Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]([CH3:16])([C:10]1[NH:14][C:13](=[O:15])[O:12][N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].CO.[C:20]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]([CH3:9])([C:10]1[N:14]([CH3:20])[C:13](=[O:15])[O:12][N:11]=1)[CH3:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1noc(=O)[nH]1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(C(C)(C)NC(=O)OC(C)(C)C)noc1=O
Temperature: 2.5 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
To a colorless solution of [1-methyl-1-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-ethyl]-carbamic acid tert-butyl ester (1.5 g, 6.17 mmol) in THF (30.0 mL) was added methanol (296 mg, 374 μl, 9.25 mmol) and triphenylphosphine (1.94 g, 7.4 mmol). The mixture was cooled to 0-5° C. and diisopropyl azodicarboxylate (1.5 g, 1.46 ml, 7.4 mmol) was added slowly over a period of 20 minutes at max: 5° C. The mixture was stirred for another 30 minutes at 0-5° C. and for 16 hours at room temperature. Solvents were removed in vacuo and the residue was purified by flash chromatography (silica gel, 70 g, 0% to 100% ethyl acetate in heptane) to give the title compound (1.4 g, 89%) as white solid; GC-MS (EI) 98%, 257.0 (M)+.
Reaction SMILES: CC(C)([O-])C.[K+].F[C:8]1[C:18]([F:19])=[C:17]([F:20])[CH:16]=[CH:15][C:9]=1[NH:10][C@@H:11]([CH3:14])[CH2:12][OH:13].C(O[CH:24]=[C:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])C>CN(C=O)C>[F:20][C:17]1[CH:16]=[CH:15][C:9]2[N:10]([CH:24]=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C@@H:11]([CH3:14])[CH2:12][O:13][C:8]=2[C:18]=1[F:19]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CN1c2ccc(F)c(F)c2OC[C@@H]1C)C(=O)OCC
Yield: 65.2 %

Procedure:
To DMF (2 ml) was added potassium tertiary-butoxide (226 mg) under ice-cooling. After dropping a solution of the compound (100 mg) obtained in Example 51 and diethyl ethoxymethylenemalonate (293 mg) in DMF (0.5 ml), the resultant mixture was stirred at room temperature for 18 hours. After treating in a conventional manner, the obtained residue was subjected to silica gel column chromatography to thereby give 113 mg (65%) of the title compound. The physical constants of the obtained compounds was identical with those described in Japanese Patent No. 2,769,174.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH3:12][S:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>>[CH3:12][S:13][C:14]1[CH:15]=[C:16]([NH:17][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=2[F:11])[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CSc1cccc(N)c1
Product: CSc1cccc(NC(=O)c2ccc(Br)cc2F)c1

Procedure:
460 mg of N1-[3-(methylsulfanyl)phenyl]-4-bromo-2-fluorobenzamide obtained in the same manner as in Production Example 32 from 4-bromo-2-fluorobenzoic acid and 3-(methylthio)aniline was stirred for 1.5 hours together with 1.23 g oxone in 15 mL tetrahydrofuran, 10 mL methanol and 10 mL water. The reaction solution was extracted with ethylacetate and purified by NH silica gel column to give 500 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([S:25]([NH2:28])(=[O:27])=[O:26])[CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]=3[N:11]=[C:10]([NH2:20])[C:9]=2[N:8]=[C:7]1[CH2:21][O:22][CH2:23][CH3:24].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH3:1][C:2]([CH3:29])([S:25]([NH2:28])(=[O:27])=[O:26])[CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:13][C:12]=3[N:11]=[C:10]([NH2:20])[C:9]=2[N:8]=[C:7]1[CH2:21][O:22][CH2:23][CH3:24]
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCC(C)(C)S(N)(=O)=O
Reactant: OB(O)c1ccccc1
Product: CCOCc1nc2c(N)nc3cc(-c4ccccc4)ccc3c2n1CCCC(C)(C)S(N)(=O)=O
Yield: 20.8 %

