Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[N:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27][CH:26]=1>>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:29]4[CH:30]=[N:25][CH:26]=[N:27][CH:28]=4)[N:3]=[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:5]=3[CH:10]=2)[CH2:13][CH2:14]1
Reactant: OB(O)c1cncnc1
Reactant: CN1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: CN1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cncnc4)nc3s2)CC1

Procedure:
2-Chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine was reacted with pyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 169. NMR (CDCl3): 2.30 (3H, s, Me), 2.48-2.64 (8H, m, CH2), 3.71 (2H, s, CH2), 3.88-3.93 (4H, m, CH2), 3.98-4.03 (4H, m, CH2), 7.15 (1H, s, Ar), 9.21 (1H, s, Ar) and 9.62 (2H, s, Ar). MS: (ESI+): MH+ 412.33
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]=O)[C:4]([CH:9]=[O:10])=[CH:3][CH:2]=1.[C:11]([C:16]1[CH:21]=[CH:20][C:19]([N:22]=C=O)=[CH:18][CH:17]=1)([O:13][CH2:14][CH3:15])=[O:12]>C(Cl)(Cl)Cl>[O:10]=[C:9]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH2:7][N:22]1[C:19]1[CH:18]=[CH:17][C:16]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: O=Cc1ccccc1C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(N2Cc3ccccc3C2=O)cc1
Temperature: 170 °C

Procedure:
A mixture of o-phthalicdicarboxaldehyde (17.54 g, 0.131 mol) and p-carbethoxyphenylisocyanate (25.0 g, 0.131 mol) is heated in an oil bath at 170° C. for 4.0 hours under nitrogen atmosphere. The hot melt is then slowly poured into CHCl3 (300 ml). The solution is then evaporated to dryness when a solid residue is obtained. The crude 4-(1,3-dihydro-1-oxo-2H-isoindol-2-yl)benzoic acid, ethyl ester is triturated with isopropyl ether and then recrystallized from CH2Cl2 --isopropyl ether (1:1, 300 ml) to give white solid. Yield 5.07 g (13.8%); mp 182°-184° C.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[NH:24][N:23]=[N:22][N:21]=3)=[CH:10][CH:9]=2)[C:5]2[C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1.[OH-].[Na+].[CH2:36](I)[CH3:37].Cl>C(O)C>[CH2:36]([S:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]3[NH:24][N:23]=[N:22][N:21]=3)=[CH:12][CH:13]=2)[C:5]2[C:25]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1)[CH3:37]
Reactant: CCOC(=O)c1cccc2nc(S)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Reactant: CCI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1cccc2nc(SCC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.9 %

Procedure:
To a solution of ethyl 2-mercapto-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.91 g) in ethanol (13 ml) containing 1N-NaOH (4 ml) was added ethyl iodide (0.34 g), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was adjusted to pH 4 with dilute hydrochloric acid to give crystals. The crystals were collected by filtration and purified by column chromatography on silica gel. Recrystallization from ethyl acetate gave colorless prisms (0.55 g, 57%), m.p. 153°-154° C. (decomp.).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4](F)[CH:3]=1.[CH2:12]([Mg]Br)[CH3:13]>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH2:12][CH3:13])[CH:3]=1
Reactant: CC[Mg]Br
Reactant: O=C(O)c1ccc(Br)cc1F
Solvent: C1CCOC1
Product: CCc1cc(Br)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 4-bromo-2-fluorobenzoic acid (2.0 g, 9.17 mmol) in THF (16 mL), was added 1.0 M ethyl magnesium bromide in THF (32 mL, 32.0 mmol) dropwise at 0° C. and the resultant reaction mixture was stirred at RT for 18 h. The reaction mixture was quenched with 2 N HCl and extracted with ethyl acetate. The combined ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude 4-bromo-2-ethylbenzoic acid as a colorless liquid that was used in the next step without purification (0.4 g): 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=8.4 Hz, 1H), 7.47 (m, 1H), 7.43 (m, 1H), 2.95 (q, J=4.0 Hz, 2H), 1.32 (t, J=4.0 Hz, 3H); ESIMS m/z 228.97 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[C:13](Cl)(=[O:17])[C:14](Cl)=[O:15].C(=O)=O.C(O)CO.[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5]3[C:4]=1[C:13](=[O:17])[C:14](=[O:15])[C:6]=3[CH:7]=[CH:8][CH:9]=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc2ccccc2c1
Agent: O=C=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: OCCO
Product: COc1ccc2cccc3c2c1C(=O)C3=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 67.1 %

