Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:11]([C:22]([F:25])([F:24])[F:23])=[CH:10][C:9]=1[NH2:26])([CH3:4])([CH3:3])[CH3:2].C([O:32][C:33](=O)[CH2:34][C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43]2[CH:48]=[CH:47][N:46]=[C:45]([CH3:49])[CH:44]=2)[CH:38]=1)=[O:36])(C)(C)C>>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:11]([C:22]([F:24])([F:25])[F:23])=[CH:10][C:9]=1[NH:26][C:33](=[O:32])[CH2:34][C:35]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43]2[CH:48]=[CH:47][N:46]=[C:45]([CH3:49])[CH:44]=2)[CH:38]=1)=[O:36])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: CC(C)(C)OC(=O)Nc1cc(COC2CCCCO2)c(C(F)(F)F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(COC4CCCCO4)cc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from [2-amino-5-(tetrahydro-pyran-2-yloxymethyl)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J38) (293 mg, 0.75 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (168 mg, 36%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14](CC(O)=O)[C:13](=[O:19])[C:12](CC)(CC)[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C>CO>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[NH:14][C:13](=[O:19])[CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCC1(CC)CC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C1=O
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C1CCC[C@@H](c2cc(F)cc(F)c2)N1
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
A solution of ethyl (5S)-5-{[(S)-tert-butylsulfinyl]amino}-5-(3,5-difluorophenyl)pentanoate from Step A (4.42 g, 12.2 mmol) in MeOH (200 mL) was cooled to 0° C. Hydrogen chloride gas (anhydrous) was bubbled through this cold solution for about 1 minute, after which time the reaction vessel was sealed and allowed to sit in the ice bath for 15 minutes. Dry nitrogen was then bubbled through the solution for 30 minutes, prior to removal of solvent in vacuo. More MeOH (˜50 mL) was added, and then removed in vacuo. After dissolving in a third volume of MeOH (100 mL), triethylamine (6.78 mL, 48.9 mmol) was introduced and the mixture was heated to 65° C. for 3 hours. After cooling to ambient temperature, the solvent was removed in vacuo and the residue was partitioned between diethyl ether (100 mL) and 1 M HCl (50 mL). The organics were washed with additional 1 M HCl (50 mL), water (50 mL) and saturated brine (50 mL). The ethereal solution was dried over sodium sulfate, filtered and then concentrated in vacuo to provide the title compound, which could be used without further purification. MS: m/z=212 (M+1).
Reaction SMILES: [OH:1][C@@H:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][C@@H:5]1[C@H:9]2[CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([OH:18])[C:16]=3[CH2:17][C@H:8]2[CH2:7][C@H:6]1[OH:19].C([O-])([O-])=O.[K+].[K+].Cl[CH2:32][C:33]#[N:34]>CC(C)=O>[OH:19][C@H:6]1[C@H:5]([CH2:4][CH2:3][C@@H:2]([OH:1])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C@H:9]2[CH2:10][C:11]3[C:16]([CH2:17][C@H:8]2[CH2:7]1)=[C:15]([O:18][CH2:32][C:33]#[N:34])[CH:14]=[CH:13][CH:12]=3
Reactant: N#CCCl
Reactant: CCCCC[C@H](O)CC[C@@H]1[C@H]2Cc3cccc(O)c3C[C@H]2C[C@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCC[C@H](O)CC[C@@H]1[C@H]2Cc3cccc(OCC#N)c3C[C@H]2C[C@H]1O
Temperature: 30 °C
Yield: 82 %

Procedure:
(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-1-((S)-3-hydroxyoctyl)-1H-cyclopenta[b]naphthalene-2,5-diol (2 g, 0.005 mol) in dry acetone (20 ml) was treated with K2CO3 (2.07 g, 0.015 mol), chloroacetonitrile (0.64 ml, 0.010 mol) and tetrabutylbromide (0.32 g, 0.001 mmol). The mixture was heated at 30° C. overnight. Then, the reaction mixture was filtered with celite pad. The filtrate was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. Yield: 82%
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[CH2:9]=[C:10]1[O:14][C:12](=[O:13])[CH2:11]1>C1(C)C=CC=CC=1>[CH3:7][C:5]1[N:6]=[C:2]([NH:1][C:12](=[O:13])[CH2:11][C:10](=[O:14])[CH3:9])[S:3][C:4]=1[CH3:8]
Reactant: Cc1nc(N)sc1C
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)Nc1nc(C)c(C)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.6 %

Procedure:
