Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([CH:21]3[CH2:23][CH2:22]3)([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]=[C:15]=3)O)[C:6]3[CH2:24][CH2:25][N:26]([CH3:28])[CH2:27][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)[OH:30]>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11]/[C:12](/[C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:21]/[CH2:22][CH2:23][OH:30])[C:6]3[CH2:24][CH2:25][N:26]([CH3:28])[CH2:27][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(O)(C2=C=C=C(F)C=C2)C2CC2)C1
Reactant: O=S(=O)(O)O
Solvent: O
Product: CN1CCc2c(c3cc(Cl)ccc3n2C/C(=C/CCO)c2ccc(F)cc2)C1
Temperature: 110 °C

Procedure:
2-(8-Chloro-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-cyclopropyl-1-(4-fluorocyclohexa-1,2,3,5-tetraenyl)ethanol (1 g, 25 mmol) was dissolved in 10 mL 25% sulfuric acid and and heated at 110° C. for 4 h. The reaction mixture was cooled to RT, diluted with water and the resultant solid was filtered, washed with water, and diethylether. The solid was purified by reverse phase HPLC, and separated from the regioisomeric Compound No. 348. 1H NMR (CD3OD, HCl salt) δ (ppm): 7.48 (d, 1H), 7.40 (m, 1H), 7.15 (m, 1H), 7.0 (m, 4H), 5.60 (m, 1H), 5.0 (m, 2H), 4.80 (m, 2H), 4.60 (m, 1H), 4.30 (m, 1H), 3.80 (m, 1H), 3.42 (m, 2H), 3.05 (s, 3H), 3.0 (m, 1H), 2.10 (m, 2H).
Reaction SMILES: [O:1]=[S:2]1(=[O:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.N1C=CC=CC=1.[C:36]([C:38]1[CH:43]=[CH:42][C:41](B2OC(C)(C)C(C)(C)O2)=[CH:40][N:39]=1)#[N:37]>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:29]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:41]3[CH:42]=[CH:43][C:38]([C:36]#[N:37])=[N:39][CH:40]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2ccc(C#N)nc2)CC1
Reaction time: 96 h
Yield: 30.6 %

Procedure:
To a mixture of (1,1-dioxo-thiomorpholin-4-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (Example 2, 150 mg, 1.0 eq.), anhydrous copper(II) acetate (131 mg, 2 eq.), pyridine (120 microL, 4 eq.) in dichloromethane (3.5 mL), 2-cyanopyridine-5-boronic acid pinacol ester (247 mg, 3 eq.) was added. The reaction mixture was stirred for 4 days and then concentrated in vacuo. The residue was then purified on silica eluting with dichloromethane/methanol 98:2 v:v. One fraction was isolated and dried in vacuo, to yield 57 mg (23%) of the desired product as light yellow oil. MS (m/e): 522.5 (MH+, 100%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:12](=[O:24])[NH:13][CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[N:18][NH:19]3)=[CH:8][C:9]=1[C:10]#[N:11])=[O:4].O.[OH-].[Li+].C1COCC1.Cl>O>[C:10]([C:9]1[CH:8]=[C:7]([C:12](=[O:24])[NH:13][CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH:17]=[N:18][NH:19]3)[S:6][C:5]=1[C:3]([OH:4])=[O:2])#[N:11]
Reactant: COC(=O)c1sc(C(=O)NCc2cccc3[nH]ncc23)cc1C#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)O
Reaction time: 4 h

