Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([CH2:15][OH:16])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.N1C=CC=CC=1>CS(C)=O>[C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([CH:15]=[O:16])[CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC[C@H]1CCCN(CC(c2ccccc2)c2ccccc2)C1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C[C@H]1CCCN(CC(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(2,2-Diphenylethyl)-3(S)-hydroxymethyl-piperidine (Example 18, Step B) (2.10 g, 7.10 mmol) and Et3N (2.97 mL, 21.3 mmol) were dissolved in dry DMSO (40 mL) and cooled in an ice bath. Pyridine SO3 complex (3.39 g, 21.3 mmol) was added slowly, and the solution was stirred for 1 hr while allowing to warm to room temperature. The solution was poured into ice water, extracted with CH2CL2 (2×), the combined organics washed with satd NaHCO3 solution, H2O, brine, and dried (MgSO4). Filtration and concentration gave the title compound without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12](S(C)(=O)=O)[N:11]=[C:10]([C:18]2[S:22][C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[N:20][CH:19]=2)[CH:9]=1.[OH-:27].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([C:18]2[S:22][C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[N:20][CH:19]=2)[N:11]=[C:12]([OH:27])[N:13]=1
Reactant: CC(C)Nc1ncc(-c2cc(-c3ccccc3Cl)nc(S(C)(=O)=O)n2)s1
Reactant: [OH-]
Agent: [Na+]
Product: CC(C)Nc1ncc(-c2cc(-c3ccccc3Cl)nc(O)n2)s1

