Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([F:17])=[C:13]([F:16])[CH:14]=2)[C:9]([CH3:18])=[CH:8][C:7]1=[O:19].C(OCC)(=O)[C:25]([O:27]CC)=[O:26].[O-]CC.[K+]>C1C=CC=CC=1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([F:17])=[C:13]([F:16])[CH:14]=2)[C:9]([CH2:18][C:25]([OH:27])=[O:26])=[CH:8][C:7]1=[O:19]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cc(=O)n(Cc2ccc(Cl)c(Cl)c2)c2cc(F)c(F)cc12
Agent: CC[O-]
Agent: [K+]
Solvent: CCO
Solvent: c1ccccc1
Product: O=C(O)Cc1cc(=O)n(Cc2ccc(Cl)c(Cl)c2)c2cc(F)c(F)cc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
A solution of 1-(3,4-dichlorobenzyl)-6,7-difluoro-1,2-dihydro-4-methyl-2-oxoquinoline (5 g.) in benzene (15 ml.) was added with stirring at ambient temperature to a mixture of diethyl oxalate (2.3 g.), benzene (2 ml.) and a 6N-solution of potassium ethoxide in ethanol (6 ml.). The mixture was allowed to stand overnight at ambient temperature under dry nitrogen. The yellow solid was filtered off, washed with benzene (5 ml.) and dried by suction on the filter. The dried solid (5.7 g.) was mixed with 2.77 N-aqueous sodium hydroxide (21 ml.) at 0° C. and kept at 0° C. overnight. Ice (11.5 g.) and then 100 vol. hydrogen peroxide (4.04 ml.) were added to the mixture and it was again kept overnight at 0° C. A further quantity of 100 vol. hydrogen peroxide (1.7 ml.) was added and the mixture kept at 0° C. for 72 hours. The mixture was then treated with manganese dioxide (1 g.). When the effervescence had ceased the mixture was warmed to 50° C. and filtered. The filter cake was washed with warm 2.77 N-aqueous sodium hydroxide (20 ml.) and the total filtrate acidified with concentrated hydrochloric acid. The precipitate was collected and recrystallised first from a mixture (1/2 v/v) of ethyl acetate and cyclohexane, and then from ethanol to give 1-(3,4-dichlorobenzyl)-6,7-difluoro-1,2-dihydro-2-oxoquinol-4-ylacetic acid m.p. 185°-7° C. (dec.), in 10% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:21]3[CH2:22][C:23]([CH3:26])([CH3:25])[O:24][C:20]=3[CH:19]=[C:18]([C:27]([O:29]C)=[O:28])[CH:17]=2)[CH:5]=[N:6][C:7]=1[C:8]([N:10]1[CH2:13][CH:12]([F:14])[CH2:11]1)=[O:9].CO.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:21]3[CH2:22][C:23]([CH3:26])([CH3:25])[O:24][C:20]=3[CH:19]=[C:18]([C:27]([OH:29])=[O:28])[CH:17]=2)[CH:5]=[N:6][C:7]=1[C:8]([N:10]1[CH2:11][CH:12]([F:14])[CH2:13]1)=[O:9]
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)N3CC(F)C3)c(F)c2)c2c(c1)OC(C)(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Cc2c(Oc3cnc(C(=O)N4CC(F)C4)c(F)c3)cc(C(=O)O)cc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a solution of methyl 4-(5-fluoro-6-(3-fluoroazetidine-1-carbonyl)pyridin-3-yloxy)-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylate (1.520 g, 3.633 mmol), in 10 mL THF and 10 mL MeOH was added 4.25 mL of 1N aqueous NaOH. The resulting solution was stirred at room temperature for 2 hr. The solvent was removed in vacuo. Water was added, and the mixture was washed with EtOAc. The aqueous layer was acidified with 1N HCl until pH˜1, and extracted with 3×EtOAc. The combined organic layer was dried over Na2SO4 and concentrated to give a white foam (1.32 g, 90% yield), which contains ˜15% impurity. LCMS for C20H18F2N2O5 m/z 405.20 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([C:14]3[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([CH2:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1.ClCCl>O1CCOCC1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[N:18]([CH3:19])[C:17]([CH3:20])=[N:16][CH:15]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([CH2:21][CH3:22])[C:3]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:28][CH:29]=1
Reactant: CCc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCc1nc2ccc(C(=O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A mixture containing (4-chloro-2-ethyl-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanol (325 mg, 0.601 mmol, Intermediate 25: step a) and manganese dioxide (308 mg, 3.01 mmol) in dioxane (3 mL) was heated to 100° C. After 2 hours, the mixture was cooled to 23° C. Dichloromethane (20 mL) was added and the mixture was filtered through Celite®, rinsing with dichloromethane. Silica gel (5 g) was added to the filtrate and the solvent was removed by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a column of silica gel for purification. Elution with hexanes-ethyl acetate provided the title compound as an off-white solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][O:23][C:24]2[CH:33]=[N:32][C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[CH:29][CH:30]=3)[N:25]=2)[CH2:17][CH2:16]1)(C)(C)C>ClCCl>[CH3:35][O:34][C:28]1[CH:27]=[C:26]2[C:31]([N:32]=[CH:33][C:24]([O:23][CH2:22][CH2:21][N:18]3[CH2:17][CH2:16][CH:15]([NH2:14])[CH2:20][CH2:19]3)=[N:25]2)=[CH:30][CH:29]=1
Reactant: COc1ccc2ncc(OCCN3CCC(NC(=O)OC(C)(C)C)CC3)nc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ncc(OCCN3CCC(N)CC3)nc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 102.5 %

