Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].C[O:11][C:12]([C:14]1[C:27]2[O:26][CH2:25][C:21]3([CH2:24][O:23][CH2:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:28][CH3:29])=[CH:16][CH:15]=1)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH2:8][C:12]([C:14]1[C:27]2[O:26][CH2:25][C:21]3([CH2:24][O:23][CH2:22]3)[CH2:20][O:19][C:18]=2[C:17]([O:28][CH3:29])=[CH:16][CH:15]=1)=[O:11]
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COC(=O)c1ccc(OC)c2c1OCC1(COC1)CO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c1OCC1(COC1)CO2

Procedure:
Following the general procedure, condensation of 3,5-dichloro-4-methylpyridine (169 mg, 1.04 mmol) with compound 514 (224 mg, 0.8 mmol) in THF (4 mL) in the presence of LiHMDS (2.4 mL, 2.4 mmol) afforded compound 121 as a white solid material after purification by column chromatography (65-80% EtOAc in light petroleum). LC-MS: RT=3.24 min.; m/z 410.07 (M+H)+, 408.19, 410.22 (M−H)−. 1H NMR (DMSO-d6): δ 8.66 (2H, s), 7.45 (1H, d, J 8.9), 6.91 (1H, d, J 9.0), 4.66 (2H, s), 4.57 (2H, s), 4.50 (2H, d, J 6.5), 4.46 (2H, d, J 6.5), 4.36 (2H, s), 3.85 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:16][C:9]2=[N:10][C:11]([Cl:15])=[C:12]([CH3:14])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].CC(C)([O-])C.[K+].[C:23]([O:27][C:28]([N:30]1[CH2:34][C@H:33]([CH3:35])OS1(=O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:16]([C@H:33]([CH3:35])[CH2:34][NH:30][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[C:9]2=[N:10][C:11]([Cl:15])=[C:12]([CH3:14])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2cc(C)c(Cl)nc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C)c(Cl)nc2n1[C@H](C)CNC(=O)OC(C)(C)C
Yield: 87.8 %

Procedure:
A stirred solution of 0.34 g (1.42 mmol) 6-chloro-5-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester in 7 mL N,N-dimethylformamide was cooled to 0° C. Potassium tert-butoxide (0.17 g, 1.50 mmol) was added and after 30 min. 0.37 g (1.57 mmol) (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester was added and the cooling bath was removed. After 3 h the reaction mixture was poured into 10% aqueous citric acid solution and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography over silica gel (0.030–0.063 mm) with ethyl acetate:n-hexane (1:5) as eluant to give the product as a colourless solid (87.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:12]=3[C:13]=2[C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:18][CH:17]=2)=[O:15])=[CH:5][CH:4]=1>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:12]=3[C:13]=2[CH:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:18][CH:17]=2)[OH:15])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2oc3cc(OC)ccc3c2C(=O)c2ccc(OCCN(C)C)cc2)cc1
Solvent: CO
Product: COc1ccc(-c2oc3cc(OC)ccc3c2C(O)c2ccc(OCCN(C)C)cc2)cc1
Yield: 68.5 %

Procedure:
1.335 g (3 mmol) of [2-(4-methoxyphenyl)-6-methoxybenzofuran-3-yl][4-[2-dimethylaminoethoxy]phenyl] methanone was reduced to the carbinol by the method described in Example 1. This yielded 920 mg of the title compound as an oil.
Reaction SMILES: FC(F)(F)C(F)=C(F)F.[F:10][C:11]([F:28])([F:27])[CH:12]([C:17](F)([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[C:13]([F:16])([F:15])[F:14].S(=O)(=O)(O)[OH:30]>O>[F:10][C:11]([F:28])([F:27])[C:12]([OH:30])([CH:17]([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[C:13]([F:16])([F:15])[F:14]
Reactant: FC(F)(F)C(C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=S(=O)(O)O
Agent: FC(F)=C(F)C(F)(F)F
Solvent: O
Product: OC(C(F)C(F)(F)C(F)(F)F)(C(F)(F)F)C(F)(F)F

