Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:9][C:8]2=[O:19])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1.[Cl-].[NH4+]>C(OCC)(=O)C.CN(C)C=O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[CH:12]=[N:11][C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:34](=[O:35])[C:33]4[CH:37]=[CH:38][C:30]([F:29])=[CH:31][CH:32]=4)[CH2:15][CH2:14]3)=[N:9][C:8]2=[O:19])=[CH:4][CH:3]=1
Reactant: O=c1nc(N2CCNCC2)ncn1Cc1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(c1ccc(F)cc1)N1CCN(c2ncn(Cc3ccc(Cl)cc3)c(=O)n2)CC1
Yield: 63.1 %

Procedure:
To an N,N-dimethylformamide solution (1 mL) of 1-(4-chlorobenzyl)-4-(piperazin-1-yl)-1,3,5-triazin-2(1H)-one (31 mg, 0.10 mmol) synthesized in Reference Synthesis Example 9, triethylamine (28 μL, 0.20 mmol) and 4-fluorobenzoyl chloride (18 μL, 0.15 mmol) were added at room temperature and the resultant mixture was stirred at room temperature for 4 hours. After the completion of the reaction, saturated ammonium chloride aqueous solution was added to the reaction solution and extraction with ethyl acetate from the resultant reaction solution was performed. The organic layer was concentrated under reduced pressure and the resultant residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/4→0/1 (v/v)) to obtain the title compound (27 mg, yield: 63%).
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[C:9](Cl)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].Cl.CCCCCCCCCC(C)C>O>[C:9]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)OO
Agent: CCCCCCCCCC(C)C
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(C)(C)OOC(=O)C(C)(C)C
Yield: 93.7 %

Procedure:
Before the start of the reaction, the loop reactor is filled with a solution of 26.0% by weight of tert-butyl hydroperoxide and 16.2% by weight of potassium hydroxide in water. Initially 26.0 kg/h of a solution of 70% by weight of tert-butyl hydroperoxide in water, 25.0 kg/h of a solution of 45% by weight of potassium hydroxide in water, 26.4 kg/h of water and 18.0 kg/h of pivaloyl chloride are then fed to the loop reactor. Cooling with cooling water keeps the internal temperature at 15° C. in the loop reactor and at 10° C. in the stirred cell reactor. The partial neutralization is effected with 6.0 kg/h of 31% by weight hydrochloric acid with addition of 8.2 kg/h of isododecane at a temperature of 8° C. The organic phase is extracted with 33.2 kg/h of a 20% by weight aqueous solution of potassium hydroxide. This affords 37.4 kg/h of aqueous extract comprising 11.6% by weight of tert-butyl hydroperoxide and 17.6% by weight of potassium hydroxide, which are feeded into the loop reactor. From the time at which aqueous extract is recycled into the loop reactor, the metered addition of the feedstocks is changed to 19.8 kg/h of a solution of 70% by weight of tert-butyl hydroperoxide in water, 10.2 kg/h of a solution of 45% by weight of potassium hydroxide in water and 9.8 kg/h of water. After the extraction, the organic phase is washed with 36.0 kg/h of a solution of 1% by weight of sodium sulphite and 0.2% by weight of sulphuric acid, and dried by stripping at 20° C. and 45 mbar. 32.4 kg/h of a 75.3% by weight solution of tert-butyl peroxypivalate in isododecane are obtained (93.7% yield based on pivaloyl chloride).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:22][N+:23]([O-])=O)[CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.N.[H][H]>C(O)C.[Ni]>[NH2:23][CH2:22][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[CH2:9][P:10]([CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])(=[O:14])[O:11][CH2:12][CH3:13]
Reactant: CCOC(OCC)P(=O)(CC(C[N+](=O)[O-])c1ccc(C)cc1)OCC
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(OCC)P(=O)(CC(CN)c1ccc(C)cc1)OCC

