Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([I:11])[C:3]=1[C:4]#[N:5].[Li+].CC([N-]C(C)C)C.[CH:20](OC)=[O:21]>C1COCC1>[F:1][C:2]1[C:9]([F:10])=[C:8]([CH2:20][OH:21])[CH:7]=[C:6]([I:11])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(I)ccc(F)c1F
Reactant: COC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1c(I)cc(CO)c(F)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 18.3 %

Procedure:
A −78° C. solution of Example 26A (5.0 g, 18.9 mmol) in THF was treated with LDA (2M in hexanes, 11.5 mL, 22.6 mmol), stirred for 1 hour at −78° C., treated with methyl formate (2.34 mL, 37.8 mmol), stirred at −78° C. for 30 minutes, warmed to 0° C. for 1 hour, quenched with saturated NH4Cl and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was immediately dissolved in ethanol (100 mL), cooled to 0° C., and treated portionwise with NaBH4 (1.08 g). The reaction was stirred at 0° C. for 2 hours, quenched with acetone, stirred for 5 minutes, poured into water, and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 2:1 hexanes/ethyl acetate to give 1.02 g of the desired product. Rf=0.84 (ethyl acetate).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:48])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([CH2:39][O:40]C3CCCCO3)[CH:34]=2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:40][CH2:39][C:35]1[CH:34]=[C:33]([C:29]2[CH:28]=[C:27]([C:26]3[CH2:25][C:24](=[O:48])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:21])([F:20])[F:22])[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:32]=[CH:31][CH:30]=2)[CH:38]=[CH:37][N:36]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(COC4CCCCO4)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-(methyl-propyl-amino)-2-(3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M282) (0.25 g, 0.36 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (109 mg, 62%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][C:10](=[CH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[O:3]1.[CH2:18]([Zn]CC)C.ICI>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:17])[CH2:11][C:10]2([CH2:18][CH2:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[O:3]1
Reactant: CC[Zn]CC
Reactant: C=C1CC(C)(C)Oc2ccc(C(=O)OC)cc21
Solvent: ICI
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)C1(CC1)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl 2,2-dimethyl-4-methylidene-3,4-dihydro-2H-chromene-6-carboxylate (34.0 mg, 0.15 mmol) and diethylzinc (1.17 mL, 1.17 mmol) in toluene (2.90 mL) under N2 atmosphere was added diiodomethane (189 μL, 2.34 mmol) dropwise via a syringe at room temperature. The mixture was stirred at room temperature overnight and then partitioned between diethyl ether (10.0 mL) and 5% aqueous HCl (10.0 mL). The aqueous layer was extracted with diethyl ether (20.0 mL, 2×). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with 0-15% EtOAc/hexanes to afford the desired product as a pale-yellow solid.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH3:22])=[C:6]([CH:23]([CH3:25])[CH3:24])[N:5]=1)([CH3:3])[CH3:2].[CH2:26](Cl)Cl.CCCCCC>>[CH:1]([C:4]1[C:9]([CH:10]([OH:11])[CH3:26])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH3:22])=[C:6]([CH:23]([CH3:24])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Reactant: ClCCl
Solvent: CCCCCC
Product: CCCCc1c(C(C)C)nc(C(C)C)c(C(C)O)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-5butylpyridine (Example 24) according to the procedures described in Example 101. 1H NMR (300 MHz, CDCl3): δ 7.1 (m, 4 H), 4.7 (dq, J=3 Hz, 1 H), 3.7 (septet, J=7 Hz, 1 H), 3.2 (septet, J=7 Hz, 1 H), 2.2 (t, J=1.5 Hz, 2 H), 1.6 (d, J=5 Hz, 1 H), 1.4 (d, J=7 Hz, 3 H), 1.3 (m, 16 H), 0.8 (t, J=7Hz, 3H). FAB-MS: calcd for (C23H32FNO) 357, found 358 (M+H). mp 103-104° C. Rf=0.2 (60% CH2Cl2/hexane).
Reaction SMILES: [N:1]12CCC(CC1)C[CH2:2]2.[O-:9][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11].[F:17][N+:18]12[CH2:25][CH2:24]C([CH2:22][CH2:23]1)[CH2:20][CH2:19]2.FF.[O-:28][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:31])=[O:30].C[N+]12CCN(CC1)CC2.[O-]S(C(F)(F)F)(=O)=O.[Li+]>C(#N)C>[O-:12][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:11])=[O:9].[O-:31][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:30])=[O:28].[F:17][N+:18]12[CH2:25][CH2:24][N+:1]([CH3:2])([CH2:22][CH2:23]1)[CH2:20][CH2:19]2
Reactant: C1CN2CCC1CC2
Reactant: F[N+]12CCC(CC1)CC2
Agent: C[N+]12CCN(CC1)CC2
Agent: FF
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Product: C[N+]12CC[N+](F)(CC1)CC2
Temperature: 25 °C
Yield: 88 %

