Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][C:11]=3[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](O)[CH3:20].C1C=CC=CC=1.S(=O)(=O)(O)O>O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]([C:15]([O:17][CH2:19][CH3:20])=[O:16])[CH2:12][C:11]=3[CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCO
Reactant: O=C(O)C1Cc2cc(-c3ccccc3)ccc2O1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C1Cc2cc(-c3ccccc3)ccc2O1

Procedure:
A mixture of 2.5 g of 1D, 60 ml of ethanol, 20 ml of dry benzene and 2 ml of concentrated sulfuric acid was refluxed for seven hours, with removal of water as it formed. The resulting mixture was concentrated, and the residue dissolved in ether. The solution was washed with saturated sodium bicarbonate solution and water. The aqueous portion was extracted with ether. The combined organic layers were dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was distilled to give ethyl 2,3-dihydro-5-phenylbenzofuran-2-carboxylate (1E), as a colorless liquid, bp: 180°-181° C., 0.35 Torr.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.OS(O)(=O)=O.[CH3:18][CH2:19]O>>[CH2:18]([O:11][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[N:1]=[CH:2][NH:3][C:4]=2[CH:9]=1)=[O:12])[CH3:19]
Reactant: CCO
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2nc[nH]c2c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a stirred solution of benzimidazole-5-carboxylic acid (Aldrich, 10 g, 61.7 mmol) in EtOH (200 mL) was added dropwise conc. H2SO4 (8 mL), and the solution was heated to reflux. After 1 h the solution was cooled to 60° C. and stirred for 16 h. The solution was then concentrated in vacuo and the residue was partitioned between EtOAc and saturated Na2CO3 solution. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated in vacuo to afford the title compound as a brown solid:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[F:12][C:13]1([F:27])[CH2:17][CH2:16][C@@H:15]([NH:18][CH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])[CH2:14]1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([N:18]([C@@H:15]2[CH2:16][CH2:17][C:13]([F:12])([F:27])[CH2:14]2)[CH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: COC(=O)C(C)(C)CN[C@@H]1CCC(F)(F)C1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(C)(C)CN(c1nc(Cl)ncc1[N+](=O)[O-])[C@@H]1CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
2,4-Dichloro-5-nitropyrimidine (2.18 g, 11.25 mmol) was added to a mixture of (R)-methyl 3-(3,3-difluorocyclopentylamino)-2,2-dimethylpropanoate (2.65 g, 11.25 mmol) and sodium bicarbonate (3.78 g, 44.98 mmol) in dichloromethane (10 mL) and petroleum ether (40 mL). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane and dried over magnesium sulfate. The solids were filtered off, rinsing with more dichloromethane. The mother liquors were adsorbed on silica gel and concentrated in vacuo. The residue was purified by flash column chromatography to afford the title compound as yellow solid (2.74 g, 62% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].N1C=CC=CC=1.[Br:14][C:15]1[C:24]([CH:25]([O:28][C:29]([CH3:35])([CH3:34])[C:30]([F:33])([F:32])[F:31])[CH2:26][OH:27])=[C:23]([CH3:36])[CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2>C(Cl)Cl>[C:3]([O:27][CH2:26][CH:25]([C:24]1[C:15]([Br:14])=[C:16]2[C:21](=[CH:22][C:23]=1[CH3:36])[N:20]=[CH:19][CH:18]=[CH:17]2)[O:28][C:29]([CH3:35])([CH3:34])[C:30]([F:31])([F:33])[F:32])(=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: Cc1cc2ncccc2c(Br)c1C(CO)OC(C)(C)C(F)(F)F
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc2ncccc2c(Br)c1C(COC(=O)C(C)(C)C)OC(C)(C)C(F)(F)F
Temperature: 25 °C

Procedure:
To a stirred solution of trimethylacetyl chloride (19 μL, 0.15 mmol) in pyridine (0.4 mL, 4.95 mmol) was added 2-(5-bromo-7-methylquinolin-6-yl)-2-(1,1,1-trifluoro-2-methylpropan-2-yloxy)ethanol (29.8 mg, 0.08 mmol) in CH2Cl2 (0.4 mL) at 0° C. The reaction mixture was allowed to warm to room temperature overnight. The mixture was quenched with water and concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give 2-(5-bromo-7-methylquinolin-6-yl)-2-(1,1,1-trifluoro-2-methylpropan-2-yloxy)ethyl pivalate. LCMS-ESI+ (m/z): [M+H]+ calc'd for C21H26BrF3NO3: 476.11; Found: 476.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH2:32][CH2:33][CH3:34])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([NH:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH2:32][CH2:33][CH3:34])[CH:27]=[CH:28][CH:29]=3)[CH2:20][CH2:19]2)=[O:11])=[CH:6][CH:7]=1
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)(C)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 80 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 9: ESMS m/e: 484.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.[P:13]([O-:25])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[K+].CCOC(C)=O>C1COCC1>[C:21]([O:20][P:13]([O:25][CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([O:2][CH3:1])=[O:12])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(COP(=O)(OC(C)(C)C)OC(C)(C)C)c1
Temperature: 70 °C
Yield: 45 %

