Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]([C:40](=[N:44][OH:45])[C:41]([OH:43])=[O:42])[C:21]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]5[CH:38]=[CH:37][C:36]6[C:31](=[CH:32][C:33]([Cl:39])=[CH:34][CH:35]=6)[N:30]=5)=[CH:23][CH:22]=4)=[CH:16][CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+:47]>CCO.C1COCC1>[Na+:47].[Cl:39][C:33]1[CH:32]=[C:31]2[C:36]([CH:37]=[CH:38][C:29]([CH2:28][O:27][C:24]3[CH:23]=[CH:22][C:21]([CH:20]([C:40](=[N:44][OH:45])[C:41]([O-:43])=[O:42])[C:17]4[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:8]5[CH:7]=[CH:6][C:5]6[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=6)[N:9]=5)=[CH:19][CH:18]=4)=[CH:26][CH:25]=3)=[N:30]2)=[CH:35][CH:34]=1
Reactant: O=C(O)C(=NO)C(c1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1)c1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C([O-])C(=NO)C(c1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1)c1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
To a solution in EtOH--THF (3:1, 4 mL) of bis(4-(7-chloro-2-quinolyl-methoxy)phenyl)methyloximinoacetic acid (240 mg, 0.4 mmol), prepared as in Example 5, was added 1N aqueous NaOH (0.5 mL, 0.5 mmol). The mixture was stirred overnight at room temperature and concentrated in vacuo. The residue was slurried in ether (15 mL), filtered, and dried in vacuo to provide bis(4-(7-chloro-2-quinolylmethoxy)phenyl)methyloximinoacetic acid sodium salt (220 mg): mp 181°-183° C.; 1H NMR (300 MHz, DMSO-d6)δ4.15 (s, 2H), 5.41 (m, 4H), 7.07 (dd, 4H, J=12, 3 Hz), 7.28 (d, 2H, J=9 Hz), 7.56 (d, 2H, J=9 Hz), 7.73 (m, 4H), 8.06 (m, 4H), 8.49 (m, 2H); MS (FAB) 660 (M+H)+, 682 (M+Na)+. Anal. Calcd. for C35H24Cl2N3O5Na×2.5 H2O: C, 59.58, H, 4.11; N, 5.96. Found C, 59.61; H, 3.94; N, 5.72.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[N+:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18])([O-:13])=[O:12]>N1C=CC=CC=1>[N+:11]([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1)=[O:18])([O-:13])=[O:12]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Oc1n[nH]c2ccccc12
Solvent: c1ccncc1
Product: O=C(c1cccc([N+](=O)[O-])c1)n1nc(O)c2ccccc21
Temperature: 95 °C
Yield: 27.9 %

Procedure:
To 16.0 (0.118 mol) of 1H-indazol-3-ol dissolved in 120 ml of dry pyridine was added 21.8 g (0.118 mol) of m-nitrobenzoyl chloride. The heterogeneous yellow mixture was heated at 95° C. for 21/2 hrs. then let cool to room temperature and poured onto 1 liter of ice/H2O. The light yellow precipitate was collected, washed well with H2O and air-dried. Recrystallization from aqueous EtOH afforded 12.7 g (27.9%) of 1-(m-nitrobenzoyl)-1H-indazol-3-ol as a colorless solid, mp 232°-234° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:40])[C:31]1[CH:36]=[C:35]([F:37])[C:34](O)=[C:33]([F:39])[CH:32]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:28][O:29][C:30](=[O:40])[C:31]1[CH:32]=[C:33]([F:39])[C:34]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:35]([F:37])[CH:36]=1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: COC(=O)c1cc(F)c(O)c(F)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1cc(F)c(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1
Yield: 59 %