Procedure:
To prepare 2-trifluoromethyl-1,1,1,3,4,4,5,5,5-nonafluoro-2-pentanol, commercially available hexafluoropropene may be oligomerized with commercially available trimethylamine in a dipolar aprotic solvent such as commercially available tetrahydrofuran to provide (CF3)2C:CFCF2CF3 which is then reacted with commercially available hydrogen fluoride to yield 2-trifluoromethyl-1,1,1,3,3,4,4,5,5,5-decafluoropentane as taught by W. Brunskill et al., "Anionic Oligomerisation of Hexafluoropropene: Fission of a Carbon-Carbon Bond by Fluoride Ion", Chemical Communications, 1444 (1970). The 2-trifluoromethyl-1,1,1,3,3,4,4,5,5,5-decafluoropentane may then be dehydrohalogenated and then reacted with sulfuric acid and then water to form 2-trifluoromethyl-1,1,1,3,4,4,5,5,5-nonafluoro-2-pentanol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:15]([C:17]3[C:18]([O:36][CH3:37])=[C:19]([CH:25]4[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]4)[C:20]([F:24])=[C:21]([Cl:23])[CH:22]=3)[CH3:16])[N:9]=[C:10]([CH:11]([OH:14])CO)[C:3]=12.C(O)(=O)C.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:15]([C:17]3[C:18]([O:36][CH3:37])=[C:19]([CH:25]4[CH2:26][N:27]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:28]4)[C:20]([F:24])=[C:21]([Cl:23])[CH:22]=3)[CH3:16])[N:9]=[C:10]([CH:11]=[O:14])[C:3]=12
Reactant: COc1c(C(C)n2nc(C(O)CO)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C(C)n2nc(C=O)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a solution of tert-butyl 3-(3-{1-[4-amino-3-(1,2-dihydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-6-fluoro-2-methoxyphenyl)azetidine-1-carboxylate (0.40 g, 0.74 mmol) in tetrahydrofuran (5.6 mL)/water (3.4 mL) was added acetic acid (0.011 mL, 0.19 mmol) and sodium periodate (0.478 g, 2.23 mmol) at 0° C. After stirring for 2 h, the reaction mixture was diluted with water, and extracted with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated to give the desired product (0.35 g, 92%) which was used directly in the next step. LCMS calculated for C23H27ClFN6O4 (M+H)+: m/z=505.2; Found: 505.1.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[CH:3]1.O[N:15]=[C:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.N>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[O:13][N:23]=[C:16]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[N:15]=3)=[CH:10][C:5]=2[N:4]=[CH:3]1
Reactant: NC(=NO)c1cccnc1
Reactant: Cn1cnc2cc(C(=O)O)ccc21
Agent: N
Product: Cn1cnc2cc(-c3nc(-c4cccnc4)no3)ccc21

Procedure:
The title compound was prepared according to Method C using 1-methyl-1H-benzo[d]imidazole-5-carboxylic acid (Maybridge) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ7.65 (ddd, J=8.0, 4.9, 0.7 Hz, 1 H), 7.68-7.88 (m, J=8.8 Hz, 1 H), 7.87-8.10 (m, 2 H), 8.14-8.37 (m, 1 H), 8.46 (dt, J=8.1, 1.9 Hz, 1 H), 8.82 (dd, J=4.7, 1.7 Hz, 1 H), 9.27 (dd, J=2.0, 0.7 Hz, 1 H) ppm; MS (DCI/NH3) m/z 278 (M+H)+.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:17])[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8]1.[C:18](=[O:20])=[O:19].C(OCC)C>CCCCCC.C(OCC)C>[CH3:6][C:7]1([CH3:17])[CH2:16][CH2:15][C:14]2[C:9](=[C:10]([C:18]([OH:20])=[O:19])[CH:11]=[CH:12][CH:13]=2)[O:8]1
Reactant: O=C=O
Reactant: CC1(C)CCc2ccccc2O1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1(C)CCc2cccc(C(=O)O)c2O1
Temperature: 0 °C