Procedure:
A solution of 2-methoxynaphthalene (5 g, 31.6 mmol) and oxalyl chloride (11 mL, 126 mmol) in 150 mL of dichloromethane was cooled to −15° C. (CO2/ethylene glycol) under nitrogen. Aluminum trichloride (10.5 g, 79 mmol) was added slowly over 30 minutes. After 3 hours, the mixture was poured onto 100 g of ice. The layers were separated, and the aqueous layer was washed with dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate, water, brine and dried over magnesium sulfate. The solution was concentrated to afford 4.5 g of a solid. The solid was triturated with dichloromethane to give 1.24 g of the title compound as a solid, mp 218°-220° C.; 1H NMR (DMSO-d6): δ8.38 (d, 1H), 8.25 (d, 1H), 7.90 (d, 1H), 7.63 (m, 2H), 4.07 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:6][CH:5]=1.[CH2:20](O)[C:21]#C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])=[CH:6][CH:5]=1)[C:20]#[CH:21]
Reactant: C#CCO
Reactant: COC(=O)c1ccc(OC(C)CCCC(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C#CCOC(=O)c1ccc(OC(C)CCCC(C)C)cc1

Procedure:
13 g of p-[(1,5-dimethylhexyl)oxy]benzoic acid methyl ester is heated to reflux with 9 g of propargyl alcohol and 0.1 g of p-toluenesulphonic acid. The excess propargyl alcohol is thereupon slowly (5hrs.) distilled off. The residue is poured onto water and extracted with diethyl ether. The ether phase is dried with sodium sulfate and evaporated. There is obtained dark-yellow p-[(1,5-dimethylhexyl)oxy]benzoic acid propargyl ester which is purified on Kieselgel.
Reaction SMILES: [C:1]([C:4]1C(=O)NC=[C:8]([C:10]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)[CH:9]=1)([OH:3])=[O:2].[OH-].[K+].[CH3:28]I.[CH3:30][N:31]([CH3:34])[CH:32]=[O:33]>O>[CH3:30][N:31]1[CH:34]=[C:8]([C:10]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)[CH:9]=[C:4]([C:1]([O:3][CH3:28])=[O:2])[C:32]1=[O:33]
Reactant: CI
Reactant: O=C(O)c1cc(-c2c(-c3ccccc3)nn3ccccc23)c[nH]c1=O
Reactant: CN(C)C=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1cc(-c2c(-c3ccccc3)nn3ccccc23)cn(C)c1=O
Reaction time: 3 h

Procedure:
To a mixture of 3-(3-carboxy-2-oxo-1,2-dihydropyridin-5-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.92 g) and potassium hydroxide powder (0.54 g) in N,N-dimethylformamide (9 ml) was added 93% methyl iodide (0.64 ml) under ice-cooling (0°-5° C.). The mixture was stirred for 3 hours under ice-cooling, and then at room temperature for 1 hour and diluted with water. The resultant precipitates were filtered off and the filtrate was acidified with 5% hydrochloric acid and extracted with ethyl acetate (20 ml). The extract was washed with water (5 ml) and sodium chloride aqueous solution (5 ml), then dried over magnesium sulfate. The solvent was removed and the residue was chromatographed on silica gel (12 g) with a mixture of chloroform and methanol (100:1) as an eluent. The fractions containing the object compound were combined and evaporated in vacuo to give 3-(1-methyl-3-methoxycarbonyl-2-oxo-1,2-dihydropyridin-5-yl)-2-phenylpyrazolo[1,5-a]pyridine (0.34 g).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10](#[N:14])[CH2:11][C:12]#[N:13].C([O-])(=O)C.[NH4+].C(O)(=O)C>C(O)(C)C.O>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[C:11]([C:10]#[N:14])[C:12]#[N:13]
Reactant: Cc1ccccc1C=O
Reactant: N#CCC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CC(C)O
Solvent: O
Product: Cc1ccccc1C=C(C#N)C#N
Yield: 91 %

