Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH:13]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17].O.NN>C(O)C>[NH2:3][CH2:12][CH:13]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: CC(C)(C)OC(=O)NC(CCS(C)(=O)=O)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC(CN)CCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl [1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-(methylsulfonyl)butan-2-yl]carbamate (25 g, 63 mmol) in ethanol (500 mL) was added dropwise hydrazine hydrate (32 g, 0.63 mol) at 0° C. The reaction mixture was stirred at room temperature for 30 minutes and then heated to reflux. After 2 hours, the reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on silica gel to give tert-butyl [1-amino-4-(methylsulfonyl)butan-2-yl]carbamate. MS ESI calc'd. for C10H23N2O4S [M+H]+ 267. found 267. 1H NMR (300 MHz, CD3OD) δ 3.59-3.54 (m, 1H), 3.29-3.09 (m, 2H), 2.96 (s, 3H), 2.71-2.56 (m, 2H), 2.08-1.76 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[C:16](=[O:33])[N:17]([CH2:29][CH:30]([CH3:32])[CH3:31])[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([F:28])[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:34].C(OCC)C>C(OCC)(=O)C>[ClH:34].[ClH:34].[F:28][C:23]1[CH:22]=[C:21]([C:19]2[CH:20]=[C:15]([CH2:14][N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:16](=[O:33])[N:17]([CH2:29][CH:30]([CH3:31])[CH3:32])[N:18]=2)[CH:26]=[CH:25][C:24]=1[CH3:27]
Reactant: Cc1ccc(-c2cc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(=O)n(CC(C)C)n2)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1ccc(-c2cc(CN3CCNCC3)c(=O)n(CC(C)C)n2)cc1F
Temperature: 50 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of 4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(3-fluoro-4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one (115 mg, 0.25 mmol) in ethyl acetate (2 mL) was added a 4 mol/L solution (2 mL) of hydrochloric acid in ethyl acetate, and the mixture was stirred at 50° C. for 1 hour. The temperature of the reaction mixture was allowed to drop back to room temperature, and then, diethyl ether was added. The precipitate was collected to yield the title compound as a colorless crystalline powder (81.1 mg, 75.0%).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([F:33])=[C:29]([F:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([F:33])=[C:29]([F:32])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Reactant: Fc1cc2ncnc(Cl)c2cc1F
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(F)c(F)cc34)c2)no1

Procedure:
To the intermediate 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A (110 mg, 0.4 mmol) was added 4-chloro-6,7-difluoroquinazoline from the previous step (80 mg, 0.4 mmol) according to the procedure described in Example 1B Step 1, to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[CH2:13]([C:15]1[S:19][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[N:17][C:16]=1[CH2:30][CH2:31]OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:31][CH2:30][C:16]2[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[S:19][C:15]=2[CH2:13][CH3:14])[CH:6]=1
Reactant: CCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCOS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCOc1cccc(CC(=O)OC)c1
Temperature: 25 °C
Yield: 32.7 %

