Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][N:17]=2)[CH3:15])=[O:12])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].C1C[O:31]CC1.[OH-].[Na+].OO>C(Cl)Cl.O>[OH:31][CH2:2][CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:25])[F:26])=[CH:18][N:17]=2)[CH3:15])=[O:12])=[CH:8][CH:9]=1)[CH3:3]
Reactant: C=C(C)c1ccc(CC(=O)N[C@H](C)c2ccc(OCC(F)(F)F)cn2)cc1
Reactant: C1CCOC1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(CO)c1ccc(CC(=O)N[C@H](C)c2ccc(OCC(F)(F)F)cn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A microwave vial was charged with 2-(4-isopropenylphenyl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide (300 mg, 0.793 mmol) and THF (500 uL). The solution was cooled to 0° C. and borane tetrahydrofuran complex (1.19 mL, 1.19 mmol) was added via syringe. The reaction was warmed to room temperature over 1.5 h., then NaOH (5M, 634 uL, 3.17 mmol) was added dropwise, followed by the slow addition of hydrogen peroxide (30 wt. % in water, 991 uL, 8.72 mmol). After stirring for 30 min, the mixture was diluted with CH2Cl2 (30 mL) and water (30 mL), and the layers were separated. The aqueous layer was washed with CH2Cl2 (2×15 mL) and the combined organic layer was dried over MgSO4, filtered, and concentrated. The resulting crude material was purified by normal phase chromatography (20-100% EtOAc/Hexanes) to give 133 mg (42%) of 2-[4-(2-hydroxy-1-methylethyl)phenyl]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 8.20 (d, J=2.57 Hz, 1H), 7.21 (m, 6H), 6.69 (d, J=6.96 Hz, 1H), 5.10 (quint. J=6.96 Hz, 1H), 4.38 (q, J=8.00, 2H), 3.71 (m, 2H), 3.57 (s, 2H), 2.96 (m, 1H), 1.40 (d, J=6.67 Hz, 3H), 1.28 (d, J=6.96 Hz, 3H); MS (Electrospray): m/z 397.4 (M+H). The two diastereomers were separable by chiral HPLC under the following conditions: Column: ChiralPak AD (4.6 mm×250 mm, 10 u), Solvent: Hex/EtOH/MeOH (85/7.5/7.5), 1 mL/L diethylamine, Flow rate: 1 mL/min, Retention times: 11.3 and 12.8 min
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:12])=[C:7]([CH:11]=1)[C:8]([O-:10])=[O:9].[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14].[C:18](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:12][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][N:15]([CH2:16][CH3:17])[CH2:13][CH3:14])=[CH:11][C:7]=1[C:8]([O:10][CH3:18])=[O:9]
Reactant: O=C([O-])[O-]
Reactant: CCNCC
Reactant: O=C([O-])c1cc(CBr)ccc1Cl
Agent: [K+]
Solvent: CC(C)=O
Product: CCN(CC)Cc1ccc(Cl)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99.5 %

