Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:9]2[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:8]=2[C:3]=1[C:4](=O)[CH2:5][CH2:6]3.C[O:18]C1C=CC=C2C=1CCCC2=O>>[OH:18][C:10]1[C:9]2[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:8]=2[C:3]([CH2:4][CH2:5][CH2:6]3)=[CH:2][CH:11]=1
Reactant: O=C1CCN2CCCCc3ccc(O)c1c32
Reactant: COc1cccc2c1CCCC2=O
Product: Oc1ccc2c3c1CCCCN3CCC2

Procedure:
The title compound was synthesized in a similar manner as 11-hydroxy-2,3,5,6,7,8-hexahydro-1H-azepino[3,2,1-ij]quinolone starting from 5-methoxytetralone: 1H NMR (DMSO-d6) δ 8.69 (s, 1H), 6.55 (d, 1H); 6.27 (d, 1H), 3.05-3.02 (m, 2H), 2.92-2.89 (m, 2H), 2.68-2.64 (m, 2H), 2.54 (t, 2H), 1.69-1.60 (m, 4H), 1.45-1.37 (m, 2H); MS expected 204 (C13H18NO, M+1), found 204.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[NH2:26][CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:26][CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1)=[O:20]
Reactant: NCc1ccc2ccccc2c1
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc2ccccc2c1)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.4 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (0.800 g, 2.20 mmol), 2-aminomethylnaphthalene (0.380 g, 2.42 mmol), triethylamine (0.240 g, 2.37 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-naphthylmethyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.200 g, 17.5% yield).
Reaction SMILES: CON(C)[C:4](=[O:32])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[N:15]=[CH:14][N:13]=2)[CH:6]=1.[C:34]([Mg]Br)#[C:35][CH2:36]C>C1COCC1>[O:25]([C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]([NH:11][C:7]3[CH:6]=[C:5]([C:4](=[O:32])[C:34]#[C:35][CH3:36])[CH:10]=[CH:9][CH:8]=3)[CH:17]=2)=[CH:20][CH:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CON(C)C(=O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Reactant: CCC#C[Mg]Br
Solvent: C1CCOC1
Product: CC#CC(=O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-methoxy-N-methyl-3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzamide (50 mg, 0.11 mmol) in THF (0.5 mL) at 0° C. was added a THF solution of 1-butynylmagnesium bromide (1.1 mL, 1.1 mmol). The reaction mixture was allowed to come to rt and was stirred at rt for 30 min. The reaction mixture was quenched with saturated NH4Cl solution (0.5 mL) and was extracted with EtOAc (2×3 mL). The combined EtOAc layer was washed with brine, was dried over anhydrous Na2SO4, was filtered and was concentrated under reduced pressure to give a white solid, which h was further purified by column chromatography (SiO2, 60-120, chloroform/methanol, 9/1) to give 1-(3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)phenyl)but-2-yn-1-one (I-88) as an off-yellow solid. 1H NMR (DMSO-d6) δ ppm: 2.22 (s, 3H), 6.16 (s, 1H), 6.97 (d, J=8.6 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 7.1 (t, J=7.2 Hz, 1H), 7.35-7.39 (m, 2H), 7.48 (t, J=8 Hz, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.66 (d, J=7.2 Hz, 1H), 7.95 (d, J=7.6 Hz, 1H), 8.32 (s, 1H), 8.39 (s, 1H), 9.22 (s, 1H), 9.47 (s, 1H); LCMS: m/e 421.1 (M+1).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]1[C:19]([F:20])=[C:18]([O:21][CH2:22][CH3:23])[CH:17]=[C:16]([CH3:24])[C:15]=1[CH:25](O)[CH2:26][CH:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:29][CH2:28]1.O>C1(C)C=CC=CC=1>[F:13][C:14]1[C:19]([F:20])=[C:18]([O:21][CH2:22][CH3:23])[CH:17]=[C:16]([CH3:24])[C:15]=1[CH:25]=[CH:26][CH:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:29][CH2:28]1
Reactant: CCCCCC1CCC(CC(O)c2c(C)cc(OCC)c(F)c2F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC1CCC(C=Cc2c(C)cc(OCC)c(F)c2F)CC1

