Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7](SC)[N:6]3[C:14](=[O:24])[N:15]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[N:16]=[C:5]3[C:4]=2[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:33])[N:6]3[C:14](=[O:24])[N:15]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[N:16]=[C:5]3[C:4]=2[CH:3]=1
Reactant: CSc1nc2ccc(Br)cc2c2nn(-c3ccc(C)cc3)c(=O)n12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-n2nc3c4cc(Br)ccc4[nH]c(=O)n3c2=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.8 %

Procedure:
To a solution of 7a (0.534 g, 1.33 mmol) in 60 mL of CH2Cl2 was added (77%) m-CPBA (0.597 g, 2.67 mmol) and mixture was stirred at room temperature for 6 h. A white precipitate was slowly formed. Saturated solutions of aqueous Na2S2O3 (20 mL) and NaHCO3 (20 mL) were subsequently added and the mixture was stirred vigorously for 30 min. The precipitate was filtered off, washed several times with water and heated in a mixture of 25 mL ethyl alcohol and 25 mL of water at reflux for 30 min. The mixture was cooled to rt. and filtered to give 8a as a white solid (0.488 g, 99%). mp: 369° C.;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[CH:14][C:9]=2S[CH:7]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[O-:37][S:38]([O-:40])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:10]2[CH:9]=[CH:14][C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[CH:12][C:11]=2[S:38](=[O:40])(=[O:37])[CH:7]=1)[CH3:2]
Reactant: O=S([O-])[O-]
Reactant: CCOC(=O)Cc1csc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CC1=CS(=O)(=O)c2cc(OCc3ccc(Cl)cc3Cl)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.6 %

Procedure:
To a mixture of ethyl(6-((2,4-dichlorobenzyl)oxy)-1-benzothiophen-3-yl)acetate (10.0 g) in anhydrous DCM (400 mL) was added mCPBA (85%, 15.7 g), and the resulting solution was stirred at 25° C. for 3 d. To the reaction mixture was added Na2SO3 (30.0 g), and the mixture was stirred at 25° C. for 0.5 h. The reaction mixture was washed successively with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo. The residue was washed with EtOAc to give the title compound (8.50 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([NH:12][C:13]([O:15][CH3:16])=[O:14])[N:11]=2)[CH:8]=1.[OH:17]O>CC(O)=O>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([NH:12][C:13]([O:15][CH3:16])=[O:14])[N:11]=2)[CH:8]=1)=[O:17]
Reactant: COC(=O)Nc1cn2cc(SC)ccc2n1
Reactant: OO
Solvent: CC(=O)O
Product: COC(=O)Nc1cn2cc(S(C)=O)ccc2n1
Temperature: 0 °C

Procedure:
A suspension of 6-(methylthio)imidazo[1,2-a]pyridine-2-carbamic acid, methyl ester (prepared as described in Example 1) (0.447 mol) in 2700 ml of HOAc is treated dropwise with 535 ml of 30% H2O2. The suspension is stirred until a solution is obtained (~5 hours) and then poured into 8 l. of ice water. The product is collected by filtration and dried.
Reaction SMILES: [I:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](O)=[N:4][CH:3]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:2]([I:1])=[CH:3][N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)ncc(I)c2c1
Product: COc1ccc2c(Cl)ncc(I)c2c1
Temperature: 0 °C
Yield: 61.2 %

Procedure:
A solution of 4-iodo-6-methoxyisoquinolin-1-ol (2 g, 6.64 mmol) in POCl3 (10 mL) was refluxed for 4 h. After concentration, the residue was taken into a mixture of 100 mL of DCM and 50 mL of water, cooled to 0° C., neutralized with 3 N NaOH, dried over MgSO4, concentrated and purified via silica gel chromatography (5-20% EtOAc:Hex) to give the pure product 1-chloro-4-iodo-6-methoxyisoquinoline (1.3 g, 4.07 mmol, 61.2% yield) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.22 (d, J=9.3 Hz, 1H), 7.54 (dd, J=9.3, 2.5 Hz, 1H), 7.33 (d, J=2.5 Hz, 1H), 4.03 (s, 3H). MS: MS m/z 320(M++1).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1.[OH-].[Na+].[I:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl>C(Cl)Cl.C(Cl)Cl.O.O>[I:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:2]2[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=C(O)C1CNC1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(O)C1CN(S(=O)(=O)c2ccc(I)cc2)C1
Yield: 43.8 %

