Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:11]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[CH:22][CH:21]=3)[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-:30].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[C:3]2[N:11]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH2:28])=[O:30])=[CH:22][CH:21]=3)[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: N#CCc1ccc(-c2nn(-c3c(F)cccc3F)c3c(Cl)c[nH]c(=O)c23)cc1
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)Cc1ccc(-c2nn(-c3c(F)cccc3F)c3c(Cl)c[nH]c(=O)c23)cc1
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a solution of (4-(7-chloro-1-(2,6-difluorophenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetonitrile (134.5 mg) obtained in Example 116 and potassium carbonate (94 mg) in DMSO (2 mL) was added 30% aqueous hydrogen peroxide (139 μL) at room temperature. The reaction mixture was stirred overnight, and poured into water. The precipitated crystals were collected by filtration, and purified by HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)), to the obtained fraction was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified to give the title compound (105 mg).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH3:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([N:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[O:24])=[CH:19][CH:18]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:34][CH2:33]1
Reactant: CC1CCNCC1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Product: CC1CCN(CCc2cc3cc(-c4ccc(C(=O)N5CCOCC5)cc4)ccc3o2)CC1

Procedure:
The product from Example 23D and 4-methyl piperidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.82 (m, 1H), 7.75 (d, J=8.1, 2H), 7.58 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 6.76 (s, 1H), 3.35-3.8 (m, 14H), 3.05 (m, 2H), 2.00 (m, 2H), 1.75 (m, 1H), 1.49 (m, 2H), 1.05 (d, J=6.6 Hz, 3H); MS (DCI) m/z 433 (M+H)+;
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:2]2[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=2)[CH2:12][CH2:11]1
Reactant: Oc1cccc(Cl)n1
Reactant: CN1CCNCC1
Product: CN1CCN(c2cccc(O)n2)CC1
Temperature: 90 °C
Yield: 66 %

Procedure:
To a stirring solution of 1-methyl-piperazine (10 ml) was added 6-chloro-2-pyridinol (1.5 g, 11.57 mmol) and the mixture was heated at 90° C. for 60 h. The reaction mixture was cooled to RT and concentrated under reduced pressure (while heating) to afford the title compound as a brown solid (66%). The crude material was used without further purification. MS (ESI) 194.2 (M+H+).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:15](Cl)(=[O:17])[CH3:16]>C(Cl)Cl>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:15](=[O:17])[CH3:16])[CH2:4][CH2:3]1
Reactant: CC(=O)Cl
Reactant: OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(O)CC1
Temperature: -78 °C
Yield: 79.1 %

Procedure:
4-hydroxypiperidine (0.534 g, 5.3 mmol) was dissolved in methylene chloride (50 mL). The solution was cooled to −78° C. and triethylamine (1.10 mL, 7.95 mmol) was added. Acetyl chloride (0.33 mL, 4.77 mmol) was added dropwise to the mixture. The mixture was warmed to r.t., concentrated under reduced pressure and purified using silica gel chromatography (50% ethyl acetate in hexanes) to give the title compound (0.540 g, 80%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[NH:7][N:6]=1)=[O:4].[C:14](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:13][O:12][C:10]([C:8]1[CH:9]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[N:6]([CH3:14])[N:7]=1)=[O:11]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(C(=O)OC)[nH]n1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cc(C(=O)OC)n(C)n1
Reaction time: 0.67 h

Procedure:
1H-Pyrazole-3,5-dicarboxylic acid dimethyl ester (639, 9.1 g, 49.0 mmol) was combined with acetone (400 mL) and potassium carbonate (10.2 g, 74.1 mmol). The mixture was stirred for 40 minutes under an atmosphere of nitrogen. To the stirring suspension, methyl iodide (3.4 mL, 54.0 mmol) was added dropwise. The reaction was stirred at room temperature overnight and then the solvent was evaporated under reduced pressure. The resulting solid was washed with water and filtered. After toluene was added, the solvent was removed under reduced pressure. The resulting compound 640 was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH2:12])[C@H:10]2[CH2:13][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2].[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[CH3:23])[CH:18]=O.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:18][C:17]2[CH:20]=[CH:21][C:22]([CH3:23])=[C:15]([F:14])[CH:16]=2)[C@H:10]2[CH2:13][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Reactant: Cc1ccc(C=O)cc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(C)c(F)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 44.2 %