Procedure:
To a solution of 1.6M n-butyllithium in hexane and 150 ml of diethyl ether were added a solution of 27 g of 2,2-dimethylchroman in diethyl ether over a one hour period at room temperature. The solution was then heated at reflux 160 minutes, cooled, and poured into dry ice/diethyl ether. The mixture was allowed to come to room temperature, poured into ice water, and layers separated. The organic layer was washed with water, dried over sodium sulfate, and concentrated in vacuo to provide 21 g of solid. The aqueous layer was acidified and the resulting precipitate extracted into diethyl ether/ethyl acetate. The organic extract was washed with water, dried over sodium sulfate, and concentrated in vacuo to provide 9 g of solid. The two isolated solids were combined and chromatographed over silica gel eluting with 10% ethyl acetate in toluene. The appropriate fractions were combined and concentrated in vacuo to provide 9.8 g of the desired title intermediate, m.p. 90°-92° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])[N:3]=1.C(N(C(C)C)CC)(C)C>CO.[Pd]>[CH3:19][O:18][CH2:17][CH2:16][CH2:15][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:6]=2)[CH:2]=[N:3]1
Reactant: COCCCn1nc(Br)c2ccc(C(=O)OC)cc21
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COCCCn1ncc2ccc(C(=O)OC)cc21
Reaction time: 1 h
Yield: 105.4 %

Procedure:
To a solution of methyl 3-bromo-1-(3-methoxypropyl)-1H-indazole-6-carboxylate (3.0 g) and diisopropylethylamine (2.4 mL) in methanol (60 mL) was added 10% palladium on carbon catalyst (600 mg), and the mixture was stirred under hydrogen for 1 hour. An insoluble was filtered, and then the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform, sequentially washed with 10% hydrochloric acid water and saturated saline, and then concentrated under reduced pressure to give methyl 1-(3-methoxypropyl)-1H-indazole-6-carboxylate [REx(18-1)] (2.40 g) as a pale yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:39]=[CH:38][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([C:36]#[N:37])=[C:15]([NH:19][C:20]([C:22]3[N:26](CC4C=CC(OC)=CC=4)[N:25]=[N:24][N:23]=3)=[O:21])[CH:16]=[CH:17][CH:18]=2)=[C:6]([CH2:40][CH2:41][CH3:42])[C:5]=1[OH:43])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[C:1]([C:4]1[CH:39]=[CH:38][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([C:36]#[N:37])=[C:15]([NH:19][C:20]([C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[O:21])[CH:16]=[CH:17][CH:18]=2)=[C:6]([CH2:40][CH2:41][CH3:42])[C:5]=1[OH:43])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2cccc(NC(=O)c3nnnn3Cc3ccc(OC)cc3)c2C#N)ccc(C(C)=O)c1O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCc1c(OCCCOc2cccc(NC(=O)c3nnn[nH]3)c2C#N)ccc(C(C)=O)c1O