Procedure:
A mixture of 5-(bromomethyl)-2-chlorobenzoate (4.0 g, 15.6 mmol), diethylamine (5 mL, 48.1 mmol), and potassium carbonate (4.3 g, 31.2 mmol) in acetone (60 mL) was stirred at room temperature for 2 days. The solid material was removed by filtration. The filtrate was recovered, evaporated, and dried in vacuo, affording methyl 2-chloro-5-[(diethylamino)methyl]benzoate (3.97 g, 99% yield). The product was used without further purification.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][N:12]=1)[C:8]#N)([CH3:4])[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.CO.C(C(C(C([O-])=O)O)O)([O-])=[O:26].[Na+].[Na+]>C1(C)C=CC=CC=1>[OH:1][C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][N:12]=1)[CH:8]=[O:26])([CH3:4])[CH3:3]
Reactant: CC(C)(O)c1cc(C#N)ccn1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(O)c1cc(C=O)ccn1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a solution of 2-(2-hydroxypropan-2-yl)isonicotinonitrile (41.4 g, 0.255 mol) in toluene (500 mL) was added dropwise a solution of diisobutylaluminum hydride (1 mol/L in hexane, 765 mL, 0.765 mol) at −70° C. over a period of 1.5 h. The reaction mixture was stirred at −70° C. for 30 min. Methanol (30 mL) was added followed by a 20% aqueous solution of sodium tartrate (700 mL) while stirring. The layers were separated and the aqueous layer was extracted with dichloromethane (400 mL×2). The combined organics were washed with a 20% aqueous solution of sodium tartrate (700 mL). The organic phase was stirred with a 10% aqueous solution of sulfuric acid (800 mL) for 15 min. The organics were dried over sodium carbonate and sodium sulfate and concentrated under reduced pressure. A saturated aqueous solution of sodium bisulfate (400 mL) was added to the residue and the mixture was extracted with ethyl acetate (100 mL×3). The aqueous layer was neutralized with aqueous sodium carbonate and extracted with ethyl acetate (200 mL×3). The combined organics were dried over sodium sulfate and concentrated under reduced pressure to afford the title compound (23 g, 54%).
Reaction SMILES: O.NN.[CH3:4][C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:34]=[CH:35][CH:36]=1)[CH2:21][O:22][N:23]1C(=O)C2=CC=CC=C2C1=O.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:4][C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:7][C:6]=1[CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:34]=[CH:35][CH:36]=1)[CH2:21][O:22][NH2:23]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CON2C(=O)c3ccccc3C2=O)c1
Agent: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CON)c1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
Hydrazine monohydrate (0.661 ml) was added to a solution of N-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]phthalimide (3.00 g) in ethanol (25 ml)-tetrahydrofuran (25 ml) and heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, an aqueous solution of potassium carbonate was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (2.04 g, yield 97%) as pale-yellow crystals. m.p. 81-82° C.
Reaction SMILES: [I:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:11]([CH3:14])[CH2:12][OH:13])[CH:3]=1.N1C=CN=C1.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>C(Cl)Cl>[Si:24]([O:13][CH2:12][CH:11]([N:4]1[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[C:2]([I:1])=[CH:3]1)[CH3:14])([C:21]([CH3:23])([CH3:22])[CH3:20])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(CO)n1cc(I)c2cnccc21
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cnccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.6 %

Procedure:
To a solution of 2-(3-iodo-1H-pyrrolo[3,2-c]pyridin-1-yl)propan-1-ol (Preparation 56, 11.5 g, 38.1 mmol) and imidazole (6.48 g, 95.2 mmol) in DCM (300 mL) was added a solution of TBDMSCl (6.95 g, 45.7 mmol) in DCM (50 mL) dropwise at 0° C. The reaction was allowed to warm to room temperature and stirred for 1.5 hours. To the reaction was added water (500 mL) and DCM (200 mL), the organic layer collected, dried over MgSO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-10% MeOH in DCM to afford the title compound (15 g, 100%).
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH2:5][S:6][CH2:7][C:8]1[C:13]([SH:14])=[CH:12][CH:11]=[CH:10][N:9]=1.[OH-].[NH4+:16]>O>[NH2:3][CH2:4][CH2:5][S:6][CH2:7][C:8]1[C:13]([S:14][S:14][C:13]2[C:8]([CH2:7][S:6][CH2:5][CH2:4][NH2:3])=[N:16][CH:10]=[CH:11][CH:12]=2)=[CH:12][CH:11]=[CH:10][N:9]=1.[Cl-:1].[NH4+:3]
Reactant: NCCSCc1ncccc1S
Reactant: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: NCCSCc1ncccc1SSc1cccnc1CSCCN
Product: [Cl-]