Procedure:
0.55 g of p-toluenesulfonic acid monohydrate was added to the compound (7) having been dissolved in 120 mL of toluene, and the mixture was heated under stirring by using a Dean-Stork trap until completion of azeotrope of water. After terminating the reaction by adding water, the aqueous layer was extracted with toluene, washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography and then subjected to recrystallization to obtain 6.53 g of 1-(2,3-difluoro-4-ethoxy-6-methylphenyl)-2-(4-pentylcyclohexyl)ethene (Compound 1-1-3-18) as colorless crystals.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(CC)CC)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][CH:32]=1>C1COCC1>[O:21]=[C:15]1[CH:14]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:38]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)=[O:39])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: COc1ccc(N=C=O)cc1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)NCc2cccc3c2CN(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
A stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and triethylamine (0.3 g, 2.7 mmol) in THF (30 mL) was cooled to 5° C. 4-Methoxyphenyl isocyanate (0.4 g, 2.7 mmol) was added, and the mixture was stirred at room temperature overnight. The reaction was quenched with methanol (1 mL), and then concentrated. The residue was stirred with 1N HCl (30 mL) for one hour then filtered. The solid was slurried with hot methanol (20 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-(4-methoxy-phenyl)-urea (0.8 g, 93%) as a white solid: mp 320-322° C.; 1H NMR (DMSO-d6) δ 2.00-2.04 (m, 1H), 2.36-2.64 (m, 2H), 2.86-3.00 (m, 1H), 3.68 (s, 3H, OCH3), 4.35-4.57 (m, 4H, 2CH2), 5.12-5.19 (dd, J=4.6 and 13.0 Hz, 1H, CH), 6.61 (t, J=5.5 Hz, 1H, NH), 6.83 (d, J=8.9 Hz, 2H, Ar), 7.27 (d, J=8.9 Hz, 2H, Ar), 7.47-7.64 (m, 3H, Ar), 8.40 (s, 1H, NH), 11.03 (s, 1H); 13C NMR (DMSO-d6) δ 22.58, 31.18, 46.20, 51.58, 55.11, 113.86, 119.70, 121.49, 128.27, 130.34, 131.62, 133.36, 135.76, 139.88, 154.08, 155.47, 168.10, 171.00, 172.84; Anal. calcd. for C22H22N4O5: C, 62.55; H, 5.25; N, 13.26. Found: C, 62.61; H, 4.95; N, 13.59.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:30][CH2:29][CH2:28][CH:17]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:30][CH2:29][CH2:28][CH:17]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)OCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)C1CCCNC1
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (43 mL, 558 mmol) was added to benzyl 1-(tert-butoxycarbonyl)nipecotate (7.11 g, 22.3 mmol) in dichloromethane (20 mL). The mixture was stirred for 3 hours. Subsequently, the reaction mixture was concentrated and water was added to the residue, followed by addition of 1 mol/L aqueous sodium hydroxide solution to make the mixture basic. The mixture was then extracted with ethyl acetate. The organic layer washed with brine and was dried over sodium sulfate. The solvent was evaporated to give 5.97 g (quant.) of the desired compound as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]2[C:9](=[O:20])[C:10]3[C:14]([C:15](=[O:17])[CH3:16])=[CH:13][S:12][C:11]=3[C:18](=[O:19])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].OC(C1SC2C(=O)C3C=CSC=3C(=O)C=2C=1)C>C(Cl)(Cl)Cl.CO>[OH:3][CH:1]([C:4]1[S:8][C:7]2[C:9](=[O:20])[C:10]3[C:14]([CH:15]([OH:17])[CH3:16])=[CH:13][S:12][C:11]=3[C:18](=[O:19])[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CC(=O)c1cc2c(s1)C(=O)c1c(C(C)=O)csc1C2=O
Agent: CC(O)c1cc2c(s1)C(=O)c1ccsc1C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(O)c1cc2c(s1)C(=O)c1c(C(C)O)csc1C2=O
Yield: 90 %

Procedure:
Compound 13 was reduced with NaBH4 as in the preparation of 10. Column chromatography on silica gel eluting with CHCl3:MeOH (100:1) gave 14 as a yellow solid (mp 218-219° C.) in a 90% yield. IR (KBr) 1650, 1670 (C═O), 3100-3500 (OH) cm−1; 1H NMR (DMSO-d6) δ 1.36 (d, J=6.0 Hz, 3H, C-7-CH3), 1.48 (d, J=6.0 Hz, 3H, C-2-CH3), 5.05 (s, 1H, C-2-OH), 5.33 (s, 1H, C-7-OH), 5.52 (m, 1H, C-7-CH), 6.17 (m, 1H, C-2-CH), 7.41 (s, 1H, H-3), 7.97 (s, 1H, H-6); 13C NMR (DMSO-d6) δ 24.8 (C-7-CH3), 25.5 (C-2-CH3), 64.1 (C-7-CH), 64.9 (C-2-CH), 120.7 (C-3), 130.1 (C-6), 174.7 (C-4), 175.3 (C-8); MS m/z 308 (M+); Anal. (C14H12O4S2) C, H.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.[F-].[K+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.O.CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: N#Cc1ccccc1Cl
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: CS(C)=O
Solvent: Cc1ccc(C)cc1
Solvent: O
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 88.7 %