Procedure:
(1S,2R,3S,4R)-3-Amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6k, 300 mg, 1.637 mmol) was suspended in ethanol (5 mL). 3-Fluoro-4-methyl-benzaldehyde (0.2 mL, 1.637 mmol) was added followed by glacial acetic acid (0.1 mL, 3.724 mmol) and 4 Å powdered molecular sieves (0.6 g). Sodium cyanoborohydride (0.593 g, 9.406 mmol) was added and the mixture was stirred under nitrogen at 50° C. for 18 h. Upon cooling, the mixture was filtered through Celite. The filtrate was diluted with half-saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (2×75 mL). The layers were separated and the organic layer was washed with saturated aqueous brine solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Further purification by flash column chromatography (Teledyne Isco RediSep column; 1st column: 0 to 25% ethyl acetate in hexanes; 2nd column: 0 to 20% ethyl acetate in hexanes) afforded the desired product, (1S,2R,3S,4R)-3-(3-fluoro-4-methyl-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (221 mg, 0.724 mmol, 44%), as a clear thick oil. 1H NMR (400 MHz, CDCl3) δ: 1.04-1.15 (2H, m), 1.21 (1H, d, J=10.1 Hz), 1.29 (3H, t, J=7.1 Hz), 1.42-1.63 (4H, m), 1.94 (1H, dt, J1=10.2 Hz, J2=2.0 Hz), 2.25 (3H, s), 2.43 (1H, d, J=3.5 Hz), 2.59 (1H, dd, J1=8.6 Hz, J2=1.6 Hz), 2.93 (1H, dd, J1=8.6 Hz, J2=1.6 Hz), 3.65 (1H, d, J=13.4 Hz), 3.79 (1H, d, J=14.2 Hz), 4.15 (2H, q, J=7.1 Hz), 6.94 (1H, d, J=7.9 Hz), 6.98 (1H, d, J=10.9 Hz), 7.08 (1H, t, J=7.8 Hz). LC-MS (ESI) calcd for C18H24FNO2 305.18, found 305.9 [M+H+].
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[Li]CCCC.[F:21]/[C:22](=[C:28](/[C:30]1[C:39]([O:40][CH2:41][CH2:42][CH3:43])=[CH:38][C:37]2[C:36]([CH3:45])([CH3:44])[CH2:35][CH2:34][C:33]([CH3:47])([CH3:46])[C:32]=2[CH:31]=1)\[CH3:29])/[CH:23]=[CH:24]/[C:25](=O)[CH3:26]>C1COCC1>[CH2:2]([O:3][C:4](=[O:5])/[C:6](/[F:7])=[C:25](\[CH3:26])/[CH:24]=[CH:23]/[C:22](/[F:21])=[C:28](\[C:30]1[C:39]([O:40][CH2:41][CH2:42][CH3:43])=[CH:38][C:37]2[C:36]([CH3:45])([CH3:44])[CH2:35][CH2:34][C:33]([CH3:47])([CH3:46])[C:32]=2[CH:31]=1)/[CH3:29])[CH3:1]
Reactant: CCCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=O)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCOc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C(/F)C(=O)OCC)C(C)(C)CCC2(C)C

Procedure:
Following General Procedure B and using triethyl 2-fluoro-2-phosphonoacetate (0.3 mL, 1.44 mmol), THF (4 mL), n-BuLi (0.9 mL, 1.6 M in hexane, 1.44 mmol), (3E,5E)-5-fluoro-6-(5,5,8,8-tetramethyl-3-propoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-hepta-3,5-dien-2-one (Intermediate 9, 177 mg, 0.48 mmol) in THF (2 mL) at −78° C. for overnight, the title compound and its 2-E isomer were obtained by flash column chromatography on silica gel (3% EtOAc-hexane) as a ˜1.4:1 mixture (222 mg). Further purification by HPLC (2.5% EtOAc-hexane) afforded the title compound as a clear oil (102 mg, 47%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[NH:17]1[C:21]([C:22]2[CH:23]=[C:24]([NH:28][C:29](=O)[O:30]C3C=CC([N+]([O-])=O)=CC=3)[CH:25]=[CH:26][CH:27]=2)=[N:20][N:19]=[N:18]1.CN(C)C=O>C(#N)C>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:29]([NH:28][C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([C:21]4[NH:17][N:18]=[N:19][N:20]=4)[CH:23]=3)=[O:30])[C:7]=2[CH:8]=1)#[N:13]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: O=C(Nc1cccc(-c2nnn[nH]2)c1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)Nc2cccc(-c3nnn[nH]3)c2)[C@@H]1O
Yield: 60 %