Procedure:
A mixture of 3-Cyano-5-[(1H-indazol-4-ylmethyl)-carbamoyl]-thiophene-2-carboxylic acid methyl ester (262.7 mg, 0.77 mmol), lithium hydroxide monohydrate (250 mg, 6.17 mmol), THF (8 mL) and water (10 mL) was stirred 4 h, acidified with 1N HCl and extracted with EtOAc (×3). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound, 0.1369 g (54%). MS m/e 327.0 (M+H+).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]2[C:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1.[CH3:35][NH2:36]>C(#N)C.CO>[CH3:35][NH:36][CH2:2][C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:25][N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]2[C:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1
Reactant: CN
Reactant: CCOC(=O)c1cccc2nc(CCl)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Solvent: CC#N
Solvent: CO
Product: CCOC(=O)c1cccc2nc(CNC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Temperature: 60 °C
Yield: 61 %

Procedure:
To a solution of ethyl 2-chloromethyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.2 g) in acetonitrile (5 ml) was added a solution of 40% methylamine in methanol (0.33 g) and the mixture was heated at 60° C. for 77 hours. The reaction solution was cooled to give pale yellow prisms (0.12 g, 61%), m.p. 248-250° C.
Reaction SMILES: [H][H].[O:3]1[CH:9]2[CH:4]1[C:5]([O:7][C:8]2([CH3:11])[CH3:10])=[O:6]>[Pd].O1CCCC1>[OH:3][CH:9]1[C:8]([CH3:11])([CH3:10])[O:7][C:5](=[O:6])[CH2:4]1
Reactant: [H][H]
Reactant: CC1(C)OC(=O)C2OC21
Agent: [Pd]
Solvent: C1CCOC1
Product: CC1(C)OC(=O)CC1O
Yield: 63 %

Procedure:
In dioxane, 2-hydroxy-4,4-dimethyl-γ-butyrolactone prepared in the same manner as in Production Example 10 was subjected to a reaction (dehydration reaction) with equivalent P2O5 at room temperature to yield a corresponding α,β-unsaturated-γ-butyrolactone in a yield of 30%. The prepared α,β-unsaturated-γ-butyrolactone was then allowed to react with m-chloroperbenzoic acid (MCPBA) in methylene chloride at room temperature to yield 2,3-epoxy-4,4-dimethyl-γ-butyrolactone in a yield of 85%. Hydrogen was bubbled in a mixture of 10 mmole of the above-prepared 2,3-epoxy-4,4-dimethyl-γ-butyrolactone, 1 g of a 5% by weight Pd-C, and 20 ml of tetrahydrofuran at room temperature for 11 hours. The reaction mixture was filtrated and was concentrated, and the concentrate was subjected to column chromatography on a silica gel to yield 3-hydroxy-4,4-dimethyl-γ-butyrolactone in a yield of 63%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][O:16][C:15]3=[O:24])[CH2:10][CH2:9]2)=[C:4]([Cl:25])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:38]([C:40]1([C:43](O)=[O:44])[CH2:42][CH2:41]1)#[N:39]>>[Cl:25][C:4]1[CH:3]=[C:2]([NH:1][C:43]([C:40]2([C:38]#[N:39])[CH2:42][CH2:41]2)=[O:44])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][O:16][C:15]2=[O:24])[CH2:12][CH2:13]1
Reactant: Nc1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c(Cl)c1
Reactant: N#CC1(C(=O)O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Product: N#CC1(C(=O)Nc2ccc(N3CCC(N4C(=O)OCc5ccccc54)CC3)c(Cl)c2)CC1

