23]=2[Cl:28])=S)=[CH:15][S:16][CH:17]=1.[OH-].[Na+].Cl>C1COCC1.O.C(OCC)(=O)C>[ClH:10].[Cl:28][C:23]1[S:24][CH:25]=[C:26]([CH3:27])[C:22]=1[NH:21][C:19]1[NH:18][C:14]2=[CH:15][S:16][CH:17]=[C:13]2[N:12]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1csc(Cl)c1NC(=S)Nc1cscc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1csc(Cl)c1Nc1nc2cscc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 108.4 mg of p-toluenesulfonyl chloride in 5 ml of anhydrous THF was added dropwise to a mixture prepared from a solution of 157 mg of N-(4-amino-3-thienyl)-N′-(2-chloro-4-methylthienyl)thiourea in 15 ml of THF and a solution of 51.08 mg of NaOH in 2 ml of water. The resulting dark solution was stirred at room temperature for 2 hours, the solvent was distilled off and the residue was admixed with water. After extraction with ethyl acetate, the organic phase was washed with water and dried over sodium sulfate. After the solvent had been distilled off, the residue was purified by column chromatography on silica gel using a mixture of 20 parts by volume of ethyl acetate, 10 parts by volume of n-heptane, 3 parts by volume of glacial acetic acid as the eluent, which was then distilled off under reduced pressure. A viscous amorphous product was obtained and was dissolved in ethyl acetate and made strongly acidic using hydrogen chloride gas-saturated diethyl ether. The crystallization of the amorphous hydrochloric acid salt which separated out was brought about by scratching. M.p.: >300° C.