Procedure:
A solution of 2-methylbenzaldehyde (9.6 mL, 83 mmol), malononitrile (5.5 g, 83 mmol) and 3.5 M ammonium acetate in acetic acid (2.4 mL, 8.4 mmol) in isopropanol (83 mL) was stirred overnight at room temperature. A precipitate formed. Water (100 mL) was added and the precipitate was collected. The precipitate was washed with water (50 mL) and vacuum dried to afford of 2-(2-methylbenzylidene)malononitrile (12.7 g) as a white solid (mp 105-106°). 1H-NMR (CDCl3) δ: 8.10 (s 1H); 8.08 (d, 1H); 7.50 (dd, 1H); 7.30-7.40 (m, 2H); 2,45 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[C:3](=[S:5])[NH2:4].[C:17]([O:21][C:22]([N:24]([C@H:26]([CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)[C:27](O)=[O:28])[CH3:25])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:17]([O:21][C:22](=[O:23])[N:24]([CH3:25])[C@@H:26]([C:27](=[O:28])[NH:1][C@@H:2]([C:3](=[S:5])[NH2:4])[CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=1)([CH3:19])([CH3:20])[CH3:18]
Reactant: NC(=S)[C@H](N)Cc1ccc2ccccc2c1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc2ccccc2c1)C(N)=S
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.5 %

Procedure:
(2R)-2-Amino-3-(2-naphthyl)propionthioamide (0.290 g; 1.2 mmol), (2R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-(2-naphthyl)propionic acid (0.436 g; 1.3 mmol), HOBT (0.176 g; 1.3 mmol) and EDAC (0.267 g; 1.4 mmol) were dissolved in methylene chloride (20 ml) and stirred 12 hours at RT. Methylene chloride (40 ml) was added and the organic phase was washed with aqueous sodium hydrogensulfate (10%; 40 ml), aqueous sodium hydrogencarbonate (satd.; 40 ml) and dried (Magnesium sulfate). The solvent was removed in vacuo to afford 0.53 g of N-methyl-N-((1R)-2-(2-naphthyl)-1-((1R)-2-(2-naphthyl)-1-thiocarbamoylethylcarbamoyl)ethyl)carbamic acid tert-butylester.
Reaction SMILES: [N:1]1([C:7]([NH2:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(OC([NH:17][CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:27]([OH:29])=[O:28])[CH:24]=2)[CH2:19]1)=O)(C)(C)C.[ClH:30].O1CCOCC1>C(O)(=O)C>[ClH:30].[N:1]1([C:7]([NH2:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:17][CH:18]1[CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:27]([OH:29])=[O:28])[CH:24]=2)[CH2:19]1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(C(=O)O)cc2C1
Agent: Cl
Agent: NC(=O)N1CCOCC1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: NC1Cc2ccc(C(=O)O)cc2C1

