Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][CH2:13][CH2:14][CH2:15][CH2:16]C#CCO.Cl.[Br:22]CC#CCCCCOC1CCCCO1>N1C=CC=CC=1>[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][Br:22]
Reactant: BrCC#CCCCCOC1CCCCO1
Reactant: OCC#CCCCCOC1CCCCO1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: BrCCCCOC1CCCCO1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (20.3 ml.) is added slowly with stirring to a solution of 7-tetrahydropyranyloxyhept-2-yne-1-ol (52.5 g.) in 400 ml. of pyridine at -20° C. The mixture is stirred one hour at -20° C., and then is poured into a stirred mixture of 3-normal hydrochloric acid (1727 ml.) and 2,540 ml. of ice water. This mixture is extracted with diethyl ether. The extract is washed with cold one normal hydrochloric acid and then with saturated aqueous sodium chloride solution, dried, and evaporated at reduced pressure. The residue is dissolved in 500 ml. of dry acetone. Lithium bromide (26 g.) is added to the acetone solution, and the mixture is stirred and heated at reflux 1 hour, and then kept at 25° C. for 15 hours. The acetone is evaporated under reduced pressure, and the residue is extracted with diethyl ether. The diethyl ether extract is washed with water and then 3 times with saturated aqueous sodium chloride solution, dried, and evaporated. The residue is chromatographed on 3.5 kg. of silica gel, eluting with 24 l. of 10% ethyl acetate in Skellysolve B, collecting 1.5 l. fractions. Fractions 5-10 are combined and evaporated to give 25 g. of 1-bromo-7-tetrahydropyranyloxyhept-2-yne.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.[S:14](Cl)([Cl:17])(=[O:16])=[O:15]>>[Br:1][CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([S:14]([Cl:17])(=[O:16])=[O:15])=[CH:6][CH:5]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: BrCCc1cccc2ccccc12
Product: O=S(=O)(Cl)c1ccc(CCBr)c2ccccc12

Procedure:
1-(2-bromoethyl)naphthalene and sulfonyl chloride can be allowed to react with each other to yield 4-(2-bromoethyl)-naphthalenesulfonyl chloride. Next, 4-(2-bromoethyl)-naphthalenesulfonyl chloride is esterified with methyl alcohol, and is then subjected to dehydrobromination, whereby methyl 4-ethenyl-1-naphthalenesulfonate as a target can be obtained.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[O:40][C:41]1[C:42]([F:48])=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:44][C:43]2[CH:45]=[CH:46][CH:47]=[C:41]([O:40][C:31]3[C:30]4[C:35](=[CH:36][C:37]([O:38][CH3:39])=[C:28]([O:27][CH3:26])[CH:29]=4)[N:34]=[CH:33][N:32]=3)[C:42]=2[F:48])=[O:19])[N:7]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3F)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c3F)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 63.2 %

Procedure:
A mixture of phenyl 3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate (prepared as described in Example 153A) (239 mg, 0.71 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluoroaniline (prepared as described in Example 265A steps 1 through 3) (150 mg, 0.475 mmol) and N,N-4-(dimethylamino)pyridine (10 mg, 0.082 mmol) in THF (5 mL) was stirred at rt for 15 h. The reaction mixture was concentrated under reduced pressure to give the crude product. Purification via silica gel flash chromatography (eluting with a gradient of 20% ethyl acetate in hexanes to 100% ethyl acetate) afforded 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)-2-fluorophenyl)urea (167 mg, 63%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 9.07 (brs, 1H), 8.85 (brs, 1H), 8.57 (s, 1H), 8.07 (m, 1H), 7.39-7.58 (m, 7H), 7.23 (m, 1H), 7.20 (m, 1H), 6.42 (s, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 1.29 (s, 9H); LC-MS (ESI) m/z 557 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:17]=[CH:16][N:15]=[C:14]3[C:10]=2[N:11](COCC[Si](C)(C)C)[CH:12]=[N:13]3)[C:5](=[O:26])[N:4]2[C:27]3([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[NH:28][C:29](=[O:30])[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:17]=[CH:16][N:15]=[C:14]3[C:10]=2[NH:11][CH:12]=[N:13]3)[C:5](=[O:26])[N:4]2[C:27]3([NH:28][C:29](=[O:30])[C:3]=12)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3
