Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[C:17][C:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[F:22][C:19]([F:20])([F:21])[C:18]([OH:24])([CH3:23])/[CH:17]=[CH:16]/[C:13]1[CH:12]=[CH:11][C:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])=[CH:15][CH:14]=1
Reactant: CC(O)(C#Cc1ccc(S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(/C=C/c1ccc(S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Reaction time: 18 h
Yield: 37.6 %

Procedure:
To a stirred solution of 1-(4-phenylsulfonylphenyl)-3-hydroxy-3-methyl-4,4,4-trifluorobut-1-yne (0.45 g, 1.27 mmol) in tetrahydrofuran (6 mL) was added lithium aluminum hydride (56 mg, 1.4 mmol) in one portion and the reaction mixture stirred for 18 hours. The reaction mixture was then treated sequentially with water (0.4 mL), 2N sodium hydroxide (0.4 mL), and water (1 mL). After 10 minutes of stirring the reaction was filtered through diatomaceous earth and the precipitate washed with ethyl acetate. The aqueous layer of the filtrate was separated and extracted further with ethyl acetate. The combined organic extracts were dried filtered, and evaporated. The crude oil was purified by chromatography, with chloroform:ethyl acetate as eluent (18:1), to yield the title compound as a white solid (0.17 g, 37%); mp 94°-97° C.; 250 MHz NMR (CDCl3): 1.56 (s,3, CH3), 2.30 (s,1, OH), 6.38 (d,1, J=16.0, vinylic), 6.89 (d,1, J=16.0, vinylic), 7.46-7.60 (m,5, Ar), 7.89-7.96 (m,4, Ar); MS (EI): m/z=356 (M+). Analysis for C17H15F3O3S: Calculated: C, 57.29; H, 4.24; Found: C, 57.24; H, 4.32.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:20]=O.[O:22]=[C:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[C:28]([NH:32][C:33](=[O:35])[CH3:34])[CH:29]=2)[NH:24]1>>[CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1/[CH:20]=[C:31]1\[C:23](=[O:22])[NH:24][C:25]2[C:30]\1=[CH:29][C:28]([NH:32][C:33](=[O:35])[CH3:34])=[CH:27][CH:26]=2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CCC2
Reactant: CC(=O)Nc1ccc2c(c1)CC(=O)N2
Product: CC(=O)Nc1ccc2c(c1)/C(=C/c1[nH]c3c(c1C)C(=O)N(CCN1CCCC1)CCC3)C(=O)N2
Yield: 80 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c obtained from step 3 of Example 28 and N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide 30d as starting materials to obtain (Z)—N-{3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-acetamide 30 (50 mg, yield 80%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:3]=1.[CH:16]1([CH2:21][C:22](Cl)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1>C(#N)C>[CH:16]1([CH2:21][C:22]([NH:8][C:7]2[C:2]([CH3:1])=[N:3][C:4]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[CH:5][C:6]=2[CH3:9])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: Cc1cc(N2CCOCC2)nc(C)c1N
Solvent: CC#N
Product: Cc1cc(N2CCOCC2)nc(C)c1NC(=O)CC1CCCC1
Temperature: 150 °C
Yield: 49 %

