Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[CH2:8][N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Br[CH:23]([CH3:39])[C:24]([C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:37][CH3:38])[C:32]=2[Cl:36])[CH:27]=1)=[O:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:36].[ClH:1].[CH3:21][O:20][C:16]1[CH:15]=[C:7]([CH:6]=[C:5]([O:4][CH3:3])[C:17]=1[O:18][CH3:19])[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH:23]([C:24]([C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[C:31]([O:37][CH3:38])[C:32]=3[Cl:36])[CH:27]=2)=[O:25])[CH3:39])[CH2:11][CH2:10]1
Reactant: COc1ccc2cc(C(=O)C(C)Br)ccc2c1Cl
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(CN2CCN(C(C)C(=O)c3ccc4c(Cl)c(OC)ccc4c3)CC2)cc(OC)c1OC
Yield: 122.7 %

Procedure:
A mixture of N1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (0.9 g, 2.7 mmol), 2-bromo-1-(5-chloro-6-methoxynaphthalen-2-yl)propan-1-one (1.05 g, 3.2 mmol) and K2CO3 (1.3 g, 9.5 mmol) in 25 ml of DMF was treated according to general preparation 2 to give 1.15 g of compound (IV-34), yield 72.7%, mp 219-222° C., M+ 512.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:33])([F:32])[CH2:29][CH2:30]O>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9](=[O:10])[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:30][CH2:29][C:28]([F:33])([F:32])[F:27])=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Reactant: OCCC(F)(F)F
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OCCC(F)(F)F)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 3,3,3-trifluoropropanol in analogy to Example 9c): MS (ISP): 492.2 and 494.2 (M+H)+, 392.0 and 394.0 ((M-Boc)+H)+ (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:12]3[S:13][CH2:14][CH:15](O)[N:11]3[N:10]=2)[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C>C(COC)OC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:12]3[S:13][CH:14]=[CH:15][N:11]3[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2nn3c(c2-c2ccncc2)SCC3O)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1cccc(-c2nn3ccsc3c2-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 60.8 %

Procedure:
Crude 6-(3-methoxy-phenyl)-7-pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazol-3-ol (120 mg, 0.369 mmol) was dissolved in dry dimethoxyethane (2 mL) under nitrogen. Trifluoroacetic anhydride (0.200 mL, 1.416 mmol, 3.8 eq) and triethylamine (0.100 mL, 0.718 mmol, 2 eq) were added and the mixture was stirred at room temperature for 20 hours. The solution was then diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine, dried and evaporated to dryness. The crude product was purified by chromatography on silica gel (eluant: DCM/MeOH 97:3) to give 69 mg (61%) of 6-(3-methoxy-phenyl)-7-pyridin-4-yl-pyrazolo[5,1-b]thiazole as white solid.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[C:7]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:8][C:9]2[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]=2[CH:17]=1)([O-:5])=[O:4].I[CH3:23]>CN(C=O)C>[CH3:23][N:15]1[C:9]2[CH:8]=[C:7]([O:18][CH:19]([CH3:21])[CH3:20])[C:6]([N+:3]([O-:5])=[O:4])=[CH:17][C:10]=2[CH2:11][CH2:12][CH2:13][C:14]1=[O:16]
Reactant: CC(C)Oc1cc2c(cc1[N+](=O)[O-])CCCC(=O)N2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc2c(cc1[N+](=O)[O-])CCCC(=O)N2C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 62.3 %

Procedure:
460 mg of potassium nitrate are added to a solution of 797 mg of 8-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 8 ml of trifluoroacetic anhydride, cooled to −5° C. The reaction medium is stirred for 5 minutes at −5° C., brought back to pH 7 by adding a saturated aqueous sodium hydrogen carbonate solution, and then extracted with 100 ml of ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. The residue is purified by flash chromatography on silica gel, elution being carried out with a heptane/ethyl acetate (1/1) mixture, so as to obtain 489 mg of 7-nitro-8-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in the form of a yellow solid. 100 mg of sodium hydride at 60% are added to a solution of 485 mg of 7-nitro-8-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 8 ml of DMF, cooled to 0° C. The reaction medium is stirred for 5 minutes and then 263 mg of iodomethane are added. The reaction medium is brought back to ambient temperature and stirred for 1 hour at this temperature. The reaction medium is poured into 100 ml of ice-cold water and the mixture is extracted with 100 ml of ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated. The residue is purified by flash chromatography on silica gel, elution being carried out with a heptane/ethyl acetate (1/1) mixture, so as to obtain 318 mg of 1-methyl-7-nitro-8-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[C:13]([CH2:22][C:23]([NH:25]O)=[NH:24])[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1.Cl>O.[Ni]>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[C:13]([CH2:22][C:23]([NH2:25])=[NH:24])[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1
Reactant: N=C(Cc1nc2cnc3ccc(Cl)cc3c2n1-c1ccccc1Cl)NO
Agent: [Ni]
Agent: Cl
Solvent: O
Product: N=C(N)Cc1nc2cnc3ccc(Cl)cc3c2n1-c1ccccc1Cl
Temperature: 2.5 °C