Procedure:
Example 318 was prepared from 5-(6-(2-chlorophenyl)-2-(methylsulfonyl)pyrimidin-4-yl)-N-isopropylthiazol-2-amine utilizing a similar procedure as described in Example 50 by substituting 1-methylpiperazine with 1N NaOH aqueous solution. Yellow solid. HPLC Ret. time: 2.55 min. LCMS MH+ (m/z) 347.20. 1H NMR: (d6-DMSO, 500 MHz) δ 11.58 (br, 1H), 8.41 (d, 1H), 8.12 (s, 1H), 7.60 (m, 1H), 7.55 (m, 2H), 7.48 (m, 1H), 6.86 (br. s, 1H), 3.86 (m, 1H), 1.18 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([CH3:10])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].[Br:35][C:36]1[CH:41]=[C:40](F)[C:39]([N+:43]([O-:45])=[O:44])=[CH:38][C:37]=1[F:46]>CS(C)=O.CCOC(C)=O>[Br:35][C:36]1[C:37]([F:46])=[CH:38][C:39]([N+:43]([O-:45])=[O:44])=[C:40]([O:8][C:7]2[C:6]([F:9])=[C:5]([CH3:10])[CH:4]=[CH:3][C:2]=2[Cl:1])[CH:41]=1
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Reactant: Cc1ccc(Cl)c(O)c1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Cl)c(Oc2cc(Br)c(F)cc2[N+](=O)[O-])c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To a solution of 6-chloro-2-fluoro-3-methylphenol (12.8 g, 80 mmol) and 18-crown-6 (4.21 g, 15.94 mmol) in DMSO (100 ml) at 0° C. was added potassium tert-butoxide (1.0 M solution in THF) (80 ml, 80 mmol) and the reaction mixture was stirred at RT for 30 minutes. Next, 1-bromo-2,5-difluoro-4-nitrobenzene (19.4 g, 80 mmol) was added dropwise (in solution of 60 mL DMSO) and the reaction mixture was stirred overnight at RT. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was triturated with methanol to give 2-[(5-bromo-4-fluoro-2-nitrophenyl)oxy]-1-chloro-3-fluoro-4-methylbenzene (21.3 g, 56.3 mmol, 71% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.26 (d, 1H), 7.34-7.40 (m, 1H), 7.21-7.34 (m, 2H), 2.23 (d, 3H).
Reaction SMILES: O.C[Si]([Cl:6])(C)C.[CH3:7][N:8]([CH2:10][CH:11]1[CH:17]([C:18]2[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=2)[CH2:16][CH:15]2[CH2:25][CH:12]1[CH2:13][CH2:14]2)[CH3:9]>CC(=O)CC>[ClH:6].[CH3:9][N:8]([CH2:10][CH:11]1[CH:17]([C:18]2[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=2)[CH2:16][CH:15]2[CH2:25][CH:12]1[CH2:13][CH2:14]2)[CH3:7]
Reactant: C[Si](C)(C)Cl
Agent: CN(C)CC1C2CCC(C2)CC1c1cccc(O)c1
Solvent: O
Solvent: CCC(C)=O
Product: Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Add H2O (70 mg, 3.89 mmol) and TMSCl (126 mg, 1.17 mmol) to a solution of 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenol (252 mg, 0.97 mmol) in 2-butanone (30 ml). Then stir the reaction mixture at ambient temperature for 12 hours. Evaporate the mixture under vacuum to give 3-(2-dimethylaminomethyl-bicyclo[3.2.1]oct-3-yl)-phenol hydrochloride as white solid (286 mg, Yield: 99.8%). 1H NMR (400 MHz, D2O) δ 7.04-7.07 (t, J=10.4, 1H), 6.58-6.72 (m, 3H), 2.80-2.91 (m, 1H), 2.52-2.54 (m, 3H), 2.44-2.48 (m, 3H), 2.33-2.41 (m, 1H), 2.20-2.29 (m, 1H), 2.11 (s, 1H), 1.99 (s, 2H), 1.36-1.47 (m, 8H).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[Br:12][CH2:13][C:14](Br)=[O:15]>CN(C=O)C.O1CCOCC1.O>[Br:12][CH2:13][C:14]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])=[O:15]
Reactant: COC(=O)c1ccccc1N
Reactant: O=C(Br)CBr
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1NC(=O)CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of methyl anthranilate (5 g, 0.033 mol) in anhydrous DMF (25 mL) and anhydrous dioxane (25 mL) was cooled to 0° C. in a 250 mL 3-necked flask, fitted with a magnetic stirrer and a constant addition funnel. Bromoacetyl bromide (6.7 g, 2.9 mL, 100 mol %) was added dropwise, keeping the internal temperature between 0° C. and 2° C. After the addition was complete (20-25 min), the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with water (100 mL) and the white crystalline compound which precipitated was filtered, washed sequentially with 5% HBr (100 mL) and water (200 mL), and then dried in a vacuum oven at 40°-45° C. overnight. The product was triturated with ether and then dried in vacuo for 5 h, yielding 7.9 g (88%) of the title compound as a white solid: mp 81°-82° C.; 1H NMR (DMSO-d6) δ11.07 (s, 1H, NH), 8.23 (dd, 1H, J=1.2, J=8.4), 7.94 (dd, 1H, J=1.6, J=8), 7.66-7.62 (m, 1H), 7.27-7.23 (m,1H), 4.23 (s, 2H), 3.87 (s, 3H); 13C NMR (DMSO-d6) δ171.64, 167.28, 138.81, 134.03, 130.67, 124.02, 122.90, 121.22, 52.51, 30.37; MS (EI, m/z) 271 (M+), 273 (M+2+). HRMS (EI) calcd for C10 H10NO3Br 270.9844, found 270.9838. Anal. Calcd for C10 H10NO3Br: C, 44.14; H, 3.70; N, 5.15. Found: C, 44.18; H, 3.67; N, 4.94.
Reaction SMILES: C([NH:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(OCC)=O.[ClH:19]>>[ClH:19].[ClH:19].[C:13]1([CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][NH2:6])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)NCCNCCCc1ccccc1
Agent: Cl
Product: NCCNCCCc1ccccc1

