Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][CH:25]=3)[S:8][C:7]=2[CH:32]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:24]3[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=3)[S:8][C:7]=2[CH:32]=1
Reactant: COC(=O)/C=C/c1ccc(Oc2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc(Oc2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.6 %

Procedure:
To a 30 mL vial containing (E)-methyl 3-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (100 mg, 0.22 mmol) in DCM (1 mL) was added BBr3 (1 M in heptane, 0.224 mL, 0.22 mmol) and the reaction was stirred for 1 h at room temperature. The reaction mixture was quenched with 4 mL MeOH and stirred for 10 min at room temperature. The crude material was concentrated onto silica gel and purified by column chromatography (SiO2, 1-100% EtOAc/Heptane) to afford (E)-methyl 3-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (11 mg, 0.03 mmol, 12% yield), and a mixture of (E)-methyl 3-(4-((2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate and (E)-methyl 3-(4-((6-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (32 mg, 0.07 mmol, 33% yield). LC/MS (m/z, MH+): 433.2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.Cl[Sn](Cl)(Cl)Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:30]([C:31](Cl)=[O:32])=[C:29]([CH3:34])[O:28][N:27]=2)=[CH:22][CH:21]=1.[N+](C)([O-])=O>C(Cl)Cl>[CH3:13][O:12][C:10]([C:7]1[CH:8]=[C:9]2[C:4]([C:3]([C:31]([C:30]3[C:26]([C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)=[N:27][O:28][C:29]=3[CH3:34])=[O:32])=[CH:2][NH:1]2)=[CH:5][CH:6]=1)=[O:11]
Reactant: Cc1onc(-c2ccc(F)cc2)c1C(=O)Cl
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: COC(=O)c1ccc2c(C(=O)c3c(-c4ccc(F)cc4)noc3C)c[nH]c2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 22.5 %