Procedure:
Using the apparatus and techniques previously employed to convert quinuclidine to N-fluoroquinuclidinium triflate in a closed reactor (R. E. Banks et al, J. Chem. Soc., Perkin Trans. I, 1988, 2805 and R. E. Banks and I. Sharif, J. Fluorine Chem., 1988, 41, 297) a degassed solution of 1-methyl-4-aza-1-azoniabicyclo[2,2,2]octane triflate (2.18 g, 7.90 mmol) and lithium triflate (1.23 g, 7.90 mmol) in cold (-35° C.), dry acetonitrile (200 cm3), was treated with neat fluorine (less than 20 mmHg (2.7 kPa) pressure) until absorption of the fluorine became imperceptible (3 hours). The reaction mixture was allowed to warm to room temperature, filtered to remove lithium fluoride which had precipitated, and the filtrate rotary evaporated and recrystallized from methanol to give 1-fluoro-4-methyl-1,4-diazoniabicyclo [2,2,2]octane ditriflate (3.10 g, 6.98 mmol, 88%). (Found: C, 24.0; H, 3.6; F, 29.8; N, 6.4%. Calc. C, 24.3; H, 3.4; F, 29.95; N, 6.3%), m.p. 220°-222° C. δF (solution in D2O; ext. CF3CO2H ref.) 1.0 (s; CF3SO3-), 124.5 (br. m; FN+) p.p.m., δH (same solution) 3.44 (s; CH3N+), 4.43 (m; 3×CH2), 4.88 (m; 3×CH2) p.p.m. [residual H in D2O, 4.68 (s) p.p.m⟧
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH:32]=O)=[CH:26]2)[CH3:18].N1CCCCC1>C(O)C>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH:32]=[C:11]1[C:10]3[C:14](=[CH:15][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][CH:9]=3)[NH:13][C:12]1=[O:16])=[CH:26]2)[CH3:35]
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: CCN(CC)CCOc1ccc2[nH]c(C=O)cc2c1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCOc1ccc2[nH]c(C=C3C(=O)Nc4cc(-c5ccccc5)ccc43)cc2c1
Temperature: 100 °C
Yield: 72 %

Procedure:
A mixture of 6-phenyl-2-oxindole (40.5 mg, 0.2 mmol), 5-(2-diethylamino-ethoxy)-1H-indole-2-carbaldehyde (50 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 65 mg (72%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][C:5]([CH2:6][CH:7]([CH2:11][C:12](=[O:30])[N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH2:15][CH2:14]2)[C:8](O)=[O:9])=[CH:4][C:3]=1[Cl:37].C([O:40][C:41](=[O:55])[CH2:42][N:43]1[CH2:48][CH2:47][N:46]([CH:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[CH2:45][CH2:44]1)C>>[NH2:1][C:2]1[C:32]([C:33]([F:35])([F:34])[F:36])=[CH:31][C:5]([CH2:6][CH:7]([CH2:11][C:12](=[O:30])[N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][C:20]3=[O:29])[CH2:15][CH2:14]2)[C:8]([N:52]2[CH2:51][CH2:50][CH:49]([N:46]3[CH2:45][CH2:44][N:43]([CH2:42][C:41]([OH:40])=[O:55])[CH2:48][CH2:47]3)[CH2:54][CH2:53]2)=[O:9])=[CH:4][C:3]=1[Cl:37]
Reactant: CCOC(=O)CN1CCN(C2CCNCC2)CC1
Reactant: Nc1c(Cl)cc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Product: Nc1c(Cl)cc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(CC(=O)O)CC3)CC2)cc1C(F)(F)F

