Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.C([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:32][CH3:33])=[CH:29][CH:30]=3)[O:25][C:24](=O)[C:23]=2[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)=[CH:18][CH:17]=1)(=O)C.Cl>O.C(OCC)(=O)C>[F:41][C:38]1[CH:39]=[CH:40][C:35]([C:23]2[CH2:24][O:25][C:26]3[C:31]([C:22]=2[C:19]2[CH:20]=[CH:21][C:16]([OH:15])=[CH:17][CH:18]=2)=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=3)=[CH:36][CH:37]=1
Reactant: COc1ccc2c(-c3ccc(OC(C)=O)cc3)c(-c3ccc(F)cc3)c(=O)oc2c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)OCC(c1ccc(F)cc1)=C2c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Lithium aluminium hydride (0.76 g, 20.03 mmol) was added in small portions to a stirred tetrahydrofuran (150 ml) solution of 4-(4-acetoxyphenyl)-3-(4-fluorophenyl)-7-methoxy-coumarin (4.04 g, 9.99 mmol). After complete addition, the mixture was stirred at room temperature for 30 min., then treated dropwise with 6M hydrochloric acid (30 ml). The resulting mixture was heated to 60-65° C. for 3 h, cooled and diluted with water (100 ml) and ethyl acetate (50 ml). The aqueous layer was separated and further extracted with ethyl acetate (3×100 ml). The combined organic solutions were washed with saturated aqueous sodium chloride, dried over sodium sulfate and evaporated to give an orange solid. This was recrystallised from ethanol/water (4:1, 75 ml) to give the first crop of solid product as colourless needles. The mother liquors were evaporated to give an orange gum, which was subjected to a second aqueous ethanol recrystallisation to give a second crop of colourless needles. The solids were combined and vacuum dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[NH:31][C@H:30]([CH3:35])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.C(=O)([O-])[O-].[K+].[K+].[C:42](OC(=O)C)(=[O:44])[CH3:43].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([N:28]5[CH2:33][C@H:32]([CH3:34])[N:31]([C:42](=[O:44])[CH3:43])[C@H:30]([CH3:35])[CH2:29]5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: C[C@@H]1CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@H](C)N1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1[C@H](C)CN(c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a mixture of 2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-((3R,5S)-3,5-dimethyl-piperazin-1-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (150 mg, 0.3 mmol), potassium carbonate (84 mg, 0.6 mmol) in DMF (5 mL) was added acetic anhydride (0.3 mL) at −15° C. The mixture was slowly warmed to room temperature and stirred for 30 min. The reaction mixture was added 30 mL of water. The solid was collected to give 100 mg of 312. Yield=62%. 1H NMR (CDCl3, 400 MHz): δ8.03 (s, 1 H), 7.51-7.46 (m, 1H), 7.19-7.00 (m, 4H), 6.50 (d, J=8.8 Hz, 1 H), 4.19 (t, J=4.4 Hz, 2 H), 3.66-3.65 (m, 2 H), 3.07 (t, J=4.8 Hz, 2H), 0.93-2.89 (m, 2 H), 2.13 (s, 3 H), 2.03 (s, 2 H), 1.29-1.24 (m, 6 H). ESI-MS: m/z=537 [M+H+]
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=O)=[CH:5][CH:4]=1.FC(F)(F)S(O)(=O)=O.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=C(c1ccc(CBr)cc1)c1ccc([N+](=O)[O-])cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cc2ccc(CBr)cc2)cc1
Reaction time: 0.08 h
Yield: 56.5 %

Procedure:
4-(4-bromomethylbenzoyl)-nitrobenzene (500 mg) was dissolved in dichloromethane (5 mL) and stirred under argon. A solution of trifluoromethanesulfonic acid (0.27 mL) in dichloromethane (2 mL) was added dropwise, followed by a solution of triethylsilane (0.37 mL) in dichloromethane (2 mL). After 5 minutes, a second portion of trifluoromethanesulfonic acid and triethylsilane (same proportions) was added. The reaction mixture was stirred at room temperature for 3 hours, poured into excess aqueous sodium bicarbonate, and extracted with dichloromethane (3×). The solution containing the crude product was evaporated, chromatographed on silica gel, eluting the product with hexane/ethyl acetate, and evaporated to dryness, to give 4-(4-bromomethylbenzyl)-nitrobenzene (270 mg, 56%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]>O1CCOCC1.O=[Mn]=O>[F:1][C:2]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(CO)cc1F
Agent: O=[Mn]=O
Solvent: C1COCCO1
Product: N#Cc1ccc(C=O)cc1F
Temperature: 100 °C