Procedure:
The title compound was prepared from the product of example 120 step (ii) (0.05 g), carbonyldiimidazole (0.025 g) and 1-cyano-1-cyclopropane carboxylic acid (0.019 g) using the method of example 115 step (i). Yield 0.003 g.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:45]([O:47]C)=[O:46])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]([N:21]([CH3:40])[CH2:22][CH2:23][N:24]([CH3:39])[CH2:25][CH2:26][CH2:27][S:28](=[O:38])(=[O:37])[NH:29]C(=O)OC(C)(C)C)[CH2:18][C:17]4[CH:41]=[CH:42][CH:43]=[CH:44][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].Cl>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:29][S:28]([CH2:27][CH2:26][CH2:25][N:24]([CH3:39])[CH2:23][CH2:22][N:21]([CH3:40])[CH:19]1[CH2:18][C:17]2[CH:41]=[CH:42][CH:43]=[CH:44][C:16]=2[C:15]2=[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]3[CH:9]=[CH:10][C:11]([C:45]([OH:47])=[O:46])=[CH:12][C:13]=3[N:14]2[CH2:20]1)(=[O:38])=[O:37]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(N(C)CCN(C)CCCS(=O)(=O)NC(=O)OC(C)(C)C)Cc1ccccc1-3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCCS(N)(=O)=O)CCN(C)C1Cc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
Methyl 13-cyclohexyl-6-[methyl(3,11,11-trimethyl-7,7-dioxido-9-oxo-10-oxa-7-thia-3,8-diazadodec-1-yl)amino]-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate was dissolved in DCM/TFA 3:1 (0.03M) and the mixture was left standing at RT. After 45 min all volatiles were evaporated in vacuo. The residue was dissolved in MeOH (0.07M) and 1M aqueous KOH solution (9 eq.) was added. The mixture was stirred at 65° C. for 4h. After cooling to 0° C. the pH of the solution was adjusted with 1 M aqueous HCl to pH 6. The resulting suspension was extracted with EtOAc. The combined organic phases were washed with brine and dried over Na2SO4. All volatiles were evaporated in vacuo. The residual material was used without further purification in the next reaction. (ES+) m/z 567 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:1]([NH:8][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzylamine (0.125 mmol) in 5 mL of THF is added diisopropylethyl amine (0.15 mmol) and benzoylchloride (0.10 mmol). The reaction mixture is stirred at room temperature for 1 hour or until TLC analysis shows consumption of the benzoyl chloride. To this mixture is added perfluorsulfonic acid resin prepared in example 8 (3 g, 0.3 mmol/g loading) and the slurry is gently agitated for 1 hour. The slurry is filtered and the resin washed with dichloromethane. The combined filtrates are combined and the solvent removed under reduced pressure to afford N-benzylbenzamide as a solid.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[NH:9][C:8](=[O:10])[CH2:7][O:6][CH2:5]1.[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C1(C)C=CC=CC=1>[CH2:22]([N:9]1[CH:4]([CH3:3])[CH2:5][O:6][CH2:7][C:8]1=[O:10])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CC1COCC(=O)N1
Reactant: CCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCN1C(=O)COCC1C
Yield: 71.1 %