Procedure:
A solution of 6.5 g of ethyl 2-(4-methylphenyl)-3-nitropropyl(diethoxymethyl)phosphinate in 60 ml of ethanol is added to 52 g of an 8% solution of ammonia in ethanol. To this are added 8 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered and the filtrate is concentrated under reduced pressure to give ethyl 3-amino-2-(4-methylphenyl)propyl(diethoxymethyl)phosphinate as a viscous oil, 31 p=+44.6 ppm (CDCl3).
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:15])[CH:8]=[CH:7][C:6]([S:9]([CH2:12][S:13][CH3:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH:16]1([CH2:22]Br)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[Cl-].[NH4+]>CCCCCC.CN(C)C=O>[CH3:15][C:3]1[CH:4]=[CH:5][C:6]([S:9]([CH:12]([S:13][CH3:14])[CH2:22][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: CSCS(=O)(=O)c1ccc(C)cc1
Reactant: BrCC1CCCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCCCCCC(SC)S(=O)(=O)c1ccc(C)cc1
Reaction time: 5 h
Yield: 88.1 %

Procedure:
990 mg (22.7 mmol) of sodium hydride (as a 55% w/w suspension in mineral oil) were washed twice with hexane, and suspended in 40 ml of dimethylformamide. 4.35 g (20.1 mmol) of methylthiomethyl p-tolyl sulfone were added to this suspension and, after 5 minutes, 3.1 ml (22.2 mmol) of cyclohexylmethyl bromide were added. The mixture was allowed to return to room temperature, after which it was stirred for 5 hours. At the end of this time, a dilute aqueous solution of ammonium chloride was added to stop the reaction. The reaction mixture was then extracted with diethyl ether, and the extract was washed with a saturated aqueous solution of sodium chloride. The solvent was then removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 100 g of silica gel. Elution with a 1:3 by volume mixture of ethyl acetate and hexane afforded 5.57 g (yield 89%) of the title compound as crystals, melting at 65°-66° C. (after recrystallization from a mixture of diisopropyl ether and hexane).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)N1CCN1CCC(C2C=C(NC(=O)C(C)C)C=CC=2)CC1.O=C1C2C(=CC=CC=2)C(=O)[N:34]1[CH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][CH:49]([C:52]2[CH:53]=[C:54]([NH:58][C:59](=[O:63])[CH:60](C)C)[CH:55]=[CH:56][CH:57]=2)[CH2:48][CH2:47]1.O=C1C2C(=CC=CC=2)C(=O)N1CCCCN1CCC(C2C=C(NC(=O)C(C)C)C=CC=2)CC1.O=C1C2C(=CC=CC=2)C(=O)N1CCCCCN1CCC(C2C=C(NC(=O)C(C)C)C=CC=2)CC1.O=C1C2C(=CC=CC=2)C(=O)N1CCCCCCN1CCC(C2C=C(NC(=O)C(C)C)C=CC=2)CC1>>[NH2:34][CH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][CH:49]([C:52]2[CH:53]=[C:54]([NH:58][C:59](=[O:63])[CH3:60])[CH:55]=[CH:56][CH:57]=2)[CH2:48][CH2:47]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN3C(=O)c4ccccc4C3=O)CC2)c1
Agent: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN3C(=O)c4ccccc4C3=O)CC2)c1
Agent: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCN3C(=O)c4ccccc4C3=O)CC2)c1
Agent: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN3C(=O)c4ccccc4C3=O)CC2)c1
Product: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1

Procedure:
Using the methods described above, the following additional intermediates were synthesized. N-(3-{1-[2-(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)ETHYL]-4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE. ESMS m/e: 420.2 (M+H)+. N-(3-{1-[3-(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)PROPYL]-4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: ESMS m/e: 434.4 (M+H)+. N-(3-{1-[4-(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)BUTYL]-4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: ESMS m/e: 448.4 (M+H)+. N-(3-{1-[5-(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)PENTYL]-4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE. ESMS m/e: 462.4 (M+H)+. N-(3-{1-[6-(1,3-DIOXO-1,3-DIHYDRO-2H-ISOINDOL-2-YL)HEXYL]-4-PIPERIDINYL}PHENYL)-2-METHYLPROPANAMIDE: ESMS m/e: 476.4 (M+H)+.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([CH:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH2:14]2)=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.Br[CH2:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(O)C.O>[C:36]1([CH2:35][CH2:34][CH2:33][N:3]2[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([CH:13]3[S:23][C:22]4[N:24]5[C:15](=[CH:16][N:17]=[C:18]5[CH:19]=[CH:20][CH:21]=4)[CH2:14]3)=[O:12])[CH2:5][CH2:4]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: BrCCCc1ccccc1
Reactant: O=C(NCC1CCNCC1)C1Cc2cnc3cccc(n23)S1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: O=C(NCC1CCN(CCCc2ccccc2)CC1)C1Cc2cnc3cccc(n23)S1