Procedure:
Using 2-(tert-butoxycarbonylamino)indan-5-carboxylic acid morpholinamide (1.0 g, 2.7 mmol), 4N hydrochloric acid-dioxane (12 ml) and acetic acid (36 ml), a similar procedure to Example 24 was carried out to obtain 2-aminoindan-5-carboxylic acid morpholinamide hydrochloride (750 mg, 2.7 mmol) having the following physical properties:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:13])=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1)[CH3:2].[N+:14]([O-])([OH:16])=[O:15]>>[CH2:1]([O:3][C:4]1[C:5]([F:13])=[C:6]2[C:12]([N+:14]([O-:16])=[O:15])=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cnc2[nH]ccc2c1F
Reactant: O=[N+]([O-])O
Product: CCOc1cnc2[nH]cc([N+](=O)[O-])c2c1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
Cold (about 0 to about 5° C.) fuming nitric acid (10 mL) was added to 5-ethoxy-4-fluoro-1H-pyrrolo[2,3-b]pyridine (340 mg, 0.944 mmol). The reaction was stirred at 0° C. for 15 minutes and then ice was added. The resulting solid was filtered and dried to yield 5-ethoxy-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (165 mg, 78% yield) as a solid.
Reaction SMILES: [B-](F)(F)(F)F.[CH3:6][N:7](C(ON1C(=O)CCC1=O)=[N+](C)C)[CH3:8].[Br:21][C:22]1[CH:23]=[C:24]([C:39]([OH:41])=O)[CH:25]=[C:26]2[C:31]=1[O:30][C:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[CH:28][C:27]2=[O:38].CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:21][C:22]1[CH:23]=[C:24]([C:39]([N:7]([CH3:8])[CH3:6])=[O:41])[CH:25]=[C:26]2[C:31]=1[O:30][C:29]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[CH:28][C:27]2=[O:38]
Reactant: O=C(O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.2 %