Procedure:
(3-Hydroxy-phenyl)-acetic acid methyl ester (166 mg, 1.0 mmol) is dissolved into anhydrous acetonitrile (ACN) (5 mL). Toluene-4-sulfonic acid 2-[5-ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethyl ester (432 mg, 0.950 mmol) is added to the reaction, followed by the addition of cesium carbonate (652 mg, 2.00 mmol). The reaction is allowed to stir under nitrogen at room temperature and monitored by TLC and HPLC. Upon complete consumption of the tosylate, the reaction is diluted with diethyl ether and quenched with 0.1N NaOH. The two phases are separated, then the organic layer washed with water and brine. The organic phase is dried over anhydrous sodium sulfate and concentrated under vacuum. The residue is further purified using either EtOAc/Hexanes (1:9) or Acetone/Hexanes (1:9) gradients on silica gel chromatography to yield (3-{2-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-acetic acid methyl ester (140 mg, 0.311 mmol) or 33%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9](Cl)=[CH:10][C:11]([C:13]1[C:14]([Cl:20])=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[O:12]>O1CCOCC1>[NH:1]([C:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:10][C:11]([C:13]1[C:14]([Cl:20])=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(C=C(Cl)Cl)c1ccc(Cl)nc1Cl
Solvent: C1COCCO1
Product: O=C(C=C(Nc1ccccc1)Nc1ccccc1)c1ccc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
A solution of aniline (1.01 mL, 11.1 mmol) in TEA (1.55 mL, 11.1 mmol) was added slowly to a cooled (0° C.) and stirred solution of 3,3-dichloro-l -(2,6-dichloro-3-pyridinyl)-2-propen-1-one (1.0 g, 3.69 mmol) in dioxane (20 mL). The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was concentrated in vacuo until most of the solvent was removed. The residue was diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with water, dried over Na2SO4 and concentrated in vacuo. Silica gel flash chromatography of the residue using 6:1 EtOAc:Hex gave 3,3-dianilino-1-(2,6-dichloro-3-pyridinyl)-2-propen-1-one as pale yellow solid (0.69 g, 49%): LCMS RT: 3.81 min; MH+: 384.2.
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13]2[N:14]([CH3:21])[N:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)=[CH:10][CH:9]=[C:8]([CH3:22])[N:7]=1)=[O:5])C.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:4]([C:6]2[C:11]([NH:12][C:13]3[N:14]([CH3:21])[N:15]=[C:16]([CH:18]4[CH2:19][CH2:20]4)[CH:17]=3)=[CH:10][CH:9]=[C:8]([CH3:22])[N:7]=2)=[O:5])=[N:25][CH:26]=1
Reactant: Nc1ccc(F)cn1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cc(C2CC2)nn1C
Product: Cc1ccc(Nc2cc(C3CC3)nn2C)c(C(=O)Nc2ccc(F)cn2)n1

Procedure:
The tide compound, was prepared from 3-(5-Cyclopropyl-2-methyl-2H-pyrazol-3-ylamino)-6-methyl-pyridine-2-carboxylic acid ethyl ester and 2-Amino-5-fluoropyridine in accordance with the general method of Example 78, step 2 to yield the final compound as a yellow cristalline solid, MS (ISP): m/e=367.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:29]([SH:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][S:36][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Reactant: SCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CSCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 48, Step 2, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and benzyl mercaptan.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[N:32]=[C:33]=[O:34]>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([C:33](=[O:34])[NH:32][C:26]3[C:27]([F:31])=[CH:28][CH:29]=[CH:30][C:25]=3[F:24])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Reactant: O=C=Nc1c(F)cccc1F
Solvent: ClCCl
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)Nc3c(F)cccc3F)CC2)c1C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester (which may be prepared as described above; 75.5 mg, 0.239 mmol) in methylene chloride (8.0 mL) was added neat 2,6-difluorophenyl isocyanate (74.1 mg, 0.478 mmol) at room temperature under nitrogen. The resulting light brown solution was stirred overnight. The reaction mixture was diluted with water (˜20 mL) and the resulting mixture was extracted with methylene chloride (2×30 mL). The combined organic layers were washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4, filtered, then concentrated to a yellowish film. Silica gel chromatography (33% ethyl acetate in hexanes) provided {4-[1-(2,6-difluoro-phenylcarbamoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (95.4 mg, 85%) as a colorless film. MS cald. for C26H26F3N2O3 [(M+H)+]: 471, obsd. 471.2.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([OH:10])[CH2:8][OH:9].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[O:9]1[C:4]2([CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[O:10][CH2:7][CH2:8]1
Reactant: OCCO
Reactant: C1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: C1CC2(CCO1)OCCO2
Yield: 90.1 %

Procedure:
Tetrahydro-4H-pyran (6.00 g, 60.0 mmol) was dissolved in benzene (120 mL), to which ethylene glycol (11.2 g, 180 mmol) and p-toluenesulfonic acid monohydrate (1.14 g, 6.00 mmol) were added. Using a Dean-Stark tube, the resulting mixture was refluxed for two hours while removing water generated. To the resulting reaction liquid, a saturated aqueous solution of sodium bicarbonate was added, followed by extraction with ethyl acetate. The resulting organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography (hexane:ethyl acetate, 100:0-0:100, V/V) to give the desired title compound (7.79 g, yield 90%).
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([O:20]COC)=[CH:16][N:15]3[CH:24]=2)=[CH:8][CH:7]=1.Cl.O>C(O)(C)C>[F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][N:15]3[CH:24]=2)=[CH:8][CH:7]=1
Reactant: COCOc1ccc2nc(-c3ccc(OCCCF)cc3)cn2c1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: Oc1ccc2nc(-c3ccc(OCCCF)cc3)cn2c1
Yield: 47.1 %