Procedure:
To a solution of 746.4 mg (1.91 mM) of N-(4-piperidyl)methyl-3,4-dihydro-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.4 ml (10.0 mM) of triethylamine in ethanol (5 ml) was added 0.35 ml (2.30 mM) of 1-bromo-3-phenylpropane at room temperature and the mixture was refluxed under nitrogen for 64 hours. This reaction mixture was diluted with water and extracted with chloroform, and the organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The residue was purified by column chromatography (methanol/ethyl acetate 20-30-50%) to provide the title compound as red amorphous substance.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C:10]([O:12]CC)=O)=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:16][NH2:17]>C(O)C>[C:1]([C:5]1[O:9][C:8]([C:10]([NH:16][NH2:17])=[O:12])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)c1ncc(C(C)(C)C)o1
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cnc(C(=O)NN)o1
Temperature: 85 °C
Yield: 96.1 %

Procedure:
To a mixture of ethyl 5-tert-butyl-1,3-oxazole-2-carboxylate (28 g, 142 mmol) in ethanol (200 mL) is added hydrazine hydrate (7.1 g, 142 mmol). The reaction mixture is heated at 85° C. for 3 h. The solvent is evaporated and the residue is washed with n-pentane to afford the title compound (25 g, 96%) as a white solid.
Reaction SMILES: [CH2:1](I)[CH3:2].CN(C=O)C.[OH:9][C:10]1[C:18]2[O:17][C:16]([CH3:20])([CH3:19])[C:15](=[O:21])[C:14]=2[C:13]([CH3:22])=[C:12]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)[C:11]=1[CH3:37].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH2:1]([O:9][C:10]1[C:18]2[O:17][C:16]([CH3:19])([CH3:20])[C:15](=[O:21])[C:14]=2[C:13]([CH3:22])=[C:12]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)[C:11]=1[CH3:37])[CH3:2]
Reactant: COc1ccc(N2CCN(c3c(C)c(O)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1c(C)c(N2CCN(c3ccc(OC)cc3)CC2)c(C)c2c1OC(C)(C)C2=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.6 %

Procedure:
Ethyl iodide (88 mg, 0.567 mmol) was added to a suspension of DMF (4 mL) containing 7-hydroxy-5-[4-(4-methoxyphenyl)piperazin-1-yl]-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one (150 mg, 0.378 mmol) synthesized in Reference Example 73 and potassium carbonate (104 mg, 0.756 mmol) at 0° C. The reaction solution was warmed to room temperature and stirred for 15 hours. The resulting mixture was poured into water and extraction was performed using ethyl acetate. The extract was washed with saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 95:5 to 80/20), and recrystallized from ethyl acetate and hexane to give 70 mg of the title compound (yield: 44%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[C:9]([NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:8][C:6]1[CH:7]=[C:2]([N:20]2[CH2:19][CH2:18][CH:17]([NH:16][C:9](=[O:10])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH2:22][CH2:21]2)[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1CCN(c2cncc(Br)c2)CC1
Yield: 75.5 %