To a solution of 2-amino-4,5-dimethylthiazole (0.05 mole) in toluene (30 ml), cooled in ice was added diketene (0.05 mole) at such a rate that the temperature did not rise above 20° C. When addition was complete the mixture was stirred at room temperature for 2 hours and evaporated to dryness to give N-(4,5-dimethylthiazol-2-yl)-3-ketobutanamide (4.1 g), Rf (silica; diethylamine/ethyl acetate 1:19) 0.47; m.p. 191°-3° C.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=1)[C:5]([C:7]1[CH:11]=[CH:10][O:9][C:8]=1[CH3:12])=O.Cl.[CH3:22][CH:23]1[O:28][CH:27]([CH3:29])[CH2:26][N:25]([C:30](=[NH:32])[NH2:31])[CH2:24]1.CC(C)([O-])C.[K+]>C(O)C>[CH3:29][C@H:27]1[O:28][C@@H:23]([CH3:22])[CH2:24][N:25]([C:30]2[N:31]=[C:5]([C:7]3[CH:11]=[CH:10][O:9][C:8]=3[CH3:12])[C:4]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=3)=[CH:3][N:32]=2)[CH2:26]1
Reactant: CC1CN(C(=N)N)CC(C)O1
Reactant: Cc1cc(C(=CN(C)C)C(=O)c2ccoc2C)ccn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Cc1cc(-c2cnc(N3C[C@@H](C)O[C@@H](C)C3)nc2-c2ccoc2C)ccn1
Temperature: 25 °C
Yield: 11 %

Procedure:
A mixture of 3-(dimethylamino)-1-(2-methyl-3-f uranyl)-2-(2-methyl-4-pyridinyl)-2-propen-1-one (1352 mg, 5 mmol) and 2,6-dimethyl-4-morpholinecarboximidamide hydrochloride (1453 mg, 7.50 mmol) (ca. 2.3:1 mixture of cis:trans isomers) in ethanol (10 ml) was stirred at room temperature. Potassium tert-butoxide (1122 mg, 10.00 mmol) was added and the mixture was heated at reflux for 3 hours. After cooling to room temperature the solvent was evaporated and the residue was diluted with water and extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 50% ethyl acetate in isohexane to give cis-2,6-dimethyl-4-[4-(2-methyl-3-furanyl)-5-(2-methyl-4-pyridinyl)-2-pyrimidinyl]morpholine as an oil (200 mg). The cross-over fractions from the column (˜800 mg) were purified by mass-directed automated HPLC to give additional cis-2,6-dimethyl-4-[4-(2-methyl-3-furanyl)-5-(2-methyl-4-pyridinyl)-2-pyrimidinyl]morpholine (200 mg) and trans-2,6-dimethyl-4-[4-(2-methyl-3-furanyl)-5-(2-methyl-4-pyridinyl)-2-pyrimidinyl]morpholine (49 mg). A solution of cis-2,6-dimethyl-4-[4-(2-methyl-3-furanyl)-5-(2-methyl-4-pyridinyl)-2-pyrimidinyl]morpholine (200 mg, 0.55 mmol) was dissolved in dichloromethane (2 ml) and hydrogen chloride (1M in ether, 0.6 ml) was added. The solvent was evaporated and the residue was evaporated with ether (×2) and then triturated with ether. The solid was collected, washed with ether and dried to give the title compound (178 mg). LC/MS [M+H]+=365. 1H NMR (400 MHz, d6-DMSO): δ 8.61 (1H, d), 8.56 (1H, s), 7.82 (1H, b), 7.58-7.53 (1H, m), 7.52 (1H, d), 6.04 (1H, d), 4.65-4.58 (2H, m), 3.64-3.55 (2H, m), 2.72-2.63 (2H, m), 2.66 (3H, s), 2.36 (3H, s), 1.18 (6H, d).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.C([O-])([O-])=O.[Na+].[Na+].[OH:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>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.COCCOC>[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2/[C:4](=[CH:12]/[C:13]2[NH:14][CH:15]=[CH:16][CH:17]=2)/[C:5](=[O:11])[NH:6]3)=[CH:27][CH:26]=1
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Reactant: OB(O)c1ccc(O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1Nc2cccc(-c3ccc(O)cc3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Yield: 79 %

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (45 mg, 0.134 mmol) (Starting Material 1), 2M aqueous Na2CO3 solution (134 μL , 0.268 mmol), (Ph3P)4Pd (5 mg, 0.004 mmol) (Aldrich), and 4-hydroxyphenylboronic acid (37 mg, 0.268 mmol) (prepared according to H. Gilman et al., J. Am. Chem. Soc. 79:3077-3081 (1957)) in 3 mL of a 3:1 mixture of 1,2-dimethoxyethane:distilled water was heated at reflux under a nitrogen atmosphere for 15 h. The reaction mixture was allowed to cool to room temperature and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 35% ethyl acetate-hexanes elution) to yield pure (Z)-1,3-dihydro-4-(4-hydroxyphenyl)-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (yield: 32 mg, 79%) as a yellow solid (mp 271-273° C.).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[C:3]1([CH3:10])[CH3:9].Cl[C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([S:20][CH3:21])[N:13]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[OH:8][CH:4]1[CH2:5][CH2:6][CH2:7][CH:2]([NH:1][C:12]2[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]([S:20][CH3:21])[N:13]=2)[C:3]1([CH3:10])[CH3:9]