Procedure:
15 g of 2-chlorobenzonitrile, 15.8 g of p-tolueneboronic acid and 15.8 g of potassium fluoride in 50 ml of p-xylene, 40 ml of glycol and 10 ml of water were heated to 120° C. At 80° C., a mixture of 24.7 mg of palladium acetate and 0.55 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 18.7 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: [C:1]([Si:5]([CH3:28])([CH3:27])[O:6][C@H:7]([CH3:26])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]3[O:21][CH2:20][C@H:19]([O:22][CH2:23][CH2:24]O)[CH2:18][C:16]3=2)[CH:11]=[N:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[N-:45]=[N+:46]=[N-:47].[Na+]>C1COCC1>[N:45]([CH2:24][CH2:23][O:22][C@H:19]1[CH2:20][O:21][C:15]2=[CH:14][CH:13]=[C:12]3[C:17]([N:9]([CH2:8][C@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:27])[CH3:28])[CH3:26])[N:10]=[CH:11]3)=[C:16]2[CH2:18]1)=[N+:46]=[N-:47]
Reactant: C[C@H](Cn1ncc2ccc3c(c21)C[C@@H](OCCO)CO3)O[Si](C)(C)C(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](Cn1ncc2ccc3c(c21)C[C@@H](OCCN=[N+]=[N-])CO3)O[Si](C)(C)C(C)(C)C
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To a cooled (0° C.) solution of the product from Step A (1.40 g, 3.45 mmol) and triethylamine (1.39 g, 1.92 mL, 1.38 mmol, 4.0 equiv.) in anhydrous THF (50 mL) was added methanesulfonic anhydride (1.20 g, 6.90 mmol, 2.0 equiv.). The mixture was stirred for 30 min and sodium azide (2.24 g, 34.5 mmol, 10 equiv.) was added. THF was evaporated and anhydrous dimethyl sulfoxide (50 mL) was added to the residue; this mixture was heated at 85° C. for 2 h. After cooling, the mixture was poured into a saturated solution of sodium bicarbonate (100 mL) and extracted with EtOAc (3×80 mL). The combined extracts were dried (MgSO4) and evaporated to a residue which was purified by chromatography (silica, gradient, 10% to 25% ethyl acetate in hexane) to give an oil (0.73 g, 49%): LC/MS (+ESI) m/z 432 (M+H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH3:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:21][CH2:22][OH:23].[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([N:13]([CH3:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:21][CH2:22][O:23][S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)(=[O:32])=[O:31]
Reactant: Cc1oc(-c2ccc(N(C)c3ccccc3)cc2)nc1CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(N(C)c4ccccc4)cc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 86.5 %

Procedure:
A solution of 2-{5-methyl-2-[4-(methyl-phenyl-amino)-phenyl]-oxazol-4-yl}-ethanol (91 mg, 0.30 mmol) in CH2Cl2 (4.0 mL) was treated with para-toluenesulfonyl chloride (68 mg, 0.36 mmol), triethyl amine (0.20 mL) and a few crystals of DMAP. The resulting mixture was stirred at room temperature for 14 h and was quenched with water (0.2 mL). The mixture was purified directly by silica gel column chromatography (40% EtOAc/hexanes) to yield the title compound (120 mg, 83%). MS (ESI) m/z 463.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:18]1([N:24]2[CH2:29][CH2:28][N:27]([C:30](OC3C=CC([N+]([O-])=O)=CC=3)=[O:31])[CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][C:30]([N:27]2[CH2:28][CH2:29][N:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:25][CH2:26]2)=[O:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(COC(=O)N2CCN(c3ccccc3)CC2)C1
Temperature: 0 °C
Yield: 86.6 %

