Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[H-].[Na+].[CH3:22]I>CN(C)C=O>[CH3:22][O:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: CI
Reactant: COC(=O)c1cc(CO)cc(-c2ccc(C)cn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1cc(C(=O)OC)cc(-c2ccc(C)cn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of methyl 3-(hydroxymethyl)-5-(5-methylpyridin-2-yl)benzoate (110 mg, 0.41 mmol) in N,N-dimethylformamide (2 mL) at 0° C. was added sodium hydride (60% in mineral oil, 21 mg, 0.52 mmol). After 30 minutes, methyl iodide (73 mg, 0.51 mmol) was added at 0° C. The mixture was warmed to room temperature and stirred for 30 minutes. The mixture was quenched with water (2 mL) and extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4 and concentrated to get the tittle compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])=[C:6]([C:8]2[CH:9]=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26].O>C(Cl)Cl>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[O:16][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:27]([CH2:25][CH3:26])(=[O:29])=[O:28])=[CH:7][C:6]=1[C:8]1[CH:9]=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[CH:13]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Cn1cc(-c2cc(N)ccc2Oc2ccc(F)cc2F)ccc1=O
Solvent: O
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2ccc(=O)n(C)c2)c1
Temperature: 30 °C
Reaction time: 12 h
Yield: 26.4 %

Procedure:
To a solution of 5-[5-amino-2-(2,4-difluorophenoxyl)phenyl]-1-methylpyridin-2-one (30 mg, 0.09 mmol) in DCM (4 mL) was added TEA (27.3 mg, 0.27 mmol) and EtSO2Cl (35.39 mg, 0.27 mmol). The mixture was stirred at 30° C. for 12 h. Water (4 mL) was added and the mixture was extracted with DCM (4 mL×3). The organic layer was concentrated and the residue was purified by prep-HPLC to give the title compound (10 mg, 26%) as light yellow gum. 1H NMR (CDCl3, 400 MHz) δ7.68-7.66 (m, 2H), 7.28 (d, J=2.4 Hz, 1H), 7.13-7.10 (m, 1H), 7.09 (s, 1H), 7.00-6.92 (m, 2H), 6.84-6.86 (m, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.73 (d, J=9.2 Hz, 1H), 3.65 (s, 3H), 3.14 (q, J=7.2 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H). LCMS (M+H)+ 421.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][C:15]3[N:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][N:16]=3)[CH:5]=[CH:4][C:3]1=2.[H-].[Na+].[CH2:29](I)[CH2:30][CH3:31].O>CN(C=O)C>[CH2:29]([N:14]([C:15]1[N:16]=[CH:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][N:20]=1)[C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:26])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1)[CH2:30][CH3:31]
Reactant: CCOC(=O)c1cnc(Nc2ccc3c(c2)C(C)(C)CCC3(C)C)nc1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(c1ccc2c(c1)C(C)(C)CCC2(C)C)c1ncc(C(=O)OCC)cn1
Yield: 63 %

Procedure:
Ethyl 2-[N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)amino]-pyrimidine-5-carboxylate (165 mg) was dissolved in dry DMF (3 ml), and the solution was added with a suspension of NaH (130 mg) in DMF (2 ml). Then, the mixture was added with n-propyl iodide (0.5 ml) and stirred. After the disappearance of the materials was observed with TLC, the reaction mixture was poured into water, and extracted with CH2Cl2. The organic layer was dried over Na2SO4, and the solvent was evaporated. The residue was purified by silica gel flash column chromatography (n-hexane: AcOEt=20:1) to obtain ethyl 2-[N-n-propyl-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-yl)amino]pyrimidine-5-carboxylate (116.5 mg, 63%).
Reaction SMILES: [Cl-].[CH3:2][CH:3]1[NH2+:8][CH:7]([CH3:9])[CH2:6][O:5][CH2:4]1.Br[CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23]>>[CH3:9][CH:7]1[N:8]([CH2:11][CH2:12][N:13]2[C:14](=[O:23])[C:15]3[C:16](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:18])[CH:3]([CH3:2])[CH2:4][O:5][CH2:6]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: CC1COCC(C)[NH2+]1
Agent: [Cl-]
Product: CC1COCC(C)N1CCN1C(=O)c2ccccc2C1=O