Procedure:
To a stirred solution of methyl-3-(bromomethyl)benzoate (0.5 g, 2 mmol) in THF (10 mL) was added potassium ditertiary butyl phosphate (0.5 g, 2 mmol). The reaction flask was heated to 70° C. for 2 h. After the flask was cooled to rt, EtOAc (50 mL) was added to the mixture. The organics were washed with brine (2×10 mL), dried over anhydrous sodium sulfate, and evaporated under vacuum to yield methyl 3-((di-tert-butoxyphosphoryloxy)methyl)benzoate (0.35 g, 0.9 mmol). 1H NMR (400 MHz, CHCl3-d): δ 1.47 (s, 18H), 3.91 (s, 3H), 5.03 (d, 2H, J=7.6 Hz), 7.44 (t, J=7.6 1H), 7.60 (dd, J=1.2 and 7.2), 7.98 (ddd, J=1.2, 2.8 and 7.6, 1H), 8.05 (t, J=0.4, 1H).
Reaction SMILES: CN(C)C(=O)C.C1(C)C=CC(S([O:16][C:17]2[CH:22]=[C:21]([C:23]([CH3:30])([CH3:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[CH:19][C:18]=2[NH2:48])(=O)=O)=CC=1.[O:50]1[CH2:55][CH2:54][N:53]([C:56]2[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][C:57]=2[S:65](Cl)(=[O:67])=[O:66])[CH2:52][CH2:51]1.Cl>N1C=CC=CC=1>[O:50]1[CH2:55][CH2:54][N:53]([C:56]2[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][C:57]=2[S:65]([NH:48][C:18]2[CH:19]=[C:20]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:21]([C:23]([CH3:29])([CH3:30])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:22][C:17]=2[OH:16])(=[O:66])=[O:67])[CH2:52][CH2:51]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)c(S(=O)(=O)Cl)c1
Reactant: CCCCCCCCCCCCCCCCOc1cc(N)c(OS(=O)(=O)c2ccc(C)cc2)cc1C(C)(C)CC(C)(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCCCCCCOc1cc(NS(=O)(=O)c2cc([N+](=O)[O-])ccc2N2CCOCC2)c(O)cc1C(C)(C)CC(C)(C)C

Procedure:
To a solution of N,N-dimethylacetamide (200 ml) containing 20 g (0.0314 mol) of 2-amino-4-hexadecyloxy-5-(1,1,3,3-tetramethylbutyl)phenol paratoluene sulfonate and 12.7 ml of pyridine was added 10.6 g (0.0346 mol) of the compound obtained in Step (b) above with stirring while introducing a nitrogen gas and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to 500 ml of aqueous solution containing 15 ml of hydrochloric acid and the precipitate was extracted with ethyl acetate. The ethyl acetate was washed with water and concentrated. To the residue was added 100 ml of methanol and the crystals thus precipitated were collected by filtration. Yield: 22 g (94%).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@H:17]3[CH3:22])[N:13]=[C:12]([NH:23][CH3:24])[N:11]=2)[CH:7]=[C:6]([S:25][CH3:26])[C:3]=1[C:4]#[N:5].[NH2:27][NH2:28].CCN(C(C)C)C(C)C>C(O)C>[CH3:24][NH:23][C:12]1[N:11]=[C:10]([C:8]2[CH:9]=[C:2]3[C:3]([C:4]([NH2:5])=[N:27][NH:28]3)=[C:6]([S:25][CH3:26])[CH:7]=2)[CH:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@H:17]2[CH3:22])[N:13]=1
Reactant: CNc1nc(-c2cc(F)c(C#N)c(SC)c2)cc(N2CCOC[C@H]2C)n1
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CNc1nc(-c2cc(SC)c3c(N)n[nH]c3c2)cc(N2CCOC[C@H]2C)n1
Temperature: 150 °C
Yield: 67.9 %