Procedure:
TSTU (6.55 g, 21.74 mmol) was added to a stirred solution of 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (7 g, 19.77 mmol) and DIPEA (3.79 mL, 21.74 mmol) dissolved in DCM (100 mL) under nitrogen. The resulting suspension was stirred at room temperature for 4 h. More TSTU (6.55 g, 21.74 mmol) and DIPEA (3.79 mL, 21.74 mmol) were added and stirring was pursued for a further 16 h. The reaction mixture was quenched with a saturated aqueous solution of sodium hydrogencarbonate and extracted with DCM and a little MeOH. The combined organic phases were dried over MgSO4, concentrated and purified by flash chromatography on silica gel eluting with 3 to 5% MeOH in DCM. The solvent was evaporated to dryness to afford 8-bromo-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (7.70 g, 102%) as a beige solid. Mass Spectrum: m/z [M+H]+=381.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[C:12]12([CH2:19][O:20][C:21]3[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=3)[CH:24]=[O:25])[O:18][CH:17]1[CH2:16][CH2:15][CH2:14][CH2:13]2.C(#N)C.[Li]>C1COCC1.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C>[C:12]12([CH2:19][O:20][C:21]3[CH:22]=[C:23]([CH:24]([OH:25])[CH2:2][C:1]#[N:3])[CH:26]=[CH:27][CH:28]=3)[O:18][CH:17]1[CH2:16][CH2:15][CH2:14][CH2:13]2
Reactant: O=Cc1cccc(OCC23CCCCC2O3)c1
Reactant: CC#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: N#CCC(O)c1cccc(OCC23CCCCC2O3)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a −78° C. solution of acetonitrile (240 uL, 4.6 mmol) in THF under argon was added a solution of LDA (2.2 mL of a 2M solution in heptane/THF/ethylbenzene, 4.4 mmol). The resulting mixture was stirred at −78° C. for 30 min. In a separate flask, a solution of 3-(7-oxabicyclo[4.1.0]heptan-1-ylmethoxy)benzaldehyde (0.90 g, 4.1 mmol) in THF was cooled to −78° C. under argon. The freshly made lithium acetonitrile solution described above was added dropwise. The reaction mixture was stirred at −78° C. for 30 min then allowed to warm to room temperature overnight. The mixture was quenched with the addition of brine followed by 1M HCl (4 mL). The layers were separated and the aqueous layer was extracted with EtOAc. The combined organics were dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (10 to 75% EtOAc-hexanes gradient) gave 3-(3-(7-oxabicyclo[4.1.0]heptan-1-ylmethoxy)phenyl)-3-hydroxypropane-nitrile as an oil. Yield (0.340 g, 32%): 1H NMR (400 MHz, CDCl3) δ 7.30 (t, J=8.0 Hz, 1H), 6.88-6.91 (m, 3H), 5.01 (br s, 1H), 3.92-4.02 (m, 2H), 3.01 (d, J=2.0 Hz, 1H), 2.76 (d, J=6.4 Hz, 2H), 2.34 (br s, 1H), 1.84-2.05 (m, 4H), 1.42-1.56 (m, 2H), 1.24-1.40 (m, 2H).
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:9])[CH2:7][OH:8].Br[CH2:11][CH:12]=[C:13]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1>O>[C:24]1([C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)=[CH:12][CH2:11][O:8][CH2:7][CH2:6][OH:9])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: OCCO
Reactant: FC(F)(F)c1cccc(C(=CCBr)c2ccccc2)c1
Agent: [Li]CCCC
Solvent: O
Product: OCCOCC=C(c1ccccc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A solution of n-butyllithium in hexanes (16 ml, 2.5 M) was added drop-wise under a nitrogen atmosphere to dry ethylene glycol (40 ml) at 10° C. When addition was complete the mixture was stirred for 0.5 h at room temperature. 3-Bromo-1-phenyl-1-(3-(trifluoromethyl)phenyl)-1-propene (12.0 g, 35 mmol, prepared similarly to the method described in Example 26) was added and the reaction mixture was stirred at room temperature for 72 h. The mixture was poured into water (300 ml) and extracted with ethyl acetate (2×100 ml). The combined organic extracts was dried (Na2SO4) and the solvent evaporated in vacuo. Flash chromatography of the residue on silica gel (150 g) using a mixture of cyclohexane and ethyl acetate (7:3) as eluent provided 5.9 g (52%) of 2-(3-phenyl-3-(3-(trifluoromethyl)phenyl)-2-propen-1-yloxy)-ethanol. 2-(3-phenyl-3-(3-(trifluoromethyl)phenyl)-2-propen-1-yloxy)ethanol (5.0 g, 15.5 mmol) was dissolved into dry dioxan (80 ml) and stirred under an atmosphere of hydrogen for 18 h at room temperature in the presence of 10% palladium on carbon catalyst (50% aqueous paste) and then filtered. The filtrate was evaporated in vacuo to give 4.0 g (95%) of 2-(3-phenyl-3-(3trifluoromethyl)phenyl)-1-propyloxy)ethanol.
Reaction SMILES: C([O:3][C:4](=O)[CH:5](Br)[CH2:6][CH2:7][CH2:8][CH3:9])C.[NH2:12][C:13]([NH2:15])=[S:14]>C(O)C>[OH2:3].[CH2:6]([CH:5]1[S:14][C:13](=[NH:12])[NH:15][C:4]1=[O:3])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCC(Br)C(=O)OCC
Reactant: NC(N)=S
Solvent: CCO
Product: CCCCC1SC(=N)NC1=O
Product: O
Yield: 1.9 %