Procedure:
352 mg (0.91 mmol) of 2-[8-chloro-1-(2-chloro-phenyl)-1H-imidazo[4,5-c]quinolin-2-yl]-N-hydroxy-acetamidine (Example 87), 0.91 ml 1N HCl, in 7.1 ml water are hydrogenated at rt (tlc-control) in the presence of ca. 190 mg Raney-Ni. The catalyst is filtered off and washed with methanol. The solvents are evaporated, the residue is dissolved in CH2Cl2-water-methanol. The two phases are separated and evaporated. From the water phase, a yellow oil separates. The oil is dissolved in hot methanol and diethyl ether is added. On stirring at 0-5° C., a solid separates. The solid, which is the title compound, is filtered off and dried for 6 h at 50° C. MS: 370 (M++1); HPLC: tret=7.38 min (Grad 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10](/[N:17]=[CH:18]/[N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH:24]1[CH2:30][O:31][C:32]1[CH:33]=[C:34](CN)[CH:35]=[CH:36][CH:37]=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([CH2:21][C:36]4[CH:35]=[CH:34][CH:33]=[C:32]([O:31][CH2:30][CH:24]5[CH2:25][N:26]([CH3:29])[CH2:27][CH2:28][N:23]5[CH3:22])[CH:37]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Reactant: CN1CCN(C)C(COc2cccc(CN)c2)C1
Solvent: CO
Product: CN1CCN(C)C(COc2cccc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)c2)C1

Procedure:
The title compound was synthesized according to Example 13c from methyl 5-(4-chlorophenyl)-3-{[(1E)-(dimethylamino)methylene]amino}thiophene-2-carboxylate (0.427 g, 1.32 mmol) and 1-{3-[(1,4-dimethylpiperazin-2-yl)methoxy]phenyl}methanamine (0.300 g, 1.20 mmol) in MeOH (2 mL), the crude product was purified by flash chromatography using EtOAc:MeOH:TEA (100:10:1) to give the title compound. Yield: 0.315 g (48%). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.58-7.62 (m, 2H), 7.38-7.42 (m, 2H), 7.45 (s, 1H), 7.22-7.27 (m, 1H), 6.82-6.93 (m, 3H), 5.16 (s, 2H), 3.91-4.01 (m, 2H), 2.76-2.87 (m, 2H), 2.66-2.73 (m, 1H), 2.47-2.55 (m, 1H), 2.36-2.44 (m, 1H), 2.34 (s, 3H), 2.27 (s, 3H), 2.09-2.27 (m, 2H). MS (ESI+) 495.01 (M+1H+)
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]([F:19])=[C:6]([N:8]=[C:9]2[N:17]3[N:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)[C:11](=[S:18])[S:10]2)[CH:7]=1.[CH2:21]([S:23](Cl)(=[O:25])=[O:24])[CH3:22].N1C=CC=CC=1>C(Cl)Cl>[Cl:20][C:3]1[C:2]([NH:1][S:23]([CH2:21][CH3:22])(=[O:25])=[O:24])=[CH:7][C:6]([N:8]=[C:9]2[N:17]3[N:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)[C:11](=[S:18])[S:10]2)=[C:5]([F:19])[CH:4]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cc(N=c2sc(=S)n3n2CCCC3)c(F)cc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cc(N=c2sc(=S)n3n2CCCC3)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.3 %