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: CC1(C)C(N)CCCC1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CSc1ncc(C#N)c(NC2CCCC(O)C2(C)C)n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
A mixture of 3-amino-2,2-dimethylcyclohexanol (1.30 g, crude) and 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (1.35 g, 7.27 mmol), and DIEA (1.93 g, 15.0 mmol) in isopropanol (14 mL) was stirred at 90° C. for 1 h. After removal of the solvent, the residue was purified by silica gel column chromatography (10%-30% ethyl acetate in petroleum ether) to afford the title compound (820 mg, 2.81 mmol, 38% yield), which was separated by chiral column (Superchiral S-AD, 0.46 cm I.D.×25 cm L, 5 μl, CO2/MeOH/DEA=80/20/0.05 (v/v/v); Flow: 2.5 ml/min, 254 nm, T=35° C.), then by chiral column: Chiralpak IC, 0.46 cm I.D.×25 cm L, 5 μl, CO2/MeOH/DEA=70/30/0.05 (v/v/v); Flow: 2.5 ml/min, 254 nm, T=35° C.) to give four isomers (peak 1: 90 mg, d.e.=100%, e.e.=100%, peak 2: 220 mg, d.e.=99.7%, e.e.=100%, peak 3: 210 mg, d.e.=100%, e.e.=97.3%, peak 4:125 mg, d.e.=99.6%, e.e.=100%. Peak 1 and peak 4 were determinated to be cis-isomers and peak 2 and peak 3 were determinated to be trans-isomers by 2D-NMR). MS (ESI) m/z 293.1 [M+H]+
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][N:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)(=[O:12])=[O:11])[C:7](=[O:21])[N:6]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:4].[OH-].[Na+].Cl>O1CCCC1.CO>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([S:10]([N:8]2[CH2:9][CH:5]([C:3]([OH:4])=[O:2])[N:6]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:7]2=[O:21])(=[O:11])=[O:12])[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C1CN(S(=O)(=O)c2cccc(OC)c2)C(=O)N1c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(S(=O)(=O)N2CC(C(=O)O)N(c3ccccc3)C2=O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of (RS)-1-(3-methoxy-benzenesulfonyl)-2-oxo-3-phenyl-imidazolidine-4-carboxylic acid methyl ester (0.043 g) in tetrahydrofuran (0.5 ml) and methanol (0.5 ml) was added a 1 M aqueous NaOH solution (0.13 ml) at 0° C. The mixture was stirred at 0° C. for 30 min. 1 M HCl (0.15 ml) was added and the organic solvents were evaporated. The colorless precipitate was collected by filtration, washed with water and dried to give (RS)-1-(3-methoxy-benzenesulfonyl)-2-oxo-3-phenyl-imidazolidine-4-carboxylic acid (0.040 g) as a colorless solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[CH2:19]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[CH3:18])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccccc2)cccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1c(N)cccc1N(Cc1ccccc1)Cc1ccccc1
Reaction time: 48 h
Yield: 40.4 %

Procedure:
The product from Example 2A (3.4 g, 16.2 mmoles) in acetic acid (20 mL) was treated with zinc powder (2.68 g, 41 mmoles, purchased from Aldrich) and stirred for 48 hours. An additional portion of zinc (1.0 g, 15.3 mmoles) was added and stirring continued for 4 hours. The reaction was filtered through a pad of Celite with CH2Cl2 and concentrated. Purification by flash chromatography (silica gel, 4:1 hexanes:ethyl acetate) provided the title compound as a yellow solid (1.98 g, 64%).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](O)=O.N>>[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: O=C(O)c1ccccc1F
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Fc1ccccc1-c1nc(-c2cccnc2)no1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2-fluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.38-7.49 (m, 2H), 7.64 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 7.70-7.79 (m, 1H), 8.28 (td, J=7.5, 1.9 Hz, 1H), 8.57 (dt, J=8.1, 1.9 Hz, 1H), 8.74 (dd, J=4.7, 1.7 Hz, 1H), 9.31 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCl/NH3) m/z 242 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C([O-])([O-])=O.[K+].[K+].[CH2:18]([NH:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]>CS(C)=O.O>[CH2:18]([N:22]([CH2:23][CH2:24][CH2:25][CH3:26])[C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[F:1])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCNCCCC
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCN(CCCC)c1ccc([N+](=O)[O-])cc1F
