Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[CH3:23])[C:9]([F:15])=[CH:10][CH:11]=2)[O:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[ClH:22].[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:8]2[C:9]([F:15])=[CH:10][CH:11]=[C:12]3[C:7]=2[O:6][C@@H:5]([CH2:4][NH2:1])[CH2:14][CH2:13]3)=[C:17]([CH3:23])[CH:18]=1
Reactant: Cc1cc(Cl)ccc1-c1c(F)ccc2c1O[C@@H](CN=[N+]=[N-])CC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cl)ccc1-c1c(F)ccc2c1O[C@@H](CN)CC2
Product: Cl
Yield: 136.4 %

Procedure:
Treatment of (2R)-2-(azidomethyl)-8-(4-chloro-2-methylphenyl)-7-fluorochroman (0.30 g, 0.90 mmol) with polymer-bound triphenylphosphine (3 mmol/g, 0.5 g, 1.50 mmol) in THF (10 mL) and water (0.5 mL) according to the procedure described for Example 69, Step 10 provided 0.21 g (69%) of ((2R)-8-(4-chloro-2-methylphenyl)-7-fluorochroman-2-yl)methanamine hydrochloride as a white solid salt, mp 100–102° C.; MS (ESI) m/z 306.1 ([M+H]+).
Reaction SMILES: [C:1]([O-])([O-:3])=[O:2].[K+].[K+].Cl[CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[S:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)=[CH:14][C:12]=2[CH:13]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CC#N>[CH:1]([OH:3])=[O:2].[N:28]1([CH2:8][C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[S:20][C:21]5[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=5[N:23]=4)=[CH:14][C:12]=3[CH:13]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C1CCNCC1
Reactant: O=C([O-])[O-]
Reactant: ClCc1cc2cc(Oc3nc4ccccc4s3)ccc2o1
Agent: [K+]
Solvent: CC#N
Product: O=CO
Product: c1ccc2sc(Oc3ccc4oc(CN5CCCCC5)cc4c3)nc2c1
Temperature: 55 °C
Yield: 67 %

Procedure:
To a suspension of K2CO3 (33 mg, 0.24 mmol) in MeCN (1 mL) was added 2-(2-chloromethyl-benzofuran-5-yloxy)-benzothiazole (27 mg, 0.08 mmol) and piperidine (5 mg, 0.09 mmol) and the reaction mixture was warmed (55° C., 12 h). The reaction mixture was filtered and concentrated and the resultant residue was purified by reverse phase HPLC to afford the title compound (22 mg, 67%). MS (ESI): mass calcd for C21H20N2O2S, 364.1; m/z found 365.1 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.75 (d, J=8.0, 1H), 7.64 (d, J=8.1, 1H), 7.62-7.55 (m, 2H), 7.40 (dt, J=8.0, 1.3, 1H), 7.35-7.18 (m, 2H), 6.85 (5, 1H), 3.85 (5, 2H), 2.76-2.53 (m, 4H), 1.73-1.60 (m, 4H), 1.56-1.42 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[N:44]=[C:15]2[N:16]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=3)[C:17]([CH3:33])=[C:18]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:19]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)[N:14]2[N:13]=1)=[O:10])[C:2]1C=CC=CC=1.[OH-].[Li+].Cl>C1COCC1.O.C(O)C>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([CH:19]2[N:14]3[N:13]=[C:12]([NH:11][C:9]([O:8][CH2:1][CH3:2])=[O:10])[N:44]=[C:15]3[N:16]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:41])([F:43])[F:42])[CH:35]=3)[C:17]([CH3:33])=[C:18]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:21][CH:22]=1)#[N:27]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nc(NC(=O)OCc3ccccc3)nn2C1c1ccc(C#N)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)Nc1nc2n(n1)C(c1ccc(C#N)cc1)C(C(=O)OCC)=C(C)N2c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, ethyl 2-[(benzyloxy)carbonyl]amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxylate (125 mg, 207 μmol) was dissolved in a mixture of THF (0.9 ml), water (0.6 ml) and ethanol (3.8 ml). After addition of solid lithium hydroxide (14.9 mg, 620 μmol, 3 eq.), the reaction mixture was heated at 55 C for 1.5 h. In an ice-bath, the mixture was acidified with 1 N hydrochloric acid (4.1 ml) and then purified by preparative HPLC (Kromasil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (4.8 mg, 5% of theory).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][C:5]=12.[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.[C:18]([N:21]1[CH2:26][CH2:25][CH:24]([C:27](=O)[CH2:28][C:29]#[N:30])[CH2:23][CH2:22]1)(=[O:20])[CH3:19]>C(#N)C>[C:18]([N:21]1[CH2:22][CH2:23][CH:24]([C:27]2[NH:12][C:13]3=[N:14][NH:15][CH:16]=[C:17]3[CH:10]([C:9]3[C:4]4[C:5](=[N:1][O:2][N:3]=4)[CH:6]=[CH:7][CH:8]=3)[C:28]=2[C:29]#[N:30])[CH2:25][CH2:26]1)(=[O:20])[CH3:19]
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1cccc2nonc12
Reactant: CC(=O)N1CCC(C(=O)CC#N)CC1
Solvent: CC#N
Product: CC(=O)N1CCC(C2=C(C#N)C(c3cccc4nonc34)c3c[nH]nc3N2)CC1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
To a solution of ethyl isonipecotate (8.0 g) in THF (100 mL) was added triethylamine (5.7 g), dimethylaminopyridine (0.6 g) and acetyl chloride (4.4 g) at 0° C. and the mixture was stirred for an hour. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give ethyl 1-acetylpiperidine-4-carboxylate (10 g) as a colorless oil. To a solution of acetonitrile (2.5 g) in THF (300 mL) was added n-BuLi (57 mmol) at −78° C. Further, ethyl 1-acetylpiperidine-4-carboxylate (10 g) was added and the mixture was stirred for an hour. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give 1-(1-acetylpiperidin-4-yl)-2-cyanoethan-1-one (7.5 g) as a colorless oil. A solution of 2,1,3-benzoxadiazole-4-aldehyde (0.3 g), 3-aminopyrazole (0.17 g) and 1-(1-acetylpiperidin-4-yl)-2-cyanoethan-1-one (0.4 g) in acetonitrile (10 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (0.49 g) as yellow crystals.
Reaction SMILES: [OH-:1].[Na+].Cl.[NH2:4]O.[CH3:6][CH:7]([C:13]([C:15]([F:18])([F:17])[F:16])=[O:14])[C:8](OCC)=[O:9].Cl>O>[F:16][C:15]([F:18])([F:17])[C:13](=[O:14])[CH:7]([CH3:6])[C:8]([NH:4][OH:1])=[O:9]
Reactant: CCOC(=O)C(C)C(=O)C(F)(F)F
Reactant: NO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C(=O)NO)C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 38.8 %