Procedure:
A solution of 7.05 g (12.06 mmol) of N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-2-cyanophenyl}-1-(4-methoxybenzyl)-tetrazole-5-carboxamide in 150 ml of trifluoroacetic acid and 15 ml of anisole is heated under reflux for 30 minutes. The reaction mixture is concentrated under reduced pressure, approximately 200 ml of ether and 300 ml of petroleum ether are added and the crystals are filtered off. The resulting N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]- 2-cyanophenyl}-1H-tetrazole-5-carboxamide having a melting point of 206°-208° is dissolved in 50 ml of acetone while hot, and the calculated amount of triethanolamine in 30 ml of acetone is added thereto. After the addition of ether, crystallisation begins. The triethanolammonium salt of N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-2-cyanophenyl}-1H-tetrazole-5-carboxamide having a melting point of 81° (decomposition) is obtained.
Reaction SMILES: Br[C:2]1[CH2:3][CH2:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([Li])(C)(C)C.C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C.Cl>C(OCC)C.CCCCC>[CH:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[B:21]([OH:22])[OH:20]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: BrC1=Cc2ccccc2CC1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: OB(O)C1=Cc2ccccc2CC1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
A solution of 3-bromo-1,2-dihydro-naphthalene (7.7 g, 37 mmol) (Adamczyk, M.; Watt, D. S.; Netzel, D. A. J. Org. Chem. 1984, 49, 4226-4237) in diethylether (370 ml) was cooled in a dry ice bath and tert.-butyllithium solution (50 ml of a 1.5 M solution in pentane) was added maintaining T<−65° C. At this temperature stirring was continued for 30 min, then triisopropylborate (17.3 ml, 75 mmol) was added. The reaction mixture was brought to rt and treated with 3N HCl (100 ml). After 15 min the organic phase was dried (Na2SO4), evaporated and precipitated with pentane to provide the title compound (3.83 g, 60%) as a white solid material. MS: m/e=173 (M−H−).
Reaction SMILES: [CH2:1]([N:4]([C@@H:17]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21]1)=[O:19])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6])[CH:2]=[CH2:3].N1C=CN=C1.[Si:37](Cl)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38].O>CN(C)C=O>[CH2:1]([N:4]([C@@H:17]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:18]([N:20]1[CH2:24][CH2:23][C@H:22]([O:25][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH2:21]1)=[O:19])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=[O:6])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCN([C@H](C(=O)N1CC[C@H](O)C1)c1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN([C@H](C(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)C1)c1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution N-allyl-N-[2-(3-(S)-hydroxy-pyrrolidin-1-yl)-2-oxo-1-(S)-phenyl-ethyl]-2-nitro-benzenesulfonamide (7.13 g, 16.0 mmol) in anhydrous dimethylformamide (16 cm3) was added imidazole (2.18 g, 32.0 mmol). When the imidazole dissolved tert-butyldimethylsilyl chloride was added and stirred at ambient temperature for 3 hours. The solution was poured into water (200 cm3), extracted with ethyl ether (3×50 cm3), washed with water (2×40 cm3), brine (40 cm3), dried over sodium sulfate, vacuum filtered and the volatile fractions removed in vacuo to a yellow glass (8.73 g, 97.4%) with a positive ion ESI (M+H)+560.3
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C:3]([O:5][C:6]1[CH:11]([OH:12])[NH:10][CH:9]=[N:8][C:7]=1[C:13]([O:15][CH3:16])=[O:14])=[O:4].[CH2:19](Br)[CH:20]=[CH2:21].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[CH2:21]([N:10]1[C:11](=[O:12])[C:6]([O:5][C:3](=[O:4])[C:2]([CH3:18])([CH3:17])[CH3:1])=[C:7]([C:13]([O:15][CH3:16])=[O:14])[N:8]=[CH:9]1)[CH:20]=[CH2:19]
Reactant: COC(=O)C1=C(OC(=O)C(C)(C)C)C(O)NC=N1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: C=CCn1cnc(C(=O)OC)c(OC(=O)C(C)(C)C)c1=O