Procedure:
A solution of 2-(2-aminoethylthiomethyl)-3-mercaptopyridine dihydrochloride (0.40 g) in water (4 mL) basified with addition of concentrated ammonium hydroxide and a stream of air was bubbled through it for 16 hours. Reaction mixture was evaporated to dryness to produce solid residue of title product and ammonium chloride which was used for next step without further purification. 1H NMR (D2O) δ 2.75 (t, J=6H, 2H), 3.15 (t, J=6H, 2H), 4.00 (s, 2H), 7.38 (dd, J=4, J=6, 1H), 8.21 (d, J=6, 1H), 8.38 (d, J=4, 1H).
Reaction SMILES: CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC.[CH2:26]([N:28]1[C:34](=[O:35])[C:33]([CH3:37])([CH3:36])[C:32](=[O:38])[N:31]([CH3:39])[C:30]2[CH:40]=[C:41]([O:44][CH2:45][CH2:46][CH2:47][NH:48][S:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[N+:58]([O-:60])=[O:59])(=[O:51])=[O:50])[CH:42]=[CH:43][C:29]1=2)[CH3:27].O[CH2:62][CH2:63][N:64]1[CH:73]=[CH:72][C:71]2[C:66](=[CH:67][C:68]([CH3:74])=[CH:69][CH:70]=2)[C:65]1=[O:75]>ClCCl.O.C1COCC1>[CH2:26]([N:28]1[C:34](=[O:35])[C:33]([CH3:37])([CH3:36])[C:32](=[O:38])[N:31]([CH3:39])[C:30]2[CH:40]=[C:41]([O:44][CH2:45][CH2:46][CH2:47][N:48]([CH2:62][CH2:63][N:64]3[CH:73]=[CH:72][C:71]4[C:66](=[CH:67][C:68]([CH3:74])=[CH:69][CH:70]=4)[C:65]3=[O:75])[S:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=3[N+:58]([O-:60])=[O:59])(=[O:51])=[O:50])[CH:42]=[CH:43][C:29]1=2)[CH3:27]
Reactant: Cc1ccc2ccn(CCO)c(=O)c2c1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCNS(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN(CCn3ccc4ccc(C)cc4c3=O)S(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.9 %

Procedure:
N,N,N′,N′-Tetra methyl azodicarboxamide (TMAD) (118 mg) and tri-n-butyl phosphine (0.17 ml) were added to a THF solution (5 ml) of N-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-2-nitrobenzenesulfonamide (231 mg) and 2-(2-hydroxyethyl)-7-methyl-2H-isoquinolin-1-one (93 mg), and stirred at room temperature overnight. Water was added to the reaction mixture, and extraction with dichloromethane was performed. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1→10:1) The purified product was concentrated to dryness under reduced pressure to thereby obtain 205 mg (yield: 65%) of N-(3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl)-N-(2-(7-methyl-1-oxo-1H-isoquinolin-2-yl)ethyl)-2-nitrobenzenesulfonamide as a white amorphous solid.
Reaction SMILES: C1(C)C=CC=CC=1.C(C(C)=O)=C.[O:13]1[C:17]2([CH2:22][CH2:21][CH:20]([CH:23]3[CH2:28][CH2:27][C:26](N4CCCC4)=CC3)[CH2:19][CH2:18]2)OCC1.C([O-])(=O)C.[Na+]>O.C(O)(=O)C>[CH:22]1[C:17](=[O:13])[CH2:18][CH2:19][CH:20]2[C:21]=1[CH2:26][CH2:27][CH2:28][CH2:23]2
Reactant: C1=C(N2CCCC2)CCC(C2CCC3(CC2)OCCO3)C1
Agent: C=CC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1C=C2CCCCC2CC1
Temperature: 25 °C
Yield: 79.4 %