Procedure:
Trifluoroacetic acid (580 μL, 7.52 mmol, 15.0 eq) is added at 0° C. to a stirred solution of {1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester (206 mg, 0.50 mmol, 1.0 eq) in dichloromethane (20 mL). After 15 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×20 mL) and water (20 mL) and the pH is adjusted to 12 by the addition of a 1N sodium hydroxide aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford 1-[2-(7-methoxy-quinoxalin-2-yloxy)-ethyl]-piperidin-4-ylamine as an orange oil (155 mg, 99.5% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][C:27]=1[N+:28]([O-])=O)[O:12][CH:13]1[C:19](=[O:20])[NH:18][C:17]2[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=2[CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.CO.[Pt]=O>[NH2:28][C:27]1[CH:26]=[CH:25][C:11]([O:12][CH:13]2[C:19](=[O:20])[NH:18][C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[CH2:15][CH2:14]2)=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccccc2CCC1Oc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: O=[Pt]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(OC2CCc3ccccc3NC2=O)cc1OCc1ccccc1

Procedure:
A solution of 3-(3-benzyloxy-4-nitrophenoxy)-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (3.0 g, 7.4 mmol) in 50 mL EtOAc/MeOH (1:1) is hydrogenated at 1 atm over platinum oxide for 2.5 h. The catalyst is filtered and the filtrate evaporated to give the title compound which is used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Li][C:12](C)(C)[CH3:13].C(I)C>C1COCC1>[CH2:12]([C:7]1[S:6][C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[CH:8]=1)[CH3:13]
Reactant: [Li]C(C)(C)C
Reactant: Cc1ccc2sccc2c1
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1cc2cc(C)ccc2s1

Procedure:
2-ethyl-5-methylbenzo[b]thiophene was prepared in the same manner as described in Example 40A. Reaction of 5-methylbenzo[b]thiophene (3.4 mmoles, 0.50 g), t-BuLi (1.7 m, 5.1 mmoles, 3.0 ml) and ethyl iodide (6.8 mmoles, 0.54 ml) in THF (10 ml) yielded 0.58 g (97%) of a light yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[N:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(Cl)nc3c2ncn3C(C)C)cc1

Procedure:
2Chloro-6-[(4-methoxybenzyl)amino]-9-(2-propyl)purine is prepared from 2,6-dichloro-9-(2-propyl)purine (see Example 19 for preparation), 4-methoxybenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:6](=[O:34])[C:5]([CH:35]=O)=[CH:4]1)[CH3:2].[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CC(O)=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:33])=[C:10]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[C:11]=2[O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[C:6](=[O:34])[C:5]([CH2:35][N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C=O)c(=O)c2cc(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCn1cc(CN2CCCC2)c(=O)c2cc(F)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.8 %