Procedure:
A 2-mL microwave vial was charged with 2-fluoro-4-{2-(methylamino)-6-[(3R)-3-methyl-4-morpholinyl]-4-pyrimidinyl}-6-(methylthio)benzonitrile (40 mg, 0.107 mmol), hydrazine (0.037 mL, 0.643 mmol), Hunig's base (0.056 mL, 0.321 mmol) and ethanol (1.5 mL). The mixture was heated at 150° C. for 90 minutes in a microwave reactor. The reaction mixture was allowed to cool, and then concentrated. The resulting residue was dissolved in DMSO and purified by RP-HPLC (0-30% CH3CN in H2O, 0.1% TFA). The product fractions were pooled, basified with NaHCO3, then extracted into EtOAc. The organic layer was dried, then concentrated to afford the title compound (28 mg) as an off-white solid. LC-MS (ES) m/z=386 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.19 (d, J=6.8 Hz, 3H), 2.61 (s, 3H), 2.83 (d, J=4.3 Hz, 3H), 3.04-3.22 (m, 1H), 3.40-3.52 (m, 1H), 3.55-3.66 (m, 1H), 3.67-3.79 (m, 1H), 3.85-3.99 (m, 1H), 4.05-4.23 (m, 1H), 4.44-4.59 (m, 1H), 5.10 (s, 2H), 6.38-6.71 (m, 2H), 7.26-7.49 (m, 1H), 7.66-7.88 (m, 1H), 11.62-11.92 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.Cl[CH2:25][CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29]>>[Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:11][CH2:12][N:13]([S:28]([CH2:27][CH2:26][CH3:25])(=[O:30])=[O:29])[CH2:14][CH2:15]2)=[N:4][CH:3]=1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCNCC2)CC1
Reactant: O=S(=O)(Cl)CCCCl
Product: CCCS(=O)(=O)N1CCC(N(C(=O)Nc2ncc(Cl)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
Prepared as described in general procedure (G) using 3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-urea and 3-chloropropane-1-sulfonyl chloride
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[O:12][CH:13]=[CH:14][C:15]=2[CH3:16])=O)[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:18][OH:19].[OH-].[Na+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[O:12][CH:13]=[CH:14][C:15]=2[CH3:16])=[N:18][OH:19])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccoc1C(=O)Cc1cccc(Cl)n1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccoc1C(Cc1cccc(Cl)n1)=NO
Temperature: 25 °C
Yield: 52.3 %

Procedure:
To a solution of 2-(6-chloro-2-pyridinyl)-1-(3-methyl-2-furyl)ethanone (52.2 g, 221 mmol) in methanol (500 mL) was added hydroxylamine hydrochloride (76.96 g, 1.11 mol) followed by an aqueous solution of sodium hydroxide (44.3 g, 1.11 mol). The resultant suspension was heated at reflux for 2 hours and then cooled to room temperature. The mixture was concentrated and water was added to the residue while stirring. After stirring for 20 minutes, a white solid precipitated. This solid was collected by filtration and washed with water to give 2-(6-chloro-2-pyridinyl)-1-(3-methyl-2-furyl)ethanone oxime (29.0 g, 52%) as a white solid. 1H NMR (CDCl3): δ 7.54 (t, 1H), 7.31 (s, 1H), 7.15 (d, 1H), 7.10 (d, 1H), 6.28 (s, 1H), 4.34 (s, 2H), 2.22 (S 3H). MS m/z 273 (M+1).
Reaction SMILES: [Cl-].[CH3:2][Zn+].Br[C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]=2[Cl:14])[N:7]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:6]=1>C1COCC1.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>[Cl:14][C:12]1[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][N:9]=[C:8]2[N:7]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:6]=[C:5]([CH3:2])[C:13]=12
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2c(Cl)c(-c3ccccc3)cnc21
Reactant: C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(-c3ccccc3)c(Cl)c12
Temperature: 80 °C
Yield: 87.8 %

Procedure:
Methyl zinc chloride (3.35 mL, 6.70 mmol) was added to 3-bromo-4-chloro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.00 g, 2.23 mmol) and Pd(PPh3)4 (0.129 g, 0.111 mmol) in THF (10 mL). The reaction was then heated to 80° C. for 2 hours, cooled to room temperature, and quenched with saturated NH4Cl. The resulting solids were filtered and discarded. The filtrate was diluted with DCM (500 mL) and was washed with water. The combined organic fractions were dried, filtered, and concentrated to give a crude solid that was purified by column chromatography (2:1 DCM:hexanes) to give 4-chloro-3-methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.75 g, 87.7% yield).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]([CH:23]=O)=[C:21]([CH:25]([CH3:27])[CH3:26])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCl.C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:23][C:22]1[C:13]([C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)=[N:14][C:15]2[C:20]([C:21]=1[CH:25]([CH3:27])[CH3:26])=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: CC(C)c1c(C=O)c(-c2ccc(F)cc2)nc2ccccc12
Reactant: BrC(Br)(Br)Br
Agent: ClCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1c(C=C(Br)Br)c(-c2ccc(F)cc2)nc2ccccc12
Reaction time: 0.33 h

