Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[N+:11]([C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[NH2:17])([O-:13])=[O:12]>O>[N+:11]([C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[NH:17][CH:5]=[O:7])([O-:13])=[O:12]
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: O
Product: O=CNc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (6.0 ml.) was added to formic acid (98- 100% w/v; 24.0 ml.) with swirling and cooling and the mixture was allowed to stand at room temperature for 30 minutes. 3,5-Dinitroaniline (6.0 g.) was then added. The reaction mixture was warmed for 5 minutes on the steam bath and allowed to stand for 40 minutes, allowing it to cool to room temperature. Water (100 ml.) was added, and the precipitate was filtered off and dried. Crystallisation from a mixture of petroleum ether (b.p. 60°-80°C.) and ethyl acetate (2:1 by volume) gave 3',5'-dinitroformanilide (4.1 g.), m.p. 121°-123°C.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][C:5]1[S:9][C:8]([NH:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:7][CH:6]=1.[Na]>C1COCC1.C(O)C>[C:11]([NH:10][C:8]1[S:9][C:5]([CH2:4][C:3]([OH:30])=[O:2])=[CH:6][N:7]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)Cc1cnc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)s1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)Cc1cnc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)s1
Yield: 102 %

Procedure:
Methyl(2-tritylamino-1,3-thiazole-5-yl)acetate (2 g, 4.8 mmol) in THF (10 ml) and ethanol (10 ml) was reacted with sodium hydroxyde (1N, 7.2 ml, 7.2 mmol) at room temperature for 1.5 hour. The solvent was evaporated, HCl (6N) was added, the solid recovered by filtration to give title compound (1.96 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[CH2:13][CH:14]=[CH:15][CH2:16][OH:17].ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)Cl>[OH:26][CH:15]([CH:14]1[O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=2[CH2:13]1)[CH2:16][OH:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)Cc1ccc(O)c(CC=CCO)c1
Solvent: ClCCl
Product: COC(=O)Cc1ccc2c(c1)CC(C(O)CO)O2
Reaction time: 1 h

Procedure:
The compound of Example 6, (700 mg, 3.0 mmoles) was taken up in about 15 ml CH2Cl2 and cooled to 0° under N2. m-Chloroperbenzoic acid (m-CPBA) was added (660 mg) to the solution and the reaction mixture was stirred 1 hour at 0°. Additional m-CPBA (70 mg) was added and the reaction mixture was stirred for 21 hours at room temperature. Ca(OH)2 (650 mg) was added and the reaction mixture was stirred for 10 minutes then filtered through Celite and concentrated. The residue was taken up in ethyl acetate (10 ml) with Et3N (2 ml) and stirred at room temperature overnight. The concentrate was then concentrated to dryness. Chromatography of the residue on silica gel using ethyl acetate gave the title compound. NMR (90 MHz) (CDCl3) (ppm): 2.5-3.1 (2H, br), 3.20 (2H, d), 3.50 (2H, s), 3.65 (3H, s), 3.6-4.0 (3H, m), 4.70 (1H, m), 6.67 (1H, d), 6.8-7.1 (2H, m).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:30]=[C:29]3[C:25]([CH2:26][CH2:27][CH:28]3[OH:31])=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:52]1[CH:53]=[C:54]([CH:61]=[CH:62][CH:63]=1)[O:55][CH2:56][C:57]([O:59][CH3:60])=[O:58]>ClCCl>[F:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:30]=[C:29]3[C:25]([CH2:26][CH2:27][CH:28]3[O:31][C:52]3[CH:53]=[C:54]([CH:61]=[CH:62][CH:63]=3)[O:55][CH2:56][C:57]([O:59][CH3:60])=[O:58])=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)COc1cccc(O)c1
Reactant: OC1CCc2ccc(-c3cccc(F)c3)cc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)COc1cccc(OC2CCc3ccc(-c4cccc(F)c4)cc32)c1
Reaction time: 16 h
Yield: 48.4 %

