Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:11]=[C:12]([CH:20]=[CH:21][N:22]=1)[CH2:13][C:14](=O)[CH2:15][C:16](=O)C)#[N:9].Cl.[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1>C(O)C>[C:8]([C:10]1[CH:11]=[C:12]([C:13]2[N:31]([C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)[N:32]=[C:15]([CH3:16])[CH:14]=2)[CH:20]=[CH:21][N:22]=1)#[N:9]
Reactant: NNc1ccc(F)cc1
Reactant: CC(=O)CC(=O)Cc1ccnc(C#N)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(-c2ccnc(C#N)c2)n(-c2ccc(F)cc2)n1
Yield: 52.8 %

Procedure:
Triethylamine (4.6 mL, 0.033 mol) was added dropwise to a mixture of 1-(2-cyanoisonicotinyl)-1,3-butanedione (6.0 g, 0.032 mol) and 4-fluorophenylhydrazine hydrochloride (5.37 g, 0.033 mol) in 100 mL of ethanol. The reaction mixture was heated at reflux overnight (about eighteen hours). The solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by recrystallization from ether/hexane to give 4.7 g (53% yield) of product as a yellow solid: mp: 94-95° C.; Anal. Calc'd. for C16H11FN4: C, 69.06; H, 3.98; N, 20.13. Found: C, 68.52; H, 3.89; N, 19.73.
Reaction SMILES: IC.[C:3](=O)([O-])[O-].[Cs+].[Cs+].[Cl:9][C:10]1[CH:19]=[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]>CN(C=O)C>[Cl:9][C:10]1[CH:19]=[C:18]([N:20]([CH3:3])[S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)cc1Cl
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(C)S(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
78 μL of iodomethane and 447 mg of Cesium Carbonate were added to 300 mg of methyl 2-chloro-4-(methylsulfonamido)benzoate in 3 mL of DMF and stirred at room temperature for 16 hours. The reaction mixture was extracted in Ethyl Acetate twice with saturated bicarbonate and once with brine, dried over Magnesium Sulfate, filtered and concentrated to give crude methyl 2-chloro-4-(N-methylmethylsulfonamido)benzoate. 295 mg of methyl 2-chloro-4-(N-methylmethylsulfonamido)benzoate was hydrolyzed via Procedure M to yield 249 mg of 2-chloro-4-(N-methylmethylsulfonamido)benzoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18](=[O:41])[C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=3[NH:26][C:27]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]4[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=4)[CH2:31][CH2:30]3)=[O:28])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:42](Cl)(=[O:44])[CH3:43]>>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18](=[O:41])[C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:42](=[O:44])[CH3:43])=[CH:21][C:20]=3[NH:26][C:27]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]4[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=4)[CH2:31][CH2:30]3)=[O:28])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(NC(=O)c3ccc(N)cc3NC(=O)C3CCN(c4ccncc4)CC3)cc21
Product: CC(=O)Nc1ccc(C(=O)Nc2ccc3ccn(C(=O)OC(C)(C)C)c3c2)c(NC(=O)C2CCN(c3ccncc3)CC2)c1
Yield: 77 %

Procedure:
Using the procedure described in Example 24, Part E, N-(1-tert-butoxycarbonyl-6-indolyl)-2-[1-(4-pyridyl)-piperidin-4 ylcarbonylamino]-4-aminobenzamide (0.18 mmol) was reacted with acetyl chloride to yield 83 mg (77%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][Si](C)(C)C.[C:10]1([S:16](N)(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.N.OS(O)(=O)=O>C(OCC)(=O)C.O>[CH3:1][Si:2]([CH3:9])([CH3:8])[NH:3][S:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:18])=[O:17]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: NS(=O)(=O)c1ccccc1
Agent: N
Agent: O=C1NS(=O)(=O)c2ccccc21
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: C[Si](C)(C)NS(=O)(=O)c1ccccc1
Reaction time: 0.42 h

Procedure:
15.6 ml of hexamethyldisilazane (75 mmoles) were added to a refluxing suspension of 15.72 g (0.1 mole) of benzenesulfonamide and 18 mg (0.1 mmole) of saccharin in 45 ml of ethyl acetate under nitrogen and the nitrogen was passed through water to determine the amount of ammonia evolved. By titrating with 1 N H2SO4, it was found that the calculated amount of ammonia was set free in 25 minutes and the residue of N-trimethylsilylbenzensulfonamide obtained after evaporating the volatile materials in vacuo melted at 62°-63° C.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[C:15]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:15][O:1][C:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(C(C)(C)O)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)c1ccc(C(C)(C)OC)cc1
Yield: 153.1 %