Procedure:
Toluene (300 ml) and methyl vinyl ketone (42 ml) were added to 1-(4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohex-1-enyl)pyrrolidine (105.8 g) obtained in the first step in a reaction vessel at room temperature under an atmosphere of nitrogen, and the mixture was refluxed for 6 hours. After the reaction mixture had been cooled to room temperature, sodium acetate (18 g), acetic acid (36 ml) and water (60 ml) were added, and the mixture was refluxed for 4 hours. After the reaction mixture had been cooled to room temperature, water (200 ml) was added, and then the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, and dried over anhydrous magnesium sulfate. The methanol was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-heptane=1/5 by volume) and then by recrystallization (solvent: Solmix/n-heptane=1/9 by volume) to give 6-(1,4-dioxaspiro[4.5]decan-8-yl))-4,4a,5,6,7,8-hexahydronaphthalene-2(3H)-one (43.3 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[H-].[Na+].Cl[CH:15]1[CH2:19][CH2:18][CH:17]=[CH:16]1>CN(C)C=O>[CH:19]1([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])[CH2:18][CH2:17][CH:16]=[CH:15]1
Reactant: COc1ccc(C=O)cc1O
Reactant: ClC1C=CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OC1C=CCC1
Reaction time: 8 h

Procedure:
A solution of 3-hydroxy-4-methoxybenzaldehyde (14.20 g) in dry dimethylformamide (300 mL) is treated portionwise with sodium hydride (60% dispersion in oil; 3.70 g) at room temperature under nitrogen. 3-Chlorocyclopentene (9.6 mL) is added and the resulting mixture is stirred overnight. The solvent is then removed under reduced pressure and the residue is partitioned between water (500 mL) and dichloromethane (500 mL) and the aqueous layer is further extracted with dichloromethane (500 mL). The combined organic extracts are dried and evaporated under reduced pressure and the residue is subjected to flash chromatography on silica gel, eluting with a mixture of ethyl acetate and pentane (1:1 v/v), to give 3-cyclopent-2-enyloxy-4-methoxybenzaldehyde, in the form of a pale brown oil (11.2 g).
Reaction SMILES: CS[C:3](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[S:4][CH3:5].[CH3:11][NH:12][NH2:13]>O>[NH2:8][C:7]1[C:6]([C:9]#[N:10])=[C:3]([S:4][CH3:5])[N:12]([CH3:11])[N:13]=1
Reactant: CNN
Reactant: CSC(SC)=C(C#N)C#N
Solvent: O
Product: CSc1c(C#N)c(N)nn1C
Reaction time: 1 h

Procedure:
9.63 g (56.6 mmol) [Bis(methylmercapto)methylene]malononitrile was suspended in 50 ml water and treated with 3.7 ml (67.9 mmol) methylhydrazine. The mixture was heated at boiling for 1 hour, the reaction solution cooled, the precipitate suction filtered and recrystallised from ethanol.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:30]([O:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:29][CH:28]=[CH:27][C:26]=2[F:38])[C:21]([Cl:39])=[CH:20][N:19]=1>>[Cl:39][C:21]1[C:22]([NH:24][C:25]2[C:30]([O:31][CH:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:29][CH:28]=[CH:27][C:26]=2[F:38])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: Fc1cccc(OC2CCOCC2)c1Nc1nc(Cl)ncc1Cl
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4OC4CCOCC4)n3)cc2CC1

