Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[CH:26]=[C:27]([CH:36]=[CH:37][CH:38]=2)[CH2:28][S:29][CH2:30][CH2:31][C:32]([O:34]C)=[O:33])=[O:24])[CH:11]=1)=[O:9].[Li+].[OH-]>O1CCCC1.O>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[CH:26]=[C:27]([CH:36]=[CH:37][CH:38]=2)[CH2:28][S:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:24])[CH:11]=1)=[O:9]
Reactant: COC(=O)CCSCc1cccc(C(=O)Nc2ccccc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCSCc1cccc(C(=O)Nc2ccccc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.5 %

Procedure:
Into a 100-mL 3-necked round bottom flask, was placed a solution of methyl 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzylthio)propanoate (250 mg, 0.41 mmol, 1.00 equiv) in tetrahydrofuran (8 mL), and a solution of LiOH (98 mg, 4.08 mmol, 10.00 equiv) in water (2 mL). The resulting solution was stirred for 2 h at room temperature. The reaction progress was monitored by LCMS. The reaction was then quenched with 50 mL of water. The solution was adjusted to pH 3 with hydrochloric acid. The resulting solution was extracted with of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product (120 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained 50 mg (20%) of a white solid. 1H-NMR (400 MHz, DMSO-d6, ppm): δ 13.02 (s, 1H), 9.60-9.56 (t, 1H), 9.01-8.99 (d, 1H), 8.60-8.57 (d, 1H), 8.42 (s, 1H), 8.05-8.03 (d, 1H), 7.93-7.82 (m, 3H), 7.72-7.51 (m, 7H), 7.35-7.30 (t, 1H), 4.65-4.63 (d, 2H), 3.91 (s, 2H), 2.64-2.59 (m, 3H). MS (ES, m/z): 594 [M+H]+.
Reaction SMILES: [Cl-].[CH:2]1([CH2:5][NH2+:6][CH2:7][CH2:8]Cl)[CH2:4][CH2:3]1.[CH3:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[N:20]=[C:21]=[S:22]>>[CH3:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[N:20]=[C:21]1[N:6]([CH2:5][CH:2]2[CH2:4][CH2:3]2)[CH2:7][CH2:8][S:22]1
Reactant: ClCC[NH2+]CC1CC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCN1CC1CC1

Procedure:
2-Hydroxyethylamine was reacted with cyclopropylmethyl bromide according to Method B2a to give N-cyclopropylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopropylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-(cyclopropylmethyl)-1,3-thiazolidine.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17].Cl.Cl.[NH2:20][C:21]1[C:36]([Cl:37])=[CH:35][C:24]([C:25]([NH:27][CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:26])=[C:23]([O:38][CH3:39])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:20][C:21]1[C:36]([Cl:37])=[CH:35][C:24]([C:25]([NH:27][CH2:28][CH:29]2[CH2:30][CH2:31][N:32]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]3[C:11](=[O:12])[C:10]4[C:9](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]3=[O:17])[CH2:33][CH2:34]2)=[O:26])=[C:23]([O:38][CH3:39])[CH:22]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN2C(=O)c3ccccc3C2=O)CC1
Reaction time: 8 h
Yield: 57.9 %

Procedure:
N-(5-Bromopentyl)phthalimide (60 g) was added to a solution of 4-amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (75.1 g) and potassium carbonate (112 g) in dimethylformamide (800 ml), and the mixture was stirred at 75°-80° C. for 8 hr. Insoluble matter was filtered off and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give 60.2 g of 4-amino-5-chloro-N-(1-(5-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)pentyl)piperidin-4-ylmethyl)-2-methoxybenzamide.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:3]=1.[CH:16]1([CH2:21][C:22](Cl)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C>[CH:16]1([CH2:21][C:22]([NH:8][C:7]2[C:2]([CH3:1])=[N:3][C:4]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[CH:5][C:6]=2[CH3:9])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: Cc1cc(N2CCOCC2)nc(C)c1N
Solvent: CC#N
Product: Cc1cc(N2CCOCC2)nc(C)c1NC(=O)CC1CCCC1
Temperature: 150 °C
Yield: 49 %