Procedure:
2,4-Dimethyl-6-morpholin-4-yl-pyridin-3-ylamine (0.22 g) and cyclopentylacetyl chloride (0.19 mL) were dissolved in acetonitrile (5 mL) and heated to 150° C. for 10 minutes in a sealed microwave process vial. The reaction mixture was concentrated in vacuo and purified by flash chromatography (SiO2, heptane/ethylacetate 3:1) to furnish 0.17 g (49% yield) of the title compound as a white solid. LC-MS (m/z) 318 (MH); tR=1.40, (UV, ELSD) 97%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.21 (m, 2H), 1.52 (m, 2H), 1.61 (m, 2H), 1.77 (m, 2H), 2.05 (s, 3H), 2.17 (s, 3H), 2.24 (m, 1H), 2.26 (m, 2H), 3.37 (m, 4H), 3.67 (m, 4H), 6.53 (s, 1H), 9.05 (s, 1H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([NH:15][CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=O)=[O:14])=[CH:10][CH:11]=2)[C:6]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[N:5]1)(=O)C.CO.[OH-].[NH4+:35].C([O-])(=O)C.[NH4+]>CN(C)C=O>[C:18]([CH2:17][CH2:16][NH:15][C:13]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][N:5]=[C:6]2[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)=[O:14])(=[O:20])[NH2:35]
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)NCCC(=O)OC(C)(C)C)ccc21
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)CCNC(=O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
A sealed tube containing tert-butyl 3-{[1-acetyl-3-(4-fluorophenyl)-1H-indazol-5-yl]carbonylamino}propanoate (115 mg, 0.270 mmol) and methanol saturated with ammonium hydroxide (2 mL) was heated to 80° C. for 18 hours. The solution was condensed to give an oil. The oil was dissolved in dimethyl formamide (5 mL) with N—N′-carbonyldiimidazole (110 mg). The solution was allowed to stir for two hours at ambient temperature. Ammonium acetate (160 mg) was added and the reaction mixture was allowed to stir at ambient conditions under nitrogen for 18 hours. The mixture was condensed and extracted with 5% sodium bicarbonate and ethyl acetate. The extracts were dried over sodium sulfate, filtered and condensed to give the title compound (17 mg, 19% yield) after purification by preparative-HPLC. 1H NMR (DMSO-d6) δ 8.65 (br s, 1H), 8.47 (s, 1H), 8.00 (m, 2H), 7.84 (d, 1H), 7.59 (d, 1H), 7.43 (br, 1H), 7.35 (t, 2H), 6.84 (s, 1H), 3.45 (m, 2H), 2.39 (m, 2H); ES-MS (m/z) 327[M+1]+.
Reaction SMILES: CO[N:3]=[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1>C1COCC1>[NH2:3][CH:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1
Reactant: CON=C(Cc1ccc(OC)cc1)c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(CC(N)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of a mixture of syn- and anti- isomers of 2-(4-methoxyphenyl)-1-phenyl-1-ethanone-O-methyl oxime (10, 1.65 g, 6.46 mmol) in THF (40 ml, freshly distilled from sodium benzophenone ketyl) under nitrogen was added borane-tetrahydrofuran solution (21.2 ml, 21.2 nmmol, 1.0 M solution, Aldrich) at room temperature. The resulting pale yellow solution was refluxed overnight, and cooled in an ice water bath. Water (50 ml) was carefully added to quench, followed by 20% NaOH (50 ml). The resulting colorless bi-phasic mixture was refluxed with vigorous magnetic stirring overnight, and allowed to cool to room temperature. Hexanes (40 ml) were added, and the layers separated. The aqueous portion was extracted with hexanes (1×40 ml). The combined organic portions were dried over potassium carbonate, and concentrated in vacuo to afford a colorless, slightly cloudy syrup. This syrup was purified by column chromatography on neutral alumina (I, 15 g) using an elution gradient of chloroform to 10% methanol/chloroform. The amine 15 was isolated as 1.263 g of a clear, colorless syrup (86% yield): Rf 0.20 (5% methanol/chloroform); IR (CDCl3) 3376 (w), 3316 (w), 3068 (w), 3031 (w), 3007 (w), 2965 (m), 2940 (m), 2910 (m), 2834 (m), 1614 (m), 1584 (m), 1514 (s), 1493 (m), 1466 (m), 1454. (m), 1441 (m), 1300 (m), 1245 (s), 1179 (m), 1106 (w), 1033 (m); 1H NMR (CDCl3) δ7.40-7.24 (m, 5H), 7.11 (d, J=8.6 Hz, 2H), 6.85 (d, 3=8.6 Hz, 2H), 4.18 (dd, J=8.6, 4.9 Hz, 1H), 3.81 (s, 3H), 2.98 (dd, J=13.5, 4.9 Hz, 1H), 2.79 (dd, J=13.5, 8.7), 1.49 (s, 2H). Low resolution mass spec. 228(M+1, 26), 211(49), 121(44), 107(69), 106(100), 79(100).
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[C:7]([C:10]12[CH2:20][C:14]3([OH:21])[CH2:15][C:16]([OH:19])([CH2:18][C:12]([OH:22])([CH2:13]3)[CH2:11]1)[CH2:17]2)(O)=[O:8]>O1CCCC1>[OH:8][CH2:7][C:10]12[CH2:11][C:12]3([OH:22])[CH2:13][C:14]([OH:21])([CH2:15][C:16]([OH:19])([CH2:18]3)[CH2:17]1)[CH2:20]2
Reactant: O=C(O)C12CC3(O)CC(O)(CC(O)(C3)C1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC12CC3(O)CC(O)(CC(O)(C3)C1)C2