Procedure:
NaOH (2.01 g, 50.5 mmol) was dissolved in water (30 mL) at 0° C. A sol. of hydroxylamine hydrochloride (1.75 g, 25.2 mmol) in water (30 mL) was added. Ethyl 2-methyl-4,4,4-trifluoroacetoacetate (5.00 g, 25.2 mmol) was added, and the mixture was stirred at 0° C. for 90 min. Aq. cone. HCl (26 mL) was added and the mixture was stirred for 1 h at 4° C. The mixture was filtered, and the precipitate was dried under high vacuum at 40° C. This delivered a first crop of title compound (0.56 g, 12%). The filtrate was extracted with EtOAc (2×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded a second crop of the title compound (1.81 g, 38%; total: 2.37 g, 50%). LC-MS: tR=0.58, ES+: not visible.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][C:4]1[CH:21]=[CH:20][C:7]([CH:8]=[C:9]([O:15][Si:16](C)(C)C)[O:10][Si](C)(C)C)=[CH:6][CH:5]=1.FO[C:25]([F:28])([F:27])[F:26].C(Cl)(Cl)(Cl)[F:30]>>[F:30][CH:8]([C:7]1[CH:20]=[CH:21][C:4]([CH2:3][CH:2]([CH3:22])[CH3:1])=[CH:5][CH:6]=1)[C:9]([O:15][SiH2:16][C:25]([F:28])([F:27])[F:26])=[O:10]
Reactant: FC(Cl)(Cl)Cl
Reactant: CC(C)Cc1ccc(C=C(O[Si](C)(C)C)O[Si](C)(C)C)cc1
Reactant: FOC(F)(F)F
Product: CC(C)Cc1ccc(C(F)C(=O)O[SiH2]C(F)(F)F)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 16.8 g (0.05 mol) of the aforesaid 4-(2-methylpropyl)-β,β-bis(trimethylsiloxy)-styrene in 250 ml of CFCl3 was cooled to -70° C. and 5.2 g (0.05 mol) of trifluoromethyl hypofluorite were passed into the solution over a period of 1 hour. The reaction mixture was warmed to room temperature (25° C.) and then evaporated under reduced pressure to give 14.1 g (100% yield) of crude trifluoromethylsilyl α-fluoro-4-(2-methylpropyl)benzeneacetate as a colorless oil: 19F NMR (CFCl3) δ-176.8 ppm (d, J=49 Hz); 1H NMR (CFCl3, ext. TMS) δ 0.01 ppm (s, 9H), 0.66 ppm (d, J=6 Hz, 6H), 1.55 ppm (m, 1H), 2.22 ppm (d, J=6 Hz, 2H), 5.30 ppm (d, J=49 Hz, 1H) and 6.7-7.2 ppm (A 2 B2).
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:21])([F:20])[C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[O:12][CH:13]1[CH2:16][NH:15][CH2:14]1.C(N(CC)CC)C.[CH3:29][N:30]([CH3:34])[C:31](Cl)=[O:32].[Cl-].[Ca+2].[Cl-]>O1CCCC1.O>[CH3:29][N:30]([CH3:34])[C:31]([N:15]1[CH2:16][CH:13]([O:12][C:11]2[CH:17]=[CH:18][CH:19]=[C:9]([C:8]([F:7])([F:20])[F:21])[CH:10]=2)[CH2:14]1)=[O:32]
Reactant: CN(C)C(=O)Cl
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Agent: O=C(O)C(=O)O
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 15 h
Yield: 76.6 %