Procedure:
A mixture of 0.45 g (0.0014 mole) of 9-(5-amino-4-chloro-2-fluorophenyl)imino-8-thia-1,6-diazabicyclo[4.3.0]nonane-7-thione, 0.18 g (0.0014 mole) of ethanesulfonyl chloride, and 0.22 g (0.027 mole) of pyridine in approximately 30 mL of methylene chloride was stirred at room temperature for two days. The reaction mixture was heated at 26° C. for approximately 24 hours, then at reflux for 36 hours. The solvent was evaporated from the mixture leaving an oily residue. The residue was washed with an aqueous, 10% hydrochloric acid solution. The washed residue crystallized upon standing and was recrystallized from ethyl acetate and n-heptane to give 0.12 g of 9-(4-chloro-5-ethylsulfonylamino-2-fluorophenyl)imino-8-thia-1,6-diazabicyclo[4.3.0]nonane-7-thione, mp 146°-148° C., Compound 11 of Table 1.
Reaction SMILES: [O:1]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[CH:16]2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:11][CH:10]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.OS([O-])=O.[Na+].CCOC(C)=O>C(Cl)Cl>[O:1]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[C:16]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:13][CH:14]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C1C(=O)c2ccccc2C1c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(c2ccc(O[Si](C)(C)C(C)(C)C)cc2)c2ccccc2C1=O
Reaction time: 2.5 h
Yield: 84.1 %

Procedure:
To a solution of ethyl (2RS,3SR)-3-(4-t-butyldimethylsiloxyphenyl)-1-oxoindane-2-carboxylate (130 mg, 0.32 mmol) in CH2Cl2 (3 ml) under an argon atmosphere was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (80 mg, 0.35 mmol). The resulting mixture was stirred for 2.5 h. Aqueous NaHSO3 and EtOAc were added, and the mixture was stirred for 5 min. The aqueous phase was separated and extracted with EtOAc, and the combined organic extracts were washed successively with aqueous NaHCO3, H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel to afford the title compound (110 mg, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[C:7]([CH:10]([OH:13])CO)=[CH:8][O:9][C:5]=2[CH:4]=1>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[C:7]([CH:10]=[O:13])=[CH:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(C(O)CO)coc2c1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(C=O)coc2c1
Yield: 52.2 %

Procedure:
NaIO4 (0.204 g, 1.12 mmol) was added to 1-(6-methoxy-benzofuran-3-yl)-ethane-1,2-diol (0.180 g, 1.196 mmol) in THF (50 mL) and water (1 mL) with stirring. The mixture was stirred overnight at room temperature under N2. Water (10 mL) was added, and the mixture was concentrated to half its volume and extracted with EtOAc. The organic layer was washed with brine and water, dried over anhyd. MgSO4, and evaporated to give a residue, which was purified on a silica gel column eluting with EtOAc/hexane (1:10) to give 6-methoxybenzofuran-3-carbaldehyde (0.110 g, 73%).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([O:12]CC)=O)[C:3]1=[O:15].[NH2:16][C:17]1[N:21]=[C:20]([CH3:22])[NH:19][N:18]=1.BrC1C=CC=CC=1>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([NH:16][C:17]2[N:21]=[C:20]([CH3:22])[NH:19][N:18]=2)=[O:12])[C:3]1=[O:15]
Reactant: Cc1nc(N)n[nH]1
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Solvent: Brc1ccccc1
Product: Cc1nc(NC(=O)c2c(O)cc(C)n(C)c2=O)n[nH]1
Temperature: 25 °C
Reaction time: 7 h
Yield: 88.6 %

Procedure:
211 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 90 mg of 3-amino-5-methyl-1,2,4-triazole were added to 2.5 ml of bromobenzene, then, the mixture was stirred for 7 hours under heat refluxing condition. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration, and washed with a mixed solvent of t-butyl methyl ether and hexane and dried to obtain 214 mg of 1,6-dimethyl-4-hydroxy-N-(5-methyl-1,2,4-triazol-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 24) represented by the formula:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[OH:14])(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[N+:22]([O-])([OH:24])=[O:23].O>ClCCl>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([N+:22]([O-:24])=[O:23])[C:5]=1[OH:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(C)=O)c(O)c1
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C(C)=O)c(O)c1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A mixture of N-(4-acetyl-3-hydroxyphenyl)acetamide (9.66 g, 50 mmol) and acetic anhydride (14.2 ml, 15.3 g, 150 mmol) in dichloromethane (150 ml) was cooled to 5° C. and nitric acid (90%, d 1.49, 4.70 ml, 7.00 g, 100 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour, poured into water (150 ml) and extracted with dichloromethane (3×150 ml). The combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure and the residue was purified by repeated flash column chromatography on silica gel, eluting with hexane/30% ethyl acetate then hexane/50% ethyl acetate. The first isomer to elute was N-(4-acetyl-5-hydroxy-2-nitrophenyl)acetamide as a yellow solid (3.87 g, 33%).
Reaction SMILES: [N:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[N:11][C:6]2=[N:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.C(OP(OCC)OCC)C>C1(C)C=CC=CC=1>[N:11]1[C:6]2=[N:5][C:4]3[C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[NH:1][C:3]=3[N:7]2[CH:8]=[CH:9][CH:10]=1
Reactant: O=Nc1c(-c2ccccc2)nc2ncccn12
Agent: CCOP(OCC)OCC
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)[nH]c1c2nc2ncccn21
Reaction time: 8 h