Procedure:
5 In an atmosphere of nitrogen, 15 mmol of aluminum lithium hydride was suspended in 15 ml of tetrahydrofuran (THF). Thereafter, 10 mmol of 1-carboxy-3,5,7-adamantanetriol was gradually added to the mixture while keeping the temperature of the mixture at 10° C. or lower by using ice bath. After the temperature of the mixture had been brought back to room temperature, the mixture was refluxed for 16 hours, giving 1-hydroxymethyl-3,5,7-adamantanetriol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([CH3:17])([CH3:16])[CH:14]=[CH2:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:19]=[CH2:20].CCN(C(C)C)C(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CCOC(C)=O>[CH2:18]([N:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:12])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:13]([CH3:17])([CH3:16])[CH:14]=[CH2:15])[CH:19]=[CH2:20]
Reactant: C=CCNc1ccccc1
Reactant: C=CC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN(C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C=C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 40.6 %

Procedure:
To a round bottom flask was added 2-(tert-butoxycarbonylamino)-3,3-dimethylpent-4-enoic acid (120 mg, 0.493 mmol), N-allylaniline (0.134 mL, 0.986 mmol), EtOAc (5 mL) and Hunig's Base (0.258 mL, 1.48 mmol). The reaction mixture was cooled to 0° C. 1-propanephosphonic acid cyclic anhydride (314 mg, 0.986 mmol) was added and the reaction was stirred at 0° C. for 5 min and then at rt for 3 days. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (10 mL) and saturated aqueous NaCl (10 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated. The residue was purified by RP prep-HPLC (Method A) to give tert-butyl 1-(allyl(phenyl)amino)-3,3-dimethyl-1-oxopent-4-en-2-ylcarbamate (70 mg, 0.20 mmol, 40% yield) as clear oil. Anal. Calcd. for C21H30N2O3 m/z 358.2. found: 359.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[N:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:31]([O:33][C:34](=[O:39])[CH2:35][CH2:36][CH2:37]Br)[CH3:32]>CN(C)C=O.C(OCC)(=O)C>[CH2:31]([O:33][C:34](=[O:39])[CH2:35][CH2:36][CH2:37][N:3]1[C:2](=[O:1])[C:6]2([CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[N:5]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:4]1)[CH3:32]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCN1CN(c2ccccc2)C2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 60 °C
Reaction time: 60 h

Procedure:
To a solution of tert-butyl 4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.15 g, 0.45 mmol) and potassium carbonate (0.124 g, 0.9 mmol) in N,N-dimethylformamide (4 mL), was added ethyl-4-bromobutyrate (0.072 mL, 0.5 mmol, d=1.35). After stirring at 60° C. for 60 hours, the reaction mixture was diluted with ethyl acetate (25 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to obtain tert-butyl 3-(4-ethoxy-4-oxobutyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][CH2:15]O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:38]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:38][CH2:15][CH2:14][CH2:13][C:5]1[CH:4]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: OCCCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: FC(F)(F)c1cc(CCCBr)cc(C(F)(F)F)c1
Yield: 76.3 %

Procedure:
Compound 50-2 (3.48 g) was dissolved in methylene chloride (45 ml), triphenylphosphine (3.73 g) and N-bromosuccinimide (2.5 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (3.27 g) as a yellow oil.
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][C:9]([Si:16]([CH3:19])([CH3:18])[CH3:17])=[CH:10][CH:11]=3)[C:6]([Si](C)(C)C)([Si](C)(C)C)[C:5]=2[CH:4]=1.[OH-].[K+]>C(O)C>[CH3:17][Si:16]([CH3:19])([CH3:18])[C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:5](=[CH:4][C:3]([Si:2]([CH3:29])([CH3:28])[CH3:1])=[CH:15][CH:14]=3)[CH2:6][C:7]=2[CH:8]=1
Reactant: C[Si](C)(C)c1ccc2c(c1)C([Si](C)(C)C)([Si](C)(C)C)c1cc([Si](C)(C)C)ccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C[Si](C)(C)c1ccc2c(c1)Cc1cc([Si](C)(C)C)ccc1-2
Yield: 93.7 %