Procedure:
A stirred slurry of 5 g (0.0163 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine oxalate in 50 ml of tetrahydrofuran was treated with 5 ml of triethylamine and after 1 hr, 1.95 g (0.018 mole) of dimethylcarbamoyl chloride was added. After stirring an additional 15 hr, the reaction mixture was treated with 20 ml of water and 10 g of calcium chloride. The tetrahydrofuran layer was decanted and the residue triturated with 20 ml of ethyl acetate, then decanted. The combined tetrahydrofuran and ethyl acetate solution was concentrated in vacuo. The crude residue was chromatographed on a Waters Prep-LC using 50% ethyl acetate/toluene as the eluent. After concentration of the main fractions, 3.6 g (76.6%) of pale yellow oil was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11]O)=[CH:8][C:6]=2[N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:39]>C(Cl)Cl>[Br:39][CH2:11][C:9]1[S:10][C:5]2[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reaction time: 1 h
Yield: 46 %

Procedure:
To a solution of (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol (1.46 g, 5.11 mmol) in anhydrous DCM (30 mL) at 0° C. were added triphenylphosphine (1.74 g, 6.64 mmol) and carbon tetrabromide (2.03 g, 6.13 mmol). The resulting brown solution was stirred at RT for 5 h, before additional quantities of triphenylphosphine and carbon tetrabromide were added (0.4 g and 0.34 g, respectively) and stirring continued at RT for 1 h. The reaction mixture was concentrated in vacuo and DCM and EtOAc were added. The resultant white precipitate was collected by filtration and air dried to give the title compound as a white solid (0.82 g, 46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.CO[C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1OC)[N:31]=[CH:30][CH:29]=[C:28]2OC1C=CC(NC(NC2CCNCC2)=O)=CC=1.[C:54]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:55]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N:31]1([CH2:30][CH2:29][CH2:28][O:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:17][CH:18]=2)[C:32]2[C:27](=[CH:26][CH:25]=[CH:34][CH:33]=2)[CH:55]=[CH:54]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc2ncnc(Oc3ccc(O)cc3)c2cc1OC
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)NC4CCNCC4)cc3)c2cc1OC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3ccc(OCCCn4ccc5ccccc54)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 4.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]phenol (100 mg), the compound (1) (59 mg), and triphenylphosphine (106 mg) were dissolved in tetrahydrofuran (3 ml) to prepare a solution. Diethyl azodicarboxylate (0.063 ml) was then added to the solution, and the mixture was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate, followed by washing with saturated brine. The extract was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using hexane/acetone for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (3 mg, yield 2%). Mass spectrometry value (FD-MS, m/z): 455 (M+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[CH:16]=[N:15][N:14]=1
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COc1ccc2c(Cl)nncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1
Reaction time: 20 h
Yield: 79.4 %