Reactant: C[Si](C)(C)CCOCn1cnc2ncnc(Nc3cc(Cl)c4n(c3=O)C3(CCCCC3)NC4=O)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC2(CCCCC2)n2c1c(Cl)cc(Nc1ncnc3nc[nH]c13)c2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8-Chloro-6-[[7-(2-trimethylsilylethoxy)purin-6-yl]amino]spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione (5, 0.6 g, 1.2 mmol) was dissolved in dichloromethane (10 mL) in a flask and trifluoroacetic acid (1.36 g, 11.95 mmol) was added dropwise and stirred the mixture at room temperature overnight. After completion, evaporated the solvent under reduced pressure and the crude was basified by saturated aqueous solution of sodium bicarbonate to pH 8 and extracted with dichloromethane (2×50 mL). The organic layer was dried over any. Sodium sulfate and concentrated to afford crude. The crude was purified by flash column chromatography eluting with 2.5% methanol in dichloromethane. The desired fractions were concentrated to dryness under vacuum to afford 8-chloro-6-(7H-purin-6-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione (Cpd. No. 117) as a yellow solid. Yield: 0.06 g, 13%; MS (ESI) m/z 386.39 [M+1]+; 1H NMR: (400 MHz, DMSO-d6) δ 10.43 (m, 1H), 10.37 (s, 1H), 8.88 (s, 1H), 8.64 (s, 1H), 8.43 (s, 1H), 2.94 (t, J=2.32 Hz, 2H), 1.77 (m, 2H), 1.63 (m, 3H), 1.57 (d, J=12.8 Hz, 2H), 1.23 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:13](=[O:17])[CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].[Br:18][CH:19]=[CH:20][CH2:21]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:18][CH:19]=[CH:20][CH2:21][N:8]1[C:9]2[CH2:10][CH2:11][CH2:12][C:13](=[O:17])[C:14]=2[C:15](=[O:16])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7]1
Reactant: BrC=CCBr
Reactant: CCOC(=O)c1c[nH]c2c(c1=O)C(=O)CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC=CBr)c2c(c1=O)C(=O)CCC2
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Ethyl-4,5-dioxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (714 mg, 3.04 mmol) was suspended in degassed N,N-dimethylformamide (8 mL) and treated with 1,3-dibromo-1-propene (0.364 mL, 3.64 mmol, 1.2 equiv) and potassium carbonate (503 mg, 3.64 mmol, 1.2 equiv). After stirring for 7 hrs at ambient temperature, the mixture was poured into water and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed once with water and brine, dried with sodium sulfate, filtered and concentrated in vacuo to afforded ethyl 1-[3-bromoprop-2-en-1-yl]-4,5-dioxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate as a mixture of E- and Z-isomers. Additional compound was obtained by concentration of the aqueous extract in vacuo and extraction of the resulting residue with a mixture of 80% chloroform and 20% methanol (v/v).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:26][C:27]([F:38])([F:37])[C:28]1([CH2:31]OS(C)(=O)=O)[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN1CCCC1=O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:31][C:28]5([C:27]([F:38])([F:37])[F:26])[CH2:30][CH2:29]5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCNCC2)C3)cc1
Reactant: CS(=O)(=O)OCC1(C(F)(F)F)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCN(CC4(C(F)(F)F)CC4)CC2)C3)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 5-(4-methanesulfonyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (435 mg), methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl ester (700 mg), potassium carbonate (850 mg), and potassium iodide (100 mg) in N-methyl-2-pyrrolidone (8 mL) is stirred at 100° C. for 4 h and then at room temperature overnight. The solvent is evaporated and the residue is triturated with methanol and filtered. The filtrate is concentrated in vacuo and the residue is purified by HPLC to give the title compound. LC (method 1): tR=1.09 min; Mass spectrum (ESI+): m/z=481 [M+H]+.