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c), 3,5-difluoro-4-hydroxy-benzoic acid methyl ester (commercially available) and di-tert-butyl azodicarboxylate. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30) to give the desired compound as a light yellow foam (59%). MS (Turbo Spray): m/z=561.2 [M+H].
Reaction SMILES: [CH:1]12[CH2:15][CH2:14][CH:4]([C:5]3[C:6]4[C:11]([NH:12][C:13]=31)=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH2:3][CH:2]2[N:16](C)[CH:17]=O.[CH2:20](O)C>[OH-].[Na+]>[CH3:17][NH:16][CH:2]1[CH2:3][CH:4]2[CH2:14][CH2:15][CH:1]1[C:13]1[N:12]([CH3:20])[C:11]3[C:6]([C:5]=12)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: CN(C=O)C1CC2CCC1c1[nH]c3ccccc3c12
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: CNC1CC2CCC1c1c2c2ccccc2n1C

Procedure:
A solution of N-(2,3,4,9-tetrahydro-1,4-ethano-1H-carbazol-2-yl)-N-methyl-formamide (3.9 g, 0.0145 mole, described in Example 7) in 20 ml of 10% sodium hydroxide and 40 ml ethanol was refluxed under nitrogen on a steam-bath for 5 hr. The solution was evaporated to dryness and the residue was taken up in diethyl ether. The organic layer was washed (3×) with 2 N hydrochloric acid and the acidic layer was washed with diethyl ether. The aqueous layer was made basic with 25% sodium hydroxide and extracted with diethyl ether. The ether extract was washed with water, dried, evaporated to afford the title compound as a pale yellow oil (3 g): NMR (CDCl3) δ 1.0 (s, 1H), 2.32 (3, 3H), 3.75 (s, 3H) and 2.1-7.7 (m, 4H). It was chromatographed on silica gel and eluted with 5% methanol-chloroform to give a pale yellow oil (2.2 g) which was dissolved in dichloromethane and treated with a solution of hydrogen chloride in diethyl ether to form a gummy precipitate. The residue was crystallized from methanol-dichloromethane-diethyl ether to yield a greenishgray compound (2.0 g). Recrystallization from methanol-dichloromethanediethyl ether afforded the hydrochloride salt of the title compound as an off-white powder (1.95 g): mp 204°-205° C.; and Anal. Calcd for C16H20N2.HCl: C, 69.41% H, 7.65% N, 10.12% and Found: C, 69.25% H, 7.55% N, 9.89%.
Reaction SMILES: [NH2:1][C:2](=[O:20])[C@@H:3]([NH:12]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][CH:6]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:12][C@@H:3]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([I:11])=[CH:9][CH:10]=1)[C:2]([NH2:1])=[O:20]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@@H](N)Cc1ccc(I)cc1
Reaction time: 2 h

Procedure:
(S)-tert-Butyl 1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamate (Example 1, step (i), 2.41 g) was stirred in dichloromethane (125 mL) and to the suspension was added trifluoroacetic acid (8 mL). The mixture was stirred for 2 h and then concentrated to ˜12 mL in vacuo. The residue was stirred for 2 days, dissolved in ethyl acetate/dichloromethane and washed with water containing an excess of sodium bicarbonate. The organic layer was dried and evaporated to the sub-titled compound (1.52 g).
Reaction SMILES: CO[CH:3]1[CH:7]=[CH:6][CH:5](OC)[O:4]1.[CH2:10]([O:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11].O>[Cl-].[Zn+2].[Cl-].C(O)(=O)C>[CH2:10]([O:12][C:13](=[O:20])[CH:14]([C:5]1[O:4][CH:3]=[CH:7][CH:6]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11]
Reactant: COC1C=CC(OC)O1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.9 %