Procedure:
To a stirred solution of 1.75 g (10 mmol) methyl indole-6-carboxylate (commercially available) in 15 mL of dry CH2Cl2 under argon at 0° C. was added 1.41 mL (12 mmol) of SnCl4 in one portion. After removing the ice-bath, the mixture was stirred for 40 min at room temperature and then 2.39 g (10 mmol) of 3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid chloride (Prepared from the corresponding acid according to: J. Agric. Food Chem. 1995, 43, 219-228.) in 5 mL of CH2Cl2 was added at 0° C. followed by the addition of 15 mL of nitromethane in one portion. The mixture was stirred for 15 minutes at 0° C., after which 50 mL of ice-water was added to quench the reaction. The organic phase was separated and the aqueous solution was extracted with CH2Cl2 (2×20 mL). The combined extracts were washed with brine (30 mL), dried over Na2SO4, and evaporated to give 3.5 g of crude product (purity ˜30%, LCMS) as brown semi-solid. The crude product was further washed with ethyl acetate to give 0.85 g of the title compound in 23% yield as a light-yellow powder. (m/e): 379.2 (MH+; 100%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1Br)[CH:12]([NH:17][C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1)[CH2:11][CH2:10]2)=[O:5].[Cu][C:32]#[N:33].N>CN1C(=O)CCC1>[CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[C:32]#[N:33])[CH:12]([NH:17][C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1)[CH2:11][CH2:10]2)=[O:5]
Reactant: N#C[Cu]
Reactant: COCC(=O)Nc1cc2c(cc1Br)C(Nc1ccc(C(=O)OC(C)(C)C)cc1)CC2
Agent: N
Solvent: CN1CCCC1=O
Product: COCC(=O)Nc1cc2c(cc1C#N)C(Nc1ccc(C(=O)OC(C)(C)C)cc1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-[N-(5-methoxyacetamido-6-bromoindan-1-yl)-amino]benzoate (0.714 g, 1.50 mmol) in NMP (8 ml) [1-methyl-2-pyrrolidone] was added copper (I) cyanide (0.230 g, 2.55 mmol). The reaction mixture was placed in an oil-bath preheated to 140° C. and stirred at this temperature for 2 h. More copper (I) cyanide (0.100 g, 1.10 mmol) was then added and stirring was continued for a longer 3 hours. The reaction mixture was allowed to cool to room temperature, then poured into a mixture of aqueous ammonia (d=0.88, 7 ml) and ice (˜20 ml) and the resulting brown mixture was stirred at room temperature for ˜5 min. The brown solid was collected by filtration washed with plenty of water, then suspended in dichloromethane (100 ml). The mixture was stirred at room temperature for 10 min, dried (Na2SO4), and concentrated in vacuo. Purification by column chromatography, on elution with 35% ethyl acetate in hexane, afforded an off white solid that was reprecipitated from dichloromethane-ethyl acetate/hexane: 0.328 g, (52%) m.p. 163-164° C. 1H-NMR (250 MHz, DMSO-d6, TMS) 1.50 (s, 9H, C(CH3)3), 1.85, 2.58 (2×m, 2H, indanyl 2-H), 2.89 (m, 2H, indanyl 3-H), 3.41 (s, 3H, OCH3), 4.05 (s, 2H, CH2OMe), 5.06 (m, 1H, indanyl 1-H), 6.73 (d, J=8.82 Hz, 2H, 3,5-H), 6.82 (d, J=8.37 Hz, 1H, N10—H), 7.59, 7.57 (2×s, each 1H, indanyl 4-H, 7-H), 7.66 (d, J=8.77 Hz, 2,6-H), 9.88 (s, 1H, CONH); MS (ESI, m/z) 444 {(M+Na)+, 100%}. Found: C, 68.21; H, 6.47; N, 9.81; C24H27N3O4 requires C, 68.39; H, 6.46; N, 9.97%.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][N:11]2[C:19]([C:20]3[N:24]([CH3:25])[CH:23]=[C:22]([C:26]([OH:28])=O)[CH:21]=3)=[C:18]3[C:13]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:15](=[O:31])[N:16]([CH3:30])[C:17]3=[O:29])=[N:12]2)=[CH:2]1.[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39][NH2:40].C(P(=O)(OCC)OCC)#N>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][N:11]2[C:19]([C:20]3[N:24]([CH3:25])[CH:23]=[C:22]([C:26]([NH:40][CH2:39][CH2:38][N:37]([CH3:41])[CH3:36])=[O:28])[CH:21]=3)=[C:18]3[C:13]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:15](=[O:31])[N:16]([CH3:30])[C:17]3=[O:29])=[N:12]2)=[CH:2]1
Reactant: CN(C)CCN
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3csc4ccccc34)nc21
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)NCCN(C)C)cn3C)n(Cc3csc4ccccc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-[2-(1-benzothien-3-ylmethyl)-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carboxylic acid and N,N-dimethylethane-1,2-diamine using diethyl cyanophosphonate as a coupling reagent. Mass: 562.18 (M+H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[C:18]([CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)(O)[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11][CH2:10][C:9]=2[CH:27]=1)(=[O:4])=[O:3].OS(O)(=O)=O.C(S(O)(=O)=O)(F)(F)F.[OH-].[Na+]>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[C:18](=[C:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11][CH2:10][C:9]=2[CH:27]=1)(=[O:3])=[O:4]
Reactant: CN1CCC(C2(O)c3ccc(S(C)(=O)=O)cc3CCc3cccnc32)CC1
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CN1CCC(=C2c3ccc(S(C)(=O)=O)cc3CCc3cccnc32)CC1
Temperature: 0 °C
Yield: 74 %