Procedure:
Prepared analogously to Example 16.4 from 108 mg (0.20 mmol) 2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 51 mg (0.20 mmol) ethyl(4-piperidin-4-yl-piperazin-1-yl)-acetate.
Reaction SMILES: Cl.[CH2:2]([C:6]1([N:16]([CH3:18])[CH3:17])[CH2:15][CH2:14][C:9]2(OCC[O:10]2)[CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5].Cl>O>[CH2:2]([C:6]1([N:16]([CH3:18])[CH3:17])[CH2:15][CH2:14][C:9](=[O:10])[CH2:8][CH2:7]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC1(N(C)C)CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Product: CCCCC1(N(C)C)CCC(=O)CC1
Yield: 96 %

Procedure:
(8-butyl-1,4-dioxa-spiro[4.5]dec-8-yl)-dimethylamine hydrochloride (41.8 g, 0.15 mmole) was dissolved in water (78 ml) and 37% hydrochloric acid (100 ml, 1.2 mole) was added while stirring and cooling with ice. The clear reaction mixture was stirred for 7 days at room temperature. After completion of the hydrolysis the reaction mixture was extracted with diethyl ether (2×70 ml). The organic extracts were discarded. The aqueous phase was made alkaline with 5N sodium hydroxide solution (approximately 250 ml) while cooling with ice, and vigorously stirred. The solution was extracted with diethyl ether (3×100 ml). The combined organic extracts were washed with water (2×70 ml), dried and concentrated by evaporation. 4-butyl-4-dimethylamino-cyclohexanone (Ket-9) was obtained as a pale brown oil in a yield of 96% (28.4 g). The yield of ketone—referred to the ketal used in the first stage—was 75%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[N:25][NH:26]3)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][N:41]([C:44](=[O:46])[CH3:45])[CH2:40][CH2:39]2)=[CH:34][CH:33]=1.C[Si](Cl)(C)C>C(O)CCC>[NH:26]1[C:27]2[C:23](=[C:22]([NH:21][C:4]3[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:6]=4[N:7]=[C:2]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([N:38]5[CH2:39][CH2:40][N:41]([C:44](=[O:46])[CH3:45])[CH2:42][CH2:43]5)=[CH:36][CH:37]=4)[N:3]=3)[CH:30]=[CH:29][CH:28]=2)[CH:24]=[N:25]1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc5[nH]ncc45)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4cccc5[nH]ncc45)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Temperature: 115 °C

Procedure:
To a mixture of 2-chloro-N-(1H-indazol-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.12 g, 0.27 mmol) and 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (0.12 g, 0.54 mmol) in nBuOH (2 ml) was added TMSCl (0.017 mL, 0.14 mmol). After heating at 115° C. for 24 h, the mixture was purified by preparative HPLC to give 1-(4-(4-(4-(1H-indazol-4-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone.
Reaction SMILES: C[O:2][C:3]([C:7]1[CH:8]=[C:9]([C:21]([F:24])([F:23])[F:22])[C:10]([O:19][CH3:20])=[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:12]=1)(OC)[CH3:4].[Br-:25].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.S([O-])([O-])(=O)=S.O>CO.C1COCC1.CC(=O)OCC>[Br:25][CH2:4][C:3]([C:7]1[CH:8]=[C:9]([C:21]([F:24])([F:23])[F:22])[C:10]([O:19][CH3:20])=[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:12]=1)=[O:2]
Reactant: [Br-]
Reactant: COc1c(N2CCOCC2)cc(C(C)(OC)OC)cc1C(F)(F)F
Agent: C[N+](C)(C)c1ccccc1
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(N2CCOCC2)cc(C(=O)CBr)cc1C(F)(F)F
Temperature: 7 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
4-[5-(1,1-Dimethoxyethyl)-2-methoxy-3-trifluormethylphenyl]morpholine (O2.004; 460 mg) was dissolved in a mixture of methanol (1.4 ml) and THF (4 ml), the mixture was cooled to 7° C., and phenyltrimethylammonium tribromide (530 mg) was added in portions while stirring. After stirring at RT for 3 h, the mixture was left to stand overnight. Then aqueous thiosulfate solution (0.8 ml; w=5%) and water (4 ml) were added, and the mixture was admixed with EA and extracted three times with EA. The combined extracts were dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in a mixture of acetonitrile (20 ml) and water (0.5 ml) and admixed with TFA (0.5 ml) while stirring. After stirring at RT for 5 h, the solvent was drawn off, and the residue was admixed with water, neutralized with saturated sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The combined extracts were dried over magnesium, filtered and concentrated. The crude product was purified using silica gel with ethyl acetate/heptane as the eluent. 200 mg of the desired compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]2[C:3]=1[CH3:12].[F:13][C:14]1[C:22]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])=[CH:21][CH:20]=[C:19]([F:30])[C:15]=1[C:16](O)=[O:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:1][C:2]1[NH:11][C:5]2=[N:6][CH:7]=[C:8]([NH:10][C:16](=[O:17])[C:15]3[C:19]([F:30])=[CH:20][CH:21]=[C:22]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])[C:14]=3[F:13])[CH:9]=[C:4]2[C:3]=1[CH3:12]
Reactant: Cc1[nH]c2ncc(N)cc2c1C
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]c(C)c(C)c3c2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.9 %