Procedure:
To a stirred solution of azetidine-3-carboxylic acid hydrochloride (1.0 g, 7.27 mmol) in DCM (25 mL) is added 5N aqueous NaOH (10 mL) and water (10 mL). p-Iodobenzenesulfonyl chloride (2.41 g, 7.98 mmol) is added portionwise. After 18 h the reaction mixture is diluted with DCM/water. The basic aqueous layer is acidified with 5N aqueous HCl. The resultant precipitate is filtered, washed with water and MeCN. Drying in air gives 1.17 g (44%) of 1-[(4-iodophenyl)sulfonyl]azetidine-3-carboxylic acid. m/z=368 [M++H].
Reaction SMILES: [ClH:1].C([NH:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH:12]([NH:16][CH2:17][CH3:18])[CH2:13]2)=[CH:8][CH:7]=1)(=O)C>Cl>[ClH:1].[NH2:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][CH:12]([NH:16][CH2:17][CH3:18])[CH2:13]2)=[CH:8][CH:7]=1
Reactant: CCNC1CCc2ccc(NC(C)=O)cc2C1
Agent: Cl
Product: CCNC1CCc2ccc(N)cc2C1

Procedure:
1.6 (5.9 mmol) (+)/(-)-7-acetamido-2-ethylamino-1,2,3,4-tetrahydronaphthalene hydrochloride are heated at the reflux temperature with 40 ml 2 N HCl for 2 hours. The solution is then concentrated i. vac., 20 ml ethanol are added to the residue and the crystals are filtered off with suction, washed with ethanol and dried to constant weight in a circulating air drying cabinet.
Reaction SMILES: [C:1]1([S:7]([C:10]([CH3:22])([CH3:21])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([OH:20])[CH2:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23]I.[H-].[Na+]>O1CCCC1>[C:1]1([S:7]([C:10]([CH3:22])([CH3:21])[CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([O:20][CH3:23])[CH2:15]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(CCCN1CCCC(O)C1)S(=O)(=O)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CCCN(CCCC(C)(C)S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(4-Benzenesulfonyl-4-methylpentyl)-3-hydroxypiperidine (0.1 g, 0.31 mmol), methyl iodide (22 μL, 0.35 mmol) and sodium hydride (60% dispersion in mineral oil, 15 mg, 0.35 mmol) were combined in tetrahydrofuran (2 ml) and stirred at room temperature for 18 hours. The reaction was quenched by the addition of water and brine and the mixture extracted with ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 2–5% methanol/dichloromethane, to give the title compound. The hydrochloride salt was obtained by treatment with ethereal hydrogen chloride and crystallisation from ethanol/diethyl ether (77 mg, 74%). NMR of hydrochloride salt:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][CH:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([CH:25]=O)[CH:11]=2.Cl.[CH3:31][O:32][NH2:33]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][CH:15]([NH:19][C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([CH:25]=[N:33][O:32][CH3:31])[CH:11]=2
Reactant: CC(C)C(=O)NC1CCc2c(c3cc(C=O)ccc3n2Cc2cccc(F)c2)C1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CCC(NC(=O)C(C)C)C1
Yield: 33.7 %