Reaction SMILES: C(OC([N:6]1[C:10]([NH:11][C:12](=[O:26])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[C:9]2[CH2:27][N:28]([C:32](=[O:42])[NH:33][C:34]3[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:41])[C:29]([CH3:31])([CH3:30])[C:8]2=[N:7]1)=O)C>CO>[Cl:40][C:39]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:41])[C:34]=1[NH:33][C:32]([N:28]1[CH2:27][C:9]2[C:8](=[N:7][NH:6][C:10]=2[NH:11][C:12](=[O:26])[C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)=[CH:17][CH:18]=2)[C:29]1([CH3:31])[CH3:30])=[O:42]
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(N3CCN(C)CC3)cc1)CN(C(=O)Nc1c(Cl)cccc1Cl)C2(C)C
Solvent: CO
Product: CN1CCN(c2ccc(C(=O)Nc3[nH]nc4c3CN(C(=O)Nc3c(Cl)cccc3Cl)C4(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
5-(2,6-Dichloro-phenylcarbamoyl)-6,6-dimethyl-3-[4-(4-methyl-piperazin-1-yl)-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester (0.6 g, 0.97 mmol) was dissolved in methanol (20 mL), treated with TEA (0.67 mL, 4.85 mmol, 5 eq) and stirred overnight at room temperature. After evaporation of the solvent, the solid was treated with diethyl ether and filtered to afford 0.28 g (yield 76%) of the title compound.
Reaction SMILES: CN(C)C=O.[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C=CN=C1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>O>[CH2:6]([N:13]1[CH2:18][CH2:17][CH:16]([O:19][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCN(Cc2ccccc2)CC1
Reaction time: 1.5 h

Procedure:
To a N,N-dimethylformamide (10 mL) solution of N-benzyl-4-hydroxypiperidine (1.90 g, 9.93 mmol) was added imidazole (1.35 g, 19.9 mmol) and tert-butyldimethylsilyl chloride (1.57 g, 10.4 mmol). After 1.5 hours, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (50 mL), dried (magnesium sulfate), filtered, and concentrated in vacuo. Chromatography over silica gel, eluting with hexanes/ethyl acetate, afforded the title compound. 1H NMR (500 MHz, CDCl3) δ 7.36-7.21 (m, 5H), 3.75-3.65 (m, 1H), 3.49 (s, 2H), 2.72-2.63 (m, 2H), 2.26-2.12 (m, 2H), 1.78-1.71 (m, 2H), 1.62-1.53 (m, 2H), 0.88 (s, 9H), 0.04 (s, 6H); LC-MS: m/z 306.1 (M+H).
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[CH:7][NH:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[H-].[Na+].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl>CN(C=O)C>[C:1]([C:4]1[C:8]([CH3:9])=[CH:7][N:6]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)c[nH]c1C
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1c(C)cn(COCC[Si](C)(C)C)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a stirred solution of 3-acetyl-2,4-dimethyl-1H-pyrrole (commercially available from Aldrich Chem. Co. Inc., 1.50 g, 10.6 mmol) in DMF (40 mL) was added NaH (60% oil dispersion, 0.85 g, 21.2 mmol) at room temperature under nitrogen. After stirring for 30 minutes at room temprature the resulting suspension was cooled to 0° C. and added 2-(trimethylsilyl)ethoxymethyl chloride (3 mL, 15.9 mmol). The reaction mixture was warm to room temperature and stirred for 3 hours. The mixture was quenched with aqueous saturated NaHCO3 solution, and the whole extracted with diethyl ether (100 mL×2). The combined organic layers were washed with brine (50 mL), dried over MgSO4, concentrated iii vaciio. Chromatographic purification of the crude product eluting ethyl acetate-hexane (1:10) gave the subtitle product (2.32 g, 82% yield).