Procedure:
1.18 g (corresponding to 3.57 mmol) of 2-[4′-(3″-fluoropropoxy)phenyl]-6-methoxymethoxyimidazo[1,2-a]pyridine was dissolved in 29 mL of isopropyl alcohol, and 0.59 mL of conc. hydrochloric acid was added thereto. Then, the mixture was refluxed for 23 hours. After the reaction solution was cooled, the solution was poured into water, and extracted twice by a salting-out extraction procedure using chloroform with addition of sodium chloride. The combined chloroform layer was dried over anhydrous magnesium sulfate. The resulting crude product was purified by silica gel column chromatography (elution solvent: chloroform/methanol=10/1), to obtain 481 mg (corresponding to 1.68 mmol) of 2-[4′-(3″-fluoropropoxy)phenyl]-6-hydroxyimidazo[1,2-a]pyridine (hereinafter referred to as Compound 2) (FIG. 3, Step 10).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18](C=O)C>O.CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)nc1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(C#N)nc1
Temperature: 70 °C
Yield: 90 %

Procedure:
Under a nitrogen atmosphere, add 3-(tert-butoxycarbonylamino-methyl)-6-chloropyridine (13.1 g, 54 mmol), zinc cyanide (9.5 g, 81 mmol), tris(dibenzylideneacetone)dipalladium(0) (494 mg, 0.54 mmol), and dppf (550 mg, 0.81 mmol) to DMF (130 mL). Heat the mixture at 70° C. overnight. Cool the mixture to room temperature and dilute with water and EtOAc. Separate the layers, and extract the aqueous layer with EtOAc. Wash the combined organic extracts with water and brine. Dry the organic solution over Na2SO4, filter, and concentrate in vacuo. Purify by chromatography on silica gel (500 g) eluting with hexane/EtOAc (1:0 to 7:3 gradient) to provide the desired intermediate as a white solid (11.3 g, 90%). MS (ES+) m/z: 234 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6](Br)=[C:5]([N+:8]([O-:10])=[O:9])[N:4]=[C:3]1[CH2:11][O:12][C:13](=[O:15])[CH3:14].[CH3:16][N:17](C)C=O>>[CH3:1][N:2]1[C:6]([C:16]#[N:17])=[C:5]([N+:8]([O-:10])=[O:9])[N:4]=[C:3]1[CH2:11][O:12][C:13](=[O:15])[CH3:14]
Reactant: CN(C)C=O
Reactant: CC(=O)OCc1nc([N+](=O)[O-])c(Br)n1C
Product: CC(=O)OCc1nc([N+](=O)[O-])c(C#N)n1C