Procedure:
Diisopropyl azodicarboxylate (57 mg, 0.28 mmol) was added to a solution of 6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-ol (55 mg, 0.24 mmol), triphenylphosphine (97 mg, 0.37 mmol), methyl 2-(3-hydroxyphenoxy)acetate (37 mg, 0.20 mmol) and dichloromethane (2 mL) in a 50 mL round bottom flask at room temperature. After stirring overnight for 16 hours, the resulting mixture was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with ethyl acetate (100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (4 g column, hexanes→100% ethyl acetate/hexanes, gradient) to afford 38 mg (40%) of methyl 2-(3-((6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenoxy)acetate.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:21])[CH:9]=2)[N:4]=1.O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:21])[CH:9]=2)[N:4]=[C:3]1[CH2:2][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][NH:28]2
Reactant: Sc1ncnc2nc[nH]c12
Reactant: O=c1c2cc(F)ccc2nc(CCl)n1-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cc(F)ccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 64.3 %

Procedure:
Prepared according to Procedure C using Intermediate 2r (118 mg, 0.365 mmol), 6-mercaptopurine monohydrate (68 mg, 0.402 mmol), K2CO3 (56 mg, 0.402 mmol), and DMF (2 mL). The crude product was recrystallized from EtOH to provide 103 mg of an off-white crystalline solid (64%), mp 232.8-233.0° C. (discolors). 1H NMR (DMSO-d6) δ: 13.56 (br s, 1H); 8.48 (s, 1H); 8.44 (s, 1H); 7.81-7.86 (m, 3H); 7.76 (d, J=7.5 Hz, 1H); 7.67 (d, J=7.5 Hz, 1H); 7.40-7.54 (m, 2H); 4.48 (br s, 2H). 13C NMR (DMSO-d6) ppm: 160.8 (d, J=247 Hz), 160.2 (d, J=3.3 Hz), 156.9, 152.3 (d, J=l.9 Hz), 151.5, 149.7, 144.0, 143.6, 134.1, 132.1, 131.7, 131.5, 130.5, 130.4, 130.2, 128.8, 124.0 (d, J=24 Hz), 122.0 (d, J=8.7 Hz), 111.7 (d, J=24 Hz), 32.0. MS (ES): m/z 439.0 (M+). Anal. calcd. for C20H12ClFN6OS.0.2C2H6O.0.1H2O: C, 54.46; H, 3.00; Cl, 7.88; N, 18.68. Found: C, 54.09; H, 2.73; Cl, 7.80; N, 18.77.
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[O:8][C:9]1[C:21]([CH:22]2[CH2:24][CH2:23]2)=[CH:20][C:12]([C:13]([O:15]C(C)(C)C)=[O:14])=[C:11]([F:25])[CH:10]=1.FC(F)(F)C(O)=O>ClCCl>[C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[O:8][C:9]1[C:21]([CH:22]2[CH2:24][CH2:23]2)=[CH:20][C:12]([C:13]([OH:15])=[O:14])=[C:11]([F:25])[CH:10]=1
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(O[C@H]2C[C@@H]3CC[C@H]2C3)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(C2CC2)c(O[C@H]2C[C@@H]3CC[C@H]2C3)cc1F
Reaction time: 1 h
Yield: 32.5 %