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:16]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17]1>CN(C=O)C>[C:1]([Si:5]([CH3:8])([CH3:7])[O:22][CH2:21][C:18]1[CH:19]=[CH:20][S:16][CH:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OCc1ccsc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCc1ccsc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyldimethylchlorosilane (1.58 g), triethylamine (2.44 ml), 3-thiophenemethanol (0.822 ml) and DMF (20 ml) was stirred at 60° C. for 1 h. Additional DMF (20 ml) was added to the reaction mixture, and the mixture was stirred at 60° C. for 2 h. The mixture was quenched with saturated NaHCO3 solution, and extracted with EtOAc. The organic layer was separated, washed with water and brine successively, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane) to give the title compound (1.6 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[CH:4][CH:3]=1.[OH:25]O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:25])=[CH:4][CH:3]=1
Reactant: OO
Reactant: Cc1ccc(SCCCCOc2ccc3c(c2)CCC(=O)N3)cc1
Product: Cc1ccc(S(=O)CCCCOc2ccc3c(c2)CCC(=O)N3)cc1

Procedure:
Prepared analogous to Example 2 from 6-[4-(4-methylphenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([C:16](C)(C)[O:17][SiH2]C(C)(C)C)[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].O[Li].O>CO.O>[OH:17][CH2:16][C:10]1[CH:9]=[C:8]([C:5]2([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: COC(=O)C1(c2ccc(OC)c(C(C)(C)O[SiH2]C(C)(C)C)c2)CC1
Agent: [Li]O
Solvent: O
Solvent: CO
Product: COc1ccc(C2(C(=O)O)CC2)cc1CO
Temperature: 40 °C
Reaction time: 8 h
Yield: 132.5 %

Procedure:
To a solution of 1-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-methoxy-phenyl]-cyclopropanecarboxylic acid methyl ester (6.2 g, 18 mmol) in MeOH (75 mL) was added a solution of LiOH.H2O (1.50 g, 35.7 mmol) in water (10 mL) at 0° C. The reaction mixture was stirred overnight at 40° C. MeOH was removed by evaporation under vacuum. AcOH (1 mol/L, 40 mL) and EtOAc (200 mL) were added. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and evaporated under vacuum to provide 1-(3-hydroxymethyl-4-methoxy-phenyl)-cyclopropanecarboxylic acid (5.3 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[C:5](=[O:13])[CH2:4][CH2:3]1.[OH-].[K+].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[S:20]>O.O1CCCC1>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][C:8]([O:12][C:19]([N:18]([CH3:22])[CH3:17])=[S:20])=[CH:9][CH:10]=2)[C:5](=[O:13])[CH2:4][CH2:3]1
Reactant: CN(C)C(=S)Cl
Reactant: CC1(C)CCC(=O)c2cc(O)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=S)Oc1ccc2c(c1)C(=O)CCC2(C)C
Reaction time: 0.17 h

Procedure:
To a solution of 4,4-dimethyl-7-hydroxy-1-tetralone (XIV) (3.07 g, 16.16 mmol) in water (10.77 mL) containing potassium hydroxide (904 mg) cooled below 10° C. was added N,N-dimethylthiocarbamoyl chloride (2.67 g, 21.6 mmol) in tetrahydrofuran (4.30 mL); the reaction temperature kept below 12° C. After 10 minutes, reaction mixture is made basic by the addition of a 10% aqueous KOH solution (5.39 mL). Product is extracted with ethyl acetate (2×50 mL), organic phases concentrated in vacuo and the residue chromatographed on silica gel (eluted with 10% ethyl acetate in hexane) to give 3.74 g (Y: 84%) of title product; 1H-NMR (CDCl3): δ 7.68 (d, J=2.6 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.27 (dd, J=8.5, 2.6 Hz, 1H), 3.46 (s, 3H), 3.34 (s, 3H), 2.73 (t, J=6.8 Hz, 2H), 2.04 (t, J=6.8 Hz, 2H), 1.41 (s, 6H); MS (DCI) m/e: 278 (MH+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH3:10]O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C(O)CCCCCBr
Reactant: CO
Product: COC(=O)CCCCCBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a 1 L round bottom flask, charged with 20 g (102.5 mmol) of 6-bromohexanoic acid and 500 mL of methanol, was bubbled hydrogen chloride gas for 2-3 minutes. The mixture was stirred at room temperature for 4 hours and concentrated to afford 21.0 g of the product as a yellow oil (99%): 1H-NMR (200 MHz, d6-DMSO); 3.57 (s, 3H), 3.51 (t, 2H), 2.30 (t, 2H), 1.78 (pentet, 2H), and 1.62-1.27 (m, 4H) ppm.
