Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][Si](C(C)(C)C)(C)C)=[C:4]([F:16])[CH:3]=1.C([Si:20]1([C:33]2[CH:38]=[CH:37]C=CC=2)[CH2:25][CH2:24][CH:23]([CH:26]2[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]2)[CH2:22][CH2:21]1)CC.Br[CH2:40][C:41]([F:47])([F:46])[C:42]([F:45])([F:44])[F:43]>>[CH2:33]([Si@H:20]1[CH2:21][CH2:22][C@H:23]([C@H:26]2[CH2:27][CH2:28][C@H:29]([C:2]3[CH:7]=[CH:6][C:5]([O:8][CH2:40][C:41]([F:47])([F:46])[C:42]([F:45])([F:44])[F:43])=[C:4]([F:16])[CH:3]=3)[CH2:30][CH2:31]2)[CH2:24][CH2:25]1)[CH2:38][CH3:37]
Reactant: CCC[Si]1(c2ccccc2)CCC(C2CCC(=O)CC2)CC1
Reactant: FC(F)(F)C(F)(F)CBr
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1F
Product: CCC[Si@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(OCC(F)(F)C(F)(F)F)c(F)c3)CC2)CC1

Procedure:
The general procedure of Example 1 was repeated using 1-bromo-3-fluoro-4-(t-butyldimethylsiloxy)benzene, 4-(4-n-propyl-4-phenyl-4-silacyclohexyl)cyclohexanone and 1-bromo-2,2,3,3,3-pentafluoro-n-propane, thereby obtaining the intended compound.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.Cl.[CH:55]([C:58]1[O:62][N:61]=[CH:60][C:59]=1[NH2:63])([CH3:57])[CH3:56]>CN(C)C=O.O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([NH:63][C:59]2[CH:60]=[N:61][O:62][C:58]=2[CH:55]([CH3:57])[CH3:56])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: CC(C)c1oncc1N
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)c1oncc1NC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.6 %

Procedure:
To a solution (15 ml) of 3-cyclopentyl-2-[4-(methylsulfonyl)phenyl]propanoic acid (2.00 g) in N,N-dimethylformamide were added N,N-diisopropylethylamine (3.49% mL), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo(4,5-b)pyridinium 3-oxide hexafluorophosphate (2.82 g) and 5-isopropylisoxazol-4-amine hydrochloride (1.15 g), and the mixture was stirred at room temperature for 48 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-100:0, volume ratio) to give the title compound (2.50 g, 92%) as colorless amorphous crystals. MS: 405 (MH+).
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].C([Li])CCC.[CH:11]1([O:16][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[CH:20]=O)[CH2:15][CH2:14][CH2:13][CH2:12]1.C[Si](C)(C)[N-:29][Si](C)(C)C.[Li+].B(F)(F)F.CCOCC>O1CCCC1>[CH:11]1([O:16][C:17]2[CH:18]=[C:19]([CH:20]([NH2:29])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])[CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CS(C)(=O)=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: FB(F)F
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C(N)CS(C)(=O)=O)cc1OC1CCCC1