Procedure:
2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-ylamine (0.22 g) and cyclopentylacetyl chloride (0.19 mL) were dissolved in acetonitrile (5 mL) and heated to 150° C. for 10 minutes in a sealed microwave process vial. The reaction mixture was concentrated in vacuo and purified by flash chromatography (SiO2, heptane/ethylacetate 3:1) to furnish 0.17 g (49% yield) of the title compound as a white solid. LC-MS (m/z) 318 (MH+); tR=1.40, (UV, ELSD) 97%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.21 (m, 2H), 1.52 (m, 2H), 1.61 (m, 2H), 1.77 (m, 2H), 2.05 (s, 3H), 2.17 (s, 3H), 2.24 (m, 1H), 2.26 (m, 2H), 3.37 (m, 4H), 3.67 (m, 4H), 6.53 (s, 1H), 9.05 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10](N)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:25].[Na+]>COCCOC.O>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([I:25])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Fc1ccc(Oc2ccc(I)cc2)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To a stirred solution of 4-(4-fluorophenoxy)benzenamine (3.4 g, 16.73 mmol, 1.00 equiv) in ethylene glycol dimethyl ether (45 mL) was added dropwise a solution of 50% sulfuric acid (7 mL) in water (34 mL) at room temperature. The reaction was cooled to −5° C. and a solution of sodium nitrite (1.73 g, 25.07 mmol, 1.50 equiv) in water (12 mL) was then added dropwise within 30 min. The resulting solution was stirred for 30 min at −5-0° C. then a solution of sodium iodide (12.6 g, 84.00 mmol, 5.02 equiv) in water (34 mL) was added dropwise at −5-0° C. After stirring for 30 min at −5-0° C., the solution was extracted with 3×200 mL of ethyl acetate. The combined organic layers was washed with 3×200 mL of saturated Na2SO3 solution, dried over anhydrous sodium sulfate and concentrated under vacuum to give 5.0 g (95%) of 1-fluoro-4-(4-iodophenoxy)benzene as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ 7.62-7.57 (m, 2H), 7.08-6.93 (m, 4H), 6.77-6.70 (m, 2H) ppm.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH:3]1[OH:10].[H-].[Na+].[O:13]1[CH:15]([CH2:16][CH2:17][CH3:18])[CH2:14]1.OS(O)(=O)=O>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH:3]1[O:10][CH2:14][CH:15]([OH:13])[CH2:16][CH2:17][CH3:18]
Reactant: CC1CCCC(C)(C)C1O
Reactant: CCCC1CO1
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCC(O)COC1C(C)CCCC1(C)C
Yield: 75 %

Procedure:
A mixture of 2.0 g of 2,6,6-trimethyl-cyclohexanol and 0.354 g of sodium hydride was heated for 24 hours at 80° in 10 ml of anhydrous toluene. 1.2 G of 1,2-epoxy-pentane were then added to the thus obtained solution and heating at 80° was maintained for 24 additional hours. After cooling, the reaction mixture was poured onto crushed iced, acidified with diluted H2SO4, whereupon the organic phase was washed with brine until neutrality. After evaporation of the volatile parts and distillation of the residue in a a bulb apparatus (bath temperature: 140°/7 Pa), the desired product was obtained in yield of about 75%. An analytical sample was purified by preparative gas chromatography.
Reaction SMILES: Cl.[F:2][C:3]1[S:7][C:6]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:5][CH:4]=1.O=[CH:17][CH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]1>>[F:2][C:3]1[S:7][C:6]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]3)[CH2:12][CH2:11]2)=[O:9])=[CH:5][CH:4]=1
Reactant: CC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: O=C(c1ccc(F)s1)C1CCNCC1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(F)s3)CC2)CC1

Procedure:
From (5-fluoro-thiophen-2-yl)-piperidin-4-yl-methanone hydrochloride (17 mg) and N-[trans-4-(2-oxo-ethyl)-cyclohexyl]-acetamide (20 mg, intermediate AG) by procedure A.2. Yield: 19 mg (73%). White solid. MS (m/z): 381.3 ([M+H]+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[N:17]=[CH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=1.Cl>CN(C=O)C.O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]2[N:17]=[CH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1
Reactant: Oc1ccc(F)cc1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Oc2ccc(F)cc2)nc1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 13.3 %

