Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](NC(C)C)(C)C.[CH2:8]([C@H:10]1[C@@H:14]([OH:15])[CH2:13][C:12](=[O:16])[N:11]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([O:25][CH3:26])[CH:18]=1)[CH3:9].IC.[Cl-].[NH4+]>O1CCCC1>[CH2:8]([C@H:10]1[C@@H:14]([OH:15])[C@H:13]([CH3:1])[C:12](=[O:16])[N:11]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([O:25][CH3:26])[CH:18]=1)[CH3:9]
Reactant: CC(C)NC(C)C
Reactant: CC[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(OC)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: CC[C@H]1[C@@H](O)[C@H](C)C(=O)N1c1ccc(C#N)c(OC)c1
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of diisopropylamine (0.291 mL) in tetrahydrofuran (8 mL) was added dropwise n-butyllithium-hexane solution (1.24 mL, 1.6 mol/L) at −78° C., the mixture was stirred for 1 hr, and a solution of 4-[(2S,3S)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]-2-methoxybenzonitrile (206.5 mg) in tetrahydrofuran (6 mL) was added dropwise. The mixture was stirred at −78° C. for 30 min, iodomethane (0.247 mL) was added dropwise at −78C, and the mixture was stirred at 0° C. for 1 hr. Aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/4) to give the title compound as a colorless solid (yield: 108.8 mg, 50%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>CN(C)C=O>[F:1][C:2]1[C:3]([N:17]=[CH:20][N:21]([CH3:23])[CH3:22])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: Nc1nc(OCc2ccc(F)cc2)ncc1F
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Nc1nc(OCc2ccc(F)cc2)ncc1F
Temperature: 0 °C
Reaction time: 16 h
Yield: 89.6 %

Procedure:
To a magnetically stirred solution of 5-fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-ylamine (1.00 g, 4.2 mmol) in N,N-dimethylformamide (DMF, 20 mL) was added N,N-dimethylformamide dimethyl acetal (0.55 g, 4.6 mmol) and stirring was continued 16 h at RT. The solution was poured into 100 mL of ice water, whereupon a white precipitate was produced. The mixture was cooled at 0° C. for 1 h and then filtered to produce the title compound (1.10 g, 89%) as a white solid: mp 113-115° C.; 1H NMR (CDCl3) δ 8.65 (s, 1H), 8.04 (d, J=2.6 Hz, 1H), 7.46-7.40 (m, 2H), 7.07-6.98 (m, 2H), 5.30 (s, 2H), 3.17 (s, 3H), 3.16 (s, 3H); MS (ESI) m/z 292 (M+H)+. Anal. Calcd for C14H14F2N4O: C, 57.53; H, 4.83; N, 19.17. Found: C, 57.67; H, 4.84; N, 19.09.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([N:17]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([CH2:35][CH3:36])=[CH:31][CH:30]=4)=[C:23]([O:37][CH3:38])[CH:22]=3)[CH2:18]2)=[O:16])[CH:10]=1)(=O)=O.[NH:39]1[CH2:44][CH2:43][NH:42][CH2:41][C:40]1=[O:45]>C(O)CC>[CH2:35]([C:32]1[CH:31]=[CH:30][C:29]([CH2:28][O:27][C:24]2[CH:25]=[CH:26][C:21]([CH:19]3[CH2:20][N:17]([C:15]([C:11]4[CH:10]=[C:9]([O:8][CH2:7][CH2:6][N:42]5[CH2:43][CH2:44][NH:39][C:40](=[O:45])[CH2:41]5)[CH:14]=[CH:13][N:12]=4)=[O:16])[CH2:18]3)=[CH:22][C:23]=2[O:37][CH3:38])=[CH:34][CH:33]=1)[CH3:36]
Reactant: O=C1CNCCN1
Reactant: CCc1ccc(COc2ccc(C3CN(C(=O)c4cc(OCCOS(C)(=O)=O)ccn4)C3)cc2OC)cc1
Solvent: CCCO
Product: CCc1ccc(COc2ccc(C3CN(C(=O)c4cc(OCCN5CCNC(=O)C5)ccn4)C3)cc2OC)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 74.4 %