Procedure:
Methyl 5-[(2,2-dimethylpropanoyl)oxy]-6-hydroxy-1,6-dihydropyrimidine-4-carboxylate (see Example 4, Step 3) was dissolved in THF, then allyl bromide (2 eq.) and Cs2CO3 (2 eq.) were added. The reaction mixture was refluxed for 2 h, then evaporated. The residue was diluted with EtOAc, washed with 1N HCl, dried (Na2SO4) and the solvent evaporated. The product was purified by flash chromatography on silica gel eluting with a gradient of petroleum ether/EtOAc.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N:18]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]([O:34][CH2:35][CH2:36][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[CH:26][CH:25]=3)[C:19]2=[O:43])[C:8]([O:16][CH3:17])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([C:5]1[CH:6]=[C:7]([N:18]2[C:22](=[O:23])[CH2:21][CH:20]([C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]([O:34][CH2:35][CH2:36][N:37]4[CH2:38][CH2:39][O:40][CH2:41][CH2:42]4)=[CH:26][CH:25]=3)[C:19]2=[O:43])[C:8]([O:16][CH3:17])=[C:9]([NH:11][S:12]([CH3:15])(=[O:13])=[O:14])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(NS(C)(=O)=O)cc(C(C)(C)C)cc1N1C(=O)C=C(c2ccc(OCCN3CCOCC3)c3ccccc23)C1=O
Agent: [Pd]
Solvent: CCO
Product: COc1c(NS(C)(=O)=O)cc(C(C)(C)C)cc1N1C(=O)CC(c2ccc(OCCN3CCOCC3)c3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
In a 20 mL scintillation vial was placed (28 mg, 0.046 mmol) N-(5-tert-butyl-2-methoxy-3-{3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-2,5-dioxo-2,5-dihydro-pyrrol-1-yl}-phenyl)-methanesulfonamide, 5 mL ethanol, and Pd/C (15 mg, 10 mole %). The vial was sealed with a septum and the reaction mixture was sparged with house nitrogen for 10 minutes. The resulting solution was then sparged with hydrogen gas via a balloon for 5 minutes. After recharging the balloon with hydrogen gas the reaction was allowed to stir at room temp for 2 hours. The resulting solution was filtered through a pad of celite and concentrated under vacuum to afford the desired product (27 mg, 100%). Calculated mass=610. Observed mass=611.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][N:15]([C:18](=[O:20])[CH3:19])[CH2:14][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Reaction time: 8 h
Yield: 33.9 %

Procedure:
To a solution of 2,8-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (1.12 g, 4.66 mol) in dichloromethane (10 ml), triethylamine (3.88 ml) and acetic anhydride (1.32 ml, 14 mmol) are added at 0° C. The reaction mixture is stirred for overnight, quenched with ice-water and extracted with dichloromethane. The combined extracts are washed with H2O, brine and dried over sodium sulphate to give crude 8-acetyl-2,8-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (1.34 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C@H:10]([C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:25]2)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.C(O)(=O)C>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C@@H:10]([CH2:22][N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[CH2:25]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1)c1ccccc1
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@@H](N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1CN1CCC[C@@H](Cc2ccc(F)cc2)C1)c1ccccc1
Reaction time: 20 h
Yield: 68.6 %