Procedure:
A mixture of (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.65 g, 0.003 mol, from Example 1, part B) and [3-(1H-tetrazol-5-yl)phenylcarbamic acid, 4-nitrophenyl ester (1.08 g, 0.0033 mol, from part A) in acetonitrile (35 mL) and dimethylformamide (20 mL) was stirred at 80° C. for two hours. The reaction mixture was concentrated in vacuo and the residue, diluted with ethyl acetate, was washed with 0.5M HCl and water. The organic layer was concentrated in vacuo, and the residue was azeotroped with toluene and triturated with ethyl acetate/hexane (1:1). The product was purified by flash chromatography (EM-60 flash silica gel, 300 mL) and eluted with EtOAc/MeOH/HOAc (20:1:0.06). The solvent was removed in vacuo, acetic acid was azeotroped with toluene and the product was triturated in hexane (40 mL) and ethyl acetate (0.5 mL) and dried in vacuo to give 0.72 g (60%) of the title compound, m.p. 204°-208° C. TLC, silica gel, EtOAc/MeOH/HOAc (20:1:0.2), Rf =0.58; 1H-NMR (DMSO-d6) δ1.3 (s, 3H), 1.5 (s, 3H), 3.7 (d, J=9.4 Hz, 1H), 4.8 (dd, J=8.8 & 8,8 Hz, 1H), 5.8 (s, 1H), 6.8 (d, J=8.2 Hz, 1H), 7.0 (d, J=8.8 Hz, 1H), 7.5 (m, 5H), 8.4 (s, 1H), 9.0 (s, 1H); 13C-NMR (DMSO-d6) δ5 156.6, 156.0. 141.6, 132.9, 132.8, 130.2, 126.2, 125.0, 120.7, 120.1, 119.4, 118.2, 116.5, 103.0, 80.7, 71.6, 49.8, 26.9, 21.4, 19.3; IR (KBr) 2980, 2932, 2228, 1663 cm-1. M.S., (M+H)+ at 406, M.W. 405; [60 ]D=-41.6° (c=0.76 DMSO).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:15]=[N:14][C:13]([C:16]2[NH:17][C:18]([CH3:21])=[N:19][N:20]=2)=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.Cl[C:23]([C:25]([O:27][CH3:28])=[O:26])=[O:24]>C(Cl)Cl.C[N+]([O-])=O>[CH3:28][O:27][C:25](=[O:26])[C:23]([C:9]1[C:8]2[C:12](=[C:13]([C:16]3[NH:17][C:18]([CH3:21])=[N:19][N:20]=3)[N:14]=[CH:15][C:7]=2[O:6][CH3:5])[NH:11][CH:10]=1)=[O:24]
Reactant: COC(=O)C(=O)Cl
Reactant: COc1cnc(-c2nnc(C)[nH]2)c2[nH]ccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: COC(=O)C(=O)c1c[nH]c2c(-c3nnc(C)[nH]3)ncc(OC)c12
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of AlCl3 (0.321 g, 2.411 mmol) in CH2Cl2 (0.8 mL) and MeNO2 (0.2 mL) was added 4-methoxy-7-(5-methyl-1,3,4-triazol-2-yl)-6-azaindole (0.0435 g, 0.190 mmol) as a solid. After dissolution of the starting material (ca. 5 min), ClCOCO2Me (0.070 mL, 0.756 mmol) was added and the mixture was allowed to stir for 5 h. The mixture was then cooled at 0° C., quenched by the slow addition of 1 M aqueous NH4OAc and extracted with EtOAc (×3). The combined organic layers were washed (H2O, brine), dried (Na2SO4) and evaporated to give 4-methoxy-7-(5-methyl-1,3,4-triazol-2-yl)-6-azaindol-3-yl-oxoacetic acid methyl ester (0.0347 g, 60%: LCMS: m/e 316 (M+H)+. This material was dissolved in MeOH (2 mL) and treated with 2.5 M NaOH (0.2 mL, 0.5 mmol). The mixture was allowed to stir for 5 h, at which point the solvent was removed and the residue was diluted with H2O (2 mL). This mixture was acidified to pH 1 with 6 M HCl and the solution was lyophilized to give the title compound (0.062 g), which contained a nominal amount of inorganic salts. This material was used as such in the following step:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]2[N:15]([C:16](=[O:26])[CH:17]=[C:18]([C:23]([OH:25])=[O:24])[CH:19]=2)[CH:14]=1)=O)(C)(C)C.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]2[N:15]([C:16](=[O:26])[CH:17]=[C:18]([C:23]([OH:25])=[O:24])[CH:19]=2)[CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc2cc(C(=O)O)cc(=O)n2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCCOc1ccc2cc(C(=O)O)cc(=O)n2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a mixture of 7-(3-tert-butoxycarbonylamino-propoxy)-4-oxo-4H-quinolizine-2-carboxylic acid (18 mg, 0.050 mmol) in anhydrous dichloromethane (1 ml) under nitrogen atmosphere was added trifluoroacetic acid (1 ml). The mixture was stirred for 2 hours at room temperature, concentrated and triturated with ether to give 17.3 mg (92% yield) of desired compound as a yellow solid which was characterized by 1HNMR (300 MHz, CD3OD) δ: 2.22-2.29 (m, 2H), 3.20-3.23 (m, 2H), 4.28-4.31 (m, 2H) 7.09 (d, J=1.5 Hz, 1H), 7.46-7.49 (dd, J=9.5 and 2.5 Hz, 1H) 7.52 (s, 1H), 7.90 (d, J=9.5 Hz, 1H), 8.71 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[N:16]=[C:15]([C:17]2[S:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](=[O:23])[N:22]=2)[CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[C:34]1([N:40]=[C:41]=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(#N)C>[O:23]=[C:21]1[C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[S:18][C:17]([C:15]2[N:16]=[C:11]([CH2:10][CH2:9][NH:8][C:41]([NH:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:42])[CH:12]=[CH:13][CH:14]=2)=[N:22]1
Reactant: O=C=Nc1ccccc1
Reactant: NCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCc1cccc(-c2nc(=O)c3ccccc3s2)n1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17.4 %