Procedure:
A solution of tert-butyl 4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoate (0.88 g, 2.54 mmol) in dichloromethane (40 mL) was added trifluoroacetic acid (1.9 mL, 25.4 mmol). The resulting mixture was stirred for 1 hour and then concentrated in vacuo. The residue was triturated with methanol to provide the title compound (0.24 g, 32%): 1H NMR (300 MHz, DMSO-d6) δ 12.77 (br s, 1H), 7.26 (d, J=8.5 Hz, 1H), 6.78 (d, J=13.2 Hz, 1H), 4.40-4.34 (m, 1H), 2.39-2.34 (m, 1H), 2.29-2.23 (m, 1H), 1.99-1.88 (m, 1H), 1.85-1.76 (m, 1H), 1.60-1.33 (m, 4H), 1.25-1.03 (m, 3H), 0.88-0.79 (m, 2H), 0.57-0.49 (m, 2H); MS (ES+) m/z 291.1 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:20]([CH3:22])[CH3:21])=[N:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[CH:2].CC(N=NC(C#N)(C)C)(C#N)C.[I:35]I>C([SnH](CCCC)CCCC)CCC.CCOCC>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH:20]([CH3:22])[CH3:21])[C:3]=2/[CH:1]=[CH:2]/[I:35])=[CH:18][CH:17]=1
Reactant: C#Cc1c(C(C)C)nc2ccccc2c1-c1ccc(F)cc1
Reactant: II
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCOCC
Product: CC(C)c1nc2ccccc2c(-c2ccc(F)cc2)c1/C=C/I
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
A mixture of 3-Ethynyl-4-(4-fluorophenyl)-2-(1-methylethyl)quinoline (1.500 gm, 5.18 mmol) (the preparation of which is described in Example 8) and AIBN (15 mg) in tri-n-butylstannyl hydride (2.1 ml) was rapidly heated to 120° C. After 3 minutes of heating, the mixture was treated with additional Bu3SnH (0.6 ml) and the temperature of the reaction was raised to 130° C. Approximately 15 mg of AIBN was added to the reaction mixture of 0.5, 1, and 2 hours after heating was initiated. After 2.5 hours, the mixture was cooled to room temperature, diluted with Et2O (30 ml) and treated with solid I2 (3.86 gm, 15.2 mmol). The dark reaction mixture was stirred for 1 hour, then quenched with 10% Na2SO3 in saturated NaHCO3. The layers were shaken and separated. The ethereal layer was washed with brine, dried (Na2SO4), filtered and stripped to yield a liquid/solid residue. The residue was chromatographed (flash, Merck SiO2, 4% EtOAc in hexane) to give slightly impure (E)-4-(4-Fluorophenyl)-3-(2-iodoethenyl)-2-(1-methylethyl)quinoline as a solid. Recrystallization of the solid from hot hexane gave (E)-4-(4-Fluorophenyl)-3-(2-iodoethenyl)-2-(1-methylethyl)quinoline (1.725 gm, 80%) as light yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([NH:11][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[N:24]=[C:25]([CH3:31])[S:26][C:27]=1[C:28](O)=[O:29].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(OCC)(=O)C.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH:13]2[CH:10]([N:11]([C:28]([C:27]3[S:26][C:25]([CH3:31])=[N:24][C:23]=3[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[F:16])=[O:29])[CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2ccccc2F)c(C(=O)O)s1
Reactant: CC(C)(C)OC(=O)N1CCC2CNC2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccc2F)c(C(=O)N2CC3CCN(C(=O)OC(C)(C)C)CC32)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
3,8-Diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester (92 mg, 0.44 mmol), 4-(2-fluoro-phenyl)-2-methyl-thiazole-5-carboxylic acid (104 mg, 0.44 mmol), di-isopropylethylamine (0.25 mL, 1.30 mmol) and HATU (247 mg, 0.65 mmol) were dissolved into DMF (5 mL) and stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with 1N NaOH (10 mL) and water (2×100 mL). The organic layers were combined, dried, filtered and concentrated to yield the title compound (125 mg, 67%). MS (ESI) mass calcd. for C12H18FN3OS, 431.41; m/z found, 432.3 [M+H]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH:8]1([C:9]([C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)=[O:10])[CH2:6][CH2:7]1
Reactant: O=C(Cl)CCCCl
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(Cl)cc1)C1CC1
Temperature: 12.5 °C
Reaction time: 1 h