Procedure:
1-(3-Cyclopentyloxy-4-methoxyphenyl)-2-methylsulfonylethylamine was prepared by the procedure of Example 1 from dimethyl sulfone (23.14 g, 246.1 mmol) and n-butyllithium (100 mL, 2.5 M, 250 mmol) in tetrahydrofuran (700 mL), and 3-cyclopentyloxy-4-methoxybenzaldehyde (49.50 g, 224.7 mmol), lithium hexamethyldisilazide (246 mL, 1.0 M, 246 mmol) and boron trifluoride etherate (58 mL, 458 mmol) in tetrahydrofuran (200 mL). The product was obtained as a white solid (26.53 g, 38% yield): mp, 155.0-158.0 ° C.; 1H NMR (CDCl3); δ 1.60-1.65 & 1.81-1.96 (m, 8H, C5H8), 2.91 (s, 3H, CH3), 3.22 (dd, J=3.7, 14.2 Hz, 1H, CHH), 3.33 (dd, J=9.1, 14.1 Hz, 1H, CHH), 3.84 (s, 3H, CH3), 4.58 (q, J=3.7, 9.0 Hz, 1H, NCH), 4.77-4.82 (m, 1H, OCH), 6.82-6.92 (m, 3H, Ar); 13C NMR (CDCl3) δ 23.95, 32.76, 42.42, 50.96, 56.11, 63.22, 80.56, 112.21, 113.00, 118.18, 135.53, 148.09, 149.89; Anal Calcd for C15H23NO4S: C, 57.49; H, 7.40; N, 4.47. Found: C, 58.14; H, 7.42; N, 4.37.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([Cl:15])[CH:8]=[CH:9][C:10]=1[NH:11][C:12](=[O:14])[CH3:13])(=[O:3])[CH3:2].[N+:16]([O-])([O-:18])=[O:17].[Na+]>S(=O)(=O)(O)O>[C:12]([NH:11][C:10]1[C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][C:7]([Cl:15])=[C:8]([N+:16]([O-:18])=[O:17])[CH:9]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccc(Cl)cc1NC(C)=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)Nc1cc(Cl)c([N+](=O)[O-])cc1NC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
A solution of 5 g (22 mmol) of 3,4-diacetamido-1-chlorobenzene in 50 ml of concentrated sulfuric acid was cooled to 0° C., and 1.9 g (8.5 mmol) of sodium nitrate were added a little at a time, and the mixture was stirred at room temperature for 15 minutes. It was then poured into ice-water, and the crude product was filtered off with suction and washed with water. A yield of 63% of the product was obtained. Melting point 232° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].CC([O-])=O.[Na+].[Br:21]Br>CC(O)=O.C(OCC)C>[Br:21][C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1ccc(C(=O)O)c(OC)c1OC
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1c(Br)cc(C(=O)O)c(OC)c1OC
Temperature: 80 °C

Procedure:
To a solution of 2,3,4-trimethoxybenzoic acid (4.7 g, 22 mmol) and NaOAc (5.5 g, 40 mmol) in 35 ml AcOH was added a solution of bromine (1.5 ml, 29 mmol) in 35 ml AcOH. The reaction became red in color, which quickly faded. The mixture was heated to 80° C. for 1 h, at which point it was cooled to ambient temperature. The material was partitioned between dichloromethane and water. The organic layer was removed and the aqueous layer was extracted once with dichloromethane. The combined organic layers were dried with Na2SO4, filtered, and concentrated to give an oil which solidified on standing. The material was dissolved in diethyl ether and hexanes. Concentration to ½ the volume resulted in precipitation of a white solid. Filtration provided the title compound as a white solid. MS m/z: 293 (M+H+); calc'd for C10H11BrO5: 291.1
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20](O)=[O:21])=[N:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]1[C:25]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)=[N:26][CH:27]=[C:28]([CH2:30][NH2:31])[CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[F:23][C:24]1[C:25]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=2)=[N:26][CH:27]=[C:28]([CH2:30][NH:31][C:20]([C:17]2[N:18]=[CH:19][C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)=[CH:15][CH:16]=2)=[O:21])[CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)nc2)CC1
Reactant: NCc1cnc(-c2ccnc(C(F)(F)F)c2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)NCc3cnc(-c4ccnc(C(F)(F)F)c4)c(F)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)picolinic acid 49-4 (92 mg, 0.3 mmol), (3-fluoro-2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methanamine 84-2 (81 mg, 0.3 mmol) and HATU (114 mg, 0.3 mmol) in DMF (1.5 mL) was added DIEA (0.15 mL, 0.9 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (100 mL), washed with H2O and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, and eluted with 5% methanol in dichloromethane to give tert-butyl 4-(6-((3-fluoro-2′-(trifluoromethyl)-2,4′-bipyridin-5-yl)methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate 49-5 as a pale yellow oil. MS m/z 561.2 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][CH2:13][C:14]2([C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH:27]1([CH:30]=O)[CH2:29][CH2:28]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)CCl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][CH2:13][C:14]2([C:20]3[CH:21]=[CH:22][C:23]([I:26])=[CH:24][CH:25]=3)[CH2:15][CH2:16][N:17]([CH2:30][CH:27]3[CH2:29][CH2:28]3)[CH2:18][CH2:19]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=CC1CC1
Reactant: O=S(=O)(NCC1(c2ccc(I)cc2)CCNCC1)c1ccc(F)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=S(=O)(NCC1(c2ccc(I)cc2)CCN(CC2CC2)CC1)c1ccc(F)c(Cl)c1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a stirred solution of 3-chloro-4-fluoro-N-[4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-benzenesulfonamide (0.0321 g, 0.04 mmol) in ClCH2CH2Cl (0.5 mL) at room temperature under Ar was added cyclopropanecarboxaldehyde (0.005 mL, 0.048 mmol, 1.2 eq) and HOAc (0.05 mL, 1%v/v). The mixture was stirred for 0.5 h. Na(OAc)3BH (0.015 g, 0.06 mmol, 1.5 eq) was added and the mixture stirred for 16 h, diluted with EtOAc (20 mL) and washed with saturated aqueous NaHCO3 solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated by rotary evaporation, then dried under high vacuum to give 3-chloro-N-[1-cyclopropylmethyl-4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-4-fluorobenzenesulfonamide (0.047 g, 0.04 mmol, 95%). MS (ESI): 563.1/565.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]3[C:21]([C:29]([F:32])([F:31])[F:30])([O:24][Si](C)(C)C)[CH2:22][CH2:23][C:5]=3[C:4]=2[C:3]=1[Cl:33].[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:21]([C:29]([F:31])([F:30])[F:32])([OH:24])[CH2:22][CH2:23][C:5]=3[C:4]=2[C:3]=1[Cl:33]
Reactant: Cc1ccc(S(=O)(=O)n2c3c(c4c(Cl)c(Cl)ccc42)CCC3(O[Si](C)(C)C)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)CCc2c1[nH]c1ccc(Cl)c(Cl)c21
Yield: 62.3 %