Procedure:
2,3-Dimethyl-1H-pyrrolo[2,3-b]pyridin-5-amine (0.048 g, 0.298 mmol), 2,6-difluoro-3-(3-propylsulfonamido)benzoic acid (0.092 g, 0.328 mmol), EDCI (0.063 g, 0.328 mmol) and HOBt (0.040 g, 0.298 mmol) were dissolved in DMF (1.6 mL) and stirred at room temperature for 16 hours. The reaction mixture was directly purified by reverse phase HPLC to give N-(2,3-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.059 g, 47%) as a solid. 1H NMR (400 MHz, d6-DMSO) 11.23 (s, 1H), 10.77 (s, 1H), 9.19 (br s, 1H), 8.27-8.09 (m, 2H), 7.59-7.39 (m, 1H), 7.28-7.10 (m, 1H), 3.17-2.95 (m, 2H), 2.32 (s, 3H), 2.15 (s, 3H), 1.84-1.65 (m, 2H), 0.98 (s, 3H); m/z (ES-MS) 423.2 (96.1%) [M+1].
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.[CH2:16]([SH:19])[CH2:17][SH:18].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[S:18]1[C:12]2([CH2:13][CH2:14][CH:9]([C:3]3[CH:4]=[CH:5][C:6]([OH:8])=[CH:7][C:2]=3[OH:1])[CH2:10][CH2:11]2)[S:19][CH2:16][CH2:17]1
Reactant: SCCS
Reactant: O=C1CCC(c2ccc(O)cc2O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Oc1ccc(C2CCC3(CC2)SCCS3)c(O)c1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a round bottomed flask equipped with magnetic stirrer was added 4-(2,4-dihydroxyphenyl)cyclohexanone (1 g) and toluene (40 ml). To the stirred solution was added ethane-1,2-dithiol (0.49 ml) and a few crystals of ptoluenesulfonic acid monohydrate and the reaction mixture was heated under reflux for 3.5 hr. The reaction mixture was cooled to room temperature, saturated sodium hydrogencarbonate solution (20 ml) was added, and the layers were separated. The aqueous layer was diluted with water (40 ml) and extracted into ethyl acetate (3×30 ml). The combined organic phases were washed with brine (30 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash chromatography (SiO2, ethyl acetate/petroleum ether 2:3 v/v) furnished the title compound (1.34 g, 98%) as a white solid. δH (CD3OD): 1.59-1.73 (2H, m), 1.75-1.84 (2H, m), 1.98-2.08 (2H, m), 2.14-2.22 (2H, m), 2.77 (1H, tt), 3.22-3.32 (4H, m), 6.18-6.24 (2H, m), 6.85 (1H, d); m/z (ES+) 283 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=1[NH:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].CN(C)C=O.[NH2:31][NH:32][C:33]([NH2:35])=[S:34]>C(Cl)Cl.N1C=CC=CC=1>[NH2:35][C:33](=[S:34])[NH:32][NH:31][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=1[NH:16][C:9]1[C:10]([Cl:15])=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[Cl:7]
Reactant: NNC(N)=S
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(=O)O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)c(Nc2ccccc2C(=O)NNC(N)=S)c1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 42.4 %