Procedure:
A solution of 3,5-dibromopyridine (0.400 g, 1.69 mmol), 4-(N-Boc-amino)-piperidine (0.238 g, 1.19 mmol), Tris(dibenzylideneacetone)dipalladium(0) (54 mg, 0.059 mmol), rac-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (73.9 mg, 0.119 mmol), and Sodium-tert-butoxide (114 mg, 1.19 mmol) in Toluene (16.9 mL) was heated at 85° C. for 18 h. The reaction was filtered thru celite then rinsed with EtOAc. The crude product was purified by Isco (EtOAc/Hep eluted at 40%) to give tert-butyl 1-(5-bromopyridin-3-yl)piperidin-4-ylcarbamate (320 mg, 75.6% yield). ESI MS m/z=357.1 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:15].Br.Br.Br.[NH:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:26]2[N:30]([CH2:31][C:32]3[CH:37]=[N:36][CH:35]=[CH:34][N:33]=3)[C:29]3[CH:38]=[CH:39][CH:40]=[CH:41][C:28]=3[N:27]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CN(C)C(=O)C>[CH3:15][C:5]1[N:6]=[C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][N:8]2[C:9](=[O:10])[C:4]=1[CH2:3][CH2:2][N:19]1[CH2:20][CH2:21][CH:22]([NH:25][C:26]2[N:30]([CH2:31][C:32]3[CH:37]=[N:36][CH:35]=[CH:34][N:33]=3)[C:29]3[CH:38]=[CH:39][CH:40]=[CH:41][C:28]=3[N:27]=2)[CH2:23][CH2:24]1
Reactant: c1ccc2c(c1)nc(NC1CCNCC1)n2Cc1cnccn1
Reactant: Cc1nc2ccccn2c(=O)c1CCCl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1nc2ccccn2c(=O)c1CCN1CCC(Nc2nc3ccccc3n2Cc2cnccn2)CC1
Temperature: 80 °C
Yield: 67.4 %

Procedure:
A mixture of 3.15 parts of 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 8.26 parts of N-(4-piperidinyl)-1-(2-pyrazinylmethyl)-1H-benzimidazol-2-amine trihydrobromide, 6.4 parts of sodium carbonate, 0.1 parts of potassium iodide and 90 parts of N,N-dimethylacetamide was stirred and heated overnight at 80° C. The reaction mixture was poured into water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 5 parts (67.4%) of 2-methyl-3-[2-[4-[[1-(2-pyrazinyl-methyl)-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-4H-pyrido-[1,2-a]pyrimidin-4-one; mp. 204.4° C. (compound 68).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[BH4-].[Na+].[OH-].[K+].CI.Br[C:19]1C=CC=C2C=1CCC2O>C1COCC1.CO.CS(C)=O.O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[O:11][CH3:19]
Reactant: O=C1CCc2c(Br)cccc21
Reactant: OC1CCc2c(Br)cccc21
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COC1CCc2c(Br)cccc21
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
To a solution of 100 g (0.474 mol) of 4-bromo-1-indanone in 530 ml of THF-methanol (2:1, vol.), 26.8 g (0.709 mol) of NaBH4 was added in small portions at vigorous stirring for 1.5 hours at 5° C. This mixture was stirred at room temperature for 12 hours and then added to 1 L of cold water. The hydrogenation product was extracted with 4×200 ml of dichloromethane, and the combined extract was evaporated to dryness. To 108 g (1.93 mol) of KOH in 700 ml of DMSO, 135 g (59.2 ml, 0.948 mol) MeI, and a solution of crude 4-bromoindan-1-ol in 300 ml of DMSO were added. This mixture was stirred for 2 hours at ambient temperature; then, 67.2 g (29.5 ml, 0.473 mol) of MeI was added, and the mixture was additionally stirred for 2 hours. The resulting mixture was added to 2 L of cold water. The crude product was extracted with 5×200 ml of dichloromethane. The combined extract was dried over Na2SO4 and, then, evaporated to dryness. Fractional distillation gave 4-bromo-1-methoxyindane, b.p. 94° C./2 mm Hg. Yield, 100 g (93%) of a colorless oil.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:17][CH3:18])[C:12]=1[O:13][CH2:14][C:15]#[CH:16])[CH:8]=O.[CH3:19][C:20]([CH3:22])=[O:21].Cl>C(OCC)(=O)C.CCCCCC.C(O)C>[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:8]=[CH:19]/[C:20](=[O:21])[CH3:22])[CH:10]=[C:11]([O:17][CH3:18])[C:12]=1[O:13][CH2:14][C:15]#[CH:16]
Reactant: C#CCOc1c(OC)cc(C=O)cc1OC
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: C#CCOc1c(OC)cc(/C=C/C(C)=O)cc1OC
Yield: 54.1 %