Procedure:
To 7,8-dichloro-4-tosyl-3-(trifluoromethyl)-3-(trimethylsilyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indole (0.2 g, 0.3 mmol) in THF (10 mL), KOH (104 mg, 1.8 mmol) in H2O (10 mL) was added and the resulting mixture was refluxed for 18 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude compound which was purified by column chromatography (10% EtOAc-hexane) to afford the title compound as a white solid (58 mg, 53%). 1H NMR (500 MHz, DMSO-d6, δ in ppm) 11.70 (s, 1H), 7.35 (d, 8.5 Hz, 1H), 7.28 (d, J=9.0 Hz, 1H), 6.90 (s, 1H), 3.12-3.07 (m, 1H), 2.97-2.88 (m, 2H), 2.88-2.50 (m, 1H).
Reaction SMILES: [NH:1]([CH:3]([CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:4])[NH2:2].C(N(CC)CC)C.[CH3:21][O:22][C:23](OC)=[C:24]([C:27]#[N:28])[C:25]#[N:26].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O>[NH2:28][C:27]1[N:1]([CH:3]([CH2:5][CH2:6][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:4])[N:2]=[C:23]([O:22][CH3:21])[C:24]=1[C:25]#[N:26]
Reactant: CC(CCCc1ccccc1)NN
Reactant: COC(OC)=C(C#N)C#N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1nn(C(C)CCCc2ccccc2)c(N)c1C#N
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 80.1 %

Procedure:
3.6 g of 2-hydrazino-5-phenylpentane are dissolved in 40 ml of methanol, and 2.8 ml of triethylamine are added. Then, 2.8 g of 1,1-dimethoxy-2,2-dicyanoethylene are added at approx. 0° C. The reaction solution is warmed to approx. 20° C. and stirred for 1.5 hours at approx. 20° C. For work-up, the mixture is diluted with water, acidified with citric acid and extracted twice with dichloromethane. The combined dichloromethane phases are dried with magnesium sulphate and evaporated in vacuo. This gives 5.1 g of a yellow oil, which crystallizes slowly. The oil is chromatographed on silica gel (Merck Si 60 0.04-0.063 mm) with a petroleum ether/ethyl acetate mixture in a ratio of 5:1 to 1:1. This gives a fraction which, after evaporation in vacuo, affords 4.6 g (=80.9% of theory) of 5-amino-4-cyano-3-methoxy-1-[(5-phenyl)-pent-2-yl]-pyrazole.
Reaction SMILES: Cl.[O:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH:3]1[CH2:12][NH2:13].[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:24][CH2:25][CH2:26]Br.C(N(C(C)C)CC)(C)C>CN(C=O)C>[O:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH:3]1[CH2:12][NH:13][CH2:26][CH2:25][CH2:24][C:18]1[C:17]2[C:21](=[CH:22][CH:23]=[C:15]([F:14])[CH:16]=2)[NH:20][CH:19]=1
Reactant: NCC1COc2ccccc2O1
Reactant: Fc1ccc2[nH]cc(CCCBr)c2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc2[nH]cc(CCCNCC3COc4ccccc4O3)c2c1
Temperature: 80 °C
Yield: 16 %