Procedure:
A mixture of 3.00 g of 60% sodium hydride and 100 ml of benzene was incorporated dropwise with a solution of 3.00 g of L-2-amino-1-propanol in 10 ml of benzene, thereafter agitated at room temperature for a whole day, freed from the solvent by distillation off at reduced pressure to obtain a residue which was dissolved in ethyl acetate and subjected to column chromatography thereby to obtain 3.25 g of 5-methyl-3-morpholinone. A mixture of 1.24 g of 60% sodium hydride and 100 ml of toluene was incorporated dropwise with a solution of 3.25 g of 5-methyl-3-morpholinone in 10 ml of toluene, refluxed for one hour, incorporated with 7.05 g of lauryl bromide, further refluxed for a whole day, filtered to remove insoluble materials. The filtrate obtained was washed, dried and freed from the solvent by distillaton off at reduced pressure, subjected to column chromatography and finally distilled to obtain 5.69 g of colorless 4-(n-dodecyl)-5-methyl-3-morpholinone having the following appearance, column temperature and analysis:
Reaction SMILES: [CH2:1]([C:12]1[N:13]=[C:14]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[S:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[F:25][C:26]([F:35])([F:36])[C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([C:14]3[S:15][CH:16]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:13]=3)=[CH:18][CH:19]=2)=[CH:29][CH:28]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCCCCc1csc(-c2ccc(C=O)cc2)n1
Product: CCCCCCCCCCCc1csc(-c2ccc(CNCc3ccc(C(F)(F)F)cc3)cc2)n1
Yield: 90 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-(4-undecyl-1,3-thiazol-2-yl)benzaldehyde and 4-(trifluoromethyl)benzylamine gave the title compound as a colorless oil (90%). 1H NMR (CDCl3, 300 MHz) δ 7.78 (d, 2H, J=8.3 Hz), 7.45 (d, 2H, J=8.1 Hz), 7.35 (d, 2H, J=8.1 Hz), 7.25 (d, 2H, J=8.3 Hz), 6.72 (s, 1H), 3.689 (s, 2H, J=7.3 Hz), 3.74 (s, 2H), 2.67 (t, J=2H, 7.7 Hz), 1.95-1.72 (m, 1H), 1.62-1.55 (m, 2H), 1.37-1.05 (m, 16H), 0.74 (t, 3H, J=6.7 Hz). M+(LC/MS(ESI)): 503.4. HPLC (Condition A), Rt: 4.99 min (HPLC purity: 91.2%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH2:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[C:13](O)(=[O:16])[CH2:14][CH3:15].CCN=C=NCCCN(C)C.OP([O-])(O)=O.[K+]>C(Cl)Cl>[Br:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH:7]([NH:12][C:13](=[O:16])[CH2:14][CH3:15])[C:6]=2[CH:5]=[N:4][CH:3]=1
Reactant: NC1CCCc2c(Br)cncc21
Reactant: CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClCCl
Product: CCC(=O)NC1CCCc2c(Br)cncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a stirred brown solution of 4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (318 mg, 1.4 mmol) and propionic acid (114 mg, 1.54 mmol) in CH2Cl2 (7.0 mL) at 0° C. under argon was added EDCI (63.3 mg, 0.330 mmol). Stirring was continued overnight and the reaction mixture was allowed to warm up to room temperature. The reaction mixture was poured onto aq. 10% KH2PO4 solution followed by extraction with AcOEt (3×). The organic phases were washed once with aq. 10% KH2PO4, aq. sat. NaHCO3 and with aq. sat. NaCl solution; the combined organic phases were dried over Na2SO4, filtered and evaporated. The residue was dissolved in CH2Cl2, evaporated with n-pentane (3×) to ca. 10 ml each time, while the product precipitated; then, the solvent was decanted and the residue washed twice with n-pentane to afford the title compound (0.365 g, 92%) as light brown solid. MS: 283.0 (M+H+, 1Br).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]([O:12]CC)=O)=[CH:8][N:7]=[C:6]([S:15][CH3:16])[N:5]=1)(=O)[CH3:2].[CH3:17][NH:18][NH2:19]>C(O)CCC>[CH3:17][N:18]1[C:10](=[O:12])[C:9]2[CH:8]=[N:7][C:6]([S:15][CH3:16])=[N:5][C:4]=2[C:1]([CH3:2])=[N:19]1
Reactant: CNN
Reactant: CCOC(=O)c1cnc(SC)nc1C(C)=O
Solvent: CCCCO
Product: CSc1ncc2c(=O)n(C)nc(C)c2n1
Temperature: 25 °C

Procedure:
A solution of Example 1B (600 mg, 2.497 mmol) and methylhydrazine (0.131 mL, 2.497 mmol) in n-butanol (12.5 mL) was heated to 140° C. by microwave irradiation (Biotage Initiator) for 30 minutes. The reaction mixture was cooled to room temperature, whereupon a solid crystallized from the solution. The solid was filtered, washed with hexane, and air-dried to provide the title compound. MS ESI(+) m/z 223 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9].[OH:10][C:11]1[C:18]([CH3:19])=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=1[CH3:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:10][C:11]1[C:12]([CH3:20])=[CH:13][C:14]([CH:15]=[O:16])=[CH:17][C:18]=1[CH3:19]
Reactant: Fc1ccccc1CBr
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C=O)cc(C)c1OCc1ccccc1F