Procedure:
To 1.35 g of 8-methylsulfonyl-6,11-dihydro-11-(1-methyl-4-piperidyl)-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol, 24 ml of a mixed solution of conc. H2SO4 and CF3SO3H (2:1) were added. The resultant mixture was stirred at 50° C. for 5 hours. After the reaction, the reaction mixture was poured into ice water, basified with a 20% sodium hydroxide solution and then extracted with methylene chloride. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous MgSO4 and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by chromatography on an alumina column, whereby 0.95 g of 8-methylsulfonyl-11-(1-methyl-4-piperidylidene)-6,11-dihydro-5H-benzo]5,6]cyclohepta[1,2-b]pyridine was obtained (yield: 74%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].C([N:21]=[C:22]=[S:23])(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:22]([NH2:21])=[S:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCNC(N)=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
A solution of 2 g (11.47 mmol) (3-Amino-propyl)-carbamic acid tert-butyl ester in 20 ml THF was treated with 1.62 ml (11.47 mmol) Benzoyl isothiocyanate and stirred for 1 h at room temperature. After removal of the volatiles the residue was suspended in 50 ml methanol and 4.8 g (34.4 mmol) K2CO3 in 50 ml water was added. The mixture was stirred at room temperature for 16 h, concentrated, and extracted with ethyl acetate. The combined organic layers were washed with NaHCO3 sat., brine, dried with MgSO4 and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica eluting with ethyl acetate/heptane. The combined product fractions were evaporated under reduced pressure to yield 1.48 g (74%) of the title compound.
Reaction SMILES: [CH3:1][Ge:2]([CH3:16])([CH3:15])[C:3]1[CH:4]=[C:5]([C:9]2([CH3:14])OCC[O:10]2)[CH:6]=[CH:7][CH:8]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CC(C)=O>[CH3:15][Ge:2]([CH3:1])([CH3:16])[C:3]1[CH:4]=[C:5]([C:9](=[O:10])[CH3:14])[CH:6]=[CH:7][CH:8]=1
Reactant: CC1(c2cccc([Ge](C)(C)C)c2)OCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1cccc([Ge](C)(C)C)c1

Procedure:
A mixture of 351 mg (1.25 mmol) of 2-(3-trimethylgermylphenyl)-2-methyl-1,3-dioxolane, 47 mg (0.187 mmol, 0.15eq) of pyridinium p-toluenesulfonate (PPTS), 1.1126 g (62.5 mmol, 50eq) of water and 10 ml of acetone was refluxed for 2.5hours. The reaction mixture was evaporated and extracted with petroleum ether. The extract was evaporated. The oily residue was purified by column chromatography to give 294 mg of colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][C@@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:22])=[C:12]([N+:17]([O-])=O)[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:29][CH3:30])=[C:5]([CH3:31])[O:4][N:3]=1.O.O.Cl[Sn]Cl>C(O)C.Cl>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][C@@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:22])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:29][CH3:30])=[C:5]([CH3:31])[O:4][N:3]=1
Reactant: COc1cc2c(N[C@H](C)c3ccccc3)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: COc1cc2c(N[C@H](C)c3ccccc3)c(N)cnc2cc1-c1c(C)noc1C
Temperature: 40 °C
Yield: 5.2 %

Procedure:
To a solution of this nitro intermediate (2.5 g, 24.82 mmol) in a mixture of ethanol (20 ml) and HCl (3.8 ml), was added portionwise SnCl2.2H2O (5.6 g, 24.82 mmol). The reaction mixture was heated to 40° C. for 1 h, then hydrolysed with sodium hydroxide N and extracted with DCM. The organic phase was washed with water, dried and concentrated to give the title compound as a brown powder (0.5 g, 17%). (APCI-MS) m/z: 389 MH+, Rt 2.95 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[NH:9][C:8]1=[O:17])[C:5]#[N:6].[C-:19]#[N:20].[K+].O>CO>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:7]1([C:19]#[N:20])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[NH:9][C:8]1=[O:17])[C:5]#[N:6]
Reactant: [C-]#N
Reactant: COC(=O)C(C#N)=C1C(=O)Nc2ccc(Cl)cc21
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)C(C#N)C1(C#N)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 86 %