Procedure:
A solution of 580 mg of N-carboethoxy-N'-(3-phenylpropyl)ethylenediamine in 10 ml of concentrated hydrochloric acid was heated in a sealed tube at 120° C. overnight. The mixture was concentrated under reduced pressure. Toluene was added and the mixture was again concentrated. Two repetitions of this procedure gave 630 mg of N-(3-phenylpropyl)ethylenediamine dihydrochloride. This product was submitted to the next step without purification.
Reaction SMILES: [C:1]1(=O)[C:17]2[C:5]([CH:6]=[CH:7][C:8]3[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:9]=3)=[CH:4][CH:3]=[CH:2]1>O1CCCC1.[C].[Pd].[Pd]>[CH2:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[C:17]3[C:5]([CH:6]=[CH:7][C:8]1=2)=[CH:4][CH:3]=[CH:2][CH:1]=3
Reactant: O=C1C=CC=c2ccc3c(c21)-c1ccccc1C=3
Agent: [Pd]
Solvent: C1CCOC1
Product: c1ccc2c(c1)Cc1ccc3ccccc3c1-2

Procedure:
9.8 grams of the benzo(c) flurenone were dissolved in 200 ml of terahydrofuran and hydrogenated in the presence of 0.5 g of a palladium carbon catalyst containing 10 wt % palladium under atmospheric pressure and room temperature. The resulting product was dried over Na2SO4, the solvent removed and the residue extracted with pentane and filtered over silica gel. Colorless platelettes of 3,4-benzofluorene, also sometimes referred to as benzo(c) fluorene, were recovered.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH3:13][CH:14]([NH2:17])[CH2:15][CH3:16]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][CH:14]([CH3:13])[CH2:15][CH3:16])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Reactant: CCC(C)N
Solvent: CN(C)C=O
Product: CCC(C)Nc1nc(Cl)nc2c(C)csc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
In DMF was dissolved 700 mg (3.2 mmol) of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine, and then an aqueous solution of 1.07 g (7.5 mmol) of 1-methylpropylamine was added dropwise to the resulting solution under ice cooling over 5 minutes. The reaction mixture was stirred at 0° C. for one hour and then allowed to resume room temperature, followed by stirring for one hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/8) to give 676 mg (yield: 82.7%) of the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([C:17]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[O:18])[C:15]([OH:16])=[C:10]2[CH:9]=[N:8]1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](I)[CH3:31]>CN(C)C=O>[CH2:30]([O:16][C:15]1[C:14]([C:17]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[O:18])=[CH:13][N:12]=[C:11]2[N:7]([CH2:6][C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[N:8]=[CH:9][C:10]=12)[CH3:31]
Reactant: CCI
Reactant: O=C(c1cccs1)c1cnc2c(cnn2Cc2ccco2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1c(C(=O)c2cccs2)cnc2c1cnn2Cc1ccco1

Procedure:
3.3 g. of [1-(2-furanylmethyl)-4-hydroxy-1H-pyrazolo[ 3,4-b]pyridine-5-yl]-2-thienylmethanone (0.01 mol.), 1.5 g. of potassium carbonate (0.011 mol.) and 3.1 g. of ethyl iodide (0.02 mol.) are stirred together in 20 ml. of dimethylformamide at 70° for 12 hours. After this time, the inorganic precipitate is filtered off and the filtrate treated with about 10 ml. of water. The product, [4-Ethoxy-1-(2-furanylmethyl)-1H-pyrazolo[ 3,4-b]pyridin-5-yl]-2-thienylmethanone, crystallizes on standing, yield 3 g. (86%); m.p. 85°-87° (methanol).
Reaction SMILES: [CH2:1]([NH:9][C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].B#B>O1CCCC1>[CH2:10]([NH:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCNC(=O)CCCCCC
Agent: B#B
Solvent: C1CCOC1
Product: CCCCCCCCNCCCCCCC