Procedure:
A solution of carbon tetrabromide (2.958 gm, 8.92 mmol) in CH2 Cl2 (10 ml) was added over a 15 minute period to a cold (-10° C.) solution of 2-(4-fluorophenyl)-4-(1-methylethyl)-3-quinolinecarboxaldehyde (1.744 gm, 5.95 mmol) (the preparation of which is described in Example 2) and triphenylphosphine (4.680 gm, 17.84 mmol) in CH2Cl2 (34 ml). After the addition was complete, the mixture was stirred for 20 minutes then quenched with saturated NaHCO3 and extracted 3× with CH2Cl2. The combined organic layers were washed with brine, dried (Na2SO4), filtered and stripped to give a yellow-orange oil. The oil was chromatographed (flash, Merck SiO2, 30% CH2 Cl2 in hexane followed by 1:1 CH2Cl2 in hexane followed by straight CH2Cl2) to give 3-(2,2-dibromoethenyl)-2-(4-fluorophenyl)-4-(1-methylethyl)quinoline as a colorless foam (2.572 gm,
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]3[CH:21]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]3[CH:21]=2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: NC(=O)c1cccn2cc(-c3ccc([N+](=O)[O-])cc3)nc12
Agent: [Pd]
Product: NC(=O)c1cccn2cc(-c3ccc(N)cc3)nc12

Procedure:
The product from Example 2 was dissolved in alcohol and, after addition of palladium/carbon, hydrogenated with hydrogen. This was followed by filtration and concentration of the filtrate in vacuo. The product was obtained.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[C:14]([C:15]#[C:16][Si](C)(C)C)=[C:13]([CH3:21])[N:12]=[C:11]([NH2:22])[N:10]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)Cl>[C:15]([C:14]1[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:23])([F:24])[F:1])[CH:4]=2)=[N:10][C:11]([NH2:22])=[N:12][C:13]=1[CH3:21])#[CH:16]
Reactant: Cc1nc(N)nc(-c2cccc(C(F)(F)F)c2)c1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1c(C)nc(N)nc1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound is synthesized according to general procedure GP3 starting from 1.2 g (3.5 mmol) 4-(3-trifluoromethyl-phenyl)-6-methyl-5-trimethylsilanylethynyl-pyrimidin-2-ylamine (A-36) and 120 mg (0.87 mmol) potassium carbonate in 5 mL MeOH. After stirring for 2 h at RT, the reaction mixture is diluted with DCM and the organic phase is extracted with water. The organic phase is dried over NGP2SO4 and the solvent is removed in vacuo. Yield: 523 mg (54%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([C:21]3[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH:22]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[K+].[C:30]([C:32]1[N:33]=[C:34]([C:45]([O-])=[O:46])[N:35]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:36]=1)#[N:31].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:45]([C:34]3[N:35]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:36]=[C:32]([C:30]#[N:31])[N:33]=3)=[O:46])=[C:16]([C:21]3[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH:22]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2cc(C3CCN(C(=O)OC(C)(C)C)CC3)ccc2N)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC=C(c2cc(C3CCN(C(=O)OC(C)(C)C)CC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A solution of 89.0 mg (0.231 mmol) 4-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (as prepared in the previous step) in 10 mL CH2Cl2 was treated with 77.8 mg (0.255 mmol) 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)), 162 mg (0.347 mmol) PyBrOP, and 121 μL (0.694 mmol) DIEA and stirred at RT for 2 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with saturated NaHCO3 (1×15 mL) and water (1×15 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a Varian MegaBond Elut 50-gm column with 10-25% EtOAc-hexane afforded 124 mg (84%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C31H44N5O4Si, 578.3 (M−C4H9+2H), found 578.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:23](C#N)#[N:24].N1C=CC=CC=1.CN1CCCC1=O>Cl>[C:23]([C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)#[N:24]
Reactant: N#CC#N
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(Br)cc3)CC2)CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(C#N)cc3)CC2)CC1