Temperature: 90 °C
Yield: 75.1 %

Procedure:
To a solution of 3,4-difluoronitrobenzene (3.18 g, 20 mmol) in DMSO (25 mL) were added K2CO3 (6.08 g, 44 mmol) and di-n-butylamine (2.84 g, 22 mmol) with stirring. The mixture was heated at 90° C. overnight, then cooled to rt, diluted with water (100 mL) and extracted with CH2Cl2 (80 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/CH2Cl2 (V/V)=10:1) to give the title compound as yellow oil (4.03 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])[CH2:16][CH2:15][CH:14]([NH:17][S:18]([CH2:21][C:22]([O:24]C)=O)(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH3:34]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[F:33])[CH2:12][CH2:13][CH:14]([NH:17][S:18]([CH2:21][C:22]([NH2:34])=[O:24])(=[O:20])=[O:19])[CH2:15][CH2:16]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: N
Reactant: COC(=O)CS(=O)(=O)NC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Solvent: CCO
Product: NC(=O)CS(=O)(=O)NC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The ester of Example 38 (40 mg, 0.07 mmol) in ethanol (1.5 ml) was treated with NH3 (1 ml of 25% aqueous solution). The reaction mixture was stirred at ambient temperature for 2 h and evaporated to give a residue (40 mg) which was purified using preparative plate thin layer chromatography eluting with ethyl acetate:hexane 2:1 to yield the desired product (10 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[N:9][OH:10].[Cl:11]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:11][C:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[N:9][OH:10]
Reactant: ON=Cc1cnccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: ON=C(Cl)c1cnccc1Cl
Yield: 75.4 %

Procedure:
Dissolve 4-chloropyridine-3-carboxaldehyde oxime (2.60 g, 0.017 mol) in N,N-dimethylformamide (20 mL). Add N-chlorosuccinimide (2.48 g, 0.018 mol) in small portions and stir overnight at ambient temperature. Pour the mixture into water and extract with ethyl acetate. Wash the combined extracts with water and dry over sodium sulfate. Concentrate in vacuo to give 2.45 g (75%) of crude product as a yellowish solid. 1H NMR was consistent with structure.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([CH3:22])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH3:22][C:14]1[CH:13]=[C:12]([CH2:11][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1cc(CCl)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc(COc2ccc(C=O)cc2)c2ccccc2n1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
p-Hydroxybenzaldehyde (3.18 g, 26.1 mmol), 4-chloromethyl-2-methyl-quinoline (5.0 g, 26.1 mmol), and potassium carbonate (7.2 g, 52 mmol) were combined in acetonitrile (100 mL) and heated to reflux overnight. The reaction was allowed to cool to room temperature, diluted with ethyl acetate, filtered to remove the solids, and concentrated to give a semi-solid residue. The crude product was crystallized from ethyl ether to give 4-(2-methyl-quinolin-4-ylmethoxy)-benzaldehyde (6.5 g, 90%) as an off white precipitate. MS found: (M+H)+=278.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[CH:16](=O)[CH2:17][CH2:18][CH2:19][CH3:20].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:14][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: CCCCC=O
Reactant: COC(=O)c1cccc(N)c1C(=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCCNc1cccc(C(=O)OC)c1C(=O)OC
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To a stirred solution of 3-amino-phthalic acid dimethyl ester (3.14 g, 15 mmol) in methylene chloride (50 ml) under a nitrogen atmosphere were added valeraldehyde (2.0 ml, 18.75 mmol) and acetic acid (5.18 ml, 90 mmol). The mixture was stirred for 5 minutes followed by addition of sodium triacetoxyborohydride (6.36 g, 30 mmol). The reaction was stirred for 30 minutes, diluted with methylene chloride (50 ml), washed with water (2×100 ml), saturated aqueous sodium bicarbonate (2×100 ml), brine (100 ml), and dried (MgSO4). The solvent was evaporated in vacuo to give 4.19 g of product (100%) that used without further purification. 1H NMR (DMSO-d6) d 7.31 (t, J=7.9 Hz, 1H), 6.81–6.75 (m, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.15 (bs, 2H), 1.68–1.60 (m, 2H), 1.45–1.32 (m, 4H), 0.89 (t, J=6.9 Hz, 3H).