Procedure:
To a solution of 1-ethyl-6-fluoro-7,8-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carbaldehyde (15 g, 30.5 mmol) in 1,2-Dichloroethane (DCE) (100 mL) was added pyrrolidine (3.78 mL, 45.8 mmol), sodium triacetoxyborohydride (12.94 g, 61.0 mmol) and AcOH (0.087 mL, 1.526 mmol). The reaction mixture was stirred at 25° C. for 3 h. LCMS showed completion of the reaction. The mixture was extracted with DCM and washed with brine. The organic solution was dried over sodium sulfate and evaporated in vacuo. The crude material was purified by normal phase automatic silica column chromatography (Combiflash RF), using a 40 g golden column and eluting with MeOH/DCM (0-20%). The product was further purified with reverse phase automatic silica column chromatography (Combiflash RF), using a 150 g golden column and eluting with acetonitrile/water (0-60%) to afford 1-ethyl-6-fluoro-7,8-bis((4-methoxybenzyl)oxy)-3-(pyrrolidin-1-ylmethyl)quinolin-4(1H)-one (9.8 g, 17.93 mmol, 58.7% yield) as a yellow solid. LCMS: (M+H)+: 547.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[NH:12][C:13]([CH3:31])=[C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:16]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[N:16]([S:39]([CH3:38])(=[O:41])=[O:40])[CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[C:14]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:13]([CH3:31])[N:12]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C1=C(C)NC(SCc2ccc(OC)cc2)=NC1c1cccc([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)N=C(SCc2ccc(OC)cc2)N(S(C)(=O)=O)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A solution of 2.0 g (0.0045 mole) of 1, 4-dihydro-2-[[(4-methoxyphenyl)methyl]thio]6-methyl-4-(3-nitrophenyl) -5-pyrimidinecarboxylic acid, ethyl ester (see example 2A) in 15 ml of dichloromethane containing 0.71 g (0.0090 mole) of pyridine was cooled to -10° C. and treated slowly with a solution of 0.62 g (0.0054 mole) of methanesulfonyl chloride in 5 ml of dichloromethane. After stirring at room temperature overnight, a small amount of the hydrochloric acid salt of 1, 4-dihydro-2-[[(4-methoxyphenyl)methyl]thio]-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, ethyl ester had precipitated. After filtration, additional dichloromethane was added and the solution was washed with water, 1N hydrochloric acid, sodium bicarbonate and brine. The dried solution was evaporated and the residue was flash chromatographed using dichloromethane to give 2.0 g of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1>>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][N:24]([C:25]2[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:29][CH:30]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:21][CH:22]=1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Reactant: CCCCCCCCc1ccc(NCc2ccc(Br)cc2)cc1
Product: CCCCCCCCc1ccc(N(Cc2ccc(Br)cc2)C(=O)C2CCCc3ccc(OC)cc32)cc1
Yield: 68.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.62 g) and [(4-bromophenyl)methyl](4-octylphenyl)amine (1.12 g) as starting materials, N-[(4-bromophenyl)methyl]-7-methoxy-N-(4-octylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.15 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][C:12]([CH3:14])=O)[C:7]=2[CH:15]=1.[CH3:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH3:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([N:27]3[CH2:28][CH2:29][N:30]([CH:12]([CH3:14])[CH2:11][C:8]4[C:7]5[CH:15]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[O:10][CH:9]=4)[CH2:31][CH2:32]3)[CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2
Reactant: Cc1cc(N2CCNCC2)c2ncccc2c1
Reactant: COc1ccc2occ(CC(C)=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc2occ(CC(C)N3CCN(c4cc(C)cc5cccnc45)CC3)c2c1