Procedure:
Dimethyl 4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide (0.66 g, 1.4 mmol) and phenyl boronic acid (0.20 g, 1.6 mmol) were coupled according to the method described in Part J of Example 1. The reaction was heated at reflux for 14 hours, and the work-up procedure used in Part F of Examples 125-135 was followed. The crude product was recrystallized from methanol and then purified by column chromatography on silica gel (eluting with chloroform:CMA in a gradient from 100:0 to 90:10). The solid was then purified by HPFC to provide 0.14 g of dimethyl 4-[4-amino-2-ethoxymethyl-7-phenyl-1H-imidazo[4,5-c]quinolin-1-yl]butane-1-sulfonamide as Off-white needles, mp 207-208° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[N:5][C:6]2[C:7](=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=2)[N:8]=1.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>C(O)C>[CH2:15]([N:17]([CH2:2][C:3]1[N:4]=[N:5][C:6]2[C:7](=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=2)[N:8]=1)[CH2:18][CH3:19])[CH3:16]
Reactant: CCNCC
Reactant: Nc1nc(N)c2nc(CCl)nnc2n1
Solvent: CCO
Product: CCN(CC)Cc1nnc2nc(N)nc(N)c2n1
Temperature: 100 °C

Procedure:
A mixture of 3-Chloromethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine 3 (200 mg; 0.95 mmol) and diethylamine (2.00 mL) in absolute ethanol (2.0 mL) was heated to 100° C. in a sealed tube for 5 h. The mixture was then allowed to cool to room temperature and concentrated in vacuo. The crude product was purified by reverse phase HPLC (Rainin C18, 0% CH3CN to 30% CH3CN gradient, CH3CN/H2O, 0.1% TFA) and the bright yellow fractions containing the product were lyophilized after removal of CH3CN in vacuo to give 65 mg of yellow colored 3-Diethylaminomethyl-pyrimido[5,4-e][1,2,4]triazine-5,7-diamine 4 as the trifluoroacetate salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].Br[CH2:35][CH2:36][O:37][Si](C(C)(C)C)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:35][CH2:36][OH:37])[CH2:14][CH2:13][CH2:12][N:11]3[C:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[O:28][C:27]([CH3:29])=[N:26][CH:25]=5)=[C:20]([O:30][CH3:31])[CH:19]=4)=[N:16][N:17]=[C:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COc1cc(-c2nnc3n2CCCC3c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2nnc3n2CCCC3(CCO)c2ccc(Cl)c(Cl)c2)ccc1-c1cnc(C)o1
Reaction time: 0.5 h

Procedure:
To a mixture of 8-(3,4-dichlorophenyl)-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine (200 mg) in DMF (5 mL) was added sodium hydride (60%, 31.6 mg) under ice-cooling, and the mixture was stirred for 30 min under a nitrogen atmosphere. (2-Bromoethoxy)(tert-butyl)dimethylsilane (113 μL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a mixture of the residue in THF (2 mL) was added TBAF (1M THF solution, 439 μL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (26.9 mg).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][C@H:14]([OH:21])[C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:22])[CH2:3]1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].N1C=CN=C1>CN(C)C1C=CN=CC=1.CN(C)C=O.CCOCC>[Si:23]([O:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][C@H:14]([OH:21])[C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:22])[CH2:3]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2C[C@H](O)[C@]2(C)C(=O)CC[C@@H]12
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2C[C@H](O)[C@]2(C)C(=O)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3α, 12α-dihydroxy-5β-androstan-17-one (4.29 g), tert-butyldimethylsilyl chloride (3.26 g), 4-dimethylaminopyridine (0.17 g) and imidazole (1.9 g) in dimethylformamide (38 ml) is stirred at room temperature for about 1 hour, diluted with ether and washed with water. The organic solution is dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product which is used, without further treatment, for the next step.
Reaction SMILES: [N+:1]([C:4]1[O:5][C:6]2[C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:7]=2[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O-:3])=[O:2].Cl.[CH2:23]([N:25]([CH2:28][CH2:29]Cl)[CH2:26][CH3:27])[CH3:24].C(N(CC)CC)C>CN(C)C=O>[N+:1]([C:4]1[O:5][C:6]2[C:18]([C:19]([O:21][CH2:24][CH2:23][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:20])=[CH:17][CH:16]=[CH:15][C:7]=2[C:8]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12
Reactant: CCN(CC)CCCl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCOC(=O)c1cccc2c(-c3ccccc3)c([N+](=O)[O-])oc12
Reaction time: 48 h