Procedure:
A mixture of 2-[6-(2-aminoethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (0.40 g, 1.0 mmol), potassium carbonate (0.41 g, 3.0 mmol) and acetonitrile (15 ml) was stirred at room temperature for 20 minutes. Successively phenyl isocyanate (0.47 g, 4.0 mmol) was added to the mixture, and the mixture was refluxed for 4 hrs. After cooling, the precipitates were collected by filtration and dissolved in chlorobenzene and water. The organic layer was dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from hexane-chlorobenzene to give the titled compound (0.07 g, 17%) as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([CH2:32][OH:33])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[CH2:36](I)[CH3:37].C(O)C>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([CH2:32][O:33][CH2:36][CH3:37])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1ccc(CC(=O)NC(CO)c2ccccc2N2CCCCC2)cc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOCC(NC(=O)Cc1ccc(C(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1
Reaction time: 1 h

Procedure:
Ethyl 2-ethoxy-4-[N-(α-hydroxymethyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate (0.64 g, 1.4 mmol) is added with stirring at ambient temperature to sodium hydride (0.061 g, 1.4 mmol) (55% in oil) in absolute tetrahydrofuran (6.4 ml). The mixture is stirred for 1 hour, then ethyl iodide (0.113 ml, 1.4 mmol) is added and the mixture is stirred for a further 16 hours at ambient temperature. Then ethanol (2 ml) is added and the mixture is evaporated down in vacuo. The evaporation residue is partitioned between chloroform and water. The organic phase is washed twice with water, dried, filtered and concentrated by evaporation in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/acetone=17/3).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][CH3:13])[CH:3]=1.[CH3:14][N:15](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:14]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][CH3:13])[CH:3]=1)#[N:15]
Reactant: CN(C)C=O
Reactant: CCc1cc(Br)ccc1C(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCc1cc(C#N)ccc1C(=O)OC
Temperature: 100 °C
Yield: 40 %

Procedure:
Charged methyl 4-bromo-2-ethylbenzoate (1.9 g, 7.85 mmol), Zn(CN)2 (1.48 g, 12.56 mmol), Pd (PPh3)4 (1.0 g, 0.94 mmol) and DMF (30 mL) to a flask, the system was then purged with nitrogen and heated at 100° C. for 6 h. The reaction mixture was then filtered. The filtrate was extracted with ethyl acetate and concentrated the organic phase for flash column chromatograph to give 0.6 g of the title compound (40%). 1H NMR (400 MHz, CDCl3): δ 1.24 (3H, t, J=7.6 Hz), 2.99 (2H, q, J=7.6 Hz), 3.92 (3H, s), 7.52-7.54 (1H, m), 7.57 (1H, s), 7.90 (1H, d, J=8.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.CN.[CH2:15]([N:17](CC)CC)C.CCOC(C)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:17][CH3:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
4-Chlorobenzenesulfonyl chloride (10 g, 47 mmol) was added to a solution of methylamine hydrochloride (3.5 g, 52 mmol) and triethylamine (16.5 ml, 12.0 g, 119 mmol) in dichloromethane (100 ml) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was reduced and chromatography (30% EtOAc/70% hexanes) afforded 4-chloro-N-methylbenzenesulfonamide (7.9 g, 81%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:36])[C:9]([C:11]1[S:35][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]4[CH:25]=[C:26]([CH2:30][C:31]([O:33]C)=[O:32])[CH:27]=[CH:28][CH:29]=4)=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[OH-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:36])[C:9]([C:11]1[S:35][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]4[CH:25]=[C:26]([CH2:30][C:31]([OH:33])=[O:32])[CH:27]=[CH:28][CH:29]=4)=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)Cc1cccc(-c2ccc3c(c2)OCCc2cc(C(=O)N(C)c4ccccc4Cl)sc2-3)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)c1cc2c(s1)-c1ccc(-c3cccc(CC(=O)O)c3)cc1OCC2)c1ccccc1Cl