Procedure:
Sodium hydride (0.653 g, 60% in mineral oil, 16.338 mmol) was suspended in DMF (10 mL) under argon, and 4-fluorophenol (0.915 g, 8.169 mmol) added in two portions. The mixture was stirred for 20 minutes then ethyl 6-chloro-3-pyridinecarboxylate (1.515 g, 8.169 mmol) was added together with additional DMF (4 mL) added to aid solubility. The mixture was heated to 80° C. for 2.5 h. The reaction mixture was allowed to cool to room temperature and water (30 mL) was added. The solution was acidified to pH 3 with 2M HCl and extracted with ethyl acetate (×3). The combined ethyl acetate layers were dried and concentrated to produce a brown oil. The crude product was purified by chromatography. Elution with a 0-25% Et2O/petroleum ether gradient gave the title compound as a colourless oil (0.284 g). δH (CDCl3, 400 MHz) 8.81 (1H, dd), 8.28 (1H, dd), 7.11 (4H, m), 6.95 (1H, d), 4.37 (2H, q), 1.38 (3H, t). MS (ES): MH+ 262.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=O)[CH3:8])[CH:2]=1.Cl.[NH2:11][OH:12].C(=O)(O)[O-].[Na+]>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[N:11][OH:12])[CH3:8])[CH:2]=1
Reactant: NO
Reactant: CC(=O)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=NO)c1cccnc1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
A mixture of 50 g (0.41 mol) of 1-(3-pyridinyl)ethanone and 29 g (0.42 mol) of hydroxylamine hydrochloride in 250 ml of methanol was heated under reflux for five hours. Upon cooling to room temperature, a white solid separated from the reaction mixture. This material was collected by filtration and the filtrate was concentrated to yield additional white solid. The combined solids were dissolved in water and the solution was made weakly basic by the addition of sodium bicarbonate solution while cooling. The white precipitate which formed was separated by filtration to yield 55.4 g of 1-(3-pyridinyl)ethanone oxime, mp 115°-117° C.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[CH2:20]([O:22][C:23](=[O:35])[CH2:24][NH:25][CH:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)[CH3:21].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:20]([O:22][C:23](=[O:35])[CH2:24][N:25]([C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1)[CH3:21]
Reactant: CCOC(=O)CNC1Cc2ccccc2C1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C1Cc2ccccc2C1
Reaction time: 8 h

Procedure:
To a solution of CBZ-L-valine (5.0 g, 0.02 mol)in CH2Cl2 (50 mL) were added 4-dimethylaminopyridine (2.44 g, 0.02 mol), N-(2-indanyl)glycine ethyl ester hydrochloride (5.6 g, 0.02 mol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (WSCDI) (3.83 g, 0.02 mol). Approximately 20 mL CH2Cl2 was used to wash the reagents into the reaction flask. After the mixture was stirred overnight the solvent was removed under vacuo and the residue treated with ethyl acetate: 1N HCl (3:1). The separated organic layer was washed with 1N HCl, 5% aqueous Na2CO3 and saturated aqueous NaCl-solution followed by drying over magnesium sulfate and filtration. After removal of the solvent under reduced pressure an oil (4.3 g) remained, which was purified over silica gel using CH2Cl2 as eluent. 3.4 g of a colorless oil was collected (Rf: 0.7, silica gel, CH2Cl2 :CH2OH 97:3 ) and used as is for saponification.
Reaction SMILES: [H-].[Na+].I[CH3:4].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[NH:20][C:19]2=[O:27])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>CN(C=O)C>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]([CH3:4])[C:19]2=[O:27])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Reaction time: 12 h

Procedure:
A mixture of 0.060 g of sodium hydride, 60% oil dispersion, 10 mL of DMF, 0.086 mL of iodomethane, and 0.4 g of 1,3-dihydro-1-(1-tert-butyloxycarbonylpiperidin-4-yl)-2H-benzimidazol-2-one was stirred for 12 h, then partitioned between 100 mL of chloroform and 50 mL of water. The chloroform extracts dried over MgSO4, and concentrated under reduced pressure. Trituration with hexane gave 0.38 g of 1,3-dihydro-1-(1-tert-butyloxycarbonylpiperidin-4-yl)-3-methyl-2H-benzimidazol-2-one as a crystalline solid: 1H NMR (300 MHz, CDCl3) 7.13-7.03 (m, 3H), 6.98 (d, 1H), 4.5 (m, 1H), 4.3 (br m, 2H), 3.4 (s, 3H), 2.85 (m, 4H), 2.3 (m, 2H), 1.8 (d, 2H), 1.5 (s, 91H).
Reaction SMILES: [C:1](OC)(OC)(OC)[CH2:2][CH2:3][CH2:4][CH3:5].Cl.N1C=CC=CC=1.[NH2:19][C:20]1[CH:21]=[N:22][C:23]2[C:28]([C:29]=1[NH:30][CH2:31][C:32]([CH3:35])([OH:34])[CH3:33])=[CH:27][CH:26]=[CH:25][CH:24]=2>C(#N)C>[CH2:2]([C:1]1[N:30]([CH2:31][C:32]([CH3:35])([OH:34])[CH3:33])[C:29]2[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[CH:21][C:20]=2[N:19]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(OC)(OC)OC
Reactant: CC(C)(O)CNc1c(N)cnc2ccccc12
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Temperature: 25 °C