Procedure:
To a solution of methyl 4-(1-hydroxy-1-methylethyl)benzoate (340 mg, 1.75 mmol) in methanol (20 mL) was added p-toluenesulfonic acid (70 mg, 0.37 mmol). The mixture was refluxed for 48 h, concentrated in vacuo, and the residue chromatographed (silica gel, 10% ethyl acetate/90%hexanes to 30% ethyl acetate/70% hexanes) to give 118 mg (32%) of the title compound.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1)[NH2:3].[C:13]([CH2:21][C:22](=O)[C:23]([F:26])([F:25])[F:24])(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[C:14]1([C:13]2[N:2]([C:4]3[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][OH:12])=[CH:8][CH:9]=3)[N:3]=[C:22]([C:23]([F:24])([F:25])[F:26])[CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1
Reactant: NNc1ccc(CCO)cc1
Agent: Cl
Solvent: CCO
Product: OCCc1ccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)cc1
Yield: 56.2 %

Procedure:
A mixture of 2-(4-hydrazinophenyl)ethanol hydrochloride (J. Med. Chem., 1999, 42, 2504, 202 mg, 1.07 mmol) and benzoyl-1,1,1-trifluoroacetone (278 mg, 1.28 mmol) in ethanol (13 mL) was heated under reflux overnight. After removal of the solvent, the resulting residue was partitioned between dichloromethane and water. Organic phase was washed with brine and dried (Na2SO4). After removal of the solvent, the crude product was purified by TLC with hexane/ethyl acetate (1:1) to afford 200 mg (56%) of the title compound as yellow solids: MS (ESI) m/z 333 [M+H]+, 1H-NMR (CDCl3) δ 7.36-7.20 (9H, m), 6.74 (1H, s), 3.86 (2H, br.s), 2.89 (2H, t, J=6.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=2[N+:23]([O-])=O)(=[O:15])=[O:14])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.O.NN>[Ni].CO>[NH2:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[S:13]([NH:12][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2)(=[O:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)c3cccnc23)c([N+](=O)[O-])c1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)c3cccnc23)c(N)c1
Yield: 27.4 %

Procedure:
In a similar fashion using route 6 general procedure 14, N-(5-chloroquinolin-8-yl)-4-methyl-2-nitrobenzenesulfonamide (Intermediate 155) (160 mg, 0.42 mmol), Raney nickel (32 mg, 20% wt), hydrazine hydrate (63 mg, 1.27 mmol) and MeOH (10 ml) gave the title compound (40 mg, 27%) after purification by column chromatography with DCM as the eluent followed by recrystallisation from DCM/n-pentane.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[Br:8].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Br:8][C:7]1[CH:6]=[N:5][N:4]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3](=[O:9])[C:2]=1[Br:1]
Reactant: O=c1[nH]ncc(Br)c1Br
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1ncc(Br)c(Br)c1=O
Yield: 110.8 %

Procedure:
4,5-Dibromopyridazin-3(2H)-one (5.0 g, 19.7 mmol) in N,N-dimethylformamide (50 mL) was stirred with ethyl bromoacetate (3.28 g, 29.5 mmol) and potassium carbonate (4.08 g, 29.5 mmol) at 80° C. for 1 hour and 40 minutes. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride three times and with saturated aqueous sodium chloride once, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (7.42 g, 100% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[N:20][CH:21]=2)[CH:13]=[CH:12][N:11]=1.Cl.Cl.[CH2:24]([N:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][C:34]=2[C:42]([F:45])([F:44])[F:43])[CH2:28][CH2:27]1)[CH3:25]>>[CH2:24]([N:26]1[CH2:27][CH2:28][N:29]([CH2:32][C:33]2[CH:41]=[CH:40][C:36]([C:37]([NH:6][C:5]3[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([NH:9][C:10]4[CH:15]=[C:14]([C:16]5[CH:17]=[N:18][CH:19]=[N:20][CH:21]=5)[CH:13]=[CH:12][N:11]=4)[CH:4]=3)=[O:38])=[CH:35][C:34]=2[C:42]([F:45])([F:43])[F:44])[CH2:30][CH2:31]1)[CH3:25]
Reactant: CCN1CCN(Cc2ccc(C(=O)Cl)cc2C(F)(F)F)CC1
Reactant: Cc1ccc(N)cc1Nc1cc(-c2cncnc2)ccn1
Agent: Cl
Product: CCN1CCN(Cc2ccc(C(=O)Nc3ccc(C)c(Nc4cc(-c5cncnc5)ccn4)c3)cc2C(F)(F)F)CC1