Procedure:
A mixture of 9.0 g of analytically pure 3-nitroso-2-phenylimidazo(1,2-a)pyrimidine (0.04 mol) and 10 ml of 97% triethylphosphite (0.05 mol) in 50 ml of anhydrous toluene is refluxed for 1 hour with stirring and under a constant flow of dry nitrogen gas. The temperature of the oil bath is kept between 110° and 120° C. After cooling the solvent and excess triethylphosphite are removed by vacuum distillation at 0.2 Torr. The temperature of the oil bath was kept under 120° C. during the distillation. The residue, which is a thick liquid, is kept overnight at 0° C. during which time it solidifies. The solid is washed on a glass filter with cold carbon tetrachloride and then recrystallized from CCl4. Yield about 5 g, m.p. 96° to 98° C.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][CH2:5][C:6]=1[C:7]#[N:8].[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1>N1C=CC=CC=1>[C:7]([C:6]1[CH2:5][CH2:4][O:3][C:2]=1[NH:1][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][C:10]([F:9])=[CH:11][CH:12]=1)#[N:8]
Reactant: N#CC1=C(N)OCC1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: N#CC1=C(NC(=O)c2ccc(F)cc2)OCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
To a solution of 2-amino-4,5-dihydrofuran-3-carbonitrile (3.5 g) obtained in Step D in pyridine (8 mL) was added dropwise 4-fluorobenzoyl chloride (5.5 g) in an ice bath, and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, and to the residue was added dropwise saturated aqueous sodium hydrogen carbonate solution in an ice bath. The resulting solid was collected by filtration, and washed with water to give the title compound (7.1 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]>CC(O)CC>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:8]([CH2:9][CH3:11])[CH3:18])=[CH:15][CH:16]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Solvent: CCC(C)O
Product: CCC(C)Oc1ccc(C(=O)C(NC(=O)OC(C)(C)C)c2ccc(Cl)c(Cl)c2)cc1

Procedure:
The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 2-butanol in analogy to Example 9c): MS (ISP): 452.1 and 454.0 (M+H)+, 352.1 and 354.1 ((M-Boc)+H)+ (100%).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:28][CH2:27][CH:26]3[C:21]([C:22]4[CH:32]=[CH:31][CH:30]=[N:29][C:23]=4[CH2:24][CH2:25]3)=[N:20]2)=[CH:15][CH:14]=1>ClCCl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:28][CH2:27][CH:26]3[C:21]([C:22]4[CH:32]=[CH:31][CH:30]=[N+:29]([O-:6])[C:23]=4[CH2:24][CH2:25]3)=[N:20]2)=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccc(N2CCC3CCc4ncccc4C3=N2)cc1
Solvent: ClCCl
Product: [O-][n+]1cccc2c1CCC1CCN(c3ccc(Cl)cc3)N=C21
Yield: 64.5 %

Procedure:
3-Chloroperoxybenzoic acid (60%) (35 mg) was added to a solution of 2-(4-Chlorophenyl)-2,3,4,4a,5,6-hexahydropyrido[2,3-h]cinnoline (example 16, 25 mg) in dichloromethane (5 ml) at 25° C. After 4 hours the reaction was diluted with dichloromethane and sequentially washed with an aqueous solution of sodium metabisulfite, saturated sodium bicarbonate solution, brine, dried and evaporated. Purification by chromatography, eluting with ethyl acetate/methanol (4:1) afforded the title compound (17 mg).
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.[F:19][C:20]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=1[CH:22]=[O:23]>O.O1CCCC1>[F:19][C:20]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=1[CH:22]([OH:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: Brc1ccccn1
Reactant: O=Cc1cc(F)ccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: OC(c1ccccn1)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, a hexane solution of n-butyl lithium (1.53M, 3.92 ml, 6 mmol) was added dropwise to a tetrahydrofuran (10 ml) solution of 2-bromopyridine (572 μl, 6 mmol) at −78° C. and the mixture was stirred for 30 minutes. To the resulting brown solution, 2,5-difluorobenzaldehyde (655 μl, 6 mmol) was added dropwise and the temperature of the mixture was gradually raised to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. After drying the solvent, the residue obtained by concentration under reduced pressure was purified by silica gel chromatography, whereby the title compound (120 mg, 9%) was obtained as a white solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]#[C:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)(=O)=O.[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([NH:19][CH2:6][CH2:7][C:8]#[C:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CS(=O)(=O)OCCC#Cc1cccs1
Reactant: CC(C)(C)N
Product: CC(C)(C)NCCC#Cc1cccs1