Procedure:
The title compound was prepared by a similar method to Preparation 6 from 3,5-dimethyl-1,4-oxazinan-4-ium chloride [see Preparation 10] and N(2-bromoethyl)phthalimide. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 8:1, by volume, hexane:ethyl acetate to afford 2-[2-(3,5-dimethylmorpholino)ethyl]-1H-isoindole-1,3(2H)-dione (455 mg) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:27][CH:28]([F:30])[F:29])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.C([Sn](CCCC)(CCCC)[C:37]1[O:38][CH:39]=[CH:40][N:41]=1)CCC.O1CCOCC1>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:27][CH:28]([F:30])[F:29])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:37]3[O:38][CH:39]=[CH:40][N:41]=3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-c2ncco2)cc1
Temperature: 100 °C

Procedure:
A mixture of [3-(4-bromobenzyl)-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy]acetic acid methyl ester (0.36 g), 2-tributylstannanyloxazole (0.46 mL), tetrakis(triphenylphosphine)palladium(0) (0.084 g) and 1,4-dioxane (3.0 mL) was heated at 100° C. for 3 hours. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with water, and then dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound as a yellow gum (1.1 g).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:10]Cl)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.[C-:20]#[N:21].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:10][C:20]#[N:21])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [C-]#N
Reactant: COc1ccc(CCl)cc1OC1CCCC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CC#N)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.2 %

Procedure:
A mixture of 3-cyclopentyloxy-4-methoxybenzyl chloride (119 grams, 0.49 mol), 120 milliliters of methylene chloride, KCN (70.7 grams, 1.09 mol), benzyltriethylammonium chloride (35 grams, 0.015 mol) and water (120 milliliters) was stirred vigorously at room temperature for 48 hours. The reaction mixture was diluted with. methylene chloride and the layers were separated. The methylene chloride solution was extracted several times with water and evaporated to yield 3-cyclopentyloxy-4-methoxyphenylacetonitrile (109 grams, 95%) for the subsequent transformation.
Reaction SMILES: [H-].[Na+].[C:3]1([NH:9][C:10](=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:20][C:21](OCC)=[O:22].O>CN(C=O)C>[C:3]1([N:9]2[CH2:20][C:21](=[O:22])[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]2=[O:18])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cc1ccccc1)Nc1ccccc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CN(c2ccccc2)C(=O)C1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred slurry of 500 mg (12 mmol) of a 60% oil dispersion of sodium hydride (which had been washed with hexane) in 12 ml dry DMF under argon atmosphere was added 1.06 g (5.0 mmol) of N-phenyl-2-phenyl acetamide (IVa) in 5 mL dry DMF. Gas evolution had ceased after 30 minutes and 0.560 mL (5.0 mmol) of ethyl bromoacetate was added via syringe. The solution was stirred at 25° C. for 30 minutes, then warmed to 80° C. for 4 hours. The cooled solution was carefully poured into 200 mL H2O, washed with ether, filtered over celite and acidified to pH=2. The white precipitate was filtered, washed well with H2O and dried under high vacuum to give 1.04 g (4.0 mmol, 80% yield) of 1,3-diphenyl-2,4-pyrrolidinedione Ia, mp 285°-287° C.
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](=[O:19])[CH3:18])[CH3:13].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1>O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:12]([O:14][C:15](=[O:20])[CH:16]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=1)[C:17](=[O:19])[CH3:18])[CH3:13]
Reactant: CCOC(=O)CC(C)=O
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCOC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(C)=O
Temperature: 70 °C

Procedure:
A suspension of potassium tert-butoxide (4.5 g) in anhydrous tetrahydrofuran (70 mL) at 0° C. was treated with a mixture of tert-butanol (0.2 mL) and 3-oxobutyric acid ethyl ester (5.2 g). After stirring at 15° C. for 15 minutes a solution of 1-bromomethyl-4-methanesulfonylbenzene (10 g) in tetrahydrofuran (30 mL) was added and the resulting mixture heated at 70° C. for 17 hours. The mixture was diluted with saturated aqueous citric acid solution (20 mL) and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of pentane and dichloromethane (2:1 to 0:1 by volume) to afford title compound as a gum, 3.5 g.
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][C:4]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:27][CH3:28])[CH2:3]1.[OH-].[Na+].C(O)(=O)C>C(O)C>[O:33]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([OH:18])=[O:17])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][C:4]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:27][CH3:28])[CH2:3]1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OCC(=O)OCC)cc2S(=O)(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OCC(=O)O)cc2S(=O)(=O)C1
Yield: 90 %