Procedure:
Add N-[9-(3-fluoro-benzyl)-6-formyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide (Example 197) (crude, 506 mg, 1.29 mmol) to a suspension of methoxyamine hydrochloride salt (140 mg, 1.48 mmol) and pyridine (10 mL). Stir the reaction at ambient temperature for 12 h. Remove the pyridine under vacuum and dissolve the resultant residue in ethyl acetate (100 mL). Wash with saturated aqueous copper sulfate (2×50 mL) and water (2×50 mL). Separate the organic layer and dry over magnesium sulfate, filter, and concentrate under vacuum to give a greasy yellow solid. The solid was purified with column chromatography (silica gel; 10% to 50% ethyl acetate in hexanes) to give 183 mg (34%) of the title compound as a white solid. mp: 180-182° C.; ESI MS m/z 422 [C25H28FN3O2+H]+; 1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 7.79 (s, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.26-7.17 (m, 2H), 6.93 (t, J=7.1 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.62 (d, J=9.1 Hz, 1H), 5.49 (br d, J=7.0 Hz, 1H), 5.24 (s, 2H), 4.40 (br s, 1H), 3.97 (s, 3H), 3.15 (dd, J=15.8, 4.7 Hz, 1H), 2.71-2.61 (m, 3H), 2.28 (septet, J=6.8 Hz, 1H), 2.07-2.00 (m, 2H), 1.14 (d, J=6.7 Hz, 3H), 1.12 (d, J=6.7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][N:16]([CH3:29])[C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([CH3:28])[CH:20]=1)=[O:18]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([C:17]([N:16]([CH3:29])[CH3:15])=[O:18])=[CH:20][C:21]=2[CH3:28])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Cc1cc(C(=O)N(C)C)ccc1C(=O)O
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: Cc1cc(C(=O)N(C)C)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
In a sealed tube, 1.94 g of dimethyl 2-bromoterephthalate was dissolved in 4 mL of HMPA and degassed with nitrogen prior to adding 1.1 mL of tetramethyl tin and 0.077 g of palladium tetrakistriphenylphosphene. After sealing the tube, the reaction was heated to 65° C. for 16 h. The reaction was then partitioned into ethylether and water and extracted. The organic layers were washed with 5% ammonium hydroxide, 1N HCl, again with 5% ammonium hydroxide, and finally with water. Filtration of the solvent through sodium sulfate and evaporation gave 1.44 g of crude dimethyl 2-methylterephthalate. 210 mg of dimethyl 2-methylterephthalate was hydrolyzed via Procedure M to give 4-(methoxycarbonyl)-3-methylbenzoic acid. Silica gel chromatography was performed (0% to 70% EtOAc gradient in Hexanes) to yield 115 mg of 4-(methoxycarbonyl)-3-methylbenzoic acid. 4-(methoxycarbonyl)-3-methylbenzoic acid was then coupled to dimethylamine hydrochloride via Procedure G. The crude methyl 4-(dimethylcarbamoyl)-2-methylbenzoate was then hydrolyzed via Procedure M to give 110 mg of 4-(dimethylcarbamoyl)-2-methylbenzoic acid. 4-chloro-3-(pyridin-2-yl)aniline was coupled to 110 mg of 4-(dimethylcarbamoyl)-2-methylbenzoic acid via Procedure G to yield N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4,N4,2-trimethylterephthalamide. MS (Q1) 394 (M)+.
Reaction SMILES: [NH2:1][C:2]1[C:12]([Cl:13])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[Cl:14].[N:15]([O-])=O.[Na+].[Sn](Cl)Cl>Cl.O>[ClH:13].[Cl:14][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([Cl:13])[C:2]=1[NH:1][NH2:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: O=N[O-]
Reactant: CCOC(=O)c1cc(Cl)c(N)c(Cl)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(Cl)c(NN)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 107.9 %

Procedure:
Part A: To a stirred suspension of 4.33 g (18.5 mmol) of ethyl 4-amino-3,5-dichlorobenzoate in 8 mL conc. HCl at 0° C. was added a solution of 1.28 g (18.5 mmol) of sodium nitrite in 8 mL water dropwise. After stirring at 0° C. for 45 min, a solution of 12.52 g (55.5 mmol) tin(II) chloride in 14 ML conc. HCl was added dropwise. The reaction was sealed and placed in the refrigerator for 18 h. The solid was collected by suction filtration, washed with brine and then 2:1 petroleum ether-diethyl ether, treated with 1 N NaOH, and filtered. This solid was dissolved in diethyl ether, acidified with 4 N HCl in dioxane, filtered and washed with diethyl ether to give 2.85 g (54%) of ethyl 3,5-dichloro-4-hydrazinobenzoate hydrochloride, mp 225-227 (dec)° C. Mass Spec.: (CI+) 249 (M+).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43]C(C)(C)C)=O)[CH2:37][CH2:36]1>C(OCC)(=O)C>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:34][CH:35]5[CH2:36][CH2:37][N:38]([C:41](=[O:43])[CH2:1][N:6]([CH3:12])[CH3:7])[CH2:39][CH2:40]5)=[O:28])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)NC2CCN(C(=O)CN(C)C)CC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 1 h

Procedure:
Using the general procedure for amide bond synthesis, 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acid was first reacted with tert-butyl 4-aminopiperidine-1-carboxylate. The product was diluted to ethyl acetate, washed by sodium bicarbonate aqueous solution and brine. Organic extract was dried and concentrated to a residue. It was then dissolved in a mixture of TFA and MeOH (1:1) and stirred for 1 h. After which, it was concentrated in vacuo, separated between ethyl acetate and sodium bicarbonate aqueous solution. Organic extract dried and concentrated to a residue, which was subjected to amide bond synthesis with 2-(dimethylamino)acetic acid. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (m, 2 H) 1.61 (m, 4 H) 1.73 (br. s., 4 H) 1.99 (s, 3 H) 2.19 (s, 6 H) 2.73 (m, 1 H) 3.14 (m, 3 H) 3.80-3.95 (m, 3 H) 3.95-4.20 (m, 4 H) 4.26 (m., 1 H) 4.81 (d, J=8.1 Hz, 1 H) 7.19 (d, J=6.8 Hz, 1 H) 7.92-8.10 (m, 2 H) 8.18-8.35 (m, 2 H). [M+H] calc'd for C30H39F3N8O4, 633; found 633.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH2:32][OH:33])[CH:30]=2)[CH:25]=[CH:24]1.[OH-].[Na+]>C(Cl)Cl>[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([CH:32]=[O:33])[CH:30]=2)[CH:25]=[CH:24]1
Reactant: OCc1ccc2cc[nH]c2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=Cc1ccc2cc[nH]c2c1
Reaction time: 1 h
Yield: 24.2 %