Procedure:
A mixture of 14.2 g (0.05 mole) of 2-nitro-3-phenyl-7-benzofurancarboxylic acid, 8.6 g (0.05 mole) of N,N-diethylamino-2-chloroethane hydrochloride, 10.1 g (0.1 mole) of triethylamine and 75 ml of N,N-dimethylformamide is heated at 90° to 100° C. for 16 hours, then left standing at 23° C. for 2 days. The mixture is cooled with an ice bath, then filtered to remove the white solid by-product. The filtrate is dissolved in diethyl ether, washed thrice with water and twice with saturated sodium chloride solution and dried. The solution is evaporated to provide an oil, N,N-diethylaminoethyl 2-nitro-3-phenyl-7-benzofurancarboxylate. This oil is dissolved in diethyl ether and treated with 25 ml of 4N-hydrochloric acid in isopropanol to provide a product which gradually solidifies. The product is recrystallized twice from ethanol to provide, N,N-diethylaminoethyl 2-nitro-3-phenyl-7-benzofurancarboxylate hydrochloride, m.p. 194.5°-195° C., as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:12]([CH3:18])[C:13](=O)[CH2:14][CH2:15]Cl.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1C=CC=CC=1>[CH3:18][N:12]1[C:3]2[CH:4]=[CH:5][C:6]3[C:11]([C:2]=2[N:1]=[C:13]1[CH2:14][CH2:15][N:28]1[CH2:29][CH2:30][N:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:26][CH2:27]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CN(C(=O)CCCl)c1ccc2ccccc2c1N
Solvent: c1ccccc1
Product: Cn1c(CCN2CCN(c3ccccc3)CC2)nc2c3ccccc3ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.4 %

Procedure:
A solution of 5.25 g (0.02 mole) of N-(1-amino-2-naphthyl)-3-chloro-N-methyl-propanamide in 150 cc of anhydrous benzene is gradually added to a solution of 9.73 g (0.06 mole) of 1-phenylpiperazine in 25 cc of anhydrous benzene under argon atmosphere over a period of time of twenty minutes. The reaction mixture is then refluxed for 21 hours. Further, 11.73 g (0.0724 mole) of 1-phenylpiperazine is added and reflux is continued for an additional 24 hours. After cooling to room temperature, the mixture is diluted with 350 cc of benzene, poured into a separatory funnel and washed with 100 cc of water containing 7.8 cc of acetic acid. The benzene phase is extracted four times with 40 cc portions of 8% HCl. The pH of the aqueous acid phase is brought to 9 by addition of concentrated NH4OH and this aqueous solution is extracted with methylene chloride. The organic extracts are combined, dried over Na2SO4 , filtered and evaporated to dryness yielding 4.03 g of raw compound which is recrystallized from 25 cc of ethanol. M.p. 153°-155° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:22][CH:23]3[CH2:40][CH:39]4[N:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]5[C:36]([C:42](O)=[O:43])([NH:37][C:38]4=[O:41])[CH2:35]5)[CH2:24]3)=[N:8][C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[N:10]2)=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.[CH3:58][C:59]1([S:62]([NH2:65])(=[O:64])=[O:63])[CH2:61][CH2:60]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:22][CH:23]3[CH2:40][CH:39]4[N:25]([C:26](=[O:46])[N:27]([CH3:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH:33][CH:34]5[C:36]([C:42]([NH:65][S:62]([C:59]6([CH3:58])[CH2:61][CH2:60]6)(=[O:64])=[O:63])=[O:43])([NH:37][C:38]4=[O:41])[CH2:35]5)[CH2:24]3)=[N:8][C:9]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: CC1(S(N)(=O)=O)CC1
Reactant: COc1ccc(-c2nc(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)c3ccc(OC)c(C)c3n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(-c2nc(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6(C)CC6)CC5C=CCCCCN(C)C(=O)N4C3)c3ccc(OC)c(C)c3n2)cc1
Temperature: 25 °C
Yield: 21.5 %

Procedure:
The acid (130) (35 mg, 0.056 mmol) was dissolved in DCM (2 ml). EDAC (13 mg, 0.067 mmol) was added and the mixture was stirred at room temperature over night. Methylcyclopropanesulfonic acid amide (8.2 mg, 0.061 mmol) and DBU (18 μl, 0.117 mmol) was added and the reaction mixture was stirred at room temperature over night. 5% Citric acid was added to the reaction mixture, and the mixture was extracted with brine, dried over Na2SO4 and purified by HPLC to give the title compound (9 mg, 22%). MS (M+H)=747.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[Br:13]Br>CC(O)=O>[Br:13][C:7]1[CH:6]=[CH:5][C:4]([NH:8][C:9](=[O:11])[CH3:10])=[C:3]([CH3:12])[C:2]=1[Cl:1]
Reactant: BrBr
Reactant: CC(=O)Nc1cccc(Cl)c1C
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Br)c(Cl)c1C
Temperature: 0 °C
Reaction time: 24 h
Yield: 90.2 %