Procedure:
A mixture of 36.3 g of trans-1-p-bromophenyl-4-(trans-4-propylcyclohexyl)-cyclohexane, 10 g of Cu2 (CN)2, 120 ml of pyridine and 60 ml of N-methylpyrrolidone is heated to 160° for 2 hours. The mixture is cooled, a solution of 120 g of FeCl3.6H2O in 600 ml of 20% hydrochloric acid and the mixture is warmed to 70° for 1.5 hours, while stirring, and worked up in the customary manner to give trans-1-p-cyanophenyl-4-(trans-4-propylcyclohexyl)-cyclohexane, m.p. 55°, c.p. 184°.
Reaction SMILES: [CH3:1][C:2]([CH:7]([CH3:9])[CH3:8])=[CH:3][C:4](Cl)=[O:5].C[CH:11](C)[C:12](=[O:14])C.[H-].[Na+]>COCCOCCOC>[CH3:1][C:2]([CH:7]([CH3:9])[CH3:8])=[CH:3][C:4]([O:14][CH2:12][CH3:11])=[O:5]
Reactant: CC(=O)C(C)C
Reactant: CC(=CC(=O)Cl)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: CCOC(=O)C=C(C)C(C)C

Procedure:
The 3,4-dimethyl-2-pentenoyl chloride (IX) utilized in the procedures of the present invention may be readily prepared from 3-methyl-2-butanone (XII) utilizing the Wittig reaction. In this procedure triethylphosphonoacetate is added to a suspension of sodium hydride in diglyme in an inert atmosphere at a temperature of between -10° C. and 5° C., suitably about 0° C. The mixture is stirred, suitably for about half an hour, to ensure formation of the Wittig reagent and the ketone (XII) added slowly thereto. There is utilized approximately 100% molar excess of the triethylphosphonoacetate with respect to the ketone (XII). The reaction is completed by allowing the reaction mixture to equilibrate with room temperature after completion of the addition, and remaining at ambient temperature from between 2 to 5 hours. The mixture is then recooled and carefully quenched with a large excess of water and the reaction product extracted therefrom with a reaction inert water insoluble organic solvent, suitably ether and the thus produced ethyl 3,4-dimethyl-2-pentenoate (XI) isolated from the ethereal extract in the usual manner.
Reaction SMILES: [C:1](=[O:32])([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:13][CH:12]=1)OC1C=CC=CC=1.[NH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1>C(Cl)Cl>[N:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[CH2:34][NH:33][C:1](=[O:32])[O:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:15][CH:16]=1
Reactant: NCc1ccccn1
Reactant: CCCCCCCCCCCCCCOc1ccc(COC(=O)Oc2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(COC(=O)NCc2ccccn2)cc1
Temperature: 100 °C
Yield: 93.2 %

Procedure:
A mixture of 0.50 g of product from Example 94 and 0.184 g of 2-(aminomethyl)pyridine is heated in a sealed tube at 100° C. for 80 minutes. The crystalline reaction product is dissolved in methylene chloride, washed with 5% potassium hydroxide and saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel: 50% ethyl acetate/hexane) to give 0.481 g of the desired product as colorless plates.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.Cl[C:9]1[N:18]=[C:17]2[C:12]([C:13](=[O:25])[C:14]([C:22]([OH:24])=[O:23])=[CH:15][N:16]2[CH:19]2[CH2:21][CH2:20]2)=[CH:11][C:10]=1[F:26]>C(#N)C>[OH:23][CH2:22][CH:14]=[C:13]1[CH2:5][CH2:4][N:3]([C:9]2[N:18]=[C:17]3[C:12]([C:13](=[O:25])[C:14]([C:22]([OH:24])=[O:23])=[CH:15][N:16]3[CH:19]3[CH2:21][CH2:20]3)=[CH:11][C:10]=2[F:26])[CH2:6][CH2:7]1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Solvent: CC#N
Product: O=C(O)c1cn(C2CC2)c2nc(N3CCC(=CCO)CC3)c(F)cc2c1=O
Reaction time: 16 h
Yield: 79.2 %

Procedure:
A solution of amine 103 (256 mg, 1.06 mmol) and triethylamine (0.5 mL, 3.55 mmol) in acetonitrile (4 mL) was treated with 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-naphthyridine-3-carboxylic acid (200 mg, 0.71 mmol) under nitrogen and the reaction mixture was allowed to stir for 16 h. The resulting mixture was concentrated in vacuo, and the residue was washed with water (3×10 mL) and allowed to dry overnight to afford the title compound 163 (105 mg, 40%). MS 374 (M+H).