Procedure:
This compound was prepared in the same manner as in Example 1, except that 4-methyl-3-[4-(5-pyrimidinyl)pyridin-2-ylamino]aniline (Reference Example 22) and 4-(4-ethylpiperazin-1-ylmethyl)-3-trifluoromethylbenzoyl chloride dihydrochloride (Reference Example 5) were used, and that the resulting crude crystals were washed with ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][C:10](=[O:13])[CH:9]([C:14]([O:16][CH3:17])=[O:15])[S:8][C:7]=2[CH:18]=1.[C:19]1([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33]Cl)[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(C(C)=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:12][CH2:11][C:10](=[O:13])[C:9]([CH2:33][CH2:32][CH2:31][N:28]3[CH2:29][CH2:30][N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)([C:14]([O:16][CH3:17])=[O:15])[S:8][C:7]=2[CH:18]=1
Reactant: ClCCCN1CCN(c2ccccc2)CC1
Reactant: COC(=O)C1Sc2cc(OC)ccc2OCC1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)C1(CCCN2CCN(c3ccccc3)CC2)Sc2cc(OC)ccc2OCC1=O

Procedure:
A mixture of methyl 7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate (10 g), 3-(4-phenylpiperazin-1yl)propyl chloride (9.8 g), anhydrous potassium carbonate (6.2 g), potassium iodide (3.0 g) and methyl ethyl ketone (150 ml) was refluxed under heating for 25 hours. After cooling, inorganic matter was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and dried. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=3:1) to give methyl 7-methoxy-3-oxo-4-[3-(4-phenylpiperazine-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate. Recrystallization from methanol yielded white crystals, melting point 110°-112° C., yield 2.1 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[O:13][C:14]([CH2:17][N:18]([CH3:20])[CH3:19])=[CH:15][CH:16]=1)=[O:6].[CH3:24][S:25][C:26](SC)=[N:27][C:28]#[N:29]>C(O)C>[C:28]([N:27]=[C:26]([S:25][CH3:24])[NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[O:13][C:14]([CH2:17][N:18]([CH3:19])[CH3:20])=[CH:15][CH:16]=1)=[O:6])#[N:29]
Reactant: CSC(=NC#N)SC
Reactant: CN(C)Cc1ccc(CSCCNC(=O)c2cccc(N)c2)o1
Solvent: CCO
Product: CSC(=NC#N)Nc1cccc(C(=O)NCCSCc2ccc(CN(C)C)o2)c1
Yield: 25.1 %

Procedure:
A mixture of 20 g of 3-amino-N-[2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyl]benzamide and 8.8 g of dimethyl cyanodithioiminocarbonate in 150 ml of absolute ethanol is heated with reflux for 30 hours, then it is concentrated under reduced pressure and the crude oil thus obtained is poured on a silica column and eluted with a mixture chloroform:methanol 4:1. The fairly pure fractions are collected and the solvent is evaporated under reduced pressure. Thus, 6.5 g of 3-(3-cyano-2-methylisothioureido)-N-[2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyl]benzamide are obtained as an oil which is mixed with 10 ml of a 33% solution of methylamine in ethanol. The mixture thus obtained is left to stand 48 hours at room temperature, then the excess of methylamine is eliminated under reduced pressure. Thus 5 g of an oil are obtained which is submitted to a flash chromatography on silica by eluting with a mixture chloroform:ethanol 1:1. The pure fractions are collected and evaporated, the residue is crystallized twice from isopropanol. Thus, 2.5 g of 3-(2-cyano-3-methylguanidino)-N-[2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyl]benzamide are obtained; m.p. 140°-142° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:6][C@H:5]2[O:7][C@H:8]([CH:10]([OH:13])[CH2:11][CH3:12])[CH2:9][C@H:4]2[O:3]1.N1C=CN=C1.[C:20]([Si:24](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:23])([CH3:22])[CH3:21].CCOC(C)=O>CN(C=O)C>[CH3:14][C:2]1([CH3:1])[O:6][C@H:5]2[O:7][C@H:8]([CH:10]([O:13][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:11][CH3:12])[CH2:9][C@H:4]2[O:3]1
Reactant: CCC(O)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Yield: 81.7 %