Procedure:
A mixture of 100 g (0.44 mole) of 2-bromohexanoic acid ethyl ester (Aldrich) and 39.0 g (0.51 mole) of thiourea (Baker) in 600 mL of ethanol was stirred and heated on a steam bath for 2 hr. The solvent was evaporated under reduced pressure to leave a solid residue. A 1.0 g sample of this solid was recrystallized from ethanol-water to yield 0.8 g title compound as a white solid, mp 179°-182° C. (lit, mp 183° C., J. Amer. Chem. Soc. 49, 2064 (1927)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([OH:23])=O)=[CH:17][C:9]1=2.[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[CH:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:29])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:44]4[CH2:45][CH2:46][CH:41]([C:34]5[C:35]6[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=6)[NH:32][CH:33]=5)[CH2:42][CH2:43]4)=[O:23])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCC(c2c[nH]c3ccccc23)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-(1H-indol-3-yl)piperidine as in General Procedure 10 to give the title compound. LCMS: m/z=630.02 (M+H+); retention time=0.98 minutes.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[C:15](=N)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[C:16]1([C:15](=[N:2][CH2:3][CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([O:7][CH3:8])=[O:6])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C(CN)c1ccccc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(CN=C(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methyl 3-amino-2-phenylpropanoate hydrochloride in CH2Cl2 was added benzophenone imine, and the solution was stirred overnight at room temperature. The mixture was then washed with H2O and the organics were dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 5-20% EtOAc/Hexanes) gave pure methyl 3-(diphenylmethyleneamino)-2-phenylpropanoate (E320).
Reaction SMILES: [Mg].Br[CH2:3][CH3:4].[F:5][C:6]([F:15])([F:14])[CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1.S(=O)(=O)(O)O>C1COCC1>[CH2:3]([C:10]1([OH:13])[CH2:11][CH2:12][CH:7]([C:6]([F:14])([F:15])[F:5])[CH2:8][CH2:9]1)[CH3:4]
Reactant: O=C1CCC(C(F)(F)F)CC1
Reactant: CCBr
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC1(O)CCC(C(F)(F)F)CC1
Temperature: -5 °C
Yield: 70 %

Procedure:
The inside of a reactor was sufficiently dried by vacuum heating, and the atmosphere inside the reactor was replaced with dry nitrogen. The reactor was charged with a Grignard reagent that was prepared in 350 ml of dehydrated tetrahydrofuran (dehydrated THF) using 9.7 g (0.40 mol) of a magnesium powder and 38.9 g (0.36 mol) of bromoethane 50 ml of a dehydrated THF solution of 49.8 g (0.30 mol) of 4-trifluoromethylcyclohexanone was added to the reactor over 15 minutes with stirring while cooling the solution at −5° C. using an ice bath. After increasing the temperature of the reactor to room temperature, the mixture was stirred for 2 hours. 500 ml of ice water and 100 ml of ice-cooled diluted sulfuric acid were then added to the mixture while sufficiently stirring the mixture. After separating the THF layer, the aqueous layer was extracted with diethyl ether to obtain an extract. The extract was combined with the THF layer, sequentially washed with a 5% sodium carbonate aqueous solution and water, and dried over sodium sulfate (desiccating agent). After removing sodium sulfate using a Buchner funnel, the organic solvent was evaporated. The residue was distilled under reduced pressure (30 mmHg). 1-Ethyl-4-trifluoromethylcyclohexanol was thus obtained (41.2 g (yield: 70%)).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[N+:9]([O-])([OH:11])=[O:10]>S(=O)(=O)(O)O>[NH2:1][C:2]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Nc1ncc(Cl)cc1[N+](=O)[O-]

Procedure:
A procedure similar to that described in Preparation 56 was repeated, except that 25.0 g of 2-amino-5-chloropyridine, 100 ml of concentrated sulfuric acid and 12.5 ml of concentrated nitric acid were used, to give 18.5 g of the title compound, melting at 138°-139° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[N:18]1([CH2:24][C:25]2[S:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.NC1N=CC(C2SC(CN3CCCCC3)=CC=2)=CC=1C(NC1C=CN=CC=1)=O>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:28]2[S:29][C:25]([CH2:24][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:26][CH:27]=2)=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][N:12]=1)=[O:9]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncn1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)s2)OC1(C)C
Agent: Nc1ncc(-c2ccc(CN3CCCCC3)s2)cc1C(=O)Nc1ccncc1
Product: Nc1ncc(-c2ccc(CN3CCOCC3)s2)cc1C(=O)Nc1ccncn1

Procedure:
6.2 “A27” is prepared from 2-amino-5-bromo-N-pyrimidin-4-yl-pyridine-3-carboxamide and 5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester according to step 2 of the synthesis of “A1”;