Procedure:
2.78 G. (0.01 moles) of 1-methyl-2-acetoxymethyl-4-nitro-5-bromoimidazole and 0.0115 moles of cupric cyanide are combined in 20 ml. of dimethylformamide and heated on a steam bath for 12 hours. The reaction mixture is cooled and poured into 200 ml. of 3% aqueous ammonia and extracted with chloroform. The extracts are washed with water, dried and evaporated under a high vacuum. The residue is recrystallized from isopropanol affording 1.0 g. 1-methyl-2-acetoxymethyl-4-nitro-5-cyanoimidazole, m.p. 92° to 93°C.
Reaction SMILES: [C:1]1([CH2:14][C@H:15](O)[CH3:16])[C:9]2[C:8]3[CH:10]=[CH:11][CH2:12][O:13][C:7]=3[CH:6]=[CH:5][C:4]=2[NH:3][N:2]=1.C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+]>C1COCC1>[N:34]([C@@H:15]([CH3:16])[CH2:14][C:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH2:12][O:13][C:7]=3[CH:6]=[CH:5][C:4]=2[NH:3][N:2]=1)=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H](O)Cc1n[nH]c2ccc3c(c12)C=CCO3
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](Cc1n[nH]c2ccc3c(c12)C=CCO3)N=[N+]=[N-]
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
To a stirred solution of the product from Step E (0.16 g, 0.70 mmol) and triethylamine (0.28 g, 0.39 mL, 7.51 mmol) in anhydrous THF (50 mL) at 0° C. was added methanesulfonic anhydride (0.24 g, 1.4 mmol). The mixture was stirred for about 30 minutes and an additional 1 eq of methanesulfonic anhydride was added. After 30 minutes sodium azide (1.10 g, 7.0 mmol) was added to the reaction mixture. The THF was evaporated and anhydrous dimethyl sulfoxide (20 mL) was added to the residue, which was heated at 90° C. for 1 hour. The reaction mixture was cooled, poured into a saturated solution of sodium bicarbonate (80 mL) and extracted with ethyl acetate (3×50 mL). The combined extracts were dried (MgSO4), filterd and evaporated to an oil. Chromatography on silica (gradient, 10% to 20% of ethyl acetate in hexane) gave an oil (0.09 g, 51%): LC/MS (+APCI) m/z 256 (M+H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22]>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][C:19]([C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=2)=[O:8])=[CH:20][C:15]=1[CH3:14]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: COc1ccccc1C
Product: COc1ccc(C(=O)c2cccc(C(F)(F)F)c2)cc1C
Temperature: 90 °C
Reaction time: 4.5 h

Procedure:
m-Trifluoromethylbenzoic acid (19.0g, 0.10 mole) and o-methylanisole(12.2g, 0.10 mole) are combined in 50 ml of polyphosphoric acid (PPA) and warmed with stirring to 90°C for 4.5 hours. The cooled reaction mixture is then poured into ice water and extracted into ethyl acetate (200 ml) to give, after extraction with 5% aqueous sodium hydroxide 15 g of product (53%), m.p. 56°-59°C, upon removal of the solvent in vacuo.
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([C:6](=[O:14])[CH2:7][CH2:8][CH2:9]2)=[CH:4][NH:3]1.I[CH2:16][CH2:17][CH2:18][CH3:19].[H-].[Na+].Cl>CN(C=O)C>[CH2:16]([N:3]1[C:2](=[O:1])[C:11]([C:12]#[N:13])=[C:10]2[C:5]([C:6](=[O:14])[CH2:7][CH2:8][CH2:9]2)=[CH:4]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCI
Reactant: N#Cc1c2c(c[nH]c1=O)C(=O)CCC2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1cc2c(c(C#N)c1=O)CCCC2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.9 %

Procedure:
3,8-Dioxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (7-010) (770 mg, 4.1 mmol) was dissolved in DMF (15 mL) and to the reaction mixture was added 1-iodobutane (0.51 mL, 4.5 mmol) and sodium hydride (60% oil suspension, 180 mg, 4.5 mmol), and the reaction mixture was stirred at room temperature for 3 h. To the reaction mixture was added dilute hydrochloric acid (1 mol/L, 60 mL) and the reaction mixture was extracted with ethyl acetate (150 mL), washed with brine (50 mL), dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (toluene/ethyl acetate) to give 2-butyl-3,8-dioxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (7-011) (610 mg, 61%) as a white crystal.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([C:19]3[N:20]=[CH:21][S:22][CH:23]=3)=[CH:17][CH:18]=2)[N:4]=[C:3]1[C:24]([O:26][CH2:27][CH3:28])=[O:25].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>C1(C)C=CC=CC=1>[S:22]1[CH:23]=[C:19]([C:16]2[N:15]=[CH:14][C:13]([CH2:12][N:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2](=[S:38])[C:3]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:4]3)=[CH:18][CH:17]=2)[N:20]=[CH:21]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1nn(Cc2ccc(-c3cscn3)nc2)c2ccccc2c1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn(Cc2ccc(-c3cscn3)nc2)c2ccccc2c1=S
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 4-oxo-1-{[6-(1,3-thiazol-4-yl)pyridin-3-yl]methyl}-1,4-dihydrocinnoline-3-carboxylate (750 mg, 2.00 mmol) was dissolved in toluene (9 mL), sparged under nitrogen and treated with Lawesson's Reagent (486 mg, 1.20 mmol, 0.6 equiv). The mixture was placed into an oil bath preheated to 105° C. for 1 hour, cooled to ambient temperature and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 60:40; hexanes:ethyl acetate) to provide the titled compound as a dark green solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C:12](=O)[CH3:13])[CH:7]=[CH:8][CH:9]=1.[C:17]1([C@H:27]([NH2:29])[CH3:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C([BH3-])#N.[Na+].CO>C(Cl)(Cl)Cl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][C@H:12]([NH:29][C@H:27]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH3:28])[CH3:13])[CH:7]=[CH:8][CH:9]=1
Reactant: C[C@@H](N)c1cccc2ccccc12
Reactant: CC(=O)CCc1cccc(OC(F)(F)F)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H](CCc1cccc(OC(F)(F)F)c1)N[C@@H](C)c1cccc2ccccc12