Procedure:
To a suspension of 0.5 g of 2,7,9,9-tetrakis(trimethylsilyl)-fluorene in 15 mL of 95% ethanol was added 1.5 mL of 10% KOH. The mixture was refluxed for 2 hours and cooled in an ice bath for one hour. The precipitated crystals were removed by filtration, rinsed with water (2×5 mL), dried in air, and recrystallized from methanol to give 0.32 g (93.8%) of pure 2,7-bis(trimethylsilyl)fluorene as colorless crystals, m.p. 117°-118° C.; 1H NMR (CDCl3): δ 0.31 (s, 18H, SiMe3), 3.90 (s, 2H, CH2), 7.20-7.90 (m, 6H, aryl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][CH2:6][C:5](=[O:8])[C:4]=1[C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17].C([N-]C(C)C)(C)C.[Li+].Cl[CH2:27][C:28]1[CH:32]=[C:31]([CH3:33])[O:30][N:29]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH2:7][CH:6]([CH2:27][C:28]2[CH:32]=[C:31]([CH3:33])[O:30][N:29]=2)[C:5](=[O:8])[C:4]=1[C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17]
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)CC1
Reactant: Cc1cc(CCl)no1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(Cc2cc(C)on2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A flask is charged with 3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (230 mg, 1 mmol), purged with nitrogen and anhydrous THF (5 ml) added. The resulting solution is cooled to −78° C. and lithium diisopropylamide (1.8M solution in hexane/THF/ethyl benzene) (0.61 ml, 1.1 mmol) is added dropwise and the reaction stirred at −78° C. for a further 30 minutes. A solution of 3-chloromethyl-5-methyl isoxazole in THF (1 ml) is then added in one portion, and the reaction is allowed to warm to ambient temperature and stirred for a further 2 hours. The reaction is quenched by the addition of saturated ammonium chloride solution (20 ml), and extracted with ethyl acetate (2×20 ml). The combined organics are evaporated under reduced pressure and the residue is purified by flash chromatography to give 3-methoxy-5-(5-methyl-isoxazol-3-ylmethyl)-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (132 mg)
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@H:11]2[C@H:19]3[N:14]([C:15]4[CH:23]=[CH:22][C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[S:30]([NH:33]C(C)(C)C)(=[O:32])=[O:31])=[CH:20][C:16]=4[O:17][CH2:18]3)[C:13](=[O:38])[O:12]2)=[O:8])=[CH:4][CH:3]=1.CC(=O)OCC>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@H:11]2[C@H:19]3[N:14]([C:15]4[CH:23]=[CH:22][C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[S:30]([NH2:33])(=[O:31])=[O:32])=[CH:20][C:16]=4[O:17][CH2:18]3)[C:13](=[O:38])[O:12]2)=[O:8])=[CH:4][CH:3]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc2c(c1)OC[C@H]1[C@H](CNC(=O)c3ccc(Cl)s3)OC(=O)N21
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccccc1-c1ccc2c(c1)OC[C@H]1[C@H](CNC(=O)c3ccc(Cl)s3)OC(=O)N21
Temperature: 40 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
Compound 5-chloro-N-(((3S,3aS)-1-oxo-7-(2-t-butylaminosulfonylphenyl)-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-3-yl)methyl)thiophene-2-carboxamide (124 mg, 0.215 mmol) was dissolved in 2 ml of TFA. The resulting mixture was heated to 40° C. and agitated for 2 h. TLC (PE/EA=1/1) was employed to monitor the reaction. After the reaction completed, TFA was evaporated, and the remainder was diluted by 20 ml of EA, washed with 8 ml of water and 8 ml of saturated saline solution for one time each, dried over anhydrous sodium sulfate, and the solvent was evaporated. Column chromatography (PE/EA=2/1) afforded 91 mg of white solid, yield: 81.22%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-])=O)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.O.NN>[Ni].CO>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Cc1cc([N+](=O)[O-])c2ncccc2c1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1cc(N)c2ncccc2c1
Yield: 62.8 %