Procedure:
0.5 M Solution of 1-bromomethyl-2-fluoro-benzene (1.51 g, 8.0 mmol) in DMF was added dropwise to a suspension containing 1.1 g of 4-hydroxy-3,5-dimethyl-benzaldehyde (7.3 mmol), 1.51 g of K2CO3 (11 mmol) and 120 mg of KI (0.73 mmol) in 100 ml DMF. The reaction followed the same procedure described in Example 3. The residue was purified on silica gel, obtaining a quantitative recovery of the title compound. (1.88 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@@:8]2([F:24])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:21]Cl)[C:9]2=[O:23])[CH:7]=1.[CH2:27]([O:34][C@@H:35]1[C@@H:41]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@H:40]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@@H:39]([CH2:58][O:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[O:38][CH:36]1[OH:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C@@:8]2([F:24])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:19])([F:18])[F:20])=[CH:14][CH:15]=3)[N:10]([CH2:21][O:37][CH:36]3[C@H:35]([O:34][CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C@@H:41]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C@@H:40]([O:50][CH2:51][C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[C@@H:39]([CH2:58][O:59][CH2:60][C:61]4[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=4)[O:38]3)[C:9]2=[O:23])[CH:7]=1
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(CCl)c2cc(C(F)(F)F)ccc21
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(COC2O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a round bottom flask containing a solution of (S)-3-(5-Chloro-2-methoxy-phenyl)-1-chloromethyl-3-fluoro-6-trifluoromethyl-1,3-dihydro-indol-2-one (S)-IV) (0.486 g, 1.2 mmol) in anhydrous acetonitrile (9 mL) was added 2,3,4,6-tetra-O-benzyl-D-glucopyranose (V; 0.648 g, 1.2 mmol) and cesium carbonate (0.390 g, 1.2 mmol). The reaction mixture was allowed to stir at room temperature overnight. The solvent was then removed, and the crude product was purified via flash chromatography (silica gel, 5:1 hexanes:ethyl acetate) to give a 1:1 mixture of α and β anomers of the title compound (0.768 g, 71%). 1H NMR (CDCl3, 400 MHz): δ 7.79 (dd, 2H, J=5.1 Hz, 1.8 Hz), 7.37-7.12 (m, 48H), 6.66 (m, 2H), 5.66 (d, 1H, J=11.0 Hz), 5.34 (m, 2H), 5.08 (d, 1H, J=3.7 Hz), 4.89-4.73 (m, 9H), 4.66-4.44 (m, 9H), 3.79 (m, 3H), 3.73-3.59 (m, 6H), 3.55-3.49 (m, 3H), 3.38 (d, 6H, J=4.1 Hz).
Reaction SMILES: [Br-].C[O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.C([Li])CCC.C[O:36][C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([O:45]C)[CH:44]=1)[CH:40]=O.O>O1CCCC1>[OH:3][C:4]1[CH:5]=[CH:6][C:7](/[CH:8]=[CH:40]/[C:39]2[CH:42]=[C:43]([OH:45])[CH:44]=[C:37]([OH:36])[CH:38]=2)=[CH:28][CH:29]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(/C=C/c2cc(O)cc(O)c2)cc1
Reaction time: 3 h
Yield: 36.7 %