Procedure:
6-methyl-8-{4-[2-(5-methoxy-1-benzofuran-3-yl)-1-methylethyl)piperazin-1-yl]quinoline was prepared by generally following the procedure outlined in example 38, step 2, starting from the 1-(5-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 6-methyl-8-piperazino quinoline (227.0 mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium triacetoxyborohydride (422 mg, 2 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a yellow oil. Yield: 62 mg (14%); (M+H): 416; 1HNMR (400 MHz, CDCl3): δ□8.82˜8.81 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H): 8.02˜8.00 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 7.99˜6.58 (m, 7H); 3.87 (s, 3H); 3.46˜2.62(m, 11H); 2.5 (s, 3H); 1.15˜1.13 (d, J=6.0 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]2[N:9]=[CH:10][N:11]([C:12]3[S:16][C:15]([C:17]([NH2:19])=[O:18])=[C:14]([O:20][C@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH3:22])[CH:13]=3)[C:5]=2[CH:4]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>ClCCl>[CH3:33][S:34]([O:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]2[N:9]=[CH:10][N:11]([C:12]3[S:16][C:15]([C:17](=[O:18])[NH2:19])=[C:14]([O:20][C@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:30])([F:31])[F:32])[CH3:22])[CH:13]=3)[C:5]=2[CH:4]=1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example 49 (step 1), 120 mg of 5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-{(1S)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide, 57 mg of methanesulfonyl chloride, and 53 mg of triethylamine in 3 ml dichloromethane give [1-(5-carbamoyl-4-{(1S)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate as crude material that is used for step 2 without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:10][C:11]([O:13]C)=O)[NH2:9])=[CH:4][CH:3]=1.[CH3:15][N:16]=[C:17]=[O:18]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:10][C:11](=[O:13])[N:16]([CH3:15])[C:17](=[O:18])[NH:9]2)=[CH:6][CH:7]=1
Reactant: CN=C=O
Reactant: COC(=O)CN(N)c1ccc(F)cc1
Solvent: CC#N
Product: CN1C(=O)CN(c2ccc(F)cc2)NC1=O
Reaction time: 1 h

Procedure:
A mixture of methyl [1-(4-fluorophenyl)hydrazino]acetate (2.12 g) and methyl isocyanate (1.63 ml) in acetonitrile (20 ml) was heated under reflux for 3 h. The solvent was removed in vacuo and the residual oil was taken into methanol (20 ml) and treated with a solution of sodium methoxide (from sodium (556 mg) in methanol (30 ml)). After 1 h at 20° the solution was neutralised with acetic acid and the solvent was removed in vacuo. The residue was taken into ethyl acetate (100 ml), washed with pH 6 phosphate buffer (100 ml), dried and evaporated. Crystallisation of the residue from System B gave the title compound (1.10 g), m.p. 205°-206°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:13][CH:14]=2)[C:9]1=[O:31].[F:32][C:33]([F:58])([F:57])[CH2:34][NH:35][C:36]([C:38]1([CH2:52][CH2:53][CH2:54][CH2:55]Br)[C:51]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[O:45][C:44]2[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:37]>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:19][CH2:20][N:21]([CH2:55][CH2:54][CH2:53][CH2:52][C:38]4([C:36](=[O:37])[NH:35][CH2:34][C:33]([F:58])([F:57])[F:32])[C:51]5[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=5[O:45][C:44]5[C:39]4=[CH:40][CH:41]=[CH:42][CH:43]=5)[CH2:22][CH2:23]3)=[CH:13][CH:14]=2)[C:9]1=[O:31]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)C(=O)N(CC2CCCCO2)CC3)CC1
Product: O=C1c2cc(N3CCN(CCCCC4(C(=O)NCC(F)(F)F)c5ccccc5Oc5ccccc54)CC3)ccc2CCN1CC1CCCCO1

Procedure:
Step (b) of Example 97 was repeated, except that the compound prepared in step (a) of Example 99 and the compound prepared in step (a) of Example 96 were used as the starting compounds. Thus, the title compound was prepared.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[N:14]3[N:15]=[C:16]([NH2:18])[N:17]=[C:13]3[CH:12]=[C:11]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:10]=2)[CH2:4][CH2:3]1.[S:25]([N:35]=[C:36]=[O:37])([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26].CO>CN(C=O)C>[S:25]([NH:35][C:36]([NH:18][C:16]1[N:17]=[C:13]2[CH:12]=[C:11]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:10]=[C:9]([NH:8][CH:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[N:14]2[N:15]=1)=[O:37])([C:28]1[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=1)(=[O:26])=[O:27]
Reactant: CN1CCC(Nc2cc(-c3cccnc3)cc3nc(N)nn23)CC1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2nc3cc(-c4cccnc4)cc(NC4CCN(C)CC4)n3n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of the product of Step 1 (376 mg, 1.16 mmol) in DMF (4 mL) was treated with TosNCO (0.25 g, 1.3 mmol), then microwaved at 60° C. for 5 min. After stirring at room temperature for 18 h, MeOH (5 mL) was added and the resulting precipitate was collected by filtration and dried in vacuo to yield 1-tosyl-3-[5-(1-methyl-piperidin-4-ylamino)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-urea.
Reaction SMILES: C12(C3C=C[C:14]([NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])=CC=3)CC3CC(CC(C3)C1)C2.N1C=CC=CC=1.[CH3:29][O:30]CC1COC(=O)O1>>[CH3:29][O:30][CH2:21][CH:20]1[O:19][C:18](=[O:22])[NH:17][CH2:14]1
Reactant: COCC1COC(=O)O1
Reactant: CCOC(=O)Nc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Solvent: c1ccncc1
Product: COCC1CNC(=O)O1
Reaction time: 20 h