Procedure:
2,3-Dihydro-1,4-benzodioxin-2-methanamine hydrochloride (2.0 g, 10.0 mmole) in DMF (100 ml) was slowly added to the mixture of 5-fluoro-3-(3-bromopropyl)indole (2.6 g, 10.0 mmole) and diisopropylethylamine (8.7 ml, 50 mmole) in 100 ml of DMF with stirring and the mixture was heated at 80° C. for 24 hours. Most of DMF was removed and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered, concentrated in vacuum and column chromatographed on silica gel using ethyl acetate as the eluant. The combined fractions of free base of the expected product (0.5 g, 1.6 mmole, 15%) were concentrated, dissolved in 50 ml of ethanol-diethyl ether (1:1). To this was added 0.25M of fumaric acid in ethanol (3.4 ml, 0.85 mmole) and then a minimum amount of hexane to precipitate the title compound as a light tan solid, (2:1) fumarate salt, m.p. 186°-188° C.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[N:5]([CH2:18][CH2:19][CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)[C:6]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]3[N:14]=[N:15][N:16]=[C:8]3[C:7]=2[N:17]=1>CO>[ClH:2].[Cl:2][CH2:3][C:4]1[N:5]([CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[C:6]2[C:11]([CH3:12])=[C:10]([CH3:13])[N:9]3[N:14]=[N:15][N:16]=[C:8]3[C:7]=2[N:17]=1
Reactant: Cc1c(C)n2nnnc2c2nc(CCl)n(CCCCNC(=O)OC(C)(C)C)c12
Agent: Cl
Solvent: CO
Product: Cc1c(C)n2nnnc2c2nc(CCl)n(CCCCN)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 171.8 %

Procedure:
Concentrated hydrochloric acid (10 mL) was added to a suspension of tert-butyl 4-[8-(chloromethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butylcarbamate (1.00 g, 2.30 mmol) in methanol (23 mL). The reaction mixture was stirred at room temperature for 2 hours, then was concentrated under reduced pressure to yield a residue. The residue was concentrated twice from toluene to remove residual water, then was triturated with methanol. A solid was isolated by filtration and was dried under vacuum to provide 0.68 g of 4-[8-(chloromethyl)-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butan-1-amine hydrochloride.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[C:33]([O:37][C:38](=[O:45])[N:39]([CH2:41][CH2:42][CH2:43][NH2:44])[CH3:40])([CH3:36])([CH3:35])[CH3:34].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:33]([O:37][C:38]([N:39]([CH3:40])[CH2:41][CH2:42][CH2:43][NH:44][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2)=[O:45])([CH3:36])([CH3:35])[CH3:34]
Reactant: CN(CCCN)C(=O)OC(C)(C)C
Reactant: Brc1cccc2cnccc12
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(CCCNc1cccc2cnccc12)C(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 85.1 %

Procedure:
Under nitrogen atmosphere, a suspension of 5-bromoisoquinoline (252 mg), tris(dibenzylideneacetone)palladium(0) (59 mg), 2-(di-tert-butylphosphino)biphenyl (74 mg), (3-aminopropyl)methylcarbamic acid tert-butyl ester (274 mg, Asta Tech), and sodium tert-butoxide (163 mg) in toluene was stirred with heating at 70° C. for 3 hours. The reaction mixture was returned to room temperature and purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (325 mg).
Reaction SMILES: C1(C2C(=CC=CC=2)CO1)=O.[C:11]([Cl:14])(Cl)=[O:12].Cl[C:16]1[C:24](CC)=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([Cl:20])=O>N1C=CC=C(C)C=1.B(O)(O)O>[Cl:20][CH2:18][C:17]1[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=1[C:11]([Cl:14])=[O:12]
Reactant: O=C(Cl)Cl
Reactant: CCc1cccc(C(=O)Cl)c1Cl
Agent: O=C1OCc2ccccc21
Agent: OB(O)O
Solvent: Cc1cccnc1
Product: O=C(Cl)c1ccccc1CCl
Temperature: 140 °C
Yield: 90 %