Procedure:
A mixture of anhydrous aluminium chloride (20 g) and chlorobenzene (100 ml) was cooled to 10-15° C and treated dropwise with a solution of 4-chlorobutyrylchloride (20 g) in chlorobenzene (20 ml) over a period of 10 minutes with continuous stirring. The solution was warmed to 20-25° C and stirring was continued for a further 1 hour. It was poured onto ice and extracted with ether and the dried ethereal extract evaporated. The resulting liquid was treated with a solution of potassium hydroxide (12 g) in methanol (60 ml) and left to stand for 30 minutes with occasional shaking. After filtration the residue was washed with methanol and the filtrate evaporated to dryness. The oil was dissolved in ether and washed with water. The dried ethereal solution (Na2SO4) was evaporated and distilled (b.p.125-127°/5mm), yield =21.3 g,nD = 1.5700
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]2[C:19]3[N:20]([CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[O:47][CH3:48])[C:21](=[O:39])[C:22]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[C:24]=3[O:25][C:15]=2[CH:14]=1>CN(C=O)C>[CH3:4][S:1]([NH:12][C:13]1[CH:18]=[CH:17][C:16]2[C:19]3[N:20]([CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=4[O:47][CH3:48])[C:21](=[O:39])[C:22]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[C:24]=3[O:25][C:15]=2[CH:14]=1)(=[O:3])=[O:2]
Reactant: CCOC(=O)c1c(-c2ccc(OC)cc2)c2oc3cc(N)ccc3c2n(Cc2ccccc2OC)c1=O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)c2oc3cc(NS(C)(=O)=O)ccc3c2n(Cc2ccccc2OC)c1=O
Reaction time: 1 h

Procedure:
Equimolar quantities of mesyl chloride and cesium carbonate are added to a solution of ethyl 7-amino-1,2-dihydro-1-(2-methoxybenzyl)-4-(4-methoxyphenyl)-2-oxobenzofuro[3,2-b]pyridine-3-carboxylate in DMF and the mixture is stirred for one hour. After customary working up, ethyl 7-methylsulphonylamino-1,2-dihydro-1-(2-methoxybenzyl)-4-(4-methoxyphenyl)-2-oxobenzofuro-[3,2-b]pyridine-3-carboxylate is obtained.
Reaction SMILES: [O:1]1[CH2:21][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:20])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)=[CH:7][CH:6]=1.[CH2:22]([NH:29][CH2:30][CH2:31][O:32][C:33]1[CH:41]=[C:37]([C:38]([NH2:40])=[O:39])[C:36]([OH:42])=[CH:35][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C)C>[CH2:22]([N:29]([CH2:30][CH2:31][O:32][C:33]1[CH:34]=[CH:35][C:36]([OH:42])=[C:37]([C:38](=[O:39])[NH2:40])[CH:41]=1)[CH2:21][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]([CH3:20])[CH:13]=[C:14]([C:16]([F:17])([F:19])[F:18])[N:15]=2)=[CH:9][CH:10]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cn1cc(C(F)(F)F)nc1-c1ccc(OCC2CO2)cc1
Reactant: NC(=O)c1cc(OCCNCc2ccccc2)ccc1O
Solvent: CC(C)O
Product: Cn1cc(C(F)(F)F)nc1-c1ccc(OCC(O)CN(CCOc2ccc(O)c(C(N)=O)c2)Cc2ccccc2)cc1

Procedure:
A solution of 5 g of 2-[4-(2,3-epoxypropoxy)-phenyl]-1-methyl-4-(trifluoromethyl)-imidazole and 4.7 g of 5-[2-(benzylamino)-ethoxy]-salicylamide in 100 ml of isopropanol is heated under reflux for 15 hours and the solvent is subsequently removed in a rotary evaporator. The crude 1-[N-benzyl-2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-[1-methyl-4-(trifluoromethyl)-imidazol-2-yl]-phenoxy]-2-propanol, obtained in the form of an oil, is further processed in that form.
Reaction SMILES: [CH3:1][N:2]([CH:4]=O)[CH3:3].[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:35]=[CH:34][O:33][CH:32]=4)[CH2:28][CH2:27][C:26]([C:36]([OH:38])=O)=[CH:25][C:24]=3[CH:39]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH3:9].S(Cl)(Cl)=O>O1CCCC1>[CH2:6]([O:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]3[N:29]([CH2:30][C:31]4[CH:35]=[CH:34][O:33][CH:32]=4)[CH2:28][CH2:27][C:26]([C:36]([NH:29][C:23]4[CH:24]=[CH:39][C:20]([CH2:4][N:2]([CH3:1])[CH:3]5[CH2:12][CH2:11][O:10][CH2:6][CH2:7]5)=[CH:21][CH:22]=4)=[O:38])=[CH:25][C:24]=3[CH:39]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccoc2)cc1
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3Cc2ccoc2)cc1
Reaction time: 1 h