Procedure:
5.42 g (18.1 mmol) of ethyl 4-adamantan-1-yl-phenylcarbamate were treated with 1.43 g (18.1 mmol) of pyridine and 18.0 g (0.136 mol) of (RS)-4-methoxymethyl-1,3-dioxolan-2-one and stirred at 160° bath temperature for 20 hours. After cooling the reaction mixture was chromatographed on 500 g of silica gel 60 with ether. 1.4 g of (RS)-3-(4-adamantan-1-yl)phenyl]-5-methoxymethyl-oxazolidin-2-one were obtained as a white crystallizate after recrystallization from methylene chloride/ether. M.p.: 145°-147°.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7](OC)(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CCOCC>[CH2:7]([OH:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCC/C=C/C=C\CCCCCCCC(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCCC/C=C/C=C\CCCCCCCCO
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
To a suspension of lithium aluminum hydride (1.5 g, 38.7 mmol) in anhydrous ether (50 mL) cooled to 0° C. under nitrogen was slowly added a solution of (9Z,11E)-methyl octadeca-9,11-dienoate (11.6 g, 38.7 mmol) in anhydrous diethyl ether (50 mL+25 mL rinse) via cannula transfer. The solution was stirred for 2 hours at 0° C. then quenched slowly with 1M NaOH (3.5 mL). The solution was dried on magnesium sulfate, filtered and concentrated in vacuo to dryness to afford the product as a colorless oil (9.5 g, 92%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[S:44]1[C:48]2[CH:49]=[CH:50][C:51]([C:53](O)=[O:54])=[CH:52][C:47]=2[CH:46]=[CH:45]1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:53]([C:51]3[CH:50]=[CH:49][C:48]4[S:44][CH:45]=[CH:46][C:47]=4[CH:52]=3)=[O:54])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(O)c1ccc2sccc2c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccc5sccc5c4)c3C2=O)C(=O)N1
Reaction time: 0.17 h
Yield: 50.8 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 1-benzothiophene-5-carboxylic acid (0.4 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight and was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL), washed with water (3×40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford benzo[b]thiophene-5-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (0.5 g, 53%) as a white solid: mp 261-263° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.22 min. (99%); 1H NMR (DMSO-d6) δ 2.07-2.11 (m, 1H), 2.55-2.65 (m, 2H), 2.86-2.98 (m, 1H), 4.99 (d, J=5.6 Hz, 2H), 5.16-5.22 (dd, J=5.0 and 12.4 Hz, 1H), 7.59 (d, J=5.4 Hz, 1H), 7.79-7.92 (m, 5H), 8.11 (d, J=8.4 Hz, 1H), 8.48 (s, 1H), 9.24 (t, J=5.5 Hz, 1H), 11.16 (s, 1H); 13C NMR (DMSO-d6) δ 21.99, 30.93, 38.44, 48.88, 121.85, 122.50, 122.91, 122.95, 124.39, 127.14, 128.84, 130.39, 131.54, 133.07, 134.79, 139.18, 139.38, 141.92, 166.79, 166.97, 167.55, 169.83, 172.74; Anal. Calcd. for C23H17N3O5S+0.2H2O: C, 61.24; H, 3.89; N, 9.32; S, 7.11. Found: C, 61.04; H, 3.57; N, 8.96; S, 7.19.