Procedure:
Trimethyl orthovalerate (3.6 mL, 21 mmol) and pyridine hydrochloride (0.22 g, 1.9 mmol) were added to a solution of 1-[(3-aminoquinolin-4-yl)amino]-2-methylpropan-2-ol (prepared as described in Part A of Example 8, approximately 4.4 g, 19 mmol) in acetonitrile (96 mL). The reaction mixture was heated at reflux for 1 hour, then was allowed to cool to room temperature and was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to yield 4.1 g of 1-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol as a white foam.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]([NH2:13])=O>>[N:1]1[C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:6])[NH:13][CH:11]=1
Reactant: Nc1ncccc1C(=O)O
Reactant: NC=O
Product: O=c1[nH]cnc2ncccc12
Yield: 70 %

Procedure:
2-aminonicotinic acid (1.381 g, 10 mM) and formamide (2.70 g, 60 mM) are heated at 165-170° C. for 2 h by means of an oil bath. The reaction mixture is cooled and the resulting solid recrystallized from water to give about 1.030 g of title compound (70% yield). mp 255-8° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].O.[C:18]1(C)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:1]([C:2]1[CH2:11][C:1]2[C:6]([CH:3]=1)=[C:5]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH:4]=[CH:3][CH:2]=2)([CH3:11])[CH3:6]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)C1=Cc2c(cccc2-c2ccccc2)C1
Reaction time: 8 h

Procedure:
The crude mix of isomeric alcohols was dissolved in toluene (150 ml) to which p-toluene sulfonic acid (0.5 g) was added. The solution was refluxed in a flask equipped with a Dean-Stark trap for 1.5 h then cooled. Solid sodium bicarbonate was added and the mixture was stored overnight in a refrigerator. The next morning water (100 ml) was added and the organic layer was separated, dried over Na2SO4, and stripped under reduced pressure. The product, 2-isopropyl-4-phenylindene (10.4 g) was obtained as a brown oil. Analysis by GC indicated a purity of >96 area percent. This material was stored cold under an inert atmosphere until ready for further conversion.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:9]=[C:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1>C1COCC1>[Br:7][C:8]1[CH:9]=[C:10]([S:14]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc(Br)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Morpholine (0.19 mL, 0.0022 mol) in 1.0 ml of THF was added dropwise to a solution of 3-bromobenzenesulfonyl chloride (0.3 mL, 0.002 mol) and TEA (0.30 mL, 0.0022 mol) in dry 4.0 mL of THF cooled in an ice bath. The reaction mixture was stirred overnight at room temperature and was then partitioned between 0.05N HCl and ethyl acetate. The organic layer was washed with water (2×), and brine (1×), and was then dried over anhydrous magnesium sulfate, filtered and then was concentrated in vacuo to give 4-[(3-bromophenyl)sulfonyl]morpholine as a white crystalline product (470 mg, 78%). LCMS (M+H)+: m/z=306, 308.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:12]C=O)([CH3:11])[CH3:10])=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.[OH-].[K+].O>C(O)CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:12])([CH3:10])[CH3:11])=[C:4]([C:15]([F:16])([F:17])[F:18])[CH:3]=1
Reactant: CC(C)(Cc1ccc(Cl)cc1C(F)(F)F)NC=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CC(C)(N)Cc1ccc(Cl)cc1C(F)(F)F