Procedure:
268 g (2 mol) of phthalide, 9.3 g (0.1 mol) of β-picoline and 3.1 g (0.05 mol) of crystalline boric acid (Riedel de Haen) were initially charged. At 140-150° C., a total of 245 g (2.45 mol) of gaseous phosgene was introduced over a period of 7 h. The mixture was then stirred at 140° C. for another hour. Excess phosgene was stripped using nitrogen, giving a discharge of 380 g having a content of 96 GC area % of o-chloro-ethylbenzoyl chloride and 1.4% of unreacted phthalide. ractional distillation of the crude discharge gave 340 g of o-chloromethylbenzoyl chloride (90% of theory) of a purity of >97%.
Reaction SMILES: [C:1](O)(=O)/[CH:2]=[CH:3]/C(O)=O.[CH:9]1([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]=[C:15]([C:19]3[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=3)[CH2:14]2)[CH2:11][CH2:10]1.CN(C)[CH:28]=[O:29].[Li]>O>[OH:25][C:21]1[CH:20]=[C:19]([C:15]2[CH2:14][N:13]([CH2:12][C:9]3([CH2:28][OH:29])[CH:11]=[CH:10][CH:1]=[CH:2][CH2:3]3)[CH2:18][CH2:17][CH:16]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Oc1cccc(C2=CCCN(CC3CC3)C2)c1
Reactant: O=C(O)/C=C/C(=O)O
Reactant: CN(C)C=O
Agent: [Li]
Solvent: O
Product: OCC1(CN2CCC=C(c3cccc(O)c3)C2)C=CC=CC1