Reaction SMILES: O1C2C=CC=C[C:4]=2[CH:3]=N1.[OH:10][C:11]1[C:15]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=2[O:13][N:12]=1.C(O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:3]([O:10][C:11]1[C:15]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=2[O:13][N:12]=1)[CH3:4]
Reactant: COc1ccc2c(O)noc2c1
Reactant: c1ccc2oncc2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1noc2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
Benzisoxazole from part (b) (193 mg, 1.17 mmol), ethanol (75 μl, 1.29 mmol) and triphenylphosphine (460 mg, 1.75 mmol) were dissolved in anhydrous THF (4 ml) and cooled (0°). Diisopropylazodicarboxylate (345 μl, 1.75 mmol) was added slowly and after 10–15 min the reaction flask was removed from the ice bath and the reaction mixture was stirred at room temperature overnight under an argon atmosphere. The solution was evaporated to dryness and the residue pre-absorbed onto silica, and chromatographed on silica (19 g); eluent: hexane (300 ml), 10–30% ethyl acetate/hexane to give 3-ethoxy-6-methoxy-1,2-benzisoxazole (101 mg, 44%) as white crystals.
Reaction SMILES: [CH2:1]([N:5](C(=O)C(Cl)Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)[CH:2]=[CH:3][CH3:4].C(O)C.[OH-].[K+]>O>[CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:14])[F:15])[CH:7]=1)[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCN(C(=O)C(Cl)Cl)c1cccc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC=CCNc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.9 %

Procedure:
64.64 grams (g) (0.198 mole) of N-crotyl-m-trifluoromethyl dichloroacetanilide and 300 milliliters (mL) of absolute ethanol were added to a round-bottomed flask, and stirred at room temperature, followed by the addition of 14.39 g of potassium hydroxide in 20 mL of water dropwise over a period of 10 minutes. After the addition was complete, the reaction mixture solidified with the precipitation of potassium dichloroacetate. The flask was swirled by hand to break up the solidified cake and stirring allowed to continue for an additional 18 hours. At the end of this time, 250 mL of ethylacetate was added and the mixture filtered. The solvent was then removed in vacuo to yield a pale orange-yellow semisolid. This was partitioned between 300 mL of ethylacetate and 300 mL of water and the layers were separated. The organic layer was washed one time with 200 mL of water and one time with 200 mL of a saturated sodium chloride solution. The organic layer was then dried with sodium sulfate and the solvent removed in vacuo to yield a yellow-orange material that was distilled at aspirator pressure to yield 36.6 g (86%) of product, N-crotyl-m-trifluoromethyl aniline.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][CH:11]([CH3:14])[CH2:12][OH:13].[H-].[Na+].O>C1COCC1>[Br:1][C:2]1[C:3]([O:13][CH2:12][CH:11]([CH3:14])[CH3:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)COc1nc(Cl)ncc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, to a solution of 5-bromo-2,4-dichloropyrimidine (2.56 mL) and 2-methyl-1-propanol (1.85 mL) in THF (80 mL) was added 60% sodium hydride (960 mg) at 0° C., and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added water at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give a crude product of the title compound (4.15 g) as a colorless oil. This compound was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[CH:7]=1.[CH3:10][C:11]([CH3:16])=[CH:12][C:13](O)=[O:14].[Cl-].[Al+3].[Cl-].[Cl-].P(Cl)(Cl)(Cl)=O>>[OH:8][C:6]1[CH:5]=[C:4]2[C:3]([C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:10])[O:9]2)=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: CC(C)=CC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(O)cc2c1C(=O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Anhydrous 5-methylbenzen-1,3-diol (3.678 g), 3,3-dimethylacrylic acid (3.3 mL) and aluminum chloride (14.76 g) were added to phosphoryl chloride (45 mL) and the mixture was shaken at room temperature for 6 hours. The reaction solution was poured into ice, and the precipitates were filtered, washed with water and dried. The precipitates were purified by column chromatography on silica gel (Solvent; petroleum ether/ethyl acetate=25/1) to give the titled compound (3.8 g) as a colorless powder.