Procedure:
Methyl 2-(3-(2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)phenyl)acetate 200 was treated with lithium hydroxide in THF and water to give 198. MS: (ESI+) 503.7
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:31][C:32](=[O:35])[CH2:33][CH3:34])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([O:24]C(C)(C)C)=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:31][C:32](=[O:35])[CH2:33][CH3:34])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:29])[C:22]([OH:24])=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: CCC(=O)CN([C@H]1CCN([C@@H](C)C(=O)OC(C)(C)C)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)CN([C@H]1CCN([C@@H](C)C(=O)O)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.8 %

Procedure:
tert-Butyl (2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](2-oxobutyl)amino]-2-oxopyrrolidin-1-yl}propanoate (0.07 g) was dissolved in DCM (2 ml), and trifluoroacetic acid (2 ml) was added. The mixture was stirred at room temperature for 1.5 h and then partitioned between water and DCM. The organic layer was separated, dried (over magnesium sulphate) and concentrated under reduced pressure to give the title compound (0.063 g) as an orange gum.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[C:8]1[C:16]([N+]([O-])=O)=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:11](=[O:20])[NH:12]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C.CCN(CC)CC>[CH3:28][O:27][C:26]1[CH:25]=[CH:24][NH:23][C:22]=1/[CH:21]=[C:10]1\[C:11](=[O:20])[NH:12][C:13]2[C:9]\1=[C:8]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:16]=[CH:15][CH:14]=2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(Br)c21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#C[Si](C)(C)C)c21

Procedure:
Using Method D above, trimethylsilyl acetylene (0.94 g, 9.63 mmol) (Aldrich) was coupled with (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (2.05 g, 6.42 mmol) (Starting Material 1 supra) using (Ph3P)2PdCl2 (0.23 g) and Cul (61 mg) as catalyst in DMF (15 mL) and Et3N (15 mL) as solvent at 80° C. for 2 days to give (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-(2-trimethylsilyl-ethynyl)-2H-indol-2-one. (Yield 1.3 g, 60%).
Reaction SMILES: [N+:1]([CH2:4][CH:5]1[CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH:7]([CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:6]1[CH:23]=[CH:24][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([O-:3])=[O:2].[C:32]1([Mg]Br)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cl-].[NH4+].C(O)(=O)C>O1CCCC1>[N+:1]([CH2:4][CH:5]1[CH2:13][C:8]2([O:9][CH2:10][CH2:11][O:12]2)[CH:7]([CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:6]1[CH:23]=[CH:24][C:25]([OH:31])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([O-:3])=[O:2]
Reactant: Br[Mg]c1ccccc1
Reactant: CCCCCC(=O)C=CC1C(C[N+](=O)[O-])CC2(OCCO2)C1CC=CCCCC(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCC(O)(C=CC1C(C[N+](=O)[O-])CC2(OCCO2)C1CC=CCCCC(=O)O)c1ccccc1

Procedure:
A solution of 1.88 g. of 7-[8-nitromethyl-7-(3-oxo-1-octenyl)-1,4-dioxaspiro[4.4]non-6-yl]-5-heptenoic acid in 80 ml. of tetrahydrofuran was treated at -10° C. with 6.6 ml. of 3 M phenyl magnesium bromide in tetrahydrofuran and was stirred at 0° C. for one hour. The reaction mixture was added to aqueous ammonium chloride solution, acidified with acetic acid and extracted with ether. After washing with water and drying with magnesium sulfate, the extract was evaporated and the residue chromatographed on silica. Elution with 30% ethyl acetate in hexane gave 0.90 g. of the title product as an oil, λmaxfilm 3.00 (shoulder), 3.50, 5.88, 6.28, 6.47, 6.95, 7.25, 13.30, 14.35 μ. NMR: δ 3.93 (S, 4, ketal), 4.35 (M, 2, --CH2NO2), 5.15-6.05 (M, 4, olefinic --H), 5.88 (S, 2, -OH), 7.45 (M, 5, aromatic-HO ppm. Mass spectrum: M+ at m/e 515 (theory 515), M+--H2O at m/e 497.2776 (theory 497.2776.