Procedure:
340 g (2.5 mmol) of zinc chloride were added in one portion to a solution of 217 g (1.67 mol) of 2,5-dimethoxy-2,5-dihydrofuran, 1500 ml (10 mol) of malonic acid diethyl ester, 167 ml of Water and 330 ml of glacial acetic acid. The temperature rose to 35°. The dark solution was stirred at room temperature overnight, poured onto ice, extracted three times with diethyl ether, washed in succession with saturated sodium bicarbonate and sodium chloride solutions, and finally dried. After evaporating the excess malonic acid diethyl ester (70°/13 Pa), the remaining oil was distilled over a Vigreux column, to obtain 109.2 g (29%) of 2-furylmalonic acid diethyl ester (purity 94%), boiling point 100°-110°/39 Pa.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:8][CH:7]([C:9]([CH2:11][S:12][C@H:13]2[N:16]([C:17](=P(CCCC)(CCCC)CCCC)[C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[O:19])[C:15](=[O:43])[C@H:14]2[NH:44][C:45](=[O:54])[CH2:46][O:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=O)[CH2:6][CH2:5]1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH:4]1[O:8][CH:7]([C:9]2[CH2:11][S:12][C@@H:13]3[C@H:14]([NH:44][C:45](=[O:54])[CH2:46][O:47][C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:15](=[O:43])[N:16]3[C:17]=2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:19])[CH2:6][CH2:5]1
Reactant: CCCCP(CCCC)(CCCC)=C(C(=O)OCc1ccc(OC)cc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SCC(=O)C1CCC(COC)O1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Product: COCC1CCC(C2=C(C(=O)OCc3ccc(OC)cc3)N3C(=O)[C@@H](NC(=O)COc4ccccc4)[C@H]3SC2)O1
Yield: 62.8 %

Procedure:
A solution of 4-methoxybenzyl 2-[(3R,4R)-4-[(2RS,5SR)-5-methoxymethyltetrahydrofuran-2-ylcarbonylmethylthio]-3-phenoxyacetamidoazetidin-2-on-1-yl]-2-tri-n-butylphosphoranylideneacetate (4.25g) and benzoic acid (20mg) in toluene (100ml) was heated to reflux for 10h. The mixture was cooled and the solvent evaporated. The product (1.93g) was isolated by column chromatography of the residue using gradient elution (silica gel 1:1 hexane : ethyl acetate going to neat ethyl acetate); vmax (CHCl3) 3409, 1784, 1722 and 1695cm-1.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)(=O)=O.C([Li])CCC.[CH2:38]([OH:41])[CH2:39][CH3:40]>>[CH2:38]([O:41][C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)[CH2:39][CH3:40]
Reactant: CCCO
Reactant: CS(=O)(=O)c1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: [Li]CCCC
Product: CCCOc1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
2-Methylsulfonyl-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 86 (50 mg, 0.1 mmol) was reacted with 2 equivalents each of n-butyl lithium and n-propanol by the procedure described in Reference Examples 6 and 7 to afford 2-(2-n-propyloxy-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine. HPLC/MS: m/e=486 (M++1); Rt4.13 min. 1H-NMR 500 MHz (CDCl3): δ 0.96 (t, 3H), 1.73-1.79 (m, 2H), 4.13-4.18 (m, 2H), 7.18-7.30 (m, 7H), 7.40-7.43 (m, 1H), 7.60 (m, 1H), 8.55 (s, 2H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])C.C1COCC1.[BH4-].[Li+].[Cl-].[NH4+]>CCOC(C)=O>[OH:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)Cc1cccc(C(=O)OCC)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(CCO)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
Ethyl 3-(2-ethoxy-2-oxoethyl)benzoate (1.41 g) was mixed with THF (20 ml), and lithium borohydride (260 mg) was added thereto at 0° C., followed by stirring at room temperature overnight. A saturated ammonium chloride solution and EtOAc were added to the reaction mixture at 0° C. The organic layer was washed with water and saturated brine, dried over Na2SO4, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain ethyl 3-(2-hydroxyethyl)benzoate (824 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][C:15]([C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1)[NH2:21])([CH3:17])[CH3:16]>>[CH3:17][C:15]([C:18]1[CH:19]=[C:20]([NH:21][C:9](=[O:11])[C:8]2[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[OH:13])[CH:22]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:24]=1)([CH3:14])[CH3:16]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Product: CC(C)(C)c1cc(NC(=O)c2cc([N+](=O)[O-])ccc2O)cc(C(C)(C)C)c1
Yield: 46.7 %

Procedure:
Using 5-nitrosalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [N:1]([CH:4]([CH:10]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1>O>[NH2:1][CH:4]([CH:10]([O:18][Si:19]([C:22]([CH3:23])([CH3:25])[CH3:24])([CH3:21])[CH3:20])[C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(N=[N+]=[N-])C(O[Si](C)(C)C(C)(C)C)c1cccnc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(N)C(O[Si](C)(C)C(C)(C)C)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 113 %