Procedure:
5.70 g (20 mmol) N-[2-(4-chloro-2-trifluoromethyl-phenyl)-1,1-dimethyl-ethyl]-formamide and 3.00 g potassium hydroxide are stirred overnight at 140° C. in 20 mL ethyleneglycol. The reaction mixture is combined with water and repeatedly extracted with dichloromethane. The combined organic phases are washed with water, dried with sodium sulphate and evaporated down. The residue is filtered through a short column containing silica gel (eluant: dichloromethane/methanol/ammonia=9:1:0.1).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][C:20]3[N:21]([N:29]=[CH:30][C:31]=3[CH:32]=[O:33])[C:22]=2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.O1CCCC1>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][C:20]3[N:21]([N:29]=[CH:30][C:31]=3[CH2:32][OH:33])[C:22]=2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1cnn2c(C3CCCCC3)c(-c3ccc(OCc4ccccc4)cc3)cnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cnn2c(C3CCCCC3)c(-c3ccc(OCc4ccccc4)cc3)cnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
To a stirred solution of 4.4 mg (0.115 mmol) of sodium borohydride (NaBH4) in 2 mL of methanol (MeOH) was added a solution of 35 mg (0.104 mmol) of 6-(4-benzyloxy-phenyl)-7-cyclohexyl-pyrazolo[1,5-a]pyrimidine-3-carbaldehyde in 3 mL of tetrahydrofuran (THF) and the resulting mixture was stirred at rt for 30 min when analysis by TLC indicated complete conversion of starting material to product. The reaction mixture was quenched by the addition of saturated ammonium chloride solution, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give (after lyophilization) 20 mg (47% yield) of [6-(4-benzyloxy-phenyl)-7-cyclohexyl-pyrazolo[1,5-a]pyrimidin-3-yl]-methanol (479) as a white solid (85% purity) as indicated by 1H NMR (containing small traces of starting material); LC-MS—calcd for C26H27N3O2 [M++H]+: 414.21, found: 414.2.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[O:6][C:5](=[O:9])[NH:4][C:3]=1[CH3:10].[C:11](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[C:7](=[O:8])[O:6][C:5](=[O:9])[N:4]([CH3:11])[C:3]=1[CH3:10]
Reactant: Cc1[nH]c(=O)oc(=O)c1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cc1c(Cl)c(=O)oc(=O)n1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
At room temperature, 2.11 g of 5-chloro-4-methyl-2H-1,3-oxazine-2,6(3H)-dione, 2.07 g of potassium carbonate and 1.3 ml of methyl iodide were sequentially added to 40 ml of acetone, then the mixture was stirred for 3 hours under heat refluxing condition. To the reaction mixture was added 0.5 ml of methyl iodide, and the mixture was further stirred for 2 hours under heat refluxing condition. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The resulting solid was dried to obtain 1.74 g of 5-chloro-3,4-dimethyl-2H-1,3-oxazine-2,6(3H)-dione represented by the formula:
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][CH:18]=[O:19])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:20].[Na+]>C(O)C.O.[N+]([O-])([O-])=O.[Ag+]>[C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH2:17][C:18]([OH:20])=[O:19])[CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: O=CCc1ccc2nc(-c3ccccc3)ccc2c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1ccc2nc(-c3ccccc3)ccc2c1
Reaction time: 3 h

Procedure:
A solution of 2.5 g of crude 2-phenyl-6-quinolineacetaldehyde in 3 ml of ethanol is slowly added dropwise at room temperature to a suspension of 3.4 g of silver nitrate and 1.6 g of sodium hydroxide in 12 ml of water. After completion of the addition, the mixture is stirred for a further 3 hours. Thereafter the suspension is clarified by filtration and the filtrate is washed with ether and adjusted to a pH of 6. The emulsion thereby produced is extracted with ethyl acetate. The ethyl acetate extracts, after drying, evaporation and recrystallisation of the residue from methanol-pentane, yield 2-phenyl-6-quinolineacetic acid of melting point 176°-179°C.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:4][CH:3]=1.C([Li])CCC.CN([CH:29]=[O:30])C>C1COCC1.CCCCCC>[CH:29]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:4][CH:3]=1)=[O:30]
Reactant: Brc1ccc(CCOC2CCCCO2)c2ccccc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(CCOC2CCCCO2)c2ccccc12
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A solution of 1-bromo-4-(2-tetrahydropyranyloxyethyl)naphthalene in anhydrous THF (15 mL) under nitrogen was cooled to −78° C. n-Butyl lithium (1.4 mL of a 2.5 M solution in hexane) was added via syringe, and the mixture was stirred at the same temperature for 30 min. DMF (1.1 mL) was added, and the mixture was allowed to reach room temperature. It was diluted with satd. NH4Cl solution (10 mL), extracted with ether (3×10 ml), dried (MgSO4) and concentrated. Flash chromatography using hexane/ethyl acetate 5:1 as eluent provided 408 mg (54%) of a colorless oil.