Procedure:
1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 8; 0.34 g) and sodium hydroxide (0.3 g) were dissolved in ethanol and the mixture was heated to reflux for 1 hour. Acetic acid (1 ml) was added and the solvent was removed at reduced pressure. The residue was partitioned between DCM/H2O and the organic layer was separated and dried. Trituration of the residue with n-hexane gave the title compound 0.29 g (90%) as a solid. NMR (500 MHz) 0.7–0.8 (m, 6H), 1.0–1.7 (m, 8H), 3.1–3.2 (m, 2H), 3.6 (brs, 2H), 4.6 (s, 2H), 6.9–7.1 (m, 4H), 7.2 (m, 2H), 7.5 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH2:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=1)[CH3:22].C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:21]([N:23]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=1)[C:15]([CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1)=[O:17])[CH3:22]
Reactant: CCNCc1cccc(C)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CCN(Cc1cccc(C)c1)C(=O)COc1ccc(C[C@H](OC)C(=O)O)cc1

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and ethyl-(3-methyl-benzyl)-amine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C22H27NO5 [M+H]+: 386.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[O:12][C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15].C(N(CC)CC)C.[CH3:26][C:27]([CH3:35])([O:29][C:30]([NH:32][NH:33][CH3:34])=[O:31])[CH3:28]>O1CCCC1.CN(C1C=CN=CC=1)C>[CH3:26][C:27]([CH3:35])([O:29][C:30]([NH:32][N:33]([CH3:34])[C:14](=[O:15])[C:13]([O:12][N:3]1[C:2](=[O:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:11])([CH3:18])[CH3:17])=[O:31])[CH3:28]
Reactant: CC(C)(ON1C(=O)c2ccccc2C1=O)C(=O)Cl
Reactant: CNNC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(NC(=O)OC(C)(C)C)C(=O)C(C)(C)ON1C(=O)c2ccccc2C1=O
Temperature: 20 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
A solution of 2-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)oxy]-2-methylpropanoyl chloride (5.3 g, 22 mmole) in 40 ml of dry tetrahydrofuran was treated with triethylamine (4.10 ml, 30 mmole) and 4-(N,N-dimethylamino)pyridine (5 mg). A solution of 1-[(1,1-dimethylethoxy)carbonyl]-2-methylhydrazine (2.90 g, 20 mmole) in 20 ml of tetrahydrofuran was added dropwise at 0° C. and the resulting mixture was stirred at 20° C. overnight. The solvent was evaporated and the solid residue was partitioned between ethyl acetate and water. The organic phase was washed successively with 0.5N hydrochloric acid, 5% sodium bicarbonate, and water. Drying over magnesium sulfate and evaporation gave 6.6 g of the title compound as a colorless solid, m.p. 140°-145° C.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[Br:6][C:7]1[CH:12]=[N:11][CH:10]([Cl:13])[N:9](Cl)[CH:8]=1.[H-].[Na+].[Cl-].[Na+].O.O>CN(C)C=O>[Br:6][C:7]1[C:8]([O:5][CH2:4][CH:2]2[CH2:1][O:3]2)=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1
Reactant: OCC1CO1
Reactant: ClC1N=CC(Br)=CN1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncc(Br)c(OCC2CO2)n1
Yield: 96.2 %

Procedure:
A solution of glycidol (13.0 g, 0.175 mole) and 5-bromo-2,3-dichloropyrimidine (40.0 g, 0.175 mole) in dimethylformamide (350 mL) was added dropwise to a stirring nitrogen-flushed, chilled suspension of sodium hydride (from 10.1 g, 0.21 mole, of NaH washed free of mineral oil) in dimethylformamide (350 mL). Following the addition, the reaction mixture was poured into 1:1 brine-water (4.5 l) and extracted with ethyl acetate (5×750 mL). Combined extracts were washed with water and brine, dried (MgSO4) and concentrated in vacuo to give 44.7 g of an oil which solidified. Trituration of the crude product in isopropyl alcohol-isopropyl ether gave 21.9 g (47%) of product, m.p. 63°-73°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:4][C:3]=1[Br:19].[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1>ClCCl>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([O:18][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:10]([F:11])([F:12])[F:13])[C:14]([F:17])([F:15])[F:16])=[CH:4][C:3]=1[Br:19]
Reactant: O=C(O)c1ccccc1
Reactant: Nc1c(Cl)cc(C(O)(C(F)(F)F)C(F)(F)F)cc1Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: Nc1c(Cl)cc(C(OC(=O)c2ccccc2)(C(F)(F)F)C(F)(F)F)cc1Br
Temperature: 25 °C
Yield: 42 %