Reaction SMILES: [N+](C1C=C([C:10]2[CH:11]=[C:12](CC3C=CN=CC=3)[CH:13]=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[CH:15]3)C=CC=1)([O-])=O.O.[NH4+].[Cl-]>CCO.[Fe]>[N:18]1[C:19]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1cccc(-c2cc(Cc3ccncc3)cc3cccnc23)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: c1ccc2ncccc2c1
Temperature: 25 °C

Procedure:
To a solution of the 8-(3-nitro-phenyl)-6-pyridin-4-ylmethyl-quinoline (1.0 eq) described in Step 1 in EtOH (0.2M) at 60° C. was added of water (final concentration 0.15M) and saturated aqueous NH4Cl (1.3 eq) followed by iron (12 eq). The final mixture was stirred at 60° C. for 2 h, cooled to room temperature, filtered on celite and concentrated to afford the title compound as a yellow solid.
Reaction SMILES: [CH:1]([NH:3][C:4]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[CH:23][CH:22]=[CH:21]2)([C:10](OCC)=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:2].[H][H]>C(O)(=O)C.[Pt]=O>[O:11]=[C:10]1[C:4]([NH:3][CH:1]=[O:2])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:15][C:16]2=[CH:17][CH:18]=[CH:19][C:20]3=[C:25]2[N:24]1[CH2:23][CH2:22][CH2:21]3
Reactant: [H][H]
Reactant: CCOC(=O)C(Cc1cccc2cccnc12)(NC=O)C(=O)OCC
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCOC(=O)C1(NC=O)Cc2cccc3c2N(CCC3)C1=O
Yield: 96.6 %

Procedure:
A mixture of diethyl (formylamino)(8-quinolinylmethyl)malonate (9.2 g, 26.7 mmol) and platinum oxide (0.7 g) in glacial acetic acid (150 mL) was hydrogenated (50 lb initial pressure) for 15 minutes (hydrogen uptake ca. 2 equiv). The mixture was filtered through celite and the solvent removed under reduced pressure. The product was partitioned between ethyl acetate and sodium hydroxide solution. The ethyl acetate phase was washed with water, the ethyl acetate was evaporated, and the product was crystallized from ether to give 7.8 g (97%) of ethyl 2,3,6,7-tetrahydro-3-oxo-2-(formylamino)- 1H,5H-benzo(ij)quinolizine-2-carboxylate, mp 103°-106° C. Anal. Calc'd for C16H18N2O4 : C, 63.56; H, 6.00; N, 9.27. Found: C, 63.51; H, 6.09; N, 9.18.