Procedure:
A mixture of 5.6 g of ethyl 2-azido-3-t-butyldimethylsilyloxy-3-(2-chloropyridin-3-yl)propionate (prepared described in Preparation 77), 7.5 g of triphenylphosphine and 18 ml of a 8:1 by volume mixture of tetrahydrofuran and water was stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation. The residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate and subsequently a 50:1 by volume mixture of methylene chloride and methanol as the eluent, to give 5.9 g of the title compound having Rf=0.59 (on silica gel thin layer chromatography using a 15:1 by volume mixture of methylene chloride and methanol as the developing solvent).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[CH3:13])(=[O:3])[CH3:2].C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1C=CC=CC=1>C(O)C>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[CH:15][C:16]([OH:18])=[O:17])=[CH:7][C:6]=1[CH3:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C=O)cc1C
Reactant: O=C(O)CC(=O)O
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(C=CC(=O)O)cc1C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A mixture of 4-acetamido-3-methylbenzaldehyde (1.23 g), malonic acid (795 mg), pyridine (549 mg) and ethanol (1.7 ml) was refluxed for 3 hours under nitrogen atmosphere. To the mixture was added ethanol (1.7 ml), and the mixture was stirred for 30 minutes under ice-bath cooling. The resulting precipitate was collected by filtration and washed with ethanol to give 4-acetamido-3-methylcinnamic acid (1.08 g).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Br[CH2:6][C:7]1[O:11][N:10]=[C:9]([CH3:12])[CH:8]=1>C(#N)C>[CH3:12][C:9]1[CH:8]=[C:7]([CH2:6][NH:3][CH2:2][CH2:1][NH2:4])[O:11][N:10]=1
Reactant: Cc1cc(CBr)on1
Reactant: NCCN
Solvent: CC#N
Product: Cc1cc(CNCCN)on1
Temperature: 20 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
Ethylenediamine (30 g) was dissolved in 120 g of acetonitrile, and a solution of 17.6 g of 5-bromomethyl-3-methylisoxazole in 30 ml of acetonitrile was added dropwise at 5 to 10° C. After the addition, the mixture was stirred for 1 hour with a care taken not to permit the temperature of the reaction system to rise above 20° C. Then, most of the volatile materials were removed under vacuum (less than 2 mmHg) while maintaining the bath temperature at 20° C. Ice water was added to the residue, and the mixture was extracted with dichloromethane. The dichloromethane layer was dehydrated, and dichloromethane was distilled off under reduced pressure to give 10.0 g of N-(3-methyl-5-isoxazolylmethyl)ethylenediamine (purity about 95%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:13][CH3:14])=[N:4][C:5]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)=[N:6][CH:7]=1.[Cl:15][S:16](O)(=[O:18])=[O:17]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([S:13][CH3:14])=[N:4][C:5]([C:8]2[O:9][C:10]([S:16]([Cl:15])(=[O:18])=[O:17])=[CH:11][CH:12]=2)=[N:6][CH:7]=1
Reactant: CSc1nc(-c2ccco2)ncc1Cl
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CSc1nc(-c2ccc(S(=O)(=O)Cl)o2)ncc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-2-(furan-2-yl)-4-(methylthio)pyrimidine (800 mg, 3.53 mmol, 1.0 equiv.) in CH2Cl2 (5 mL) was added ClSO3H (25 mL) dropwise at −20° C. The reaction mixture was stirred at 25° C. for 2 h, then, quenched with cracked ice at −20° C. The mixture was extracted with ethylacetate. The combined organic layers was dried with Na2SO4 to give a solution of 5-(5-chloro-4-(methylthio)pyrimidin-2-yl)furan-2-sulfonyl chloride in ethylacetate, to which t-butylamine (10 mL) was added. The mixture was stirred at 20° C. for 2 h, then, concentrated. The residue was purified by column chromatography to afford N-tert-butyl-5-(5-chloro-4-(methylthio)pyrimidin-2-yl)furan-2-sulfonamide (147 mg, 12% over 2 steps). LC-MS (m/z)=362.0 [M+H]+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH:31]([CH3:35])[N:30]1[CH2:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1>>[CH3:35][CH:31]1[CH2:32][CH2:33][CH2:34][CH:29]([CH3:28])[N:30]1[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([NH:41]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:42][CH:43]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CC1CCCC(C)N1Cc1ccc(N)cc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2C(C)CCCC2C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-[(2,6-dimethyl-piperidin-1-yl)-methyl]-aniline Rf value: 0.5 (RP 8, methanol/five percent saline solution=4:1) C31H33N3O3
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[O:5].Br[CH2:13][CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:1][C:2]1[C:9]([O:10][CH2:13][CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(F)ccc(O)c1F
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1c(F)ccc(OCCOC2CCCCO2)c1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.2 %