Procedure:
One droplet of DMF was added to a solution of 7-(4-butoxyethoxyphenyl)-1-(3-furylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (200 mg) in tetrahydrofuran (10 ml). Then, thionyl chloride (155 mg) was added at 0° C., the temperature was returned to room temperature, and the mixture was stirred under nitrogen atmosphere for 1 hour. The solvent and excess thionyl chloride were evaporated under reduced pressure, the resulting residue was suspended in tetrahydrofuran (25 ml), and the suspension was added to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (115 mg) and triethylamine (526 mg) in tetrahydrofuran (10 ml) at 0° C. The suspension was stirred under nitrogen atmosphere at room temperature for 4.5 hours, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was separated and purified with silica gel column chromatography (methanol:ethyl acetate=1:8), which was recrystallized from hexane-ethyl acetate to give 7-(4-butoxyethoxyphenyl)-1-(3-furylmethyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 62) (125 mg) as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([N:19]([CH3:23])[CH:20]([CH3:22])[CH3:21])[C:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][C:3]=1[C:24]([O:26]C)=[O:25].[OH-].[Li+]>O1CCCC1.O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([N:19]([CH3:23])[CH:20]([CH3:22])[CH3:21])[C:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][C:3]=1[C:24]([OH:26])=[O:25]
Reactant: COC(=O)c1cc2nc(N(C)C(C)C)c(-c3ccc(F)cc3)nc2cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(C)c1nc2cc(C(=O)O)c(F)cc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of methyl 7-fluoro-2-(4-fluorophenyl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (150 mg, 0.40 mmol) in tetrahydrofuran (30 ml) and water (1.0 ml) was added lithium hydroxide (38.8 mg, 1.62 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 ml), and adjusted to pH 5 with hydrochloric acid (3N) to give the precipitate, which was collected by filtration to afford 7-fluoro-2-(4-fluorophenyl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylic acid as a light yellow solid (120 mg, 83%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH:19]([CH:25](OC)OC)[CH:20](OC)OC)[CH2:15][C@H:14]1[C@@H:13]([CH3:30])[S:12][C:11]([NH:31]C(=O)C1C=CC=CC=1)=[N:10]2.[CH3:40][NH:41][NH2:42].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O.C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]12[CH2:18][O:17][CH:16]([C:19]3[CH:25]=[N:42][N:41]([CH3:40])[CH:20]=3)[CH2:15][CH:14]1[CH:13]([CH3:30])[S:12][C:11]([NH2:31])=[N:10]2
Reactant: CNN
Reactant: COC(OC)C(C(OC)OC)[C@H]1C[C@H]2[C@@H](C)SC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1SC(N)=NC2(c3ccc(F)cc3F)COC(c3cnn(C)c3)CC12
Temperature: 70 °C