Procedure:
Title compound was prepared from 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(tetrahydro-pyran-4-yloxy)-phenyl]-amine in an analogous manner to Example 1221d. Title compound was isolated as a white solid (70 mg, 48%). LCMS 542.26 (M+H), HPLC purity 99%, 1H-NMR (DMSO-d6, 400 MHz) δ 9.71 (bs, 1H), 9.35 (s, 1H), 8.57 (s, 1H), 8.13 (s, 1H), 7.39-7.36 (m, 1H), 7.25 (s, 1H), 7.12 (d, J=7.9 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 6.95 (dd, J=8.6 Hz, 1H), 6.85 (d, J=8.2 Hz, 1H), 4.64-4.60 (m, 1H), 3.71-3.69 (m, 2H), 3.60-3.58 (m, 2H), 3.36-3.33 (m, 4H), 3.33 (s, 3H), 3.15-2.85 (m, 6H), 1.84-1.80 (m, 2H), 1.51-1.47 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[CH:4][C:3]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH2:13][CH2:12]1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].[ClH:35]>ClCCl.O1CCOCC1>[ClH:35].[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:23](=[O:24])[N:10]([CH:11]3[CH2:12][CH2:13][N:14]([CH:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)[CH2:15][CH2:16]3)[C:3]=2[CH:4]=1)[CH3:9]
Reactant: CCc1ccc(N)c(NC2CCN(C3CCOCC3)CC2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCc1ccc2[nH]c(=O)n(C3CCN(C4CCOCC4)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
To a solution of (2-amino-5-ethylphenyl)[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]amine D26 (251 mg, 0.83 mmol) in dichloromethane (10 mL) was added 1,1′-carbonyldiimidazole (403 mg, 2.49 mmol). The mixture was stirred under room temperature for 1 hour and 2 mL of 4 M HCl in 1,4-dioxane was added. The resulting mixture was stirred for 5 min and concentrated in vacuo. The residue was dissolved in MeOH and purified by using a Gilson preparative HPLC system with a Waters Xterra (C-18) column 100 mm by 50 mm ID, eluting with 10% B to 90% B in 10 min, where A=H2O and B=CH3CN pumped at 150 mL/min to yield 89 mg of the title compound (29% yield). MS (ESI): 330 [M+H]+; 1H NMR (HCl salt) (400 MHz, CDCl3): δ 1.30 (3H, t), 1.99 (5H, m), 2.25 (2H, d), 2.75 (2H, q), 3.03 (2H, m), 3.44 (4H, d), 3.68 (2H, m), 4.14 (2H, d), 4.69 (1H, m), 6.91 (1H, d), 7.00 (1H, d), 7.84 (1H, s), 9.36 (1H, s), 12.91 (1H, br).
Reaction SMILES: [CH:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:27]([NH2:29])=[O:28])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])=[CH2:2].[CH3:30][NH2:31]>CC#N>[CH3:30][NH:31][CH2:2][CH2:1][S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:27]([NH2:29])=[O:28])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4]
Reactant: C=CS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Reactant: CN
Solvent: CC#N
Product: CNCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Temperature: 80 °C
Yield: 54 %

Procedure:
To a solution of 3-[1-(ethenylsulfonyl)-4-piperidinyl]-5-phenyl-1H-indole-7-carboxamide (26 mg, 0.063 mmol) in CH3CN (1.0 mL), were added methylamine (19.5 mg, 0.63 mmol). The reaction solution was heated to 80° C. overnight. After which time the reaction mixture was purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (15 mg, 54%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[CH2:25](I)[CH3:26]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:25][CH3:26])[C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2n1CC
Reaction time: 0.5 h
Yield: 104.6 %

Procedure:
A mixture of 4-benzyloxy-1H-indole-2-carboxylic acid ethyl ester (1.0 g, 3.40 mmol) in DMF (2 mL) was added drop wise to a suspension of NaH (100 mg, 4.0 mmol) in DMF (5 mL). The reaction mixture was stirred for 30 min. Ethyl iodide (624 mg, 4.0 mmol) diluted in 1 mL of DMF was added drop wise at room temperature and the mixture was stirred for an additional 1 hr. The reaction mixture was diluted with 100 mL of EtOAc and washed with 100 mL of saturated ammonium chloride, brine (50 mL), dried over anhydrous sodium sulfate and the solvent was removed to afford crude 4-benzyloxy-1-ethyl-1H-indole-2-carboxylic acid ethyl ester (1.15 g). This material was diluted in 30 mL of ethanol and 100 mg of 10% Pd/C was added. The mixture was placed on a Parr shaker for hydrogenation at 50 psi for 3 hr. The mixture was filtered and the solvent was removed to afford 1-ethyl-4-hydroxy-1H-indole-2-carboxylic acid ethyl ester (0.730 g, 92% yield) as a white solid. LCMS for C13H15NO3 calcd. (m/e) 233, observed 234 (M+H).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([NH2:13])=[CH:12][C:7]=2[N:6]=[CH:5]1)([CH3:3])[CH3:2].[I:14]I.N>CC(O)=O.[Hg](OC(C)=O)OC(C)=O>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([NH2:13])=[C:12]([I:14])[C:7]=2[N:6]=[CH:5]1)([CH3:3])[CH3:2]
Reactant: II
Reactant: CC(C)n1cnc2cc(N)ccc21
Agent: CC(=O)O[Hg]OC(C)=O
Agent: N
Solvent: CC(=O)O
Product: CC(C)n1cnc2c(I)c(N)ccc21
Yield: 35 %