Procedure:
A solution of 3,5-dichloro-4-methyl-pyridine (11.32 g, 70 mmoles) in dry DMF (100 ml) was stirred under N2 at room temperature, then added with 60% NaH in oil (2.8 g, 70 mmoles). After 1 hour at room temperature a solution of 1-chloro-6-methoxy-phthalazine (6.8 g, 35 mmoles), prepared as described in example 4, in DMF (250 ml) was added. The mixture was left at room temperature for 20 hours, then poured into water/ice (pH≅8) and extracted more times with CH2Cl2. The organic phases were washed with water, anhydrified and brought to dryness to give a solid which was triturated in isopropyl ether (100 ml) and filtered. The mother liquors were dried and the residue flash chromatographed with ethyl acetate to give 8.9 g of the title compound (yield: 79.5%). m.p.: 173-175° C.
Reaction SMILES: [N:1]1([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(O[C:22]1(O[Si](C)(C)C)[CH2:24][CH2:23]1)C.C(O)(=O)C.C([BH3-])#N.[Na+]>O1CCCC1.CO>[CH:22]1([N:4]2[CH2:5][CH2:6][CH2:7][N:1]([C:8]3[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=3)[CH2:2][CH2:3]2)[CH2:24][CH2:23]1
Reactant: CCOC(=O)c1ccc(N2CCCNCC2)cc1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(N2CCCN(C3CC3)CC2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 117.8 %

Procedure:
A solution of ethyl 4-(1,4-diazepan-1-yl)benzoate (0.621 g, 2.5 mmol), (1-ethoxycyclopropoxy)trimethylsilane (2.51 mL, 12.50 mmol) and acetic acid (0.286 mL, 5.00 mmol) in tetrahydrofuran (50 mL), methanol (5 mL) was treated with sodium cyanoborohydride (0.393 g, 6.25 mmol) at 20° C. The resulting solution was stirred at 60° C. for 18 h. The reaction mixture was cooled, filtered and evaporated to dryness. 1N HCl (40 ml) and water (60 ml) were added and the solution extracted with ethyl acetate (3×50 ml). The aqueous layer was basified to pH 10 with solid potassium carbonate and extracted with ethyl acetate (4×50 ml). The organic extracts washed with saturated NaCl (50 ml) and dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford ethyl 4-(4-cyclopropyl-1,4-diazepan-1-yl)benzoate (0.849 g, 118%) as a colourless oil.
Reaction SMILES: C(O)C.[CH2:4]([CH:7]1[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][CH:15]([CH:18]=[O:19])[CH2:14][CH2:13]2)[CH2:8]1)[CH2:5][CH3:6].[BH4-].[Na+]>O>[CH2:4]([CH:7]1[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]2)[CH2:8]1)[CH2:5][CH3:6]
Reactant: CCCC1CCC(C2CCC(C=O)CC2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCC1CCC(C2CCC(CO)CC2)C1
Temperature: 0 °C
Reaction time: 20 h
Yield: 90.5 %

Procedure:
Ethanol (30 ml) was added to 4-(3-propylcyclopentyl)cyclohexanecarboaldehyde (2.3 g) obtained in the second step in Example 3, in a reaction vessel under an atmosphere of nitrogen, and the mixture was cooled to 0° C., and sodium borohydride (0.22 g) was added slowly. After the mixture had been returned to room temperature and stirred for another 20 hours and water (30 ml) was added. The mixture was separated, and the water layer was extracted with diethyl ether three times, and then the combined organic layer was washed with brine. The solution was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/n-heptane=½ by volume) to give (4-(3-propylcyclopentyl)cyclohexyl)methanol (2.1 g).
Reaction SMILES: C([O-])(=O)C.[NH4+].[C:6]([N:11]1[CH2:16][CH2:15][C:14](=O)[CH:13]([CH3:18])[CH2:12]1)([O:8][CH2:9][CH3:10])=[O:7].C([BH3-])#[N:20].[Na+]>CO>[NH2:20][CH:14]1[CH2:15][CH2:16][N:11]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:12][CH:13]1[CH3:18]
Reactant: CCOC(=O)N1CCC(=O)C(C)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)N1CCC(N)C(C)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Ammonium acetate (5 g, 64.93 mmol) was added to the stirred solution of 1-carbethoxy-3-methyl-4-piperidone (1.4 g, 7.56 mmol) in methanol (25 ml) and stirring was continued for 3 hr at ambient temperature. The resulting mixture was cooled at 0° C. and sodium cyanoborohydride (0.5 g, 7.93 mmol) was added to it. Cooling was removed after 10 min. and resulting mixture was stirred for 6 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water, acidified with conc. HCl (pH 3˜4) and extracted with ethyl acetate to remove impurities. The aqueous layer was basified with 1 M sodium hydroxide solution (pH˜10) and extracted with ethyl acetate. Ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 4-amino-1-carbethoxy-3-methylpiperidine. Yield 1.0 g (72%), C9H18N2O2, m/z 187 (M+1), PMR (CDCl3): 0.94 (dd, 3H), 1.22 (m, 1H), 1.26 (t, 3H), 1.6 (m, 1H), 1.82 (m, 1H), 2.4 (m, 1H), 2.82 (m, 1H), 3.34 (m, 2H), 3.64 (m, 1H) 4.14 (q, 2H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:11][C:10]2[CH:12]=[C:13]([Br:16])[CH:14]=[CH:15][C:9]=2[C:8]=1[CH3:17].[C:18]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)#N.Cl.[OH-:27].[Na+]>CCCCCC.CCOCC>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]([C:7]2[S:11][C:10]3[CH:12]=[C:13]([Br:16])[CH:14]=[CH:15][C:9]=3[C:8]=2[CH3:17])=[O:27])[CH:21]=1
Reactant: Cc1c(Br)sc2cc(Br)ccc12
Reactant: [OH-]
Reactant: N#Cc1cccnc1
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1c(C(=O)c2cccnc2)sc2cc(Br)ccc12
Reaction time: 0.5 h