Procedure:
To a solution of 2-(4-amino-3-bromo-5-chlorophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (Example 3.3) (3.725 g, 10.0 mmol) and benzoic acid (1.28 g, 10.5 mmol) in dichloromethane (30 ml) was added pyridine (4.18 ml, 30 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (“BOP-Cl”) (2.80 g, 11 mmol). The reaction mixture was heated to reflux for 24 hours. The reaction mixture was cooled to ambient temperature and quenched by addition of aqueous hydrochloric acid (1N) (50 ml). The mixture was then extracted three times with dichloromethane. The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (Buchi fraction collector C-660, prepacked cartridges Silicagel 60, particle size: 40-63 μm, D 40×150 mm, Gradient 99 to 1% methanol in toluene over 15 min, 60 mL/min, fraction 20 mL) to give benzoic acid 1-(4-amino-3-bromo-5-chlorophenyl)-2,2,2-trifluoro-1-trifluoromethylethyl ester (2 g, 42% yield). 1H NMR (400 MHz, CDCl3): 8.18 (d, 1H), 8.11 (d, 1H), 7.68 (m, 1H), 7.53 (m, 2H), 7.41 (s, 1H), 7.29 (s, 1H), 4.74 (bs, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:23][C:24]1[CH:33]=[C:32]([CH3:34])[C:31]2[C:26](=[CH:27][C:28]([OH:35])=[CH:29][CH:30]=2)[N:25]=1>>[CH3:23][C:24]1[CH:33]=[C:32]([CH3:34])[C:31]2[C:26](=[CH:27][C:28]([O:35][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]5[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:29][CH:30]=2)[N:25]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Cc1cc(C)c2ccc(O)cc2n1
Product: COc1cc2c(Oc3ccc4c(C)cc(C)nc4c3)ncnc2cc1OCC1CCN(C)CC1
Yield: 33.3 %

Procedure:
Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (0.13 g, 0.4 mmol), (prepared as described for the starting material in Example 10), was reacted with 2,4-dimethyl-7-hydroxyquinoline (87 mg, 0.5 mmol), (Chem. Berichte, 1903, 36, 4016), to give 4-(2,4-dimethylquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (61 mg, 33%).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[N:11]=[C:10]([C:13]34[CH2:20][CH:19]5[CH2:21][CH:15]([CH2:16][CH:17]3[CH2:18]5)[CH2:14]4)[NH:9][C:8]=2[C:7](=[O:22])[NH:6][C:5]1=[O:23])[CH:2]=[CH2:3].[H-].[Na+].I[CH2:27][CH2:28][CH3:29].O>CN(C)C=O>[CH2:1]([N:4]1[C:12]2[N:11]=[C:10]([C:13]34[CH2:14][CH:15]5[CH2:21][CH:19]([CH2:18][CH:17]3[CH2:16]5)[CH2:20]4)[NH:9][C:8]=2[C:7](=[O:22])[N:6]([CH2:27][CH2:28][CH3:29])[C:5]1=[O:23])[CH:2]=[CH2:3]
Reactant: C=CCn1c(=O)[nH]c(=O)c2[nH]c(C34CC5CC(CC3C5)C4)nc21
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(=O)n(CCC)c(=O)c2[nH]c(C34CC5CC(CC3C5)C4)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
1.00 g (3.21 mmol) of Compound G was dissolved in 30 ml of dimethylformamide, and 256 mg of sodium hydride (60%, 6.41 mmol) was added slowly to the solution at 0° C. After 30 minutes, 0.33 ml (3.4 mmol) of 1-iodopropane was added dropwise slowly at the same temperature and stirred at room temperature overnight. The resulting reaction mixture was poured into 300 ml of water, neutralized and extracted three times with 100 ml of chloroform. The organic layer was washed with a saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluate: 30% ethyl acetate/hexane) to give 225 mg (yield 20%) of Compound H as a colorless needle crystal.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16]([CH:18]=[N:12][C:10]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=1)=[S:11])[CH3:17]
Reactant: N#Cc1cccc(NC(N)=S)c1
Reactant: COC(OC)N(C)C
Product: CN(C)C=NC(=S)Nc1cccc(C#N)c1
Temperature: 100 °C
Yield: 91 %