Procedure:
To a solution of 2-(2-{3-[4-(4-ethylbenzyloxy)-3-methoxyphenyl]azetidine-1-carbonyl}-pyridin-4-yloxy)ethyl methanesulfonate (0.4 g) prepared in Example 6 (1) in 1-propanol (5.0 mL) was added 2-piperazinone (0.22 g). The reaction mixture was stirred at 100° C. for 18 hr. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (Developing solvent: chloroform/methanol=8/1 to 7/1) to give the title compound (0.3 g, 76%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=1.[CH:30]([C:33]1[NH:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)([CH3:32])[CH3:31]>>[CH:30]([C:33]1[N:34]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])[CH2:17][CH2:18]4)[N:8]3[CH3:11])=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:3]=2)[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)([CH3:32])[CH3:31]
Reactant: Cn1c(CN2CCN(C(C)(C)CO)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)c1nc2ccccc2[nH]1
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)CO)CC3)n(C)c2n1

Procedure:
2-(4-((2-Chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-1-yl)-2-methylpropan-1-ol (70 mg) was reacted with 2-isopropylbenzimidazole via General Procedure I for Buchwald coupling to give 28 mg 476 following reverse phase purification. MS (Q1) 548.3 (M)+
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C:11]2([CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[CH2:13][CH2:12]2)[CH:3]=1.C([Li])CCC.[Br:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([CH:39]=1)[C:33](N(OC)C)=[O:34]>C(OCC)C>[Br:27][C:28]1[CH:39]=[C:32]([C:33]([C:2]2[C:10]3[CH:9]=[N:8][CH:7]=[N:6][C:5]=3[N:4]([C:11]3([CH2:14][O:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][O:17]4)[CH2:13][CH2:12]3)[CH:3]=2)=[O:34])[CH:31]=[N:30][CH:29]=1
Reactant: Ic1cn(C2(COC3CCCCO3)CC2)c2ncncc12
Reactant: CON(C)C(=O)c1cncc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(c1cncc(Br)c1)c1cn(C2(COC3CCCCO3)CC2)c2ncncc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a stirred solution of 5-Iodo-7-[1-(tetrahydro-pyran-2-yloxymethyl)-cyclopropyl]-7H-pyrrolo[2,3-d]pyrimidine (Preparation 249, 450 mg, 1.13 mmol) in diethyl ether (6 mL) was added n-butyl lithium (2M in hexane, 0.62 mL, 1.24 mmol) drop wise at −70° C. Then a solution of 5-Bromo-N-methoxy-N-methyl-nicotinamide (304 mg, 1.24 mmol) in diethyl ether (2.5 mL) was added drop wise at −70° C. and stirred at same temperature for another 30 minutes. The reaction was allowed to warm to room temperature slowly. The reaction was quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with water (20 mL), brine (20 mL), dried over sodium sulphate and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of dichloromethane:methanol 100:0 to 98:2) to afford the title compound as a light brown sticky solid in 35% yield, 250 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](/[CH:19]=C/C)=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]=[O+][O-].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:18]([CH:19]=[O:22])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[O+][O-]
Reactant: C/C=C/c1ccc2ncccc2c1OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=Cc1ccc2ncccc2c1OCc1ccccc1