Procedure:
A solution of Example 52B (1.23 g, 8.17 mmol) in 1,4-dioxane (30 mL) was treated with MnO2, heated to 100° C. for 1 hour, and cooled to room temperature. The cooled solution was filtered through diatomaceous earth (Celite®) on a fritted funnel rinsing with 1:1 dichloromethane/methanol (200 mL). The filtrate was concentrated and the concentrate was purified by flash column chromatography on silica gel with a solvent gradient of 19:1 to 4:1 hexanes/ethyl acetate to provide the desired product. MS (APCI) m/z 149 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 10.06 (s, 1H), 7.88-7.71 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:29])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:27][CH3:28])=[C:16]([CH2:19][NH:20][C:21]4([C:24]([OH:26])=[O:25])[CH2:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:30]=O>>[Cl:1][C:2]1[C:3]([F:29])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:27][CH3:28])=[C:16]([CH2:19][N:20]([CH3:30])[C:21]4([C:24]([OH:26])=[O:25])[CH2:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNC1(C(=O)O)CC1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(=O)O)CC1

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxyquinazoline-6-carbaldehyde was coupled with 1-aminocyclopropanecarboxylic acid using an analogous method to that described for the equivalent step in Example 1 to give 1-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]cyclopropanecarboxylic acid; 1H NMR Spectrum: (DMSO d6) 0.90-1.00 (m, 2H); 1.10-1.20 (m, 2H); 3.93 (s, 2H); 3.96 (s, 3H); 7.14 (s, 1H); 7.28 (m, 1H); 7.40-7.55 (m, 2H); 8.29 (s, 1H); 8.40 (s, 1H); Mass Spectrum: (M+H)+ 417. 1-[({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)amino]cyclopropanecarboxylic acid reacted with para-formaldehyde using an analogous method to that described for the equivalent step in Example 11 to give 1-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]cyclopropanecarboxylic acid; 1H NMR Spectrum: (DMSO-d6) 1.08 (m, 2H); 1.21 (m, 2H); 2.43 (s, 3H); 3.94 (s, 3H); 4.08 (s, 2H); 7.17 (s, 1H); 7.28 (t, 1H); 7.52 (m, 2H); 8.21 (s, 1H); 8.42 (s, 1H); 9.73 (s, 1H); Mass Spectrum: (M+H)+ 431
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[C:22]([C:29]5[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=5[Cl:36])=[N:23][O:24][C:25]=4[CH:26]4[CH2:28][CH2:27]4)=[CH:15][C:14]=3[Cl:37])([OH:12])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:44]1([CH2:50][SH:51])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:50]([S:51][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[C:22]([C:29]5[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=5[Cl:36])=[N:23][O:24][C:25]=4[CH:26]4[CH2:28][CH2:27]4)=[CH:15][C:14]=3[Cl:37])([OH:12])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: OC1(c2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C3CC3)cc2Cl)CC(c2cccc(Br)c2)C1
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: OC1(c2ccc(OCc3c(-c4c(Cl)cccc4Cl)noc3C3CC3)cc2Cl)CC(c2cccc(SCc3ccccc3)c2)C1
Temperature: 115 °C
Reaction time: 4 h
Yield: 30.2 %

Procedure:
To a solution of compound 2b (619 mg, 1 mmol) in toluene (20 mL) under argon atmosphere were added K2CO3 (276 mg, 2 mmol), phenylmethanethiol (125 mg, 1 mmol), Pd2(dba)3 (200 mg, 0.22 mmol) and Xantphos (75 mg, 0.16 mmol). Then the mixture was stirred at 115° C. for 4 h. After being cooled to rt, the reaction was diluted with water (100 mL) and extracted with EA (100 mL×2). The combined organic layers were washed with brine (100 mL×2), dried over Na2SO4 and concentrated to dryness. Purification by CC gave compound the compound 5a (200 mg; 30%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ: 7.36-7.32 (m, 3H), 7.28-7.07 (m, 9H), 7.01 (d, J=7.2 Hz, 1H), 6.82 (d, J=2.0 Hz, 1H), 6.66 (dd, J=8.8, 2.0 Hz, 1H), 4.75 (s, 2H), 4.04 (s, 2H), 3.06-3.00 (m, 2H), 2.84-2.78 (m, 2H), 2.44-2.38 (m, 3H), 2.09 (m, 1H), 1.24-1.18 (m, 2H), 1.11-1.08 (m, 2H). MS (ESI+) m/z: 662 [M+1]+.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][N:7]=[C:8]([CH2:10][OH:11])[CH:9]=[C:4]2[CH2:3][CH2:2]1>ClCCl.[O-2].[O-2].[Mn+4]>[O:1]1[C:5]2=[CH:6][N:7]=[C:8]([CH:10]=[O:11])[CH:9]=[C:4]2[CH2:3][CH2:2]1
Reactant: OCc1cc2c(cn1)OCC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cc2c(cn1)OCC2
Yield: 69.4 %

Procedure:
2,3-Dihydrofuro[2,3-c]pyridin-5-ylmethanol (1.31 g, 8.7 mmol) was dissolved in dichloromethane (100 ml), treated with manganese (IV) dioxide (6 g, 69 mmol) and heated under reflux for 18 h. Filtration through kieselguhr and evaporation of the filtrate to dryness gave an oil (0.9 g, 70%).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11](O)=[O:12])[C:4]=2[CH:3]=1.[CH:20]([C:23]1[CH:29]=[C:28]([S:30][CH3:31])[CH:27]=[C:26]([CH:32]([CH3:34])[CH3:33])[C:24]=1[NH2:25])([CH3:22])[CH3:21]>>[CH:32]([C:26]1[CH:27]=[C:28]([S:30][CH3:31])[CH:29]=[C:23]([CH:20]([CH3:22])[CH3:21])[C:24]=1[NH:25][C:11]([CH:10]1[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[CH2:7][O:6][C:5]2[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][C:4]1=2)=[O:12])([CH3:34])[CH3:33]
Reactant: Cc1ccc2c(c1)C(C(=O)O)c1ccccc1CO2
Reactant: CSc1cc(C(C)C)c(N)c(C(C)C)c1
Product: CSc1cc(C(C)C)c(NC(=O)C2c3ccccc3COc3ccc(C)cc32)c(C(C)C)c1
Yield: 84 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.12 g of Compound A and 1.18 g of 2,6-diisopropyl-4-methylthioaniline in place of aniline to obtain 1.70 g of Compound 30.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([N:8]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:20][O:19]3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([N:8]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([OH:19])[CH2:20][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:14][CH:13]=2)(=[O:10])=[O:11])[CH:7]=1
Reactant: C1COCCN1
Reactant: CC(C)CN(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(C2CO2)cc1
Solvent: CCO
Product: CC(C)CN(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(C(O)CN2CCOCC2)cc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a stirred solution of N-(5-chloro-2-fluorophenyl)-N-isobutyl-4-(oxiran-2-yl)benzenesulfonamide (200 mg, 0.521 mmol) in ethanol (2 mL) at 25° C. was added morpholine (0.045 ml, 0.521 mmol) and the reaction mixture stirred at 50° C. for 24 hours. The mixture was then purified by mass directed autoprep (ammonium carbonate modifier). The appropriate fractions were combined and evaporated in vacuo to give the required product, 51.4 mg. LCMS [LCMS2] Rt 1.25 min, m/z (ES+) 471 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH:5]=[CH:6][C:7]1=[N:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2.[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH:5]=[CH:6][C:7]1=[N:8][CH2:9][CH2:10][N:11]([C:25]([NH:24][CH2:22][CH3:23])=[O:26])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]1=2
Reactant: Clc1ccc(C=CC2=NCCNc3ccccc32)cc1Cl
Reactant: CCN=C=O
Product: CCNC(=O)N1CCN=C(C=Cc2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 41.2 %

Procedure:
A solution of 32 mg (0.1 mmol) of (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-1H-benzo-1,4-diazepine and 10 mg (0.14 mmol) of ethyl isocyanate was heated at 85° C. for 48 hours, a further 10 mg of ethyl isocyanate being added after 6 hours and again after 30 hours. The solvent was removed by evaporation and the residue chromatographed on silica gel using dichloromethane/methanol (19:1) for the elution. The product was recrystallized from diethyl ether. There was obtained 16 mg of (E)-5-(3,4-dichlorostyryl)-N-ethyl-2,3-dihydro-1H-1,4-benzodiazepine-1-carboxamide as an off-white solid. MS: m/e 387.9 [M+H]+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]([O:13][CH3:14])=[CH:11][N:10]=[C:9]([CH2:15][CH2:16][NH2:17])[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:25](Cl)(=[O:33])[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH:1]1([O:6][C:7]2[C:12]([O:13][CH3:14])=[CH:11][N:10]=[C:9]([CH2:15][CH2:16][NH:17][C:25](=[O:33])[O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1cnc(CCN)cc1OC1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cnc(CCNC(=O)Oc2ccccc2)cc1OC1CCCC1
Temperature: 2.5 °C
Yield: 77.7 %

Procedure:
A mixture of 4-(cyclopentyloxy)-5-methoxy-2-pyridineethanamine (0.026 mol) and triethylamine (0.03 mol) in CH2Cl2 (75ml) was stirred at 0-5° C. A mixture of phenyl carbonochloridate (0.03 mol) in CH2Cl2 (25ml) was added dropwise. The mixture was stirred at RT for 1 hour and then washed with NaOH (1N) and water. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated. The residue was dried, yielding 7.2g (77.7%) of phenyl [2-[4-(cyclopentyloxy)-5-methoxy-2-pyridinyl]ethyl]carbamate (interm. 3).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl.[CH3:14]O>>[Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:14])=[O:8]
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(Cl)c(F)cc1F

Procedure:
A solution of 5-chloro-2,4-difluorobenzoic acid (2.8 g, 15 mmol) in a solution of HCl in methanol (4 M, 10 mL) was stirred at 60° C. for 4 hours. The reaction was cooled down and the solvent was evaporated to afford the title compound, which was used for the next step without further purification.
Reaction SMILES: [OH:1][C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:10](Cl)(=[O:21])[O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>C(#N)C.CN(C1C=CN=CC=1)C.O>[CH3:8][C:2]([O:1][C:10]([O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1)=[O:21])([CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(C)(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.5 %

Procedure:
To a solution of ethyl 2-hydroxy-2-methylpropanoate (1.2 g) and 4-nitrophenyl chlorocarbonate (1.2 g) in acetonitrile (20 mL) was added DMAP (0.77 g) at 0° C., and the mixture was stirred at room temperature for 3 days. The mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (solvent gradient; 0→25% ethyl acetate/hexane) to give ethyl 2-methyl-2-{[(4-nitrophenoxy)carbonyl]oxy}propanoate (1.3 g, 74%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]([C:17](=[O:25])[CH2:18][N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:6]=12.[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]Br.C(N(CC)CC)C.N>CO.C(Cl)(Cl)Cl>[CH3:1][C:2]1[S:3][CH:4]=[C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]([C:17](=[O:25])[CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][Br:26])[CH2:21][CH2:20]3)[C:6]=12
Reactant: BrCCCCCCCCCCBr
Reactant: Cc1scc2c1N(C(=O)CN1CCNCC1)c1ccccc1NC2=O
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1scc2c1N(C(=O)CN1CCN(CCCCCCCCCCBr)CC1)c1ccccc1NC2=O

Procedure:
A solution of 38 (20 mg, 57 μmol), 1,10-dibromodecane (0.22 g. 0.73 mmol), and triethylamine (0.2 mL) was stirred in MeOH (0.5 mL) at 25° C. for 3 days. The reaction was judged complete by TLC (Rf of product on silica, with chloroform:methanol:ammonia, 90:10:1, by volume was 0.66), and all volatile materials were removed in vacuo. The remaining residue was dissolved in 0.5N HCl. The acidic aqueous layer was washed with ether (2×), and then made basic (=pH 9) by addition of 10% sodium carbonate. The product was extracted into CHCl3 (3×), and the combined organic layers were dried over Na2SO4, filtered and evaporated in vacuo to give the crude product as a glass. Yield 20 mg (61%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12](S)=[N:11][C:10]=2[CH3:15])=[CH:5][CH:4]=1)#[N:2]>[Ni].C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][CH:12]=[N:11][C:10]=2[CH3:15])=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1nc(S)sc1-c1ccc(C#N)cc1
Agent: [Ni]
Solvent: CCO
Product: Cc1ncsc1-c1ccc(C#N)cc1
Temperature: 80 °C

Procedure:
Raney Nickel (1 g) was added to a solution of the product of (a) (1.2 g, 5 mmol) in absolute ethanol (120 ml) and the reactants heated at 80° C. in an autoclave for 18 hours. After cooling to ambient temperature, further Raney Nickel (1 g) was added to the reaction mixture and the reactants heated at 80° C. in an autoclave for an additional 6 hours. The reaction mixture was then filtered through Arbocel and the filtrate evaporated to dryness. The residue was flash chromatographed (Merck 60 Kieselgel-ethyl acetate:hexane:diethylamine, 25:75:2) to give the title product a gum which solidified on standing (0.36 g, 35%), and was used directly in Preparation 19.
Reaction SMILES: C[Si](C)(C)[O:3][C@H:4]1[CH2:8][CH2:7][CH2:6][C@@H:5]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[OH:3][C@H:4]1[CH2:8][CH2:7][CH2:6][C@@H:5]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1O
Yield: 89.8 %

Procedure:
tert-Butyl N-[(1S,2S)-2-trimethylsilyloxycyclopentyl]carbamate (15.5 g, 56.7 mmol) and tetrabutylammonium fluoride (85.0 mL, 85.0 mmol) in THF (113 mL) are stirred at room temperature for 1 h. Water (50 mL) is added and the mixture is concentrated in vacuo to remove the THF. The resulting mixture is extracted with EtOAc (3×75 mL). The combined organic portions are washed with brine (2×30 mL), dried over sodium sulfate, filtered, and concentrated to give 14.7 g of crude product as a yellow oil. The material is purified on silica gel (330 g) using 25% EtOAc/hexanes to give the title compound as a white solid (10.25 g, 90%). LC-ES/MS m/z 224 (M+Na).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[CH:12]=[C:13]([C:31]([OH:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])[CH:14]=[CH:15][C:16]=1[N:17]1[CH2:22][CH2:21][N:20]([S:23]([C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)(=[O:25])=[O:24])[CH2:19][CH2:18]1>>[F:39][C:36]([F:37])([F:38])[C:31]([C:13]1[CH:12]=[CH:11][C:16]([N:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)(=[O:24])=[O:25])[CH2:19][CH2:18]2)=[C:15]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:14]=1)([OH:40])[C:32]([F:35])([F:34])[F:33]
Reactant: OB(O)c1cccnc1
Reactant: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2Br)CC1
Product: O=S(=O)(c1cccs1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2-c2cccnc2)CC1

Procedure:
Following the procedure outlined for Example 69, 3-pyridineboronic acid (21.33 mg, 0.173 mmol) was coupled to 2-(3-bromo-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol to afford 1,1,1,3,3,3-hexafluoro-2-(3-(3-pyridinyl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1H NMR (400 MHz, CD3OD) δ 8.67 (d, J=1.6 Hz, 1H), 8.47 (dd, J=4.9, 1.6 Hz, 1H), 8.02-7.94 (m, 1H), 7.89 (dd, J=5.1, 1.2 Hz, 1H), 7.71 (d, J=9.2 Hz, 1H), 7.60-7.53 (m, 2H), 7.43 (dd, J=7.8, 4.9 Hz, 1H), 7.31-7.22 (m, 2H), 2.97 (s, 8H). m/z (ESI, +ve ion) 551.6 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=0.775 μM; GK-GKRP EC50 (LC MS/MS)=0.783 μM.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[C:11]([CH2:31][CH:32]([CH3:34])[CH3:33])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([C:27]([O:29][CH3:30])=[O:28])=[CH:15][CH:14]=2)=O)(C)(C)C.[ClH:35]>O1CCOCC1>[ClH:35].[ClH:35].[NH2:8][CH2:9][C:10]1[C:11]([CH2:31][CH:32]([CH3:34])[CH3:33])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[CH:17][C:16]([C:27]([O:29][CH3:30])=[O:28])=[CH:15][CH:14]=2
Reactant: COC(=O)c1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(CC(C)C)c(CN)c(-c3ccc(C)cc3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To methyl 3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-4-(4-methylphenyl)quinoline-6-carboxylate (0.10 g, 0.22 mmol) was added 4N solution of hydrogen chloride in 1,4-dioxane (5 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give methyl 3-(aminomethyl)-2-isobutyl-4-(4-methylphenyl)quinoline-6-carboxylate dihydrochloride (0.12 g, yield 92%) as white crystals.