Procedure:
2-Hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester (4.13 g, 19.0 mmol) was dissolved in anhydrous THF (20 mL) and the solution cooled to 0° C. NaH (60% wt dispersion in oil; 2.28 g, 57.0 mmol) was added and the grey suspension stirred for 10 minutes before 4-nitrophenyl 4-phenylpiperazine-1-carboxylate (Intermediate 2; 7.46 g, 22.8 mmol) was added. The reaction was stirred at room temperature over the weekend. A further 1.5 equivalents of NaH (60% wt dispersion in oil) (1.14 g, 28.5 mmol) was added and the reaction stirred at room temperature overnight. The reaction mixture was cooled to 0° C. and quenched with sat aq NaHCO3 solution (50 mL) before the THF was removed in vacuo. The organic product was extracted with EtOAc (3×50 mL) and the organic layers combined, washed with sat aq NaHCO3 solution (3×50 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by reverse phase column chromatography (LiChroprep RP-18, 40-63 μm, 460×36 mm (200 g), 30 mL/min, gradient 0% to 80% (over 120 mins) MeOH in water with 1% formic acid) to afford 2-(4-phenylpiperazine-1-carbonyloxymethyl)-morpholine-4-carboxylic acid tert-butyl ester (6.67 g, 87% yield) as a dark brown oil.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:5])[CH3:4].[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]>C(N(CC)CC)C>[CH3:1][N:2]([Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[C:3](=[O:5])[CH3:4]
Reactant: CNC(C)=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N(C)[Si](C)(C)C(C)(C)C
Reaction time: 24 h

Procedure:
To a vigorously stirred solution of 73.1 g (1.0 mole) N-methylacetamide dissolved in 1400 ml of dry triethylamine was added 196 g (1.30 mole) of t-butyldimethylsilyl chloride. The flask was purged with dry nitrogen and then equipped with a drying tube. Hard stirring of the mixture was continued for 24 hours at room temperature. Then, under a layer of dry air, the reaction mixture was filtered to remove the precipitate of triethylamine hydrochloride. The resulting filter cake was then washed three times with 150 ml each of dry triethylamine. The filtrate and washings were combined and reduced in volume by distillation at 35 degrees C. at 10 mm Hg. The remaining straw colored liquid was then fractionally distilled.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.IC.[CH3:22]COC(C)=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.[OH-].[Na+].C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:22])[C:7](=[O:12])[CH:6]=[C:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1
Reactant: CCOC(C)=O
Reactant: O=c1cc(-c2cccc(Cl)c2)c2cc(Br)ccc2[nH]1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1c(=O)cc(-c2cccc(Cl)c2)c2cc(Br)ccc21
Reaction time: 8 h
Yield: 86 %

Procedure:
A mixture of intermediate 4 (0.045 mol), iodomethane (0.225 mol) and benzyltriethylammonium chloride (0.0045 mol) in NaOH (150 ml) and THF (150 ml) was stirred overnight. EtOAc was added. The mixture was washed with water. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated till dryness. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/EtOAc; 95/5; 20–45 μm). The pure fractions were collected and the solvent was evaporated, yielding 13.5 g (86%) of 6-bromo-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (intermediate 28), melting point 182° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[CH3:2].[C:15]1(O)[C:24]2CCCCC=2C=C[CH:16]=1>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][O:6][C:7]1[C:8]2[CH2:13][CH2:24][CH2:15][CH2:16][C:9]=2[CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)COc1ccccc1C
Reactant: Oc1cccc2c1CCCC2
Product: CCOC(=O)COc1cccc2c1CCCC2