Procedure:
Octylamine was acrylated with one equivalent of heptanoyl chloride to provide N-octylhexanecarboxamide. The amide was reduced by reaction with diborane in tetrahydrofuran to provide N-heptyloctylamine. To a cold stirred solution of 19.79 g. of N-heptyloctylamine and 23.4 g. of sodium carbonate in 82 ml. of acetone and 82 ml. of water was added dropwise over thirty minutes a solution of 13.7 ml. of acetyl chloride in 164 ml. of acetone. The reaction mixture was stirred for twelve hours following complete addition, after which time the solvent was removed by evaporation under reduced pressure. The residual oil was dissolved in diethyl ether and washed with water and with 2 N hydrochloric acid. The ethereal solution then was dried and the solvent was removed by evaporation to provide 22.48 g. of N-heptyl-N-octylacetamide.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([F:28])([F:27])[C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[CH:5]=[CH:4][C:3]=1[C:29]1[CH:34]=[CH:33][C:32]([C:35]([OH:37])=[O:36])=[CH:31][CH:30]=1.[F:38][C:39]([F:92])([F:91])[C@H:40]([O:47][C:48]([C:50]1[CH:55]=[CH:54][C:53](OC(C2C=CC(C3C=CC(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)=C(F)C=3F)=CC=2)=O)=[CH:52][CH:51]=1)=[O:49])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>>[F:38][C:39]([F:91])([F:92])[C@H:40]([O:47][C:48]([C:50]1[CH:51]=[CH:52][C:53]([O:36][C:35]([C:32]2[CH:33]=[CH:34][C:29]([C:3]3[CH:4]=[CH:5][C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([F:27])([F:28])[C:17]([F:25])([F:26])[C:18]([F:23])([F:24])[C:19]([F:22])([F:20])[F:21])=[C:7]([F:8])[C:2]=3[F:1])=[CH:30][CH:31]=2)=[O:37])=[CH:54][CH:55]=1)=[O:49])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: O=C(O)c1ccc(-c2ccc(OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c2F)cc1
Reactant: CCCCCC[C@@H](OC(=O)c1ccc(OC(=O)c2ccc(-c3ccc(OCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c3F)cc2)cc1)C(F)(F)F
Product: CCCCCC[C@@H](OC(=O)c1ccc(OC(=O)c2ccc(-c3ccc(OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(F)c3F)cc2)cc1)C(F)(F)F

Procedure:
2′,3′-Difluoro-4′-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-biphenyl-4-carboxylic acid 4-[(R)-1-trifluoromethyl-heptyloxycarbonyl]-phenyl ester (15B) was prepared from 2′,3′-difluoro-4′-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-biphenyl-4-carboxylic acid (14B) as described in the preparation 2′,3′-difluoro-4′-(5,5,6,6,7,7,8,8,8-nonafluoro-octyloxy)-biphenyl-4-carboxylic acid 4-[(R)-1-trifluoromethyl-heptyloxycarbonyl]-phenyl ester (15A) yielding 2′,3′-difluoro-4′-(7,7,8,8,9,9,10,10,10-nonafluoro-decyloxy)-biphenyl-4-carboxylic acid 4-[(R)-1-trifluoromethyl-heptyloxycarbonyl]-phenyl ester (15B)) as a white solid (88%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:31][C@H:32]([OH:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]C)=[O:24])=[C:19]([O:27][CH:28]([CH3:30])[CH3:29])[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>CO.O>[C:1]([O:5][C:6]([N:8]([CH2:31][C@H:32]([OH:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[C:19]([O:27][CH:28]([CH3:30])[CH3:29])[CH:18]=2)=[CH:15][CH:16]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)cc1OC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)Oc1cc(-c2ccc(CCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 102.7 %