Procedure:
In a similar fashion an equal molar amount of 4-(3-trifluoromethoxyphenyl)-2-butanone, (R)-1-(1-naphthyl)ethylamine and 1.25 equivalents titanium(IV) isopropoxide were mixed and the intermediate imine reduced with ethanolic sodium cyanoborohydride. Work-up and repetitive preparative thin-layer chromatography using 5% methanol in chloroform afforded (S,R)-N-[4-(3-trifluoromethoxyphenyl)-2-butyl]-1-(1-naphthyl)ethylamine, 22X; m/z (rel. int.) 387 (M+, 3), 372 (15), 198 (15), 176 (12), 155 (100), 128 (8), 115 (6), 109 (4), 103 (5), 77 (8) and (R,R)-N-[4-(3-trifluoromethoxyphenyl)-2-butyl]-1-(1-naphthyl)ethylamine, 22Y; m/z (rel. int.) 387 (M+, 2), 372 (12), 198 (16), 176 (11), 155 (100), 128 (8), 115 (6), 109 (4), 103 (5), 77 (8).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:14]([CH2:15][OH:16])=[C:13](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:12][N:11]=2)=[N:8][CH:9]=1.Cl[C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][N:27]=1.[Cl-].[NH4+]>C1COCC1.O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:14]([CH2:15][O:16][C:26]3[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][N:27]=3)=[C:13](/[CH:17]=[CH:18]/[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[O:12][N:11]=2)=[N:8][CH:9]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: OCc1c(-c2ccc(F)cn2)noc1/C=C/c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccc(F)cn3)noc2/C=C/c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a suspension of sodium hydride (129 mg, 3.22 mmol) in THF (4.5 mL) was added a solution of (E)-(3-(5-fluoropyridin-2-yl)-5-styrylisoxazol-4-yl)methanol (866 mg, 2.92 mmol) in THF (9 mL) at room temperature. The reaction mixture was stirred for 1 h at room temperature. A solution of methyl 6-chloronicotinate (602 mg, 3.51 mmol) in THF (9 mL) was added. The reaction was stirred at room temperature overnight and water (150 mL) and saturated aqueous ammonium chloride solution (100 mL) were added. Extraction with ethyl acetate and chromatography (silica, ethyl acetate:heptane=1:9 to 2:3) afforded the title compound (906 mg, 66%) as a white solid. MS: m/e=432.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[N:7]=[N:8][C:9]([Cl:12])=[CH:10][CH:11]=1)[CH3:2].Br[CH2:15][CH2:16]Br>>[CH2:1]([O:3][C:4]([C:5]1([C:6]2[N:7]=[N:8][C:9]([Cl:12])=[CH:10][CH:11]=2)[CH2:16][CH2:15]1)=[O:13])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(Cl)nn1
Reactant: BrCCBr
Product: CCOC(=O)C1(c2ccc(Cl)nn2)CC1
Yield: 20 %

Procedure:
The title compound was prepared from (6-chloro-pyridazin-3-yl)-acetic acid ethyl ester and 1,2-dibromoethane following a procedure analogous to that described in Step 3 for Intermediate 4. Yield: 20% of theory; LC (method 1): tR=1.45 min; Mass spectrum (ESI+): m/z=227/228 (Cl) [M+H]+.