Procedure:
Dess-Martin periodane (2.56 g, 6.04 mmol) was dissolved into anhydrous CH2Cl2 (25 ml). (1H-Indol-6-yl)-methanol (883 mg, 6.04 mmol) in anhydrous CH2Cl2 (20 ml) was added and the mixture was stirred for 1 h. Aqueous sodium hydroxide (12 ml of 1N solution) was added and the reaction was stirred for 30 min. The organic layer was separated and washed with water (10 ml), brine (10 ml), dried over MgSO4, filtered and concentrated to a thick brown oil. Purification by column chromatography (silica gel, gradient elution of 2% MeOH/CH2Cl2 to 5% MeOH/CH2Cl2) gave 1H-indole-6-carbaldehyde (212 mg, 24%) as a brown solid: 1H NMR (300 MHz, DMSO-d6) δ 11.67 (bs, 1H), 9.99 (s, 1H), 7.97 (s, 1H), 7.70-7.65 (m, 2H), 7.54-7.50 (m, 1H), 6.59-5.54 (m, 1H).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[NH2:13][C:14]1[C:15]([NH:24][S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[N:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.[CH:30]1([C:36](O)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C(Cl)Cl>[CH2:28]([S:25]([NH:24][C:15]1[C:14]([NH:13][C:36]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:37])=[CH:19][C:18]([C:20]([F:23])([F:21])[F:22])=[CH:17][N:16]=1)(=[O:27])=[O:26])[CH3:29]
Reactant: CCS(=O)(=O)Nc1ncc(C(F)(F)F)cc1N
Reactant: O=C(O)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1ncc(C(F)(F)F)cc1NC(=O)C1CCCCC1
Reaction time: 10 h
Yield: 62.5 %

Procedure:
An alternative process will be described. In 20 ml of methylene chloride, 0.5 g of 4-diemthylaminopyridine was dissolved, and 0.78 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added and dissolved. Then, 1 g of N-(3-amino-5-trifluoromethyl-2-pyridyl)ethanesulfonamide was added thereto, and 30 minutes later, 0.52 g of cyclohexanecarboxylic acid was added thereto, and stirring was conducted for 10 hours. After completion of the reaction, 40 ml of methylene chloride was added to the reaction product, and the reaction product was washed with 10% hydrochloric acid and then washed with an aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. From the extract layer, solvent was distilled off and the obtained residue was purified by silica gel column chromatography to obtain 0.88 g of the desired product.
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[C:24]2[NH:26][N:27]=[C:28](I)[C:23]2=[CH:22][N:21]=1.[CH3:30][N:31]([CH3:50])[CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=1>>[F:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([F:19])[C:10]=1[C:20]1[N:25]=[C:24]2[NH:26][N:27]=[C:28]([C:38]3[CH:39]=[CH:40][C:35]([O:34][CH2:33][CH2:32][N:31]([CH3:50])[CH3:30])=[CH:36][CH:37]=3)[C:23]2=[CH:22][N:21]=1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Reactant: CN(C)CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc(OCCN(C)C)cc4)n[nH]c3n2)c1F