Reaction SMILES: N(OC(C)(C)C)=O.[O:8]1[CH2:12][CH2:11][C:10]([C:13]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:14]=2N)=[N:9]1.[CH3:21][S:22]SC>[Cu]>[CH3:20][C:19]1[CH:18]=[CH:17][CH:16]=[C:14]([S:22][CH3:21])[C:13]=1[C:10]1[CH2:11][CH2:12][O:8][N:9]=1
Reactant: Cc1cccc(N)c1C1=NOCC1
Reactant: CSSC
Agent: [Cu]
Agent: CC(C)(C)ON=O
Product: CSc1cccc(C)c1C1=NOCC1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
19.5 g (170 mmol) of tert-butyl nitrite and 20 g of copper powder are initially charged in 30 ml of dimethyl disulfide, and a solution of 20 g (114 mmol) of 2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline in 100 ml of dimethyl disulfide is added dropwise at from 50 to 55° C. The mixture is then stirred at 60° C. for 1.5 hours. For work-up, the solid is filtered off with suction and the solution is diluted with methylene chloride and extracted with dilute hydrochloric acid. The organic phase is washed with saturated aqueous NaHCO3 solution, dried over sodium sulfate, filtered off and concentrated. Excess dimethyl disulfide is removed under oil pump vacuum.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[CH:30][NH:31]2)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[NH:31]1[C:32]2[C:28](=[CH:27][CH:26]=[C:25]([O:24][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH:33]=2)[CH:29]=[CH:30]1
Reactant: Oc1ccc2cc[nH]c2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc4cc[nH]c4c3)ncnc2cc1OCCCN1CCCCC1
Temperature: 90 °C
Yield: 94 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-piperidinopropoxy)quinazoline (200 mg, 0.59 mmol), (prepared as described for the starting material in Example 67), 6-hydroxyindole (96 mg, 0.715 mmol) in DMF (3 ml) containing cesium carbonate (291 mg, 0.894 mmol) was heated at 90° C. for 4 hours. After cooling, the mixture was diluted with water, the precipitate was filtered, washed with water and dried under vacuum. The solid was purified by column chromatography eluting with methylene chloride/methanol (90/10 increasing to 50/50) to give 4-(indol-6-yloxy)-6-methoxy-7-(3-piperidinopropoxy)quinazoline (240 mg, 93%).
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:4][C:3]1([CH2:6][OH:7])[CH3:5].[F:9][C:10]1[CH:11]=[C:12]([C:17]2[O:18][C:19]3[CH:24]=[C:23]([O:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])[N:22]=[CH:21][C:20]=3[N:33]=2)[CH:13]=[CH:14][C:15]=1O>>[F:1][C:2]1([F:8])[CH2:4][C:3]1([CH2:6][O:7][C:15]1[CH:14]=[CH:13][C:12]([C:17]2[O:18][C:19]3[CH:24]=[C:23]([O:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:32])[CH3:31])[CH3:28])[N:22]=[CH:21][C:20]=3[N:33]=2)=[CH:11][C:10]=1[F:9])[CH3:5]
Reactant: CC1(CO)CC1(F)F
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(O)c(F)c3)nc2cn1
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCC4(C)CC4(F)F)c(F)c3)nc2cn1

Procedure:
Using (2,2-difluoro-1-methylcyclopropyl)methanol and N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide, and in the same manner as in Step B of Example 4, the title compound was obtained.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.Cl.[CH3:13][O:14][C:15]1[C:19]([NH2:20])=[CH:18][N:17]([CH3:21])[N:16]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[F:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][NH:6]2)=[C:2]([NH:20][C:19]2[C:15]([O:14][CH3:13])=[N:16][N:17]([CH3:21])[CH:18]=2)[N:10]=1
Reactant: COc1nn(C)cc1N
Reactant: Fc1nc(Cl)c2nc[nH]c2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1nn(C)cc1Nc1nc(F)nc2[nH]cnc12
Temperature: 25 °C
Reaction time: 19 h
Yield: 86.7 %

Procedure:
A suspension of 6-chloro-2-fluoro-9H-purine (5.49 g, 31.8 mmol, 1.00 eq), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (6.60 g, 40.34 mmol, 1.26 eq), and N,N-diisopropylethylamine (16.6 mL, 95.5 mmol, 3.00 eq) in DMSO (31.8 mL) was stirred at ambient temperature for 19 hr. The reaction mixture was then concentrated in vacuo at 50° C., poured into water (250 mL), and stirred vigorously at 0° C. for 1 hr. The resulting solids were filtered off, washed with ice cold water (20 mL), and dried for 16 hr at 50° C. to give the title compound (7.26 g, 87% yield, 96% purity) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.03 (br. s., 1 H) 9.21 (br. s., 1 H) 8.18 (br. s., 1 H) 7.74 (br. s., 1 H) 3.81 (br. s., 3 H) 3.71 (s, 3H). m/z (APCI+) for C10H11FN7O 264.2 (M+H)+.