Procedure:
To a solution of methyl 4′-[2-[(tert-butoxycarbonyl)-[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-isopropoxy-4biphenylcarboxylate (1.40 g) in methanol (15 ml)/tetrahydrofuran (6 ml) was added aqueous solution of sodium hydroxide (1N, 7.89 ml) at room temperature and the mixture was stirred at room temperature for 18 hours. The mixture solution was acidified with aqueous hydrochloric acid solution (1N), poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=5/5) to give 4′-[2-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-phenylethyl]amino]-ethyl]-3-isopropoxy-4-biphenylcarboxylic acid (1.40 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][N:13]=[CH:14]2)=[CH:9][CH:8]=1)(=O)=O.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:19]1([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][N:13]=[CH:14]3)=[CH:9][CH:8]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Oc1ccc2ccncc2c1)C(F)(F)F
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: c1ccc(-c2ccc3ccncc3c2)cc1
Temperature: 90 °C
Yield: 83 %

Procedure:
To a slurry of 7-(trifluoromethanesulfonyloxy)isoquinoline (prepared by the method of D. F. Ortwine et al., J. Med. Chem., 1992, 35, 1345) (2.1 g, 7.5 mmol) in toluene (20 ml) was added phenyl boronic acid (1.21 g, 10 mmol) and a 2M solution of sodium carbonate (15 ml). The reaction vessel was filled with nitrogen, tetrakis(triphenylphosphine)palladium(0) (0.25 g, 0.22 mmol) was added and the reaction mixture was heated at 90° C. for 18 h. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with sodium carbonate solution (50 ml). The aqueous solution was extracted with ethyl acetate (2×50 ml). The ethyl acetate extracts were combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give an oil. The oil was purified by flash chromatography using hexane/ethyl acetate (1:1) as eluant to give the title compound (1.27 g, 83%); δH (DMSO-d6) 7.41-7.88 (6H, m, ArH and isoquinolinyl H), 7.95 (1H, d, J 6.2 Hz, isoquinolinyl H), 8.14 (1H, dd, J 8.5, 1.75 Hz, isoquinolinyl H), 8.44 (1H, t, J 0.85 Hz, isoquinolinyl H), 8.52 (1H, d, 5.75 Hz, 3-H), and 9.31 (1H, s, 1-H); m/z (CI+, NH3) 206 (M+1)+.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25](Br)=[CH:24][C:23]=3[F:29])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CC(C)([O-])C.[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:24][C:23]=3[F:29])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: Cc1c(Oc2ccc(Br)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1COCCO1
Product: Cc1c(Oc2ccc(N3CCOCC3)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 150 °C
Yield: 46.3 %

Procedure:
A mixture of 4-[6-(4-bromo-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (Compound C130, 500 mg, 1.07 mmole), morpholine (121 mg, 1.39 mmole), palladium acetate (3 mg, 0.011 mmole), biphenyl-2-yl-di-tert-butyl-phosphane (4 mg, 0.012 mmole) and sodium t-butoxide (257 mg, 2.14 mmole) in dioxane (3 mL) was heated under microwave irradiation at 150° C. for 1 hours. The crude mixture was purified by HPLC to provide Compound C3 as a yellow oil (235 mg, 46%). 1H NMR (CDCl3, 400 MHz) δ 1.28 (d, J=6.3 Hz, 6H), 1.81-1.85 (m, 2H), 1.99-2.04 (m, 2H), 2.20 (s, 3H), 3.44-3.47 (m, 2H), 3.49-3.51 (m, 4H), 3.73-3.78 (m, 2H), 4.08-4.10 (m, 2H), 4.95 (sep, J=6.3 Hz, 1H), 5.35-5.37 (m, 1H), 7.25 (d, J=10.1 Hz, 2H), 7.32 (t, J=8.6 Hz, 1H), 8.26 (s, 1H). Exact mass calculated for C24H31FN4O5 474.2, found 475.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]=[C:5]1[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1.[H][H]>[C].[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH:5]1[CH2:14][CH2:13][C:8]2([O:9][CH2:10][CH2:11][O:12]2)[CH2:7][CH2:6]1
Reactant: [H][H]
Reactant: COC(=O)C=C1CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CC1CCC2(CC1)OCCO2
Reaction time: 24 h
Yield: 75.2 %