Procedure:
In a similar fashion using route 6 general procedure 14, 6-methyl-8-nitroquinoline (Intermediate 42) (300 mg, 1.6 mmol), Raney nickel (60 mg, 20% wt) hydrazine hydrate (0.32 ml, 6.30 mmol) and MeOH (8 ml) gave the title compound (159 mg) which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([C:11]4[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[CH2:15][CH:16]=4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1
Product: O=C(Nc1ccc2[nH]cc(C3=CCN(CCc4ccccc4)CC3)c2n1)c1ccc(F)cc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.061 mMol) 4-fluorobenzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12]([O:22]C)[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.CC(O)=O.Br>O.[OH-].[Na+]>[NH2:21][C:19]1[CH2:18][O:17][CH2:16][C@:15]2([C:14]3[CH:13]=[C:12]([OH:22])[N:11]=[CH:10][C:9]=3[O:8][C:5]3[C:4]2=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)[N:20]=1
Reactant: COc1cc2c(cn1)Oc1ccc(Br)cc1[C@@]21COCC(N)=N1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: NC1=N[C@@]2(COC1)c1cc(Br)ccc1Oc1cnc(O)cc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
(S)-7-bromo-3-methoxy-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.611 g, 1.624 mmol) was dissolved in HOAc (6.14 mL, 107 mmol). Hydrobromic acid (48% aq.; 6.06 mL, 53.6 mmol) was added and the reaction was stirred at 100° C. for two hours. The reaction was diluted with water, slowly neutralized to pH 7 with 6N NaOH, and stirred overnight, during which a light pink solid crashed out of solution. The solution was filtered, and the solid was air dried to afford (S)-5′-amino-7-bromo-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-3-ol (0.554 g, 1.530 mmol, 94% yield) as an off-white solid. [M+H]+=363.9
Reaction SMILES: C([O:5][C:6](=[O:44])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:36][NH:37][C:38]([O:40][CH:41]([CH3:43])[CH3:42])=[O:39])(C)(C)C.Cl>C1COCC1>[CH:41]([O:40][C:38]([NH:37][CH2:36][C:10]1[CH:11]=[C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][C:27]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])[CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][C:6]([OH:44])=[O:5])=[O:39])([CH3:43])[CH3:42]
Reactant: Cc1oc(-c2ccc(-c3cccnc3)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(-c3cccnc3)cc2)nc1CCOc1ccc(CCC(=O)O)c(CNC(=O)OC(C)C)c1

Procedure:
This ester (225 mg, 0.375 mmol) was dissolved in THF (15 mL) and treated with 1N HCl (1 mL). The mixture was heated at reflux for 7 h, cooled, and concentrated. The residue was azeotroped twice with acetonitrile and dried in a vacuum oven to give the title compound, isolated as the HCl salt (140 mg, 64%). 1H NMR (DMSO-d6) δ1.15 (d, 6H), 2.41 (s, 3H), 2.45 (t, 2H), 2.76 (t, 2H), 2.95 (t, 2H), 4.17 (overlapping t and d, 4H), 4.75 q, 1H), 6.77 (m, 2H), 7.07 (dd, 1H), 7.55 (t, 1H), 8.02 (m, 4H), 8.73 (d, 1H), 8.85 (d, 1H), 9.25 (s, 1H). MS [EI+] m/z 544 (M+H).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:4]([NH:6][C@H:7]([C:25]([N:27]1[CH2:41][CH2:40][CH2:39][C@H:28]1[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:24])[NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:5])[CH3:3].C(Cl)(Cl)[Cl:50].CO>Cl.C(OCC)(=O)C>[NH:1]([Cl:50])[C@H:2]([C:4]([NH:6][C@H:7]([C:25]([N:27]1[CH2:41][CH2:40][CH2:39][C@H:28]1[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:24])[NH:13][S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:5])[CH3:3]
Reactant: ClC(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](C)NCl)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1

Procedure:
The solution of 137 mg (0.2 mmol) of Boc-Ala-Arg(Tos)-Pro-OBzl in 3 ml of hydrogen chloride in ethyl acetate (4 mol/L) was stirred at room temperature for 2 h and TLC (chloroform/methanol, 20:1) indicated complete disappearance of Boc-Ala-Arg(Tos)-Pro-OBzl. The reaction mixture was evaporated under reduced pressure with ethyl acetate, repeatedly, to remove hydrogen chloride. The residue was triturated with ether to provide the title compound as a colorless powder, which was used for the next reaction directly.
Reaction SMILES: O[CH:2]1[CH2:11][CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:18][OH:19])[CH:8]=2)[O:3]1.[CH:20]([NH:23][CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21]>CO>[CH:20]([N:23]([CH:24]([CH3:26])[CH3:25])[CH2:2][CH2:11][CH:10]([C:9]1[CH:8]=[C:7]([CH2:18][OH:19])[CH:6]=[CH:5][C:4]=1[OH:3])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:22])[CH3:21]
Reactant: CC(C)NC(C)C
Reactant: OCc1ccc2c(c1)C(c1ccccc1)CC(O)O2
Solvent: CO
Product: CC(C)N(CCC(c1ccccc1)c1cc(CO)ccc1O)C(C)C
Reaction time: 1 h

Procedure:
(2-Hydroxy-4-phenyl-3,4-dihydro-2H-chromen-6-yl)methanol (Example 13, 830 g, 3.24 mol, 1.0 eq) was stirred in methanol (4150 mL, 5.0 mL/g). Diisopropylamine (1362 mL, 9.72 mol, 3.0 eq) was then added over 15 minutes via dropping funnel. The resulting solution was then stirred for one hour under nitrogen.