Procedure:
Treatment of 5-(benzyloxy)-6-[(1E)-prop-1-enyl]quinoline in methylene chloride with excess ozone at −78° C. followed by addition of diisopropylethylamine, aqueous work-up, and subsequent purification by flash column chromatography provides 5-(benzyloxy)quinoline-6-carbaldehyde.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)[CH2:2][CH3:3].C(OC([NH:25][CH2:26][C:27]1[CH:28]=[C:29]([CH2:35][CH:36]([O:40][CH:41]([CH3:43])[CH3:42])[C:37]([O-:39])=[O:38])[CH:30]=[CH:31][C:32]=1[O:33][CH3:34])=O)(C)(C)C>>[CH:41]([O:40][CH:36]([CH2:35][C:29]1[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:27]([CH2:26][NH:25][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:5]=2[O:4][CH2:1][CH2:2][CH3:3])[CH:28]=1)[C:37]([OH:39])=[O:38])([CH3:43])[CH3:42]
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CNC(=O)OC(C)(C)C
Reactant: CCCOc1cc(C(F)(F)F)ccc1C(=O)O
Product: CCCOc1cc(C(F)(F)F)ccc1C(=O)NCc1cc(CC(OC(C)C)C(=O)O)ccc1OC

Procedure:
Using 2-propoxy-4-(trifluoromethyl)benzoic acid and 3-[3-([(tert-butoxycarbonyl)amino]methyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 2-isopropoxy-3-[4-methoxy-3-([2-propoxy-4-(trifluoromethyl)benzoyl]aminomethyl)phenyl]propanoic acid was obtained in the same method as in Example 38).
Reaction SMILES: COC1C=CC(C[N:8]2[C:17](=[O:18])[C:16]3[N:15]=[CH:14][C:13]([CH3:19])=[C:12]([C:20]4[CH:21]=[C:22]5[C:27](=[CH:28][CH:29]=4)[N:26]=[C:25]([NH:30][CH3:31])[N:24]=[CH:23]5)[C:11]=3[CH:10]=[CH:9]2)=CC=1.C(O)(C(F)(F)F)=O.Cl>>[CH3:19][C:13]1[CH:14]=[N:15][C:16]2[C:17](=[O:18])[NH:8][CH:9]=[CH:10][C:11]=2[C:12]=1[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([NH:30][CH3:31])[N:24]=[CH:23]2
Reactant: CNc1ncc2cc(-c3c(C)cnc4c(=O)n(Cc5ccc(OC)cc5)ccc34)ccc2n1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CNc1ncc2cc(-c3c(C)cnc4c(=O)[nH]ccc34)ccc2n1
Temperature: 175 °C

Procedure:
7-(4-Methoxybenzyl)-3-methyl-4-(2-(methylamino)quinazolin-6-yl)-1,7-naphthyridin-8(7H)-one (0.900 g, 2.06 mmol) was taken in a clear microwave vial and treated with 14 ml of TFA and 1 ml of conc HCl. The vial was capped and heated in a Personal Chemistry SmithSynthesizer to 175° C. for 45 minutes. The volatiles were evaporated under reduced pressure and residual TFA/water was azeotroped with toluene. The residue was taken up in DCM/2M MeOH and loaded unto silica. The residue was purified by column chromatography on silica gel using a gradient of 3 to 12% MeOH in DCM to give 3-methyl-4-(2-(methylamino)quinazolin-6-yl)-1,7-naphthyridin-8(7H)-one as a yellow solid. MS (M+H)+ 318.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[N:26]=[CH:25][NH:24][N:23]=1.C(N(CC)CC)C>ClCCl>[C:1]([N:24]1[CH:25]=[N:26][C:22]([CH3:21])=[N:23]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 86.6 %

Procedure:
Trityl chloride (19.0 g) was added portionwise to a stirred solution of 3-methyl-1,2,4-triazole (5.6 g, commercial) and triethylamine (9.5 ml) in dichloromethane (200 ml). The mixture was diluted with dichloromethane (100 ml), washed with water (50 ml), dried over magnesium sulphate and evaporated under reduced pressure to give 1-trityl-3-methyl-1,2,4-triazole (19.0 g). Recrystallisation of a 2 g sample from toluene-hexane (1:1) gave pure material (1.32 g, m.p. 194°-196° C.). NMR (CDCl3): δ2.41(3H,s), 7.03-7.40(15H,m), 7.83(1H,s).
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][O:13][C:14]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21](O)[CH:22]=2)[CH:17]=1)=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:21]2[CH:22]=[C:23]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([C:14]([O:13][CH3:12])=[O:15])[CH:25]=[CH:24]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1