Procedure:
To a suspension of N-(3-chloro-2-methylphenyl)acetamide (35 g, 0.19 mol) in 350 mL of glacial AcOH cooled to 0° C. was added bromine (29.5 mL, 0.57 mol) dropwise. The ice bath was removed and the solution was stirred for 24 h and then poured into ice water with stirring. The solid was then filtered and dried to give the title compound (45 g, 90%) which was used for the next step without any further purification.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]3[C:17]4[C:22]([C:23](=O)[C:8]=23)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=CC([N:30]([C:38]2C=CC=[CH:40][CH:39]=2)[C:31]2[CH:36]=[CH:35][C:34](C)=[CH:33][CH:32]=2)=CC=1.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[C:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]3[C:17]4[C:22]([C:23]([C:34]5[CH:35]=[CH:36][C:31]6[N:30]([C:6]7[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=7)[C:38]7[C:39]([C:32]=6[CH:33]=5)=[CH:40][CH:7]=[CH:8][CH:9]=7)([C:34]5[CH:33]=[CH:32][C:31]6[N:30]([C:11]7[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=7)[C:38]7[C:18]([C:36]=6[CH:35]=5)=[CH:17][CH:22]=[CH:40][CH:39]=7)[C:8]=23)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(N(c2ccccc2)c2ccc(C)cc2)cc1
Reactant: O=C1c2ccccc2-c2nc3ccccc3c(-c3ccccc3)c21
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: c1ccc(-c2c3c(nc4ccccc24)-c2ccccc2C3(c2ccc3c(c2)c2ccccc2n3-c2ccccc2)c2ccc3c(c2)c2ccccc2n3-c2ccccc2)cc1
Yield: 188.7 %

Procedure:
Referring to the reaction formula above, 10-phenyl-11H-indeno[1,2-b]quinolin-11-one (860 mg, 2.80 mmol) and 4-methyl-N-phenyl-N-(p-tolyl)aniline (1668 mg, 6.10 mmol) are placed in a round bottom flask and then dissolved in 5 ml of dichloromethane. Subsequently, 800 μl of Eaton's reagent is slowly dripped into the flask to promote reaction. After 12 hours of reaction at 100° C., the crude product is extracted with 20 ml of dichloromethane and sodium bicarbonate for three times. Finally, an organic layer of the crude product is dehydrated with magnesium sulfate and concentrated to be sublimated and purified to obtain 2050 mg of 10-phenyl-11,11-bis(9-phenyl-9H-carbazol-3-yl)-11H-indeno[1,2-b]quinoline. The percentage yield is 87.6%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=O)[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:11]3([C:15](=[O:16])[NH:14][C:13](=[S:33])[NH:12]3)[CH2:10][CH:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(c1)C1(CC(c3ccccc3)O2)NC(=O)NC1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)C1(CC(c3ccccc3)O2)NC(=S)NC1=O
Yield: 16.6 %

Procedure:
A suspension of 6-methyl-2-phenylspiro[chroman-4,4′-imidazolidine]-2′,5′-dione (200 mg, 0.65 mmol) and Lawesson's Reagent (263 mg, 0.65 mmol) in anhydrous 1,4-dioxane (8 mL) was refluxed for 24 h. The mixture was concentrated in vacuo and the residue was purified by preparative TLC to give 6-methyl-2-phenyl-2′-thioxospiro[chroman-4,4′-imidazolidin]-5′-one (35 mg, 17%). 1H-NMR (CDCl3): 2.28 (s, 3H), 2.47 (d, 1H), 2.51 (d, 1H), 5.30 (s, 1H), 6.92 (s, 1H), 6.70 (d, 2H), 7.10 (m, 1H), 7.41 (m, 1H), 8.18 (s, 1H).
Reaction SMILES: B.[Na].[CH2:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]1=[O:20])[CH3:4].CC(C)=O>C(O)C>[CH2:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]1[OH:20])[CH3:4]
Reactant: CCC1Cc2c(cccc2-c2ccccc2)C1=O
Agent: B
Agent: [Na]
Solvent: CCO
Solvent: CC(C)=O
Product: CCC1Cc2c(-c3ccccc3)cccc2C1O
Yield: 99.3 %