Procedure:
To an aqueous 10% sodium hydroxide solution (4.3 mL, 1.0 M) was added slowly dropwise a mixture of an ethanol (4.3 mL, 1.0 M) solution of 3,5-dimethoxy-4-prop-2-ynyloxybenzaldehyde (0.95 g, 4.3 mmol) and acetone (1.27 mL, 17.3 mmol), and the resultant mixture was stirred for 1 hour at room temperature, followed by addition of 10% hydrochloric acid. The mixture was then extracted with ethyl acetate, washed with saturated saline, dried over magnesium sulfate, and evaporated under reduced pressure to give a residue which was subjected to silica gel chromatography. A white solid (605 mg, 54%) was obtained from an ethyl acetate/hexane eluent (1:1 v/v).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl-].[NH4+]>C(OCC)C>[Cl:18][C:16]1[CH:15]=[CH:14][C:10]([CH2:11][OH:12])=[C:9]([CH:17]=1)[CH:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: OCc1ccc(Cl)cc1C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 120 g. of 2-benzoyl-4-chlorobenzoic acid in 900 ml. of anhydrous ethyl ether is added dropwise to 41 g. LiAlH4 suspended in 700 ml. of anhydrous ethyl ether with stirring at about 0° C. When the addition is completed, the mixture is stirred for 4 hours at room temperature and the reaction complex is decomposed by adding 125 ml. of 20% ammonium chloride with stirring. The inorganic precipitate is filtered off and washed with ethyl ether. The ether solutions are combined, dried over sodium sulfate and evaporated to dryness. The oily residue is triturated with light petroleum and the solid obtained is crystallized from diisopropyl ether. M.p. 102°-107° C. Yield 105 g.
Reaction SMILES: Cl[C:2]1C=CC(S(N2[C@@H](C)CC(=O)C[C@@H]2C)(=O)=O)=CC=1.CN(C(OC)OC)C.O.NN.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([N:41]2[CH2:46][CH2:45]C(=O)[CH2:43][CH:42]2[C:48]2[CH:49]=[N:50]C=[N:52][CH:53]=2)(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([N:41]2[C@@H:46]([CH3:45])[CH2:2][C:53]3[NH:52][N:50]=[CH:49][C:48]=3[C@@H:42]2[CH3:43])(=[O:39])=[O:40])=[CH:36][CH:37]=1
Reactant: O=C1CCN(S(=O)(=O)c2ccc(Cl)cc2)C(c2cncnc2)C1
Reactant: C[C@H]1CC(=O)C[C@H](C)N1S(=O)(=O)c1ccc(Cl)cc1
Agent: COC(OC)N(C)C
Agent: NN
Solvent: O
Product: C[C@H]1Cc2[nH]ncc2[C@H](C)N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
trans-1-(4-Chlorophenylsulfonyl)-2,6-dimethylpiperidin-4-one (94) was treated with DMF-DMA followed by hydrazine hydrate as described for compound 71 in Example 4. 1H-NMR (CD3OD) δ 7.81-7.79 (m, 2H), 7.62 (m, 3H), 5.38 (q, J=7.1 Hz, 1H), 4.20-4.13, (m, 1H), 2.78 (dd, J=16.2, 4.4 Hz, 1H), 2.56-2.48 (m, 1H), 1.54-1.47 (m, 6H); MS (m/z) 326.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH:11]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:9]#[N:10].[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O>[C:9]([CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([C:24]#[N:25])[CH:31]=1)[CH:11]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)#[N:10]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: N#CC(c1ccccc1Br)C(c1cccnc1)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cccc(-c2ccccc2C(C#N)C(c2cccnc2)c2cccnc2)c1
Temperature: 160 °C