Procedure:
To a solution of 4-methoxy-benzyltriphenylphosphonium bromide (12.5 g) in anhydrous tetrahydrofuran (200 mL) at −78° C. was added n-butyllithium (2.44 M, 1.0 equiv), and the resulting red solution was stirred under argon for 2-4 h. A solution of 3,5-dimethoxybenzaldehyde (4.5 g) in tetrahydrofuran was added dropwise over 30 min and the mixture stirred for 6-15 h. The resulting cream suspension was poured into water and extracted with dichloromethane. The organic phase was washed with water, and removal of the solvent in vacuo afforded an oil. The oil was separated by flash column chromatography (49:1 hexane/ethyl acetate). The cis-stilbene eluted first as a clear oil followed by the trans isomer as a colorless solid or oil. Overall yield: 91%. To a solution of the trans isomer (3.1. g) in anhydrous dichloromethane (150 mL) at −78° C. was added (dropwise) boron tribromide (1.0 M, 34.5 mL), and the resulting red solution was stirred under argon for 30 min. The solution was poured into water and extracted with dichloromethane. The organic phase was washed with water, and removal of the solvent in vacuo afforded an oil, which was separated by flash column chromatography (1:1 hexane/ethyl acetate) to afford a colorless solid (2.26 g, 86%): mp 260° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[NH2:15][CH2:16][CH2:17][OH:18]>>[OH:18][CH2:17][CH2:16][NH:15][C:11]([C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:14])[C:4]=2[NH:3][C:2]=1[CH3:1])=[O:13]
Reactant: NCCO
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Product: Cc1[nH]c2c(c1C(=O)NCCO)CCCC2=O
Yield: 84.6 %

Procedure:
Similar procedure as Example 2, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and 2-aminoethanol 0.13 g (2.1 mmol) was reacted. The reaction solution was concentrated and purified by a silica gel column, eluted with CH2Cl2/MeOH (10:1), to give 0.20 g (85%) of the titled compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH3:12]N(C=O)C.C(Cl)(=O)C(Cl)=O>ClCCl.C(OCC)(=O)C>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][N:10]=[C:2]([Cl:1])[C:3]=1[Cl:11]
Reactant: O=C(O)c1ccnc(Cl)c1Cl
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccnc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 2,3-dichloro-isonicotinic acid (7.7 g, 40 mmol) in dichloromethane (45 mL) were added DMF (0.1 mL) and oxalyl chloride (17.5 mL, 200 mmol). The reaction mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The resultant residue was azeotroped with toluene, then cooled to 0° C. and dissolved in methanol (135 mL). The mixture was allowed to warm to room temperature and then concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate and the resulting solution was washed with a saturated solution of sodium hydrogen carbonate, water and brine, dried (Na2SO4), filtered and concentrated to give the title compound as a colourless oil that crystallised on standing (7.9 g, 96%). 1H NMR (CDCl3, 400MHz) 8.38 (d, J=5.0 Hz, 1H), 7.52 (d, J=5.0 Hz, 1H), 3.99 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[O:11]([C:13]1[CH:14]=[C:15]([CH:30]=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:16][C:17]1[S:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[C:18]=1[S:26](Cl)(=[O:28])=[O:27])[CH3:12]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:26]([C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:17]=1[CH2:16][C:15]1[CH:30]=[C:31]([O:35][CH3:36])[C:32]([O:33][CH3:34])=[C:13]([O:11][CH3:12])[CH:14]=1)(=[O:27])=[O:28]
Reactant: COc1cc(Cc2sc3ccccc3c2S(=O)(=O)Cl)cc(OC)c1OC
Reactant: Cc1noc(N)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Cc2sc3ccccc3c2S(=O)(=O)Nc2onc(C)c2Br)cc(OC)c1OC

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-(3,4,5-trimethoxybenzyl)benzo[b]thiophene-3-sulfonamide was prepared in the same manner as described in Example 41. Reaction of 4-bromo-3-methyl-5-amino-isoxazole (0.55 mmoles, 97 mg), NaH (1.4 mmoles, 55 mg), and 2-(3,4,5-trimethoxylbenzyl)-benzo[b]thiophene-3-sulfonyl chloride (0.66 mmoles, 0.27 g) in THF (2 ml) yielded, after flash chromatography using 50% ethyl acetate/haxanes and recrystallization from chloroform and hexanes, 94 mg of a tan solid, m.p. 154°-156° C.