Procedure:
A mixture of cis-4-tert-butylcyclohexanol (9.27 mg, 0.00593 mol), 6-hydroxy-naphthalene-2-carboxylic acid methyl ester (1.00 g, 0.00494 mol) and triphenylphosphine (1560 mg, 0.00593 mol) in toluene (10 mL, 0.1 mol) was heated to reflux, and diisopropyl azodicarboxylate (1.17 mL, 0.00593 mol) was added dropwise and was stirred and refluxed for 6 hours. The mixture was taken up into dichloromethane and was purified via column chromatography with ethyl acetate:hexane (0:100 to 40:60) to give methyl 6-(trans-4-tert-butylcyclohexyloxy)-2-naphthoate as a white solid (0.95 g, 56%). 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.01 (dd, J=8.7, 1.7 Hz, 1H), 7.84 (d, J=9.6 Hz, 1H), 7.73 (d, J=8.7 Hz, 1H), 7.17 (m, 2H), 4.34 (m, 1H), 3.97 (s, 3H), 2.30 (m, 2H), 1.92 (m, 2H), 1.52-1.14 (m, 5H), 0.91 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][C:5](=[O:9])[CH2:4]1.[NH2:10][C:11]1[CH:18]=[C:17](OCCOC)[C:14]([C:15]#[N:16])=[CH:13][N:12]=1>>[NH2:10][C:11]1[CH:18]=[C:17]([O:1][CH2:2][CH:3]2[CH2:8][CH2:7][NH:6][C:5](=[O:9])[CH2:4]2)[C:14]([C:15]#[N:16])=[CH:13][N:12]=1
Reactant: COCCOc1cc(N)ncc1C#N
Reactant: O=C1CC(CO)CCN1
Product: N#Cc1cnc(N)cc1OCC1CCNC(=O)C1

Procedure:
From (racemic) 4-(hydroxymethyl)piperidin-2-one, synthesized in an analogous manner to intermediate 20, the title compound was obtained as a beige solid. (UPLC-MS 6) tR 0.42; ESI-MS 247.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([C:26]([CH3:31])([CH3:30])[C:27]([OH:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:13]=1.CC1(C)[O:37][CH:36]([CH2:38]O)[CH2:35][O:34]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[OH:37][CH:36]([CH2:35][OH:34])[CH2:38][O:28][C:27](=[O:29])[C:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:14]2[CH:13]=[C:12]([NH:11][CH2:10][CH2:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:17]=[C:16]([O:18][CH3:19])[N:15]=2)[CH:21]=1)([CH3:31])[CH3:30]
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Reactant: CC1(C)OCC(CO)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)OCC(O)CO)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.2 %

Procedure:
To a solution of 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [145 mg, 0.315 mmol, Example 49(b)] in N,N′-dimethylformamide (4 mL) is added (2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol [62 mg, 0.472 mmol] and TBTU (151 mg, 0.472 mmol) followed by triethylamine (1 mL). The reaction mixture is stirred for 16 hours at ambient temperature, quenched with the addition of water (200 mL) and brine (25 mL) and extracted twice with EtOAc (200 mL). The extracts are concentrated in vacuo and the residue is stirred in MeOH (4 mL). 1 N hydrochloric acid is added (4 mL). After one hour the reaction is poured into water (150 mL) and extracted twice with EtOAc (150 mL). The extracts are concentrated and the residue is subjected to flash column chromatography on silica (4 g) eluting with 60 to 80% EtOAc in heptane to afford 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid 2,3-dihydroxy-propyl ester (135 mg, Example 89) as an oil. MS: 534 (M+H), 1H NMR [300 MHz, (CD3)2SO]: δ 7.9 (1H, s); 7.8 (1H, s); 7.6 (2H, s); 7.45 (2H, m); 7.35 (2H, s); 6.6 (1H, s); 4.8 (1H, d); 4.55 (1H, t); 4.05 (1H, m); 3.9 (1H, m); 3.85 (3H, s); 3.6 (3H, m); 3.25 (2H, t); 2.95 (2H, t), 1.5 (6H, s). IC50=18 nM
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[Na]>O>[C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccc3ccccc3n2)cc1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: c1ccc(C2CCc3ccccc3N2)cc1
Temperature: 25 °C