Procedure:
A solution of n-butyl-lithium in hexane (16.3 ml of 1.55 M solution) was added to a stirred solution of 2,6-dibromo-3-methylbenzo[b ]thiophene (7.65 g) in dry ether (150 ml) at -70° under dry nitrogen. The mixture was stirred for 30 minutes at -70° and then 3-cyanopyridine (2.60 g) in dry ether (50 ml) was added dropwise over 5 minutes. The resulting mixture was stirred at -70° for 3 hours and then at room temperature for a further 2 hours. Concentrated hydrochloric acid (40 ml) was added dropwise with stirring and the layers were separated. The ether layer was extracted with concentrated hydrochloric acid (20 ml) and the acid extracts were combined and warmed to complete hydrolysis of the intermediate ketimine salt. The solution was cooled and made alkaline with sodium hydroxide solution. The mixture was extracted several times with ethyl acetate and the combined extracts were washed with water and dried (Na2SO4). Evaporation of the solvent gave a solid which was chromatographed on silica gel. Elution with chloroform/petrol (b.p. 40°-60°) (2:1) gave a solid which was crystallised from ethyl acetate/petrol (b.p. 40°-60') to give 6-bromo-3-methylbenzo[b]thien-2-yl pyrid-3-yl ketone (4.70 g), m.p. 110°-111°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[C:23]([CH2:25][OH:26])[N:22]([CH3:27])[N:21]=1)=[CH:16][CH:15]=3.[CH2:33]([O:35][CH2:36][CH2:37]Cl)[CH3:34]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[C:23]([CH2:25][O:26][CH2:34][CH2:33][O:35][CH2:36][CH3:37])[N:22]([CH3:27])[N:21]=1)=[CH:16][CH:15]=3
Reactant: Cn1nc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)cc1CO
Reactant: CCOCCCl
Product: CCOCCOCc1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)nn1C

Procedure:
The process is carried out as in Example 101 above, with the compound from Example 82, 3-(2,4-dichlorophenyl)-6-(5-hydroxymethyl-1-methyl-1H-pyrazol-3-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and 2-chloroethyl ethyl ether
Reaction SMILES: C([O:8][C:9]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:10]=1[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])C1C=CC=CC=1.[H][H]>CCO.C(OCC)(=O)C.[Pd]>[F:24][C:22]1[CH:21]=[CH:20][C:10]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:9]([OH:8])[CH:23]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(F)cc1O
Yield: 101.3 %

Procedure:
A solution of tert-butyl 2-(benzyloxy)-4-fluorobenzylcarbamate (Example 14; 9 mmol) in EtOH (80 ml) and ethyl acetate (240 ml) was treated with 1 atm of hydrogen at 25° C. over 10% Pd/C (0.4 gr) for 24 hours. The catalyst was removed by filtration through celite, washed with EtOH and the filtrate was concentrated to afford the title compound (2.2 g) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:20]1[CH:21]=[CH:22][N:23]2[CH2:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[NH:26][CH2:25][C:24]=12.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([N:26]3[C:27]4[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=4[CH2:29][N:23]4[CH:22]=[CH:21][CH:20]=[C:24]4[CH2:25]3)=[O:16])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)c2ccc(C(=O)Cl)cc2)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)cc1
Reaction time: 16 h
Yield: 54.1 %

Procedure:
A mixture of 2.13 g of 4-[(4-methylphenyl)-sulfonyl]benzoyl chloride (Reference Example 42) and 1.0 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 30 ml of methylene chloride containing 7 ml of triethylamine is stirred under nitrogen atmosphere for 16 hours. The reaction mixture is diluted with ? ml of chloroform and washed with 2N HCl, water, saturated NaHCO3 and water. The organic layer is dried (Na2SO4) and columned on silica gel by elution with 7:1 to 3:1 ethyl acetate:hexane to give 1.3 g of the desired product as a solid. M+H 443.2; M+Na 465.2.