Procedure:
A mixture of 2-(2-bromophenyl)-3,3-dipyridin-3-ylpropanenitrile (0.050 g, 0.137 mmol), 3-cyanophenylboronic acid (0.030 g, 0.206 mmol), cesium carbonate (0.045 g, 0.137 mmol) and Pd(dppf)2 (0.100 g, 0.137 mmol) in THF (0.75 mL) and water (0.75 mL) at −78° C. was heated to 160° C. in microwave for 15 min. The reaction was diluted with water and extracted with CH2Cl2. The combined organic layer was dried, filtered, and concentrated. The residue was purified by silica gel chromatography (0-5% MeOH in CH2Cl2) to give (±)-2′-(1-cyano-2,2-dipyridin-3-ylethyl)-1,1′-biphenyl-3-carbonitrile. 1H-NMR (500 MHz, CDCl3) δ 8.57 (d, 1H, J=3.9), 8.45 (d, 1H, J=4.2), 8.42 (s, 1H), 7.88 (s, 1H), 7.71 (m, 1H), 7.66-7.56 (m, 3H), 7.51 (td, 1H, J=7.5, 1.2), 7.41 (td, 1H, J=7.6, 1.3), 7.34-7.32 (m, 2H), 7.18-7.07 (m, 3H), 7.00 (d, 1H, J=7.8), 4.57 (d, 1H, J=10.0), 4.33 (d, 1H, J=9.8). LRMS m/z (M+H) Calcd: 387.1604, found: 387.1592.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C:10]([CH2:16][S:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH2:13][CH2:14][CH3:15])[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][Mg]I.[Cl-].[NH4+]>C(OCC)C>[CH2:18]([S:17][CH2:16][C:10]([CH2:9][S:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:13][CH2:14][CH3:15])[CH:11]([OH:12])[CH3:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C[Mg]I
Reactant: CCCC(C=O)(CSCc1ccccc1)CSCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCC(CSCc1ccccc1)(CSCc1ccccc1)C(C)O
Reaction time: 0.5 h

Procedure:
A solution of 2,2-di-(benzylthiomethyl)pentanal (3.54 g) in dry diethyl ether was added dropwise to a stirred solution of methyl magnesium iodide [prepared from methyl iodide (1.2 ml) and magnesium (0.48 g)] in dry diethyl ether (60 ml). The reaction mixture was refluxed for 2 hours and then cooled. Saturated aqueous ammonium chloride solution was added. The mixture was stirred for 30 minutes and extracted with diethyl ether. The ethereal extracts were dried over anhydrous magnesium sulphate and the solvent was removed in vacuo. 3,3-Di-(benzylthiomethyl)hexan-2-ol was obtained as a yellow oil (1.7 g)
Reaction SMILES: [CH3:1][C@@H:2]([NH2:5])[CH2:3][CH3:4].[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[N:16][N:17]([C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][N:21]=3)[C:18]=2[OH:19])=[C:10]([CH3:29])[CH:9]=1)#[N:7].C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[C@H:2]([NH:5][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([N:17]2[C:18]([OH:19])=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]#[N:7])=[CH:9][C:10]=3[CH3:29])[CH:15]=[N:16]2)=[N:21][CH:22]=1)([CH2:3][CH3:4])[CH3:1]
Reactant: CC[C@@H](C)N
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC[C@@H](C)NC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Combined (R)-butan-2-amine (22.8 mg, 0.312 mmol) and a solution consisting of 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (50 mg, 0.156 mmol), HOBT hydrate (35.9 mg, 0.234 mmol), EDCI (44.9 mg, 0.234 mmol), and Hunig's base (0.103 mL, 0.624 mmol) in DMA (1 mL) and stirred at 50° C. for 4 h. The reaction mixture was then purified via preparative HPLC to give the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.90 (t, J=7.45 Hz, 3H) 1.17 (d, J=6.57 Hz, 3H) 1.44-1.63 (m, 2H) 2.44 (s, 3H) 3.95 (dt, J=14.02, 7.14 Hz, 1H) 7.57-7.90 (m, 3H) 7.92-8.73 (m, 4H) 8.82-8.97 (m, 1H) 13.20 (br. s., 1H). MS m/z [M+H]+ 376.