Procedure:
A stirred suspension of crude (5-chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-cyanoacetic acid methyl ester, intermediate 1 (56.0 g, 0.21 mol) in methanol (750 ml) was treated, in portions, with potassium cyanide (13.8 g, 0.21 mol) followed by water (45 ml). The mixture was stirred at ambient temperature for 7 hours and the resultant black solution was left to stand overnight. The solvent was removed in vacuo, water (500 ml) was added and the mixture acidified by the addition of 2M hydrochloric acid [CAUTION: TRACES OF CYANIDE MAY STILL BE PRESENT!]. The mixture was extracted with dichloromethane (3×300 ml). The combined extracts were washed with water (2×300 ml) and dried (MgSO4). The solvent was removed in vacuo to give the crude (5-chloro-3-cyano-2-oxo-2,3-dihydro-1H-indol-3-yl)-cyanoacetic acid methyl ester as a pale-brown solid (53.3 g, 86%). This was a mixture of diastereomers, which was sufficiently pure by 1H NMR for subsequent reaction.
Reaction SMILES: ClC1CCCCC1.C([O:10][CH:11](OCC)[C:12]1[O:16][CH:15]=[CH:14][CH:13]=1)C.[Li].[B:21](OC)([O:24]C)[O:22]C.Cl>C1COCC1.C1CCCCC1.O>[CH:11]([C:12]1[O:16][C:15]([B:21]([OH:24])[OH:22])=[CH:14][CH:13]=1)=[O:10]
Reactant: COB(OC)OC
Reactant: CCOC(OCC)c1ccco1
Agent: Cl
Agent: [Li]
Solvent: C1CCCCC1
Solvent: ClC1CCCCC1
Solvent: O
Product: O=Cc1ccc(B(O)O)o1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
A mixture of 20.88 g of chlorocyclohexane (0.176 mol) and 27.2 g of furfural diethyl acetal (0.16 mol) is added dropwise to a suspension of 2.35 g of lithium granules (0.34 mol) in 300 g of THF at −65° C., with an addition time of 2 hours being selected. After a conversion of the chlorocyclohexane of >97% determined by GC (total of 10 h), 18.3 g of trimethyl borate (0.176 mol) are added dropwise at the same temperature over a period of 30 minutes. After stirring for another 30 minutes at −65° C., the reaction mixture is poured into 120 g of water, the pH is adjusted to 6.3 by means of 37% HCl, and THF and cyclohexane are distilled off at a maximum of 35° C. under reduced pressure. The pH is subsequently adjusted to 1.5, the mixture is stirred until all the product has precipitated and the product is filtered off. After washing with a little cold water and a little cold acetone and drying, 17.2 g of 5-formyl-2-furanboronic acid (0.123 mol, 77%) are obtained in the form of a fine beige powders, HPLC purity >99% a/a.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Fe]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc2c(cnn2Cc2ccccc2)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccc2c(cnn2Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
7.61 g (136 mmol, 5 equiv) of Iron powder (4.03 g, 72.1 mmol) was added slowly to the solution of 1-Benzyl-5-nitro-1H-indazole (6.9 g, 27.2 mmol) in acetic acid (200 mL). After stirring at room temperature overnight, the reaction mixture became milky with formation of a white precipitate. The precipitate was filtered off and the filtrate was concentrated to ca. 20 mL. The residue was diluted with water (200 mL) and neutralized by slow addition of sodium hydroxide. The mixture was then extracted with ethyl acetate (500×5 mL). The organic layer were combined, dried over sodium sulfate, filtered and concentrated to dryness to afford 1-benzyl-1H-indazol-5-ylamine (5.23 g, 82%) as a brown solid. 1H NMR (DMSO-d6): δ 7.72 (s, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.24–7.14 (m, 5H), 6.74 (m, 2H), 5.49 (s, 2H), 4.80 (br, 2H). ES-LCMS: RT=0.93 min; [M+H]+=224.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[C:10](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: Oc1cc(F)ccc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
10 g of 2-bromo-5-fluorophenol was dissolved in 105 mL of N,N-dimethylformamide, and added with 10.9 g of potassium carbonate and 4.9 mL of iodomethane under cooling, and stirred at room temperature for 3 hours. The reaction solution was added with water, extracted with diethyl ether, and the resultant organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated, to afford 9.75 g of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:40](=[O:48])([O:45][CH2:46][CH3:47])[O:41][CH:42](Cl)[CH3:43]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CCOC(C)=O>[C:40](=[O:48])([O:45][CH2:46][CH3:47])[O:41][CH:42]([N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1)[CH3:43]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CCOC(=O)OC(C)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(C)OC(=O)OCC)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.3 %

Procedure:
To a solution of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.1 g, 0.2 mmol) in DMF (1 mL) was added K2CO3 (85 mg, 0.6 mmol). The reaction was stirred at rt for 10 min, followed by the addition of TBAB (132 mg, 0.4 mmol) and a solution of 1-chloroethyl ethyl carbonate (35 mg, 0.25 mmol) in DMF (100 μA). The mixture was stirred at rt for 16 h, then diluted with EtOAc (40 mL) and filtered. The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1) to afford the title compound as a white solid (61 mg, 50%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].[OH-].[Na+]>C(O)(=O)C>[OH:12][C:10]1[C:9]2[C:8](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:17](=[O:19])[CH:18]=1
Reactant: O=C(O)c1ccccc1Nc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=c1cc(O)c2ccccc2n1-c1ccccc1
Temperature: 0 °C