Procedure:
In Scheme A, step 2, the 2-phenyl-1,2,3,4-tetrahydroquinoline of formula (3) is prepared by reducing 2-phenylquinoline of formula (2). For example, 2-phenylquinoline of formula (2) is dissolved in a suitable alcoholic solvent, such as absolute ethanol. Sodium metal is then added and the reaction is allowed to cool to room temperature. The reaction mixture may then be diluted with water and extracted with a suitable organic solvent, such as methylene chloride, ethyl acetate, or chloroform. The combined extracts may then be washed with water and brine, the organic layer is separated and dried and the solvent is evaporated in vacuo to provide the 2-phenyl-1,2,3,4-tetrahydroquinoline of formula (3) which may be used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:30])[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C@H:15]([NH:19]C(=O)OC(C)(C)C)[CH:16]([CH3:18])[CH3:17])[CH2:10][C:9]2([CH3:29])[CH3:28])=[CH:4][C:3]=1[O:31][CH3:32].Cl>O1CCOCC1>[ClH:1].[NH2:19][C@H:15]([CH:16]([CH3:18])[CH3:17])[C:14]([N:11]1[CH2:12][CH2:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:31][CH3:32])[CH:4]=2)([OH:30])[C:9]([CH3:28])([CH3:29])[CH2:10]1)=[O:27]
Reactant: COc1cc(C2(O)CCN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)CC2(C)C)ccc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(C2(O)CCN(C(=O)[C@H](N)C(C)C)CC2(C)C)ccc1Cl
Reaction time: 1 h

Procedure:
tert-Butyl (2R)-1-(4-(4-chloro-3-methoxyphenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (153 mg, 0.33 mmol) was added 4N HCl in dioxane (2 mL) and stirred for 60 min. The solvents were removed in vacuo and the resulting solids were dried azeotropically with toluene and then further dried under high vacuum to afford (2R)-2-amino-1-(4-(4-chloro-3-methoxyphenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methylbutan-1-one hydrochloride as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:8](=O)[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[O:13][CH2:14][C:15]([O:17]CC)=[O:16].[C:20]1([CH:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27]([NH2:29])=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([CH:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27]2[S:28][C:7]3[CH2:6][CH2:5][C:4]4[C:9](=[CH:10][CH:11]=[CH:2][C:3]=4[O:13][CH2:14][C:15]([OH:17])=[O:16])[C:8]=3[N:29]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)COc1c(Br)ccc2c1CCCC2=O
Reactant: NC(=S)C(c1ccccc1)c1ccccc1
Product: O=C(O)COc1cccc2c1CCc1sc(C(c3ccccc3)c3ccccc3)nc1-2
Yield: 31 %

Procedure:
Using ethyl [(2-bromo-5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy]acetate and diphenylthioacetamide, the procedure of Example 52 was otherwise repeated to synthesize the title compound. Yield 31%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5]2.[CH2:17](I)[CH2:18][CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][CH2:17][CH2:18][CH3:19])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cc2cc(O)ccc2n1C
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCOc1ccc2c(c1)cc(C(=O)OCC)n2C
Temperature: 100 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
A mixture of ethyl 5-hydroxy-1-methyl-1H-indole-2-carboxylate (103 mg, 0.47 mmol), propyl iodide (141 mg, 0.56 mmol) and cesium carbonate (230 mg, 0.70 mmol) in 1 mL dimethylformamide was stirred vigorously at 100° C. in a sealed vessel for 16 h. After cooling to room temperature, solids were filtered and the liquor concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (20-40% ethyl acetate in hexanes) to give ethyl 1-methyl-5-propoxy-1H-indole-2-carboxylate (96 mg, 55%). Used without further characterization.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][CH2:9][CH2:10]Cl>>[CH3:7][O:8][CH2:9][CH2:10][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: COCCCl
Product: COCCN1CCCCC1
Reaction time: 48 h