Procedure:
N-[(4R,4aR,6R,8aS)-8a-(2,4-Difluorophenyl)-4-methyl-6-(1,1,3,3-tetramethoxypropan-2-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C75) [prepared from P4 via a method similar to that used for the conversion of P1 to C44 in Preparation P3 and Example 5] (297 mg, 0.526 mmol) was combined with ethanol (1.75 mL) and methyl hydrazine (36.4 mg, 0.789 mmol) followed by addition of water (0.6 mL). Concentrated sulfuric acid (55 μL, 1.0 mmol) was slowly added and the reaction mixture was heated at 70° C. for 18 hours. Saturated aqueous sodium bicarbonate solution was added, and the aqueous layer was extracted three times with ethyl acetate; the combined organic layers were extracted three times with 0.2 M aqueous hydrochloric acid, and the combined aqueous layers were washed with ethyl acetate. The pH was adjusted to 9-10 by addition of 1 M aqueous sodium hydroxide solution, and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel chromatography (Gradient: 0% to 15% methanol in dichloromethane) provided the product as an off-white solid. Yield: 109 mg, 0.287 mmol, 55%. LCMS m/z 379.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 7.48 (s, 1H), 7.36 (s, 1H), 7.22-7.28 (m, 1H), 6.85-6.92 (m, 2H), 4.57 (dd, J=11.3, 2.3 Hz, 1H), 4.16 (dd, J=11.1, 2.1 Hz, 1H), 3.76 (s, 3H), 3.69 (d, J=11.3, 1H), 3.01-3.06 (m, 1H), 2.78 (dt, J=11.9, 3.8 Hz, 1H), 1.75-1.80 (m, 1H), 1.59-1.68 (m, 1H), 1.10 (d, J=7 Hz, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:9]2[CH2:10][CH2:11][CH:5]1[CH2:6][CH:7]([C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=1)[CH2:8]2.[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][C:30]=2[SH:32])[CH:25]=[CH:24][CH:23]=1>>[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[CH:7]1[CH2:6][CH:5]2[N:4]([CH2:3][CH2:2][S:32][C:30]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:31]=3[N:22]=[CH:23][CH:24]=[CH:25]4)[CH:9]([CH2:10][CH2:11]2)[CH2:8]1
Reactant: Sc1cccc2cccnc12
Reactant: ClCCN1C2CCC1CC(c1ccc3ccccc3c1)C2
Product: c1ccc2cc(C3CC4CCC(C3)N4CCSc3cccc4cccnc34)ccc2c1

Procedure:
The title compound was prepared by the procedure described in Example 8, Step 5, except that 8-(2-chloroethyl)-3-(2-naphthyl)-8-azabicyclo[3.2.1]octane was used in place of 8-(2-chloroethyl)-3-(2-naphthyl)-8-azabicyclo[3.2.1]oct-2-ene, and 8-quinolinethiol was used in place of 6-methoxyquinolin-8-ol. Yield: 36% of a tan solid. The corresponding oxalate salt was prepared by combining the title compound with 1 equiv. of oxalic acid in CH2Cl2/MeOH to precipitate a white solid. Yield: 71%; mp: 200-203° C.; MS (ES) m/z: 425.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][Si:5]([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[O:6][Si:7]([CH3:10])([CH3:9])[CH3:8].[NH2:21][CH2:22][CH2:23][CH2:24][Si:25]([O:36][Si:37]([CH3:40])([CH3:39])[CH3:38])([O:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[O:26][Si:27]([CH3:30])([CH3:29])[CH3:28].C(=O)([O-])[O-].[Na+].[Na+]>CC(N(C)C)=O>[CH3:8][Si:7]([CH3:10])([CH3:9])[O:6][Si:5]([CH2:4][CH2:3][CH2:2][N:21]([CH2:2][CH2:3][CH2:4][Si:5]([O:16][Si:17]([CH3:19])([CH3:18])[CH3:20])([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[O:6][Si:7]([CH3:8])([CH3:9])[CH3:10])[CH2:22][CH2:23][CH2:24][Si:25]([O:36][Si:37]([CH3:39])([CH3:38])[CH3:40])([O:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[O:31][Si:32]([CH3:35])([CH3:34])[CH3:33])([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[O:11][Si:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: C[Si](C)(C)O[Si](CCCI)(O[Si](C)(C)C)O[Si](C)(C)C
Reactant: C[Si](C)(C)O[Si](CCCN)(O[Si](C)(C)C)O[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C[Si](C)(C)O[Si](CCCN(CCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C)CCC[Si](O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C)(O[Si](C)(C)C)O[Si](C)(C)C
Temperature: 80 °C
Reaction time: 15 h

Procedure:
14.3 g of 3-iodopropyltris(trimethylsiloxy)silane (28), 5.7 g of 3-aminopropyltris(trimethyl-siloxy)silane and 9.6 g of sodium carbonate are added to 50 ml dimethylacetamide and stirred for 15 hours at 80° C. The dimethylacetamide is then evaporated and the residue taken up in methylene chloride. The organic phase is washed with water, dried and evaporated. The product is purified by column chromatography on silica gel to give 7 g of a slightly yellowish oil of formula (30); 1H-NMR (ppm, CDCl3): 2.21 6H t, 1.38 6H txt, 0.28 6H t, 0 81H s.