Procedure:
The title compound was prepared according to the method described for preparing compound 10.1, using 5,6,7,8-tetrahydro-1-naphthol as the starting material.
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH2:14][C:15]1[O:16][C:17]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1)C(OCC1C=CC=CC=1)=O.C(O)(=O)C>CO.[Pd]>[CH3:1][NH:2][CH2:13][CH2:14][C:15]1[O:16][C:17]([C:26]2[CH:27]=[CH:28][C:29]([S:32]([NH2:35])(=[O:33])=[O:34])=[CH:30][CH:31]=2)=[C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:19]=1
Reactant: CN(CCc1nc(-c2ccccc2)c(-c2ccc(S(N)(=O)=O)cc2)o1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CNCCc1nc(-c2ccccc2)c(-c2ccc(S(N)(=O)=O)cc2)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-[2-[2-(N-methyl-N-phenylmethoxycarbonylamino)ethyl]-4-phenyloxazol-5-yl]benzenesulfonamide and 4-[2-[2-(N-methyl-N-phenyl-methoxycarbonylamino)ethyl]-5-phenyloxazol-4-yl]benzenesulfonamide (0.7 g, 1.4 mmol) from Step 3, in MeOH (15 mL) containing acetic acid (0.1 mL) was treated with 10% Pd on carbon (0.4 g) and stirred under an atmosphere of hydrogen at 50 psi at room temperature for 3 h. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the resulting substance was purified by reverse-phase HPLC using a gradient of 5–70% CH3CN in water to give 0.42 g of 4-[2-[2-(N-methylamino)ethyl]-4-phenyloxazol-5-yl]benzenesulfonamide and 4-[2-[2-(N-methylamino)ethyl]-5-phenyloxazol-4-yl]benzenesulfonamide trifluoroacetate salts as a white powder: 1H NMR (CD3OD/300 MHz) δ 7.88 (d, 2H, J=8.7 Hz), 7.74 (d, 2H, J=8.7 Hz), 7.6 (m, 2H), 7.43 (m, 3H), 3.55 (t, 2H, J=6.6 Hz), 3.36 (t, 2H, J=6.6 Hz), 2.82 (s, 3H); FABMS m/z=358 (M+H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.N1C2C(=CC=CC=2)C=CC=1.[Cl:16][C:17]1[C:18](O)=[N:19][CH:20]=[C:21]([N+:23]([O-:25])=[O:24])[CH:22]=1>>[Cl:3][C:18]1[C:17]([Cl:16])=[CH:22][C:21]([N+:23]([O-:25])=[O:24])=[CH:20][N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(O)c(Cl)c1
Solvent: c1ccc2ncccc2c1
Product: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Yield: 85.4 %

Procedure:
Place phosphorus oxychloride (11.28 mL, 121 mmol) in a round-bottom flask and cool to 0° C. Add quinoline (7.15 mL, 60.5 mmol) followed by 3-chloro-5-nitro-pyridin-2-ol (21.13 g, 121 mmol) in portions. Heat reaction to 120° C. for 2 hours. Pour reaction onto ice and triturate with water. Filter off the solid and wash with water. Dry thoroughly to yield 19.95 g (86%) of the title compound: 1H NMR δH (400 MHz, DMSO) 9.20 (s, 1H), 8.97 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:30](O)=[O:31])=[N:22][N:23]([CH2:25][C:26]([F:29])([F:28])[F:27])[CH:24]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:21]3[C:20]([Cl:19])=[CH:24][N:23]([CH2:25][C:26]([F:28])([F:27])[F:29])[N:22]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1nn(CC(F)(F)F)cc1Cl
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3nn(CC(F)(F)F)cc3Cl)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 4-chloro-1-(2,2,2-trifluoro-ethyl)-1H-pyrazole-3-carboxylic acid (CAS1006448-63-0) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=470.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.CO[C:15](OC)([CH3:17])[CH3:16].FC(F)(F)C(O)=O.FC1C=CC(N)=C([N+]([O-])=O)C=1>C1(C)C=CC=CC=1.FC(F)(F)C(O)=O.N1C=CC=CC=1.CCOC(C)=O.CCCCCC>[CH:15]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])([CH3:17])[CH3:16]
Reactant: COC(C)(C)OC
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: Nc1ccc(F)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(NC(C)C)c([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 62.8 %

Procedure:
4-methoxy-2-nitroaniline (16.8 g; 0.1 mole), 2,2-dimethoxypropane (24.6 ml; 0.2 mole) and trifluoroacetic acid [TFA] (23.1 ml; 0.005 moles) were dissolved in toluene (500 ml) and stirred for 1 hr. BH3 * pyridine (10.0 ml; 0.1 moles) was added in 1.0 ml increments. The reaction was exothermic, and the reaction progress was monitored by tlc 40% EtOAc/Hexane. .Additional TFA, BH3 * pyridine and 2,2-dimethoxypropane were added until the tlc indicated that the 4-fluoro-2-nitroaniline was consumed. The reaction mixture was placed on a bed of silica and eluted with 10% methyl-t-butylether/hexane. The product was the first major component to elute, which produced 13.2 g (62%) of a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[NH:17]1[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[CH:19]=[C:18]1[CH:26]=O>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[C:9](=[CH:26][C:18]2[NH:17][C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[CH:19]=2)[C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: O=Cc1cc2c([nH]1)CCCC2
Product: O=C1Nc2cccc(-c3ccncc3)c2C1=Cc1cc2c([nH]1)CCCC2

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde to give the title compound.