Procedure:
A solution of N-phenyl anthranilic acid (30.1g.; 0.146 mole) and acetic anhydride (74 ml.) in glacial acetic acid (74 ml.) was refluxed for 4 hrs. The resulting red solution was cooled, poured onto crushed ice-water (600 ml) and brought to pH 9 with dilute sodium hydroxide solution. After filtration the clear liquid was taken to pH 5 with hydrochloric acid and the white solid filtered off and dried, m.p. (AcOH) 298°-300°C. (Found: C, 75.40; H, 4.58; N, 5.70; C15H11NO2 requires; C, 75.94; H, 4.67; N, 5.90%).
Reaction SMILES: C([O-])CCC.C([O-])CCC.[Mg+2:11].C(OCCOCCO)CCC.COC1C=CC(O)=CC=1.[C:32]([OH:36])(=[O:35])[CH:33]=[CH2:34]>C(O)CCC>[C:32]([O-:36])(=[O:35])[CH:33]=[CH2:34].[C:32]([O-:36])(=[O:35])[CH:33]=[CH2:34].[Mg+2:11]
Reactant: C=CC(=O)O
Agent: CCCC[O-]
Agent: COc1ccc(O)cc1
Agent: [Mg+2]
Solvent: CCCCO
Solvent: CCCCOCCOCCO
Product: C=CC(=O)[O-]
Temperature: 48 °C

Procedure:
Into the flask described hereinabove there were placed 510.55 g of magnesium dibutanolate, 498.6 g of diethylene glycol monobutyl ether, and 2.8 g of 4-methoxyphenol. To this mixture there were quickly added in drops 431.7 grams of acrylic acid by means of a dropping funnel. The temperature thereby increased to 48° C. The product remained liquid and stable so that it could be heated to 90° C. during 30 minutes. The co-product butanol was expelled during 1 hour using vacuum up to 200 mbar.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]([CH3:12])[CH:9]=[C:8]2[S:13](Cl)(=[O:15])=[O:14].[NH3:17]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]([CH3:12])[CH:9]=[C:8]2[S:13]([NH2:17])(=[O:15])=[O:14]
Reactant: N
Reactant: COc1cccc2c(S(=O)(=O)Cl)cn(C)c12
Solvent: C1CCOC1
Product: COc1cccc2c(S(N)(=O)=O)cn(C)c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 7-methoxy-1-methyl-1H-indole-3-sulfonyl chloride (0.80 g, 3.08 mmol) in THF (20 mL) was added ammonia gas until saturation at ca. 10° C., then the flask was stoppered, and the reaction mixture was stirred at rt for 4 h. The reaction mixture was then quenched with water, and the organic solvent was slowly evaporated under vacuum. The precipitate formed was filtered off, washed with water and dried over P2O5 under high vacuum to obtain the desired compound (0.64 g) as a yellowish solid. MS (ISN): m/e 239.4 (M−H)−
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[CH:11]=[N:12][N:13]([C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([NH:7][C:8]([C:10]2[CH:11]=[N:12][N:13]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:27][CH:28]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCc1c(C(=O)NC2CCCCC2)cnn1-c1ccc(C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(C(=O)NC2CCCCC2)cnn1-c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl 4-[4-(cyclohexylcarbamoyl)-5-propyl-pyrazol-1-yl]benzoate (130 mg, 0.34 mmol) (Intermediate #21) was dissolved in methanol (10 mL) and treated at ambient temperature with 2M aqueous sodium hydroxide solution (2.5 mL). The mixture was stirred at ambient temperature for 18 h and then methanol was removed by evaporation under reduced pressure. The remaining aqueous solution was acidified with 2M aqueous hydrochloric acid to pH=2. A white solid precipitated out of solution, it was filtered, dried under vacuum and identified as the desired product (120 mg, quantitative reaction).