Procedure:
In an autoclave of 100 mL, piperidine (40.0 g, 470 mmol) was made reacted with chloroethyl methyl ether (22.0 g, 232 mmol) at 130 deg C. for 48 hours. Solid salt that was formed was removed by filtration, and residue (filtrate) was subjected to reduced-pressure distillation by using a Vigreux column of 25 cm. Then 1H-NMR measurement of obtained amine is performed, and it was confirmed that chemical shifts, δ (ppm), are 3.49-3.46 (t, 2H), 3.31(s, 3H), 2.51-2.48(t, 2H), 2.40-2.36(m, 4H), 1.59-1.53(m, 4H), and 1.42-1.36(m, 2H), and that N-2-methoxyethylpiperidine was synthesized.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[S:5]1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1>C(OCC)(=O)C>[F:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH:27]=[CH:26][N:25]([CH2:2][CH2:3][CH:4]3[C:9](=[O:10])[NH:8][C:7]4[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=4[S:5]3)[CH:24]=[CH:23]2)=[CH:20][CH:21]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C1Nc2ccccc2SC1CCBr
Solvent: CCOC(C)=O
Product: O=C1Nc2ccccc2SC1CCN1C=CN(c2ccc(F)cc2)C=C1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
In 20 ml of ethyl acetate were dissolved 1.36 g of 2-(2-bromoethyl)-2H-1,4-benzothiazin-3(4H)-one and 1.8 g of 1-(4-fluorophenyl)piperazine. The solvent was evaporated off, and the residue was stirred at 110° C. for one hour. The reaction product was extracted with ethyl acetate, and the extract was washed with water and dried over MgSO4. The crystals obtained by evaporation of the solvent were recrystallized from methanol to give 2-[2-[4-(4-fluorophenyl)-1-pyrazinyl]ethyl]-2H-1,4-benzothiazin-3(4H)-one as prisms, m.p. 158°-159° C. The yield was 0.94 g (50.5%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][C:5]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[NH:18][C:17]2=[O:27])=[C:4]([F:28])[CH:3]=1.[CH3:29]OS(OC)(=O)=O.C(=O)(O)[O-].[Na+]>CC(C)=O.CCOCC>[Cl:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][C:5]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:29])[C:17]2=[O:27])=[C:4]([F:28])[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(OCc2ccccc2)c(Cl)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCc3ccccc3)c(Cl)cc2F)c1=O
Yield: 62.2 %

Procedure:
A mixture of 1.85 g (4.46 retool) of 3-[4-chloro-2-fluoro-5-(phenylmethoxy) phenyl]-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione, 492 μL (5.20 mmol) of dimethylsulfate, and 749 mg (8.92 mmol) of sodium bicarbonate in 20 mL of acetone was warmed under reflux for 3 h. Evaporation removed the solvent to give a viscous residue. It was dissolved in 50 mL of ether and washed twice with 30 mL of water, dried (MgSO4) and concentrated in vacuo to give white solid which was flash chromatographed over silica gel, eluting with a 1:4 v:v mixture of ethyl acetate and hexane to give 1.19 g of the title compound as a white solid, m.p.: 145°-147° C.; 1 -NMR (CDCl3, 200 MHz) ppm 7.4 (m, 6H), 6.85 (d, 1H), 6.4 (s, 1H), 5.1 (s, 2H), 3.55 (s, 3H) .