Procedure:
A solution of 1 g of 1b in 10 ml of tert-BuNH2 was stirred overnight at RT. The mixture, consisting of desired product as well as elimination product, was concentrated, diluted with 20 ml of 5% NaHCO3 and extracted with ether. The extract was dried and concentrated (45° C./100 mm). The residue (˜450 mg) containing 1c was used without further purification in the next step;
Reaction SMILES: C[C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[H-].[Na+].[CH3:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)=[O:16].CO>C1C=CC=CC=1>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([C:15](=[O:16])[CH2:14][C:4](=[O:6])[C:3]2[CH:2]=[CH:10][C:9]([Br:11])=[CH:8][CH:7]=2)=[CH:18][CH:19]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: O=C(CC(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Temperature: 60 °C

Procedure:
In a 1-liter three neck round bottom flask, 43 g (0.2 mol) methyl 4-bromobenzoic acid and 17.6 g (0.4 mol) sodium hydride were dissolved in 200 ml dried benzene and heated to 60° C. Next, 39.8 g (0.2 mol) 4-bromoacetophenone in 100 ml dry benzene was slowly added through a dropping funnel, and 1 ml methanol was added to the flask to initiate the reaction. After the mixture was refluxed overnight, the reaction was quenched by adding methanol and pouring it into ice water. The pH of the mixture was brought down to 7.0 using 5 N sulfuric acid. A solid was collected, washed with water, and recrystallized from benzene to give a light yellow product. Characterization. Yield: 30.3 g (40%). 1H NMR (300 MHz, CDCl3, 20° C., δ): 7.84 (d, 4H, ArH); 7.62 (d, 4H, ArH); 6.77 (s, 2H, CH2). EI-MS: 382(M+), 301, 225, 183, 157.
Reaction SMILES: C([C:5]1[C:6]([O:12][CH3:13])=[C:7]([SH:11])[CH:8]=[CH:9][CH:10]=1)(C)(C)C.Br[CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1>>[CH3:13][O:12][C:6]1[CH:5]=[CH:10][CH:9]=[CH:8][C:7]=1[S:11][CH2:15][CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1
Reactant: COc1c(S)cccc1C(C)(C)C
Reactant: BrCCCOC1CCCCO1
Product: COc1ccccc1SCCCOC1CCCCO1

Procedure:
In an analogous manner to that described in Example 44 e), by alkylating tert-butyl 2-methoxy-thiophenol with (RS)-2-(3-bromo-propoxy)-tetrahydro-pyran there was obtained (RS)-2-[3-(2-methoxy-phenylsulphanyl)-propoxy]-tetrahydro-pyran.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:53]=[C:52]([O:54][CH3:55])[CH:51]=[CH:50][C:4]=1[CH2:5][N:6]([CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[N:23](S(C3C=CC(C)=CC=3)(=O)=O)[C:24]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([O:37][CH3:38])=[C:32]([O:35][CH3:36])[CH:33]=4)[N:28]([CH3:39])[CH:27]=3)=[CH:25][C:18]=12)[S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8].[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:53]=[C:52]([O:54][CH3:55])[CH:51]=[CH:50][C:4]=1[CH2:5][N:6]([CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[NH:23][C:24]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([O:37][CH3:38])=[C:32]([O:35][CH3:36])[CH:33]=4)[N:28]([CH3:39])[CH:27]=3)=[CH:25][C:18]=12)[S:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:9])=[O:8]
Reactant: COc1ccc(CN(Cc2ccnc3c2cc(-c2cn(C)c4cc(OC)c(OC)cc24)n3S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccccc2)c(OC)c1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(CN(Cc2ccnc3[nH]c(-c4cn(C)c5cc(OC)c(OC)cc45)cc23)S(=O)(=O)c2ccccc2)c(OC)c1
Yield: 138.4 %

Procedure:
N-(2,4-Dimethoxybenzyl)-N-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]-benzenesulfonamide is prepared as described in Example 179a starting with 0.090 g of N-(2,4-dimethoxybenzyl)-N-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]benzenesulfonamide instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 0.6 cm3 of 5N potassium hydroxide. 0.100 g of N-(2,4-dimethoxybenzyl)-N-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]benzenesulfonamide is obtained, the characteristics of which are as follows: