Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:4]=[O:5])[CH2:3][CH2:2]1.[Si:6]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Mg]Br)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[CH:1]1([CH:4]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][O:13][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:7])[CH3:8])[OH:5])[CH2:3][CH2:2]1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccccc1[Mg]Br
Reactant: O=CC1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccccc1C(O)C1CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Magnesium (2.20 g) was suspended in tetrahydrofuran (4 ml) and iodine (2 mg) was added. Thereto was added dropwise a solution of 2-bromo-1-(tert-butyldimethylsilyloxymethyl)benzene (24.0 g) obtained in Step 1 in tetrahydrofuran (10 ml) over 30 min and the reaction mixture was heated under reflux for 1 hr. Thereto was added tetrahydrofuran to give 1M 2-(tert-butyldimethylsilyloxymethyl)phenylmagnesium bromide-tetrahydrofuran solution. Then cyclopropanecarboxaldehyde (2.80 g) was dissolved in tetrahydrofuran (120 ml), and 1M 2-(tert-butyldimethylsilyloxymethyl)phenylmagnesium bromide-tetrahydrofuran solution (80 ml) was added dropwise under ice-cooling over 50 min. The reaction mixture was stirred at room temperature for 12 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution (8 ml) under ice-cooling and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5) to give the title compound (8.20 g).
Reaction SMILES: [Cl-].[Li+].CS(C)=O.[CH2:7]([C:10]([CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)(C(OCC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH2:9]>O>[CH:21]1([CH:10]([CH2:7][CH:8]=[CH2:9])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C=CCC(C(=O)OCC)(C(=O)OCC)C1CCCC1
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCC(C(=O)OCC)C1CCCC1
Temperature: 185 °C
Reaction time: 6 h

Procedure:
Lithium chloride (3.60 g, 84.9 mmol) and water (0.76 mL, 41.9 mmol) were added to a dimethyl sulfoxide (20 mL) solution of diethyl allyl(cyclopentyl)malonate (10.10 g, 37.7 mmol), and the mixture was stirred at 185° C. for 6 hours. The mixture was treated with water, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to obtain the compound of interest as a brown oil substance (6.10 g, 84%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:14](=[O:15])[CH2:13][CH:12]([C:16]([NH:18][CH:19]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.CC(O)=O>C1COCC1.CO.O.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([N:10]2[C:14](=[O:15])[CH2:13][CH:12]([C:16]([NH:18][CH:19]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CC(NC(=O)C1CC(=O)N(c2cccc([N+](=O)[O-])c2)C1)c1cccnc1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CC(NC(=O)C1CC(=O)N(c2cccc(N)c2)C1)c1cccnc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Ethyl 3-{(1-(3-nitrophenyl)-5-oxopyrrolidin-3-yl)carbonylamino}-3-(3-pyridyl)propanoate was dissolved in THF/MeOH/H2O solution at 0° C. AcOH was added followed by activated Zn powder. The reaction was then stirred at room temperature for 5 hours. The Zn powder was filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue was re-dissolved in EtOAc. A white precipitate formed and was removed by filtration. The organic solution was concentrated in vacuo to afforded yellow foam. MS (ES+): 397.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:25])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:17]=1)=[O:5]
Reactant: O=C(Cl)c1ccccc1F
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2ccccc2F)cc1
Yield: 55.6 %

Procedure:
In a manner similar to that described in Example 3, 2-fluorobenzoyl chloride (0.053 g, 0.00033 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol) (Example 1, Step (c)), and the resulting intermediate was hydrolyzed to give 0.0438 g of 4-[4-(2-fluoro-benzoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; mp 191-193° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][C@H:9]1[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.[BH4-].[Na+].CCOCC>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][C@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN1CCOCC1
Product: C=C1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Reaction time: 1.5 h
Yield: 67.4 %

Procedure:
To 14.7 g (64.7 mmol) (2S)-4-Methylene-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester in 80 ml THF were added 7.13 ml (64.7 mmol, 1.0 eq) N-methylmorpholine and 8.5 ml (64.0 mmol, 1.0 eq) isobutylchloro formate at −5° C. and the solution was stirred at that temperature for 1.5 h. The mixture was filtered and added to a suspension of 3.7 g (97.8 mmol, 1.5 eq) NaBH4 in 30 ml water over a period of 25 min at 0° C. The reaction was stirred at 0° C. for 2 h and at RT over night. Ether was added, the layers were separated and the inorganic layer was extracted with ether and CH2Cl2, the organic layers were washed with brine, dried over Na2SO4, filtered and evaporated, yielding 9.3 g (68%) (2S)-2-Hydroxymethyl-4-methylene-pyrrolidine-1-carboxylic acid tert-butyl ester as light brown oil, MS: 182 (M-CH2OH.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9]1=[N:8][N:7]([C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:19])[CH2:6]2)=[O:4].C(N(CC)CC)C.[CH3:38][CH:39]([O:42][C:43]([S:45]Cl)=[O:44])[CH2:40][CH3:41]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]12[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[C:9]1=[N:8][N:7]([C:18]([N:20]([C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)[S:45][C:43]([O:42][CH:39]([CH3:38])[CH2:40][CH3:41])=[O:44])=[O:19])[CH2:6]2)=[O:4]
Reactant: CCC(C)OC(=O)SCl
Reactant: COC(=O)C12CCc3ccccc3C1=NN(C(=O)Nc1ccc(C(F)(F)F)cc1)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)OC(=O)SN(C(=O)N1CC2(C(=O)OC)CCc3ccccc3C2=N1)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the title compound of Step B (Example 1) 0.4 g, 0.96 mmol)in 5 ml methylene chloride was added triethylamine (0.12 g) and cooled to 0° C. To this solution was added (1-methylpropoxycarbonyl)sulfenyl chloride (Step A) (0.2 g, 0.0012 mol). The mixture was stirred at room temperature for one hour. At this stage thin layer chromatography indicated only partial conversion, therefor, additional amounts of (1-methylpropoxycarbonyl)sulfenyl chloride (0.2 g) and triethylamine (0.12g) was added and the mixture was let stand over night. The reaction mixturewas subjected to silica gel column chromatography using hexane-ether (7:1) as eluent. The title compound was obtained (0 g) in high purity; m.p.: 125°-126° C.
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:41][CH3:42])([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[C:27]([CH3:40])[CH:26]=2)[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:43])[C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH2:44]([O:46][C:47](=[O:56])[CH2:48][C:49]1[CH:50]=[CH:51][C:52](Cl)=[N:53][CH:54]=1)[CH3:45].O>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:44]([O:46][C:47](=[O:56])[CH2:48][C:49]1[CH:54]=[N:53][C:52]([C:28]2[CH:29]=[CH:30][C:25]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:17]([CH3:43])[CH:18]=3)([CH2:23][CH3:24])[CH2:41][CH3:42])=[CH:26][C:27]=2[CH3:40])=[CH:51][CH:50]=1)[CH3:45]
Reactant: CCOC(=O)Cc1ccc(Cl)nc1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2ccc(C(CC)(CC)c3ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c3)cc2C)nc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 15.5 %

Procedure:
A solution of t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 23-(1); 13 mg, 0.021 mmol) in N,N-dimethylformamide (0.2 mL) was added to 2-chloropyridine-5-acetic acid ethyl ester (7.4 mg, 0.037 mmol) and a [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex (1:1) (2.0 mg, 0.0024 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 76 to 84° C. for seven hours and 30 minutes. Water was added to the reaction mixture, followed by extraction with ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=10/1) to give the title compound (2.1 mg, 16%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7](Br)[CH:6]=1.[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1B(O)O)=[O:15]>>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:6]=[C:7]([C:21]2[CH:20]=[C:19]([O:22][CH3:23])[CH:18]=[CH:17][C:16]=2[CH:14]=[O:15])[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: COC(=O)Cc1cc(Cl)cc(Br)c1
Reactant: COc1ccc(C=O)c(B(O)O)c1
Product: COC(=O)Cc1cc(Cl)cc(-c2cc(OC)ccc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (3-bromo-5-chloro-phenyl)-acetic acid methyl ester and 2-formyl-5-methoxyphenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(OCC)(=O)C>O1CCCC1.CCCCCC>[C:31]([N:7]([CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH2:10]1)[CH2:6][C:5]1[CH:22]=[CH:23][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(CNCc2ccc(Cl)cc2)CC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N(Cc1ccc(Cl)cc1)CC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 91.1 %

Procedure:
To a solution of 4-(N-(4-chlorobenzyl)aminomethyl)-1-t-butoxycarbonylpiperidine(300 mg, 0.89 mmol) and triethylamine (180 mg, 1.78 mmol) in tetrahydrofuran (15 mL) stirring at room temperature under argon, was added acetic anhydride (109 mg, 1.07 mmol) in a single portion. After 16 h the mixture was evaporated under vacuum. Column chromatography (silica gel, 65% ethyl acetate in hexane) provided 4-(N-acetyl-N-(4-chlorobenzyl)aminomethyl)-1-t-butoxycarbonylpiperidine (309 mg, 91% yield). TLC Rf=0.30, 65% ethyl acetate in hexane.
Reaction SMILES: C(Cl)Cl.[OH:4][CH2:5][C:6](=[O:8])[CH3:7].CCN(CC)CC.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C1C=CN=CC=1)C.O>[Si:20]([O:4][CH2:5][C:6](=[O:8])[CH3:7])([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To a DCM (5 mL) solution of 1-hydroxypropan-2-one (500 mg, 6.8 mmol), DMAP (41 mg, 0.34 mmol) and Et3N (1.2 mL, 8.16 mmol) was added TBSCl (1.133 g, 7.5 mmol) at 0° C. under nitrogen atmosphere. The mixture was stirred at r.t. for 2 h. Then the mixture was added water and extracted with EtOAc. The organic layer was purified by silica gel chromatography using PE/EA (10/1) to give the title compound (950 mg, 75%). EDI-MS (M+1): 189. 1H NMR (300 MHz, CDCl3) δ 4.057 (s, 2H), 2.080 (s, 3H), 0.832 (s, 9H), 0.001 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]4)[N:17]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:38][C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([C:39]([Cl:38])=[O:41])[CH2:24]4)[N:17]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Fc1ccc(-c2nc3occn3c2-c2ccnc(N[C@@H]3CCCNC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Cl)N1CCC[C@@H](Nc2nccc(-c3c(-c4ccc(F)cc4)nc4occn34)n2)C1
Yield: 95.8 %

Procedure:
To a solution of 4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-[(3R)-piperidin-3-yl]pyrimidin-2-amine (200 mg, 0.45 mmol) and Hunig's base (145 μL, 0.90 mmol) in 10 mL DCM was added a solution of triphosgene (660 mg; 2.25 mmol) in 10 mL DCM dropwise over 10 min with stirring. The mixture was allowed to stir at ambient temperature for 1.5 hr. The reaction mixture was then concentrated under reduced pressure. The residue was diluted with 20 mL ether and concentrated under reduced pressure yielding (3R)-3-({4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carbonyl chloride as an off-white solid (190 mg). The solid was diluted in 10 mL DCM. To the resulting solution was added morpholine (60 μL, 0.67 mmol) and triethylamine (70 μL, 0.50 mmol). The mixture was allowed to stir at ambient temperature for 20 hr. The reaction mixture was then concentrated under reduced pressure and the residue purified by flash chromatography on silica gel (1:4, ethyl acetate:hexanes) to yield 4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]-N-[(3R)-1-(morpholin-4-ylcarbonyl)piperidin-3-yl]pyrimidin-2-amine as an off-white solid (50.2 mg, 23%). 400 MHz 1H NMR (DMSO-d6) δ: 8.75 (s, 1H), 8.20 (s, 1H), 8.11 (d, J=5.2 Hz, 1H), 7.62-7.66 (m, 2H), 7.30-7.34 (m, 2H), 6.37 (s, 1H), 3.76 (m, 2H), 3.53 (m, 4H), 3.15 (m, 2H), 3.09 (m, 2H), 2.75 (m, 2H), 2.62 (m, 1H), 1.99 (s, 1H), 1.78 (br.s, 1H), 1.50-1.54 (m, 2H). LCMS: 492 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:3](/[C:19](/[OH:26])=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:4]([C:8]2([C:14](OCC)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CC[O-].[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:19]([OH:26])[CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:14](=[O:15])[C:8]12[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: CCOC(=O)/C=C(\O)c1c(Cl)cccc1C1(C(=O)OCC)CCOCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1C(=O)C2(CCOCC2)c2cccc(Cl)c2C1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
A mixture of (Z)-ethyl 4-(3-chloro-2-(3-ethoxy-1-hydroxy-3-oxoprop-1-enyl)phenyl)-tetrahydro-2H-pyran-4-carboxylate (0.14 g, 0.37 mmol) in 5 mL EtOH was treated with NaOEt (from 0.1 g Na reacted with 5 mL EtOH). The mixture was stirred at room temperature for 2 hours, quenched with 20 mL water, and neutralized with 5N HCl to pH=5. The mixture was extracted with EtOAc 3×50 mL. The combined organic layers were washed with saturated NaCl (20 mL), dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography (10-40% EtOAc/hexane) to give 67 mg white solid. MS m/e: (M+H)+ 337.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[N+:11]([O-])=O.[H][H]>C(O)C.[Pd]>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([NH:2][CH3:1])=[C:4]([NH2:11])[CH:5]=1
Reactant: CNc1ccc(OC)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CNc1ccc(OC)cc1N
Yield: 120.7 %

Procedure:
A solution of 1.16 g of N-methyl-4-methoxy-2-nitroaniline (prepared as described in Preparation 24) in 50 ml of ethanol was shaken in an atmosphere of hydrogen and in the presence of 0.3 g of 10% w/w palladium-on-charcoal for 3 hours. At the end of this time, the palladium-on-charcoal was filtered off, and the filtrate was freed from the solvent by evaporation under reduced pressure, to give 1.17 g of the title compound having an Rf value=0.50 (on thin layer chromatography on silica gel; developing solvent: a 1:3 by volume mixture of ethyl acetate and hexane).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4](O)=[O:5].CO.Cl>O1CCCC1>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(CO)c1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
The 2-amino-5-chloro-3-methylbenzoic acid (15.6 g, 84.3 mmol) was dissolved in tetrahydrofuran (200 ml) and cooled to 0° C. A solution of borane dimethylsulfide complex (16.8 mL, 16.8 mmol) was dissolved in tetrahydrofuran (40 mL) and added dropwise. The solution was kept at 0° C. for an additional 30 minutes and warmed to room temperature for 2 h and finally refluxed for 16 h. The solution was cooled to room temperature and methanol (10 mL) added slowly to control the gas evolution. The solution was stirred for 30 minutes at room temperature and 1 N hydrochloric acid added. The solution was stirred for 3 h and solvent removed to a volume of about 100 mL. Water (200 mL) was added and the solution extracted with diethylether (200 mL). The aqueous layer was collected, adjusted to pH=12 with 1N sodium hydroxide which formed a solid in the solution. The solid was collected, dissolved in ethyl acetate (100 mL), dried over sodium sulfate and solvent removed at reduced pressure. (2-Amino-5-chloro-3-methylphenyl)methanol (10.8 g, 63.1 mmol) was obtained as a light yellow solid (75% yield). HRMS m/z 172.0544; calcd for M+H 172.0524.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:22]#[C:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Ic1ccc(OC2CCCCC2)nc1
Reactant: C#Cc1ccccc1
Product: C(#Cc1ccc(OC2CCCCC2)nc1)c1ccccc1

Procedure:
The title compound, brown oil, MS: m/e=278.1 (M+H+), can be prepared in accordance with the general method of example 18, step 2 from 2-(cyclohexyloxy)-5-iodopyridine and phenylacetylene.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].O.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([F:16])[C:10]=1[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=2)[C:20]([CH:31]=C)=[CH:19][N:18]=1.C1C[O:36]CC1>S([O-])([O-])=O.[Na+].[Na+].[Os](=O)(=O)(=O)=O>[CH:31]([C:20]1[C:21]2[C:26](=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=2)[C:17]([C:10]2[C:9]([F:8])=[CH:14][C:13]([F:15])=[CH:12][C:11]=2[F:16])=[N:18][CH:19]=1)=[O:36]
Reactant: C1CCOC1
Reactant: C=Cc1cnc(-c2c(F)cc(F)cc2F)c2cc(C(=O)OC)ccc12
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc2c(C=O)cnc(-c3c(F)cc(F)cc3F)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Osmium tetraoxide (2.5% isobutanol solution, 0.05 mL), sodium periodate (280 mg), and water (4 mL) were added to a mixture of methyl 1-(2,4,6-trifluorophenyl)-4-vinylisoquinoline-7-carboxylate (180 mg) and THF (4 mL), followed by stirring at room temperature for 12 hours. The reaction mixture was diluted with an aqueous sodium sulfite solution, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (hexane/ethyl acetate) to obtain methyl 4-formyl-1-(2,4,6-trifluorophenyl)isoquinoline-7-carboxylate (153 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:9][C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)=[CH:4][CH:3]=1.O=[C:22]([CH3:36])[CH2:23][CH2:24][N:25]1C(=O)C2C(=CC=CC=2)C1=O>>[NH2:25][CH2:24][CH2:23][CH:22]([N:18]1[CH2:17][CH2:16][CH:15]([N:8]([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9][C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[CH2:20][CH2:19]1)[CH3:36]
Reactant: Clc1ccc(N(Cc2ccsc2)C2CCNCC2)cn1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Product: CC(CCN)N1CCC(N(Cc2ccsc2)c2ccc(Cl)nc2)CC1

Procedure:
Using general procedure B with the amine from above (65 mg, 0.21 mmol) and 2-(3-oxo-butyl)-isoindole-1,3-dione (115 mg, 0.529 mmol) and then using general procedure D gave [1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(6-chloro-pyridin-3-yl)-thiophen-3-ylmethyl-amine as a yellow oil (60 mg, 75% over 2 steps).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.Cl[C:39]([O:41][C:42]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=1)=[O:40]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:39]([O:41][C:42]4[CH:43]=[CH:44][C:45]([N+:48]([O-:50])=[O:49])=[CH:46][CH:47]=4)=[O:40])[CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:27][CH:28]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIATE M, 0.200 g, 0.479 mmol) and Hunig's base (0.092 ml, 0.527 mmol) in DCM (2.395 ml) was added 4-nitrophenyl chloroformate (0.097 g, 0.479 mmol) (change from colorless to light yellow solution). The reaction was stirred at RT overnight, at which point starting material remained. Additional 4-nitrophenyl chloroformate (0.097 g, 0.479 mmol) was added and the reaction was stirred overnight once more until completion. After concentration in vacuo, the material was purified via MPLC (12-g Redi Sep Gold) eluting with 0-100% ethyl acetate in heptanes, to yield 4-nitrophenyl 7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate as a white solid. m/z (ESI) 583.0 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH:10](SC)[C:9]2[C:4](=[C:5]([O:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)[CH:6]=[CH:7][CH:8]=2)[NH:3]1>[Ni].O1CCOCC1>[O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([O:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)[CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: CSC1C(=O)Nc2c(Oc3ccc4ccccc4c3)cccc21
Agent: [Ni]
Solvent: C1COCCO1
Product: O=C1Cc2cccc(Oc3ccc4ccccc4c3)c2N1
Yield: 82.9 %

Procedure:
A mixture of 2-oxo-3-methylthio-7-(β-naphthoxy)indoline (7.6 g) and Raney nickel (17 ml) in dioxane (100 ml) was treated in a similar manner to that of Example 39-(1) to give 2-oxo-7-(β-naphthoxy)indoline (5.4 g). mp 195°-197° C.