Procedure:
An ethanol (50 mL) suspension of (1,4-dioxa-spiro[4.5]dec-8-ylidene)-acetic acid methyl ester (6.57 g) obtained in Example (1a) and palladium carbon (10% by weight) was hydrogen-reduced at room temperature for 24 hours. The reaction mixture was filtered and concentrated. The residue was purified by chromatography (hexane/ethyl acetate=5:1) to obtain the title compound (4.99 g, 75%) as a colorless oil.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([O:30][C:31]([N:33]1[CH2:39][CH2:38][CH:37]([OH:40])[CH:36]([NH:41][C:42](=[O:44])[CH3:43])[CH2:35][CH2:34]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[CH2:23]([O:30][C:31]([N:33]1[CH2:39][CH2:38][C:37](=[O:40])[CH:36]([NH:41][C:42](=[O:44])[CH3:43])[CH2:35][CH2:34]1)=[O:32])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(=O)NC1CCN(C(=O)OCc2ccccc2)CCC1O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)NC1CCN(C(=O)OCc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
11 g Dess Martin Periodane was added to 6.2 g 4-acetylamino-5-hydroxy-azepane-1-carboxylic acid benzyl ester in 100 mL dichloromethane and stirred for 1 h at RT. The mixture was diluted with dichloromethane and washed with 2 mol/L sodium hydroxide solution. The organic layer was washed with brine, dried and concentrated. The residue was purified by chromatographie on silica gel (EtOAc) to yield 5.5 g of the desired product. (M+H)+: 305
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[Br:10].BrC1C=C2C(=CC=1)C=[N:17][CH:16]=[CH:15]2>>[F:1][C:2]1[CH:9]=[C:8]2[C:5](=[CH:4][C:3]=1[Br:10])[CH:6]=[N:17][CH:16]=[CH:15]2
Reactant: Brc1ccc2cnccc2c1
Reactant: O=Cc1ccc(F)c(Br)c1
Product: Fc1cc2ccncc2cc1Br

Procedure:
Starting from 4-Fluoro-3-bromobenzaldehyde, the title compound was synthesized by the protocol described for 6-Bromo-isoquinoline (3). Rt=0.91 min (Method B). Detected mass: 226.0/228.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:10]=2)[NH:5][C:4](=[O:24])[CH:3]=1.I([O-])(=O)(=O)=[O:26].[Na+]>C(O)(=O)C.O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:26])[CH:10]=2)[NH:5][C:4](=[O:24])[CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cc1cc(=O)[nH]c2ccc(OCCCCSc3ccccn3)cc12
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(=O)[nH]c2ccc(OCCCCS(=O)c3ccccn3)cc12
Reaction time: 22 h

Procedure:
A solution of 0.170 gm (0.0005 mol) of 4-methyl-6-[4-(2-pyridyl-mercapto)-butoxy]-carbostyril in 5 ml of glacial acetic acid and a solution of 0.107 gm (0.0005 mol) of sodium metaperiodate in 6 ml of water were admixed and allowed to stand at room temperature for 22 hours. Subsequently, the light brown reaction solution was diluted with 20 ml of water, and the reaction product was extracted with chloroform. The extract was shaken once with an aqeuous sodium carbonate solution and dried over anhydrous magnesium sulfate. After evaporating the organic phase, the residue was recrystallized from toluene.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17].N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:16](=[O:17])[C:15]3[CH:19]=[CH:20][CH:21]=[C:13]([Cl:12])[CH:14]=3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cccc(Cl)c1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 3-chlorobenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.84-2.05 (m, 5H), 2.11 (s, 1H), 2.29 (s, 1H), 2.32 (s, 1H), 2.39 (s, 2H), 3.47-3.53 (m, 2H), 3.62-3.74 (m, 1H), 3.77-3.88 (m, 1H), 4.38 (s, 1H), 7.43-7.52 (m, 1H), 7.54-7.61 (m, 1H), 7.73-7.80 (m, 1H), 7.78-7.88 (m, 1H); MS (APCI/NH3) m/z 291 (M+H)+.