Procedure:
To 2,6-difluoro-3-hydroxy-benzaldehyde (540, 0.150 g, 0.95 mmol) in N,N-dimethylformamide (8.0 mL) were added 2-(2-bromo-ethoxy)-tetrahydro-pyran (0.218 g, 1.04 mmol) and potassium carbonate (0.52 g, 3.8 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 72 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the compound as colorless oil (541, 180 mg, 66%).
Reaction SMILES: Cl[C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1.[Br:14][C:15]1[CH:33]=[CH:32][C:18]([O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH:21]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:17][CH:16]=1.C(N(CC)CC)C>CN(C)C=O>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([C:2]3[N:12]4[C:13]5[C:8]([CH2:9][CH2:10][CH2:11]4)=[CH:7][CH:6]=[CH:5][C:4]=5[N:3]=3)[CH2:22][CH:21]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:32][CH:33]=1
Reactant: Clc1nc2cccc3c2n1CCC3
Reactant: Brc1ccc(OC2CCNCC2c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Brc1ccc(OC2CCN(c3nc4cccc5c4n3CCC5)CC2c2ccccc2)cc1
Yield: 55.9 %

Procedure:
A solution of 2-chloro-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline (3.00 g), 4-(4-bromophenoxy)-3-phenylpiperidine (5.20 g), triethylamine (1.62 g) and dimethylformamide (50 ml) was stirred at 115° C., under nitrogen, overnight. The solution was poured onto ice water (600 ml) and the precipitate was collected. The precipitate was dissolved in dichloromethane and the solution was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated. The residue was triturated with ethyl acetate and then recrystallized from chloroform-ether to give 4.25 g (56%) of product, mp 188°-189° C.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH:9]=[C:8]1[C@H:7]([CH3:22])[C:6](=[O:23])[CH2:5][C@@H:4]2[CH3:24].CS(C)=O.C1C=CC=CC=1.FC(F)(F)C(O)=O>C(OCC)(=O)C.N1C=CC=CC=1>[CH3:24][C@@H:4]1[C@@:3]2([CH:2]=[O:1])[C:8](=[CH:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]2=[O:21])[C@H:7]([CH3:22])[C:6](=[O:23])[CH2:5]1
Reactant: C[C@@H]1C(=O)C[C@H](C)[C@@]2(CO)C1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: C[C@@H]1C(=O)C[C@H](C)[C@@]2(C=O)C1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
19-Hydroxy-1α,4α-dimethyl-5-androstene-3,17-dione is added to a mixture containing dimethylsulfoxide, benzene, pyridine, trifluoroacetic acid and N,N-dicyclohexylcarbodiimide and allowed to react for about 12 hours at room temperature. Ethyl acetate is added and the reaction mixture is filtered, extracted with a cold solution of sodium bicarbonate, washed with water, and dried over magnesium sulfate. After evaporation of the volatile solvents at room temperature under reduced pressure, the residue which remains is crystallized from an ether-pentane mixture to yield 1α,4α-dimethyl-5-androstene-3,17,19-trione.
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=[CH:29][C:28]=1[C:37](O)=[O:38].FC(F)(F)C(O)=O>ClCCl>[CH2:19]([N:18]([C:37]([C:28]1[CH:29]=[N:30][C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:27]=1)=[O:38])[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C(O)c1cnc2ccccc2n1
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)C(=O)c1cnc2ccccc2n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and quinoxaline-2-carboxylic acid as starting materials and by an operation similar to that of Example 312-1 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=50:1) to give the title compound.