Procedure:
A mixture of 3 g (16.9 mmol) 1-(3-Cyanophenyl)-2-thiourea and 20 ml N,N-Dimethylformamide dimethyl acetal was heated to 100° C. for 1 h. After evaporation of the volatiles the precipitate was suspended in DCM, filtered and dried to yield 3.56 g (91%) of the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([O:19][CH3:20])=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)(=O)=O.[CH2:21]([S-:23])[CH3:22].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH2:21]([S:23][CH2:6][CH2:7][CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([O:19][CH3:20])=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)[CH3:22]
Reactant: CC[S-]
Reactant: COC(=O)C12CCC(CCCOS(C)(=O)=O)(CC1)CC2
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCSCCCC12CCC(C(=O)OC)(CC1)CC2
Temperature: 45 °C
Reaction time: 3 h

Procedure:
Mesylate 11-5 (3.30 g, 10.9 mmol) was dissolved in DMF (20 mL) and treated with sodium ethanethiolate (1.82 g, 21.7 mmol). The solution was stirred at 45° C. for 3 h, then the mixture was diluted with 100 mL of ethyl acetate and washed twice with 1N aqueous HCl, then with saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated to afford methyl 4-[3-(ethylthio)propyl]bicyclo[2.2.2]octane-1-carboxylate (11-6) as a crude oil which was used without purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](I)[CH:5]=[CH:4][N:3]=1.Cl.[NH:11]1[CH2:16][CH2:15][C:14]2([C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][O:17]2)[CH2:13][CH2:12]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CC#N>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([N:11]2[CH2:16][CH2:15][C:14]3([C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH2:18][O:17]3)[CH2:13][CH2:12]2)[CH:5]=[CH:4][N:3]=1
Reactant: c1ccc2c(c1)COC21CCNCC1
Reactant: Clc1nccc(I)c1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Clc1nccc(N2CCC3(CC2)OCc2ccccc23)c1Cl
Temperature: 110 °C

Procedure:
A mixture of D10 (1 g, 3.655 mmol), spiro[isobenzofuran-1(3H),4′-piperidine], hydrochloride [CAS 37663-44-8] (0.83 g, 4.386 mmol) and DIPEA (1.273 ml, 7.309 mmol) in CH3CN (9 ml) was heated in a sealed tube at 110° C. for 16 h. The mixture was then treated with NaHCO3 (aqueous sat. solution) and extracted with EtOAc. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/EtOAc up to 2% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D21 (0.199 g, 16%) as a white solid. M.P. 160.8° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:12][C:13]([OH:15])=[O:14])[C:4]2[CH2:5][CH2:6][CH2:7][C:8](=O)[C:9]=2[CH:10]=1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>C(O)C>[OH:18][N:17]=[C:8]1[CH2:7][CH2:6][CH2:5][C:4]2[N:3]([CH2:12][C:13]([OH:15])=[O:14])[C:2]([CH3:1])=[CH:10][C:9]1=2
Reactant: NO
Reactant: Cc1cc2c(n1CC(=O)O)CCCC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc2c(n1CC(=O)O)CCCC2=NO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)acetic acid (4.0 g, 19 mmol), hydroxylamine hydrochloride (2.0 g, 29 mmol) and anhydrous sodium acetate (2.4 g, 29 mmol) in ethanol (40 mL) was heated under reflux for 6 h with stirring. After cooling to r.t. and holding overnight, the mixture was further cooled to 4° C. The solid product was collected by filtration, washed with water (15 mL) followed by ethanol (15 mL) then dried under vacuum at 40° C. to afford the title compound as a pale brown solid; 3.68 g (86%); purity: 96.7 area % by HPLC; m/z: 223 (MH+); 1H-NMR: 9.82 (1H, br s), 6.48 (1H, d, J=0.90 Hz), 4.58 (2H, s), 2.56-2.51 (2H, m), 2.29-2.24 (2H, m), 2.09 (3H, s), 1.86-1.79 (2H, m).