Procedure:
To a 200-ml three-necked round flask (equipped with stirrer chip, Dimroth condenser, dropping funnel and thermometer) were introduced 0.85 g (22.6 mmol) of sodium boron hydride and 28 ml of ethanol. In a nitrogen atmosphere at room temperature, to the flask was dropwise added a solution obtained by dissolving 10.6 g (45.1 mmol) of the 2-ethyl-4-phenyl-l-indanone obtained above in 20 ml of ethanol. After the dropping was completed, the temperature of the system was elevated to 50° C. so as to further perform reaction for 3.5 hours. After the reaction, the system was cooled, and acetone was dropwise added to decompose the unreacted sodium boron hydride. Then, the reaction mixture was concentrated under reduced pressure and extracted with 50 ml of water and 50 ml of ether. The organic phase was separated, and the aqueous phase was extracted twice with 50 ml of ether, followed by mixing the organic phases together. The whole organic phase was washed with 100 ml of a saturated saline solution and dried with anhydrous Na2SO4. Then, the solvent was distilled off under reduced pressure to obtain 10.67 g of the aimed product (mixture of two kinds of isomers) as a viscous light yellow liquid (yield: 99%). The properties of the product thus obtained are described below.
Reaction SMILES: B(F)(F)F.CCOCC.C([NH2:13])(=O)C.[C:14]([C:18]1[CH:58]=[CH:57][C:21]([C:22]([NH:24][C@H:25]([C:53]([O:55][CH3:56])=[O:54])[CH2:26][C:27]2[CH:52]=[CH:51][C:30]([C:31]([O:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:39][CH:38]=3)=O)=O)=[CH:29][CH:28]=2)=[O:23])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>CC(=O)OCC>[C:14]([C:18]1[CH:58]=[CH:57][C:21]([C:22]([NH:24][C@@H:25]([CH2:26][C:27]2[CH:52]=[CH:51][C:30]([C:31]3[O:33][CH:34]=[C:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:39][CH:38]=4)[N:13]=3)=[CH:29][CH:28]=2)[C:53]([O:55][CH3:56])=[O:54])=[O:23])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(N)=O
Reactant: CCCCCCCOc1ccc(C(=O)COC(=O)c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC)cc2)cc1
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCCCCOc1ccc(-c2coc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)OC)cc3)n2)cc1
Temperature: 140 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
To boron trifluoride diethyl etherate (33.3 μl, 0.27 mmol) was added a mixture of acetamide (763 mg, 12.9 mmol) and (S)-2-(4-(heptyloxy)phenyl)-2-oxoethyl 4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate (159 mg, 0.26 mmol). The reaction mixture was stirred at 140° C. for 1 h. The reaction mixture was allowed to cool to room temperature, diluted with EA (15 mL) and extracted with NaHCO3 (3×15 mL) and brine (15 mL). The combined organics were dried over MgSO4, filtered and concentrated. The residue was recrystallized from Et2O (5 mL), filtered and rinsed with Et2O. The filtrate was concentrated to afford 55 mg (16%) of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)oxazol-2-yl)phenyl)propanoate as an orange oil. LCMS-ESI (m/z) calculated for C37H44N2O5: 596.8. found 597.0 [M+H]+, tR=3.11 min. (Method 4).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1.N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C=O>[Si:30]([O:1][CH2:2][CH2:3][S:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@]12CC[C@H](SCCO)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCS[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Yield: 90.4 %

Procedure:
To a solution of 1.0 g of 3β-(2-hydroxyethylthio)-androst-5-en-17-one in 20 ml of dimethylformamide, 1.7 g of imidazole and 2.0 g of t-butyldimethylsilyl chloride were added at 0° C. After 12 hrs the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give 1.2 g of crude 3β-(2-tert-butyldimethylsilyloxyethythio)-androst-5-en-17-one.
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]1)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:20][C:17]([F:18])([F:19])[C:10]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=2[N:8]([CH2:7][C:6]([OH:21])=[O:5])[N:9]=1
Reactant: CC(C)(C)OC(=O)Cn1nc(C(F)(F)F)c2c1CCCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(3-Trifluoromethyl-4,5,6,7-tetrahydroindazol-1-yl)-acetic acid tert-butyl ester was dissolved in a solution of DCM (30 mL) and TFA (30 mL), and the resulting mixture stirred at RT for 30 min, before concentration in vacuo to afford the title compound (4.50 g). This was used directly in the next step without any further purification.