Procedure:
(3R,4S)-3-[(S)-3-(4-fluorobenzyl)-piperidine-1-carbonyl]-4-[(R)-1-phenyl-ethylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 294 μmol)) was treated with borane-tetrahydrofuran complex in tetrahydrofuran (1.0 M; 11.64 mL, 11.64 mmol) and stirred for 20 h. The mixture was treated slowly with 20% acetic acid in methanol (20 mL), and the resulting mixture was stirred at room temperature for 36 h. The solvents were removed, and the residue was dissolved in water, made basic (pH 11) with 50% sodium hydroxide, and extracted with dichloromethane. The combined organic phases were dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (60% ethyl acetate/hexane) to provide the product (100 mg, 68%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:20]=[CH:19][C:18]3[N:17]([CH3:21])[C:16]4[CH2:22][CH:23]5[NH:27][CH:26]([C:15]=4[C:14]=3[C:13]=2C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[ClH:35]>ClCCl.CO.C(OCC)C>[ClH:35].[F:8][C:6]1[CH:5]=[C:4]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16]2[CH2:22][CH:23]4[NH:27][CH:26]([C:15]3=2)[CH2:25][CH2:24]4)(=[O:11])=[O:10])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cc(F)cc(F)c4)ccc31)C1CCC(C2)N1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: Cn1c2c(c3cc(S(=O)(=O)c4cc(F)cc(F)c4)ccc31)C1CCC(C2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product of step A in dichloromethane (0.9 mL) and methanol (0.1 mL) was added 2M HCl in diethyl ether (5 mL). The reaction mixture was stirred at ambient temperature overnight, filtered, washed with diethyl ether and dried in vacuo to give 2-(3,5-difluorophenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride (15 mg, 50%, AUC HPLC 98.0%) as an off-white solid: mp 230-235° C. dec; 1H NMR (CD3OD, 300 MHz) δ 8.32 (d, J=1.8 Hz, 1H), 7.77 (dd, J=8.7, 1.8 Hz, 1H), 7.57-7.61 (m, 3H), 7.20-7.28 (m, 1H), 5.32 (d, J=4.8 Hz, 1H), 4.55 (br s, 1H), 3.73 (s, 3H), 3.49 (dd, J=17.4, 4.5 Hz, 1H), 3.25-3.40 (m, 1H), 3.08 (d, J=17.4 Hz, 1H), 2.26-2.48 (m, 2H), 1.96-2.00 (m, 1H); ESI MS m/z 389 [M+H]+.
Reaction SMILES: [CH2:1]([O:9][C:10]1[C:11](=[O:22])[O:12][C:13]2[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:14]=2[C:15]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:1]([O:9][C:10]1[C:11](=[O:22])[O:12][C:13]2[C:20]([O:21][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:19][CH:18]=[CH:17][C:14]=2[C:15]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCOC(=O)CCBr
Reactant: CCCCCCCCOc1c(O)c2cccc(O)c2oc1=O
Product: CCCCCCCCOc1c(O)c2cccc(OCCC(=O)OCC)c2oc1=O

Procedure:
In the same manner as in Reference Example 3, except that an equimolar amount of 3-octyloxy-4,8-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-hexyloxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and ethyl 3-bromopropionate was used in place of ethyl bromoacetate in Reference Example 3, 3-octyloxy-4-hydroxy-8-(2-ethoxycarbonylethoxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:32](=[O:33])[N:13]2[CH2:14][CH:15]3[CH2:20][CH2:19][C:18]([NH:21][C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])([C:12]2=[N:11][C:10]=1[C:34]([O:36]CC)=[O:35])[CH2:17][CH2:16]3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O[Li].O>CCO>[CH2:1]([O:8][C:9]1[C:32](=[O:33])[N:13]2[CH2:14][CH:15]3[CH2:16][CH2:17][C:18]([NH:21][C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])([C:12]2=[N:11][C:10]=1[C:34]([OH:36])=[O:35])[CH2:19][CH2:20]3)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Agent: [Li]O
Solvent: O
Solvent: CCO
Product: O=C(NC12CCC(CC1)Cn1c2nc(C(=O)O)c(OCc2ccccc2)c1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
To a solution of ethyl 3-(benzyloxy)-10-(((benzyloxy)carbonyl)amino)-4-oxo-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate, Intermediate 3 (250 mg, 0.483 mmol) in EtOH (5 mL) was added water (1.250 mL) followed by LiOH—H2O (20.27 mg, 0.483 mmol) and the mixture was stirred at room temp for 16 h. Water (10 mL) was then added and the mixture was extracted with ether (100 mL). The aqueous layer was then acidified with 1N HCl and then extracted with ethyl acetate (2×100 mL), washed with brine, dried (Na2SO4), filtered and concentrated to afford the title compound (180 mg, 76% yield) as a light yellow solid. 1H NMR (500 MHz, CDCl3) δ: 7.51 (d, 2H, J=6.71 Hz), 7.30-7.40 (m, 9H), 5.46 (s, 2H), 5.06 (s, 2H), 4.10-4.15 (m, 2H), 2.47-2.61 (m, 3H), 2.03-2.11 (m, 2H), 1.91-2.01 (m, 2H), 1.63-1.73 (m, 2H). LCMS (M+H)=490.23.