Procedure:
To a solution of 1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propan-1-ol (compound 1e, 2.02 g, 10 mmol) in DMF (30 mL) was added imidazole (6.5 g, 100 mmol) and tert-butylchlorodiphenylsilane (8.22 g, 30 mmol) with stirring. After being stirred at room temperature for 2 hours, the resulting solution was diluted by EtOAc (200 mL), washed with water, brine and dried over Na2SO4. The organic layer was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:10 EtOAc in petroleum ether) to afford 3.6 g of 1-[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]propoxy-tert-butyl-diphenyl-silane (compound 3a).
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[NH:6][C:5]2[C:15]([CH3:25])=[CH:16][C:17]([N:19]3[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]3)=[N:18][C:4]1=2)[CH3:2].[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[C:26]([O:24][CH:21]1[CH2:22][CH2:23][N:19]([C:17]2[CH:16]=[C:15]([CH3:25])[C:5]3[NH:6][C:7](=[O:14])[C:8]4[CH:13]=[CH:12][CH:11]=[N:10][C:9]=4[N:3]([CH2:1][CH3:2])[C:4]=3[N:18]=2)[CH2:20]1)(=[O:28])[CH3:27]
Reactant: CCN1c2ncccc2C(=O)Nc2c(C)cc(N3CCC(O)C3)nc21
Reactant: CC(=O)OC(C)=O
Product: CCN1c2ncccc2C(=O)Nc2c(C)cc(N3CCC(OC(C)=O)C3)nc21

Procedure:
The title compound, m.p. 188°-189.5° C., was synthesized from 5,11-dihydro-11-ethyl-2-(3- hydroxypyrrolidin-1-yl)-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and acetic anhydride using procedures analogous to those described above. The product was chromatographed over silica gel with ethyl acetate/hexane, and was then crystallized from diisopropyl ether.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=O)(C)(C)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16].NC[C@@H]1CCCN1CC.C(=O)C>>[CH3:14][S:15]([N:11]1[CH2:12][CH2:13][C@@H:9]([NH2:8])[CH2:10]1)(=[O:17])=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: CS(=O)(=O)Cl
Agent: CC=O
Agent: CCN1CCC[C@H]1CN
Product: CS(=O)(=O)N1CC[C@@H](N)C1

Procedure:
By using (R)-(+)-3-(t-butoxycarbonylamino)pyrrolidine (2.0 g) and methanesulfonyl chloride (1 ml) as starting materials, the title compound (0.98 g) was obtained in the same manners as those of Reference Example 58, (1) and Reference Example 39, (2).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:15][O:16]CC)[N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]=2[C:5]([CH3:19])=[C:4]([CH3:20])[N:3]=1.ClCCl.B(Br)(Br)Br>CO>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:15][OH:16])[N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]=2[C:5]([CH3:19])=[C:4]([CH3:20])[N:3]=1
Reactant: CCOCc1nc2c(Cl)nc(C)c(C)c2n1CC(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Cc1nc(Cl)c2nc(CO)n(CC(C)C)c2c1C
Temperature: 0 °C
Yield: 68 %

Procedure:
A 500 mL round bottom flask was charged with 4-chloro-2-(ethoxymethyl)-1-isobutyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridine (10.0 g, 33.8 mmol) and dichloromethane (250 mL) under a nitrogen atmosphere. The solution was cooled to 0° C. and boron tribromide (101 mL of 1M in dichloromethane, 101 mmol) was added through an addition funnel over 30 minutes. The reaction mixture was allowed to warm to room temperature and was stirred over night. Methanol was added slowly until no more fizzing occurred, then the solvent was partially removed under reduced pressure. More methanol was added (100 mL) as well as 6N hydrochloric acid (100 mL) and the solution was heated at reflux for 1 hour. The reaction mixture was then allowed to cool to room temperature and stirred over night. The solvent was partially removed under reduced pressure until a solid precipitated, which was isolated by filtration and washed with water, then triturated with ethyl acetate and hexanes to give 6.15 g of (4-chloro-1-isobutyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-2-yl)methanol as an off-white solid.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:28]=[CH:27][C:13]([C:14]([C:16]2[CH:17]=[CH:18][C:19]([Cl:26])=[C:20]([S:22]([NH2:25])(=[O:24])=[O:23])[CH:21]=2)=[O:15])=[CH:12][CH:11]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[Cl:26][C:19]1[CH:18]=[CH:17][C:16]([C:14](=[O:15])[C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][OH:6])=[CH:28][CH:27]=2)=[CH:21][C:20]=1[S:22]([NH2:25])(=[O:24])=[O:23]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)c2ccc(OCCO)cc2)ccc1Cl
Reaction time: 1 h
Yield: 99.7 %