Procedure:
To a solution of 1-isopropyl-5-aminobenzimidazole (0.70 g, 3.7 mmol) and Hg(OAc)2 (2.1 g, 5.6 mmol) in 10 ml of AcOH was added solution of I2 in AcOH until it produces a precipitation; The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOR/CH2Cl2) to provide 0.40 g (1.3 mmol, 35%) of the product.
Reaction SMILES: Br[CH:2]([CH2:5][CH3:6])[CH2:3][CH3:4].[Mg].[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1)=[O:9].[NH4+].[Cl-]>CCOCC.C1COCC1>[CH2:3]([CH:2]([CH2:5][CH3:6])[CH:8]([C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=1)[OH:9])[CH3:4]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: CCC(Br)CC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(CC)C(O)c1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A solution of 3-bromopentane (0.331 mol) in (C2H5)2O (200 ml) was added dropwise to a solution of magnesium turnings (0.331 mol) in (C2H5)2O, the mixture was stirred at RT for 2 hours and then cooled to 0° C. A solution of N-(4-formylphenyl)acetamide (0.11 mol) in THF (400 ml) was added dropwise and the mixture was stirred for 10 minutes. The mixture was poured into aqueous NH4Cl and extracted with EtOAc. The organic layer was dried, filtered off and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH/NH4OH 97/3/0.1). The pure fractions were collected and evaporated, yielding 13.5 g (52%) of (±)-N-[4-(2-ethyl-1-hydroxybutyl)phenyl]acetamide (interm. 13).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:12])[CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[OH:25])([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[C:14]([C:6]1[CH:7]=[C:8]([C:9](=[O:10])[CH2:22][CH2:23][CH2:18][C:19]([C:22]2[CH:21]=[C:20]([CH3:24])[C:19]([OH:25])=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:23]=2)=[O:25])[CH:21]=[C:20]([CH3:24])[C:5]=1[OH:12])([CH3:15])([CH3:16])[CH3:17]
Reactant: O=C(Cl)CCCC(=O)Cl
Reactant: Cc1cccc(C(C)(C)C)c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C(=O)CCCC(=O)c2cc(C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
27 g (200 mmol) of aluminium chloride, 6.5 ml (50 mmol) of glutaric acid chloride and 250 ml of methylene chloride are initially introduced into a 500 ml three-necked round-bottomed flask. The suspension is cooled to -60° C. and a solution of 18 g (110 mmol) of 2-tert-butyl-6-methylphenol in 30 ml of methylene chloride is added dropwise in the course of about 30-40 minutes. The hydrochloric acid gas which evolves is collected in water. The reaction mixture is stirred at -50° C. for 30 minutes and is then poured onto ice. After addition of 20 ml of concentrated hydrochloric acid, the mixture is stirred for about 10 minutes. The phases are separated and the organic phase is dried over sodium sulfate and freed from the solvent on a rotary evaporator. The 20 g of crude product thus obtained are purified by column chromatography (SiO2, toluene/ethyl acetate 19:1). 12 g (56% of theory) of 1,5-di(3'-tert-butyl-5'-methyl-4'-hydroxyphenyl)-1,5-pentanedione of melting point 156°-158° C. result. The vibration band of the CO groups in the infra-red spectrum appears at 1663.7 cm-1.