Procedure:
Oxalyl chloride (2.85 g, 22.5 mmol) in 10 ml of methylene chloride is added dropwise to a 0° C. suspension of 2-[(2,6-dichloro-3-methylphenyl)amino]-benzoic acid (3.17 g, 10.6 mmol) and dimethylformamide (830 μl, 10.6 mmol) in 50 ml of methylene chloride. The clear yellow solution is stirred at 0° C. for 15 minutes and then at room temperature for 30 minutes. The solution is then concentrated in vacuo to give a yellow solid. This solid is added in portions to a suspension of thiosemicarbazide (1.95 g, 21.4 mmol) in 20 ml of pyridine. The suspension is stirred at 0° C for 30 minutes then at room temperature overnight. The reaction mixture is concentrated in vacuo and the residue is partitioned between ethyl acetate and water. The organic layer is concentrated, then slurried with equal volumes of ethyl acetate and hexane. The off-white solid is collected by filtration providing 1.66 g (42%) of 2-[(2,6-dichloro-3-methylphenyl)amino]-benzoic acid, 2-(aminothioxomethyl) hydrazide, mp is undefined.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]1[N:17]([CH3:29])[C:18](=[O:28])[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:20][C:10]2=1)=O.O.[NH2:32]N>>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[C:18](=[O:28])[N:17]([CH3:29])[C:11]3[N:12]([CH3:16])[C:13]4[C:9]([C:10]=3[CH:20]=2)=[CH:8][C:7]([C:5]2[NH:32][N:2]=[CH:3][CH:4]=2)=[CH:15][CH:14]=4)=[CH:26][CH:25]=1
Reactant: NN
Reactant: CN(C)C=CC(=O)c1ccc2c(c1)c1cc(-c3ccc(F)cc3)c(=O)n(C)c1n2C
Solvent: O
Product: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21

Procedure:
The process is carried out as in Example 40 above, using compound B 6-(3-dimethylaminoacryloyl)-3-(4-fluorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and hydrazine hydrate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH2:31]Cl)[CH:26]=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCCC1.CN(C)C=O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:31][C:30](=[O:33])[NH:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH:24]=3)[CH2:13][CH2:14]2)=[CH:16][CH:17]=1
Reactant: O=C(CCl)Nc1cccc(F)c1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)Nc1cccc(F)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 300 mg of 1-[bis(4-fluorophenyl)methyl]piperazine and 234 mg of N-(3-fluorophenyl)chloroacetamide was dissolved in 20 ml of a 1:1 by volume mixture of tetrahydrofuran and N,N-dimethylformamide, and 400 mg of anhydrous potassium carbonate were added to the solution. The reaction mixture was then stirred at 70° C. for 2 hours, after which ethyl acetate was added to it and the organic layer was separated. The organic layer was washed three times with water, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was subjected to silica gel thin layer chromatography using a 2:1 by volume mixture of cyclohexane and ethyl acetate as the developing solvent, to give a purified 1-[bis(4-fluorophenyl)methyl]-4-(3-fluorophenylcarbamoylmethyl)piperazine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:9]=[CH:8][C:7]=2[N:6]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:5]=1.[CH2:30](I)[CH3:31]>>[CH2:30]([O:1][CH2:2][CH2:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:20])[CH3:21])[N:9]=[CH:8][C:7]=2[N:6]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[CH:5]=1)[CH3:31]
Reactant: CCI
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CCO)cn2COCC[Si](C)(C)C)c1=O
Product: CCOCCc1cn(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Yield: 63.1 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Reference example 57-(f) except for using 1.15 g (2.61 mmol) of 3-(2-hydroxyethyl)-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained by the same manner as in Reference example 57-(e), and using 1.3 ml (18.7 mmol) of ethyl iodide in place of methyl iodide, whereby 0.77 g of the title compound was obtained as a slightly yellowish oil. (Yield: 63%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc3c(c2)OCO3)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccc3c(c2)OCO3)cc1

Procedure:
A mixture of 4.6 g (21.67 m moles) of 4-methyl-3', 4'-methylenedioxy-1,1-biphenyl and 5.0 g (28 m mole) of N-bromosuccinimide in 70 ml of carbon tetrachloride containing 0.1 g of benzoyl perioxide is heated under reflux for 2.5 hours. The mixture is filtered and the filtrate evaporated. The residue is recrystallized from hexane to afford (m.p. 78°-81°).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[C:22]1([C:28]2[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:16]1([C:3]2[C:2]([C:31]3[CH:32]=[CH:33][C:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:29][CH:30]=3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=3)[N:4]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(-c3ccc(-c4ccccc4)cc3)nc2c1
Yield: 51.4 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and 4-phenyl-phenylboronic acid (100 mg, 0.51 mmol, 1.50 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (15:1)) yielded 60 mg (51%) of 2-phenyl-3-(4-phenyl-phenyl)quinoxaline-6-carboxylic acid as a light yellow solid.