Procedure:
5-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzoyl}-2-chloro-benzenesulfonamide (1.84 g, 3.92 mmol) is dissolved in tetrahydrofuran (50 mL), and treated with a solution of tetrabutylammonium fluoride reagent (1 M in tetrahydrofuran, 2.2 mmol). The reaction is allowed to stir for 1 hour. The reaction is diluted with water and extracted with ether. The organic phase is separated and concentrated in vacuo affording 1.39 g (100% yield) of the title compound. 1H NMR (DMSO) δ 3.75 (t, 2H, J=4.55 Hz), 4.12 (t, 2H, J=4.80 Hz), 4.95 (s, 2H), 7.12 (d, 2H, J=8.84 Hz), 7.76-7.90 (m, 4H), 8.24 (d, 1H, J=2.02). MS (m/z): 354 (M−1).
Reaction SMILES: Cl[C:2](=[O:25])[CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][C:12]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.N1C=CC=CC=1>O1CCOCC1>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:2](=[O:25])[CH2:3][CH2:4][C:5]2[CH:14]=[CH:13][C:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)=[C:11]3[C:6]=2[CH:7]=[CH:8][CH:9]=[N:10]3)[CH2:29][CH2:28]1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc(-c2ccc(CCC(=O)Cl)c3cccnc23)cc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2ccc(CCC(=O)N3CCN(C)CC3)c3cccnc23)cc1

Procedure:
A mixture of Example 201I (300 mg, 0.85 mmol), 1-methylpiperazine (111 mg, 1.11 mmol), and pyridine (74 mg, 0.94 mmol) in dioxane (4 mL) at room temperature was stirred for 75 minutes and purified by flash column chromatography on silica gel with 90:10:0.5 dichloromethane/methanol/concentrated ammonium hydroxide to provide the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:14][C:15]([OH:17])=[O:16]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][CH2:14][C:15]([OH:17])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCl
Reactant: OCCc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)COCCc1cccc(F)c1
Temperature: 60 °C
Reaction time: 36 h
Yield: 63.2 %

Procedure:
To a solution of 2-(3-fluoro-phenyl)-ethanol (4.0 g, 28.5 mmol) in DMF (60 ml) was added a 60% dispersion of sodium hydride in oil (2.40 g, 60 mmol). The suspension was heated to 60° C. for 0.75 hours. Chloroacetic acid (4.72 g, 50 mmol) was added dropwise. After 36 hours at 60° C. the brown reaction mixture was brought to dryness under reduced pressure, dissolved in EtOAc and washed with 1M HCl, water and brine. The organic layers were dried over MgSO4, filtrated, the solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, EtOAc/heptane, 3/1) to yield [2-(3-fluoro-phenyl)-ethoxy]-acetic acid (2.02 g, 18 mmol; 36%) as colorless liquid. MS (m/e): 197.4 [M−H]−.
Reaction SMILES: O.[Cl-:2].[OH:3][C@H:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[C:7]([C:12]#[C:13]/[C:14](/[CH3:36])=[CH:15]/[CH2:16][P+:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([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:6]([CH3:37])[CH2:5]1.[H][H]>CO.OCCSCCSCCO>[Cl-:2].[OH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[C:7]([CH:12]=[CH:13][C:14]([CH3:36])=[CH:15][CH2:16][P+:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:6]([CH3:37])[CH2:5]1
Reactant: [H][H]
Reactant: CC1=C(C#C/C(C)=C/C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)C(C)(C)C[C@H](O)C1
Agent: OCCSCCSCCO
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CC(C=CC1=C(C)CC(O)CC1(C)C)=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A suspension of 46.6 g of water-moist Raney-nickel and 518 mg of 1,2-bis(2-hydroxyethylthio)ethane in 1 l of methanol was pre-hydrogenated at 30° C. under normal pressure in a sulphonation flask provided with a gasification stirrer. Subsequently, a solution of 320 g of (4R,2E)-[5-(4-hydroxy-2,6,6-trimethyl-1-cyclohexen-1-yl)-3-methyl-2-penten-4-ynyl]triphenylphosphonium chloride in 2.1 l of methanol was added thereto and the mixture was hydrogenated at 40° C. and 1.1 bar of hydrogen. 15.6 l of hydrogen were taken up within 5 hours. The catalyst was filtered off and the filtrate was concentrated to a weight of 575 g. The product was crystallized by slowly pouring in 9.6 l of ethyl acetate. The suspension was stirred at room temperature for 2 hours and filtered. The crystals were washed with a small amount of methanol/ethyl acetate and dried at 60° C./0.01 mbar, there being obtained 272.2 g (84.7%) of [5-(4-hydroxy-2,6,6-trimethyl-1-cyclohexen-1-yl)-3-methyl-2,4-pentadienyl]triphenylphosphonium chloride (containing 97% of the (4R,2E,4Z)-isomer and 2% of the (4R,2Z,4Z)-isomer in accordance with HPLC) of melting point 211°-212° C. and [α]D20 =-26.2° (c=1, chloroform).