Procedure:
A mixture of 5 g of the product of Step B, 200 ml of dimethylformamide and 4.3 g of lithium thiomethylate was refluxed for 3 hours and the mixture was cooled and poured into iced water. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 95-5 chloroform-methanol mixture to obtain 5 g of 1-[{3-(3-hydroxyphenyl)-1,2,5,6-tetrahydropyridin-1-yl}-methyl]-benzenemethanol.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]3[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][C:19]([CH3:26])=[C:18]3[C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]([NH:29][CH2:30][CH2:31]O)=[N:9]1)=O)(C)(C)C.C[N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.S(Cl)(C)(=O)=O.N1CCOCC1>C1COCC1.C(N(CC)CC)C>[CH3:25][C:21]1[NH:20][C:19]([CH3:26])=[C:18]([C:27]#[N:28])[CH:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][N:9]=[C:10]3[NH:29][CH2:30][CH2:31][N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[C:22]=1[C:23]#[N:24]
Reactant: CN1CCOCC1
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(NCCO)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Agent: CS(=O)(=O)Cl
Solvent: C1COCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1=C(C#N)C(c2ccc3[nH]nc(NCCN4CCOCC4)c3c2)C(C#N)=C(C)N1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
To a stirred and chilled (ice/water bath) solution of crude 5-(3,5-dicyano-2,6-dimethyl-1,4-dihydro-pyridin-4-yl)-3-(2-hydroxy-ethylamino)-indazole-1-carboxylic acid tert-butyl ester (1 g) in THF (157 mL), under argon, was added sequentially 4-methylmorpholine (5.2 mL) and mesyl chloride (MsCl, CH3SO2Cl, 0.89 mL) dropwise. The mixture was allowed to warm to room temperature overnight before morpholine (41 mL) was added. Stirring was continued overnight before heating to 35° C. On cooling, triethylamine was added, the mixture concentrated to ca. one third the volume and the residue cooled (ice/water bath). The mixture was quenched with ice and aqueous sodium carbonate solution and the extracted with EtOAc. The combined organic extracts were dried and concentrated. The residue was taken up in THF (15 mL), HCl (15 mL) was added and the mixture was heated for 1.5 h at 60° C. (bath temperature). On cooling, the mixture was poured carefully onto aqueous sodium hydrogencarbonate solution and extracted with EtOAc. The combined organic extracts were dried and concentrated. The residue was purified by preparative reverse phase HPLC to give 1,4-dihydro-2,6-dimethyl-4-[3-[[2-(4-morpholinyl)ethyl]amino]-1H-indazol-5-yl]-3,5-pyridinedicarbonitrile (60 mg) (Cpd. No. 307, Table 8). 1H-NMR (DMSO-D6, 300 MHz): δ=11.46 (br s, 1H), 9.50 (br s, 1H), 7.56 (s, 1H), 7.25 (d, 1H), 7.17 (dd, 1H), 5.93 (t, 1H), 4.40 (s, 1H), 3.60 (m, 4H), 3.40 (partially obscured by solvent, 2H), 2.59 (t, 2H), 2.44 (m, 4H), 2.05 (s, 6H) ppm.
Reaction SMILES: [C:1]([C:9]1[CH:19]=[C:18](Cl)[CH:17]=[CH:16][C:10]=1[NH:11][C:12](=O)CI)(=O)C1C=CC=CC=1.[N-:21]=[N+]=[N-].[Na+].[OH-].[CH2:26]([N+](C)(C)C)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CO>[N:11]1[C:12]2[C:18](=[CH:19][CH:9]=[C:1]3[NH:21][C:32]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:26]3=2)[CH:17]=[CH:16][CH:10]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: O=C(CI)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: c1cnc2c(c1)ccc1[nH]c3ccccc3c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 120 g. of 2'-benzoyl-4'-chloro-2-iodo-acetanilide (mp 125°-127°) and 39.0 g. of sodium azide in 3.2 l of methanol was heated to reflux for 15 minutes. The mixture was allowed to cool at room temperature. A methanolic solution of benzyltrimethylammonium hydroxide (35% concentration, 25 ml.) was added while the mixture was still warm. After standing overnight, 70.5 g. (79%) of 3-azido-6-chloro-4-phenylcarbostyril, as yellow needles, were collected and washed with methanol, melting point was indefinite because of decomposition in the range of 120°-150°, forming high-melting indoloquinoline. An analytical sample was obtained by recrystallization from methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].C(O)(=O)C.[C:14]([CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=O)[CH3:15]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:14]([CH3:15])=[C:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: COc1ccccc1N
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(C)=C(C)Nc1ccccc1OC

Procedure:
A mixture of 2-methoxyaniline (10 g), acetic acid (1 ml) and ethyl 2-acetylpropionate (12.3 g) in benzene (30 ml) was refluxed for 24 hours, and then the solvent was removed to give crude ethyl 3-(2-methoxyanilino)-2-methyl-2-butenoate, which was used as a starting compound at the following example without further purification.
Reaction SMILES: [CH3:1][CH2:2][CH2:3]Br.[Mg].Cl[SiH:7]1[CH2:12][CH2:11][CH:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)[CH2:9][CH2:8]1.[CH2:28]1COC[CH2:29]1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][C@H:16]2[CH2:17][CH2:18][C@H:13]([C@H:10]3[CH2:11][CH2:12][Si@H:7]([CH2:1][CH2:2][CH2:3][CH2:28][CH3:29])[CH2:8][CH2:9]3)[CH2:14][CH2:15]2)=[CH:22][CH:23]=1
Reactant: CCCBr
Reactant: C1CCOC1
Reactant: Fc1ccc(CC[C@H]2CC[C@H](C3CC[SiH](Cl)CC3)CC2)cc1
Agent: [Mg]
Product: CCCCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CCc3ccc(F)cc3)CC2)CC1

Procedure:
3.1 g (20 mmol) of n-propyl bromide was dripped into a mixture of 0.5 g (21 mmol) of magnesium and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 6.8 g (20 mmol) of 1-chloro-4-(trans-4-(2-(4-fluorophenyl) ethyl) cyclohexyl)-1-silacyclohexane. The silacyclohexane rings of the reacted mixture thus obtained were a mixture of trans isomers and cis isomers. After a conventional after treatment, they were separated by means of chromatography to obtain 6.4 g (yield 85%) of trans-4-(trans-4-(2-(4-fluorophenyl) ethyl) cyclohexyl)-1-n-pentyl-1-silacyclohexane.