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 7, Step 3 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and N,N-dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethanamine (Combi-Blocks, Cat. No. PN-3972). LCMS (M+H)+=456.1.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([S:7]([N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[N:4]=[CH:3]1.Cl>O1CCOCC1>[CH3:1][N:2]1[CH:6]=[C:5]([S:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)(=[O:8])=[O:9])[N:4]=[CH:3]1
Reactant: Cn1cnc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1cnc(S(=O)(=O)N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To an ice-cold solution of tert-butyl 4-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazine-1-carboxylate (36, 6.0 g, 18.18 mmol) in 1,4-dioxane (30 mL) was slowly added concentrated HCl (30 mL) drop wise over 30 minutes. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under vacuum, azeotroped with toluene (3×100 mL) and the resultant solids dissolved in H2O (100 mL). The aqueous mixture was washed with CH2Cl2 (2×100 mL) then carefully neutralized with solid K2CO3 (15 g). The aqueous mixture was then extracted with CH2Cl2 (4×100 mL) and combined organic extracts were washed with brine (1×50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to afford 1-(1-methyl-1H-imidazol-4-ylsulfonyl)piperazine (37) as off-white foam (3.8 g, 90%): 1H NMR (400 MHz, CDCl3) δ (dd, J=1.1 Hz, 16.8 Hz, 2H), 3.80-3.75 (m, 5H), 3.74-3.65 (m, 2H), 3.37-3.1 (m, 2H), 3.0-3.25 (m, 2H); MS (ESI+) m/z 231 (M+H).
Reaction SMILES: Cl.C[C:3]1[C:8]2[C:9](Cl)=[N:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[S:13](=[O:15])(=[O:14])[C:7]=2[CH:6]=[C:5]([C:21]([O-:23])=[O:22])[CH:4]=1.[CH3:24]COCC>>[CH:3]1[C:8]2[CH:9]=[N:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[S:13](=[O:14])(=[O:15])[C:7]=2[CH:6]=[C:5]([C:21]([O:23][CH3:24])=[O:22])[CH:4]=1
Reactant: CCOCC
Reactant: Cc1cc(C(=O)[O-])cc2c1C(Cl)=Nc1ccccc1S2(=O)=O
Agent: Cl
Product: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccccc1N=C2

Procedure:
Stir a suspension of 12.766 gm (67.33 mmole) of anhydrous stannous chloride in 350 ml of dry ether while passing dry hydrogen chloride through the suspension at a rate sufficient to cause brisk reflut. When the suspension is saturated, add 5.63 gm 16,83 mmole) of methyl-11-chlorodibenzo[b,f][1,4]thiazepin-3-carboxylate 5,5-dioxide in portions over 15 minutes. Continue introduction of hydrogen chloride for 1 hour. Decant the ether layer and pour the residue into a mixture of 200 ml of ether and 100 ml of water. Separate the ether layer and wash with 25 ml of 5 N aqueous sodium hydroxide and then with 50 ml of saturated sodium chloride solution. Dry the ether layer over magnesium sulfate and evaporate to 20 ml. Separate the precipitate by filtration. Chromatograph over silica gel eluting with 1:4 ethyl acetate in toluene. Disolve the product in boiling methanol, filter and evaporate to 10 ml. Separate the solid by filtration to obtain the title product (m.p. 181°-181.5° C.).
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)(=O)C>[N:19]1(/[C:1](/[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:9]2\[C:10](=[O:18])[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[S:13]\2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C1CCNC1
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Solvent: CC(=O)O
Product: O=C1/C(=C(/c2ccccc2)N2CCCC2)Sc2ccccc21
Yield: 5 %

Procedure:
Prepared as in Example 31 from 2-benzoyl-benzo[b]thiophen-3-ol and pyrrolidine in glacial acetic acid with a yield of 5% of theory. Egg-yellow crystals, m.p. 157° C. (ethyl acetate/petroleum ether 1:3).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([CH3:26])=[C:7]([CH2:14][N:15]3[C:19](=[O:20])[C:18]4=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]4[C:16]3=[O:25])[C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Cl:35][C:36]([CH2:38]Cl)=[CH2:37]>CN(C=O)C.C(Cl)Cl>[Cl:35][C:36](=[CH2:37])[CH2:38][O:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([CH3:26])=[C:7]([CH2:14][N:15]3[C:16](=[O:25])[C:17]4=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]4[C:19]3=[O:20])[C:8](=[O:13])[O:9]2)=[CH:4][CH:3]=1
Reactant: C=C(Cl)CCl
Reactant: Cc1c(CN2C(=O)c3ccccc3C2=O)c(=O)oc2c(C)c(O)ccc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=C(Cl)COc1ccc2c(C)c(CN3C(=O)c4ccccc4C3=O)c(=O)oc2c1C
Temperature: 25 °C

Procedure:
A slurry of 7-hydroxy-4,8-dimethyl-3-phthalimidomethylcoumarin (649 mg, 1.86 mmol), potassium carbonate (320 mg, 2.60 mmol), potassium iodide (15 mg, 0.093 mmol), and 2,3-dichloro-1-propene (0.20 mL, 2.23 mmol) in DMF (15 mL) was stirred at 55-65° C. for 8 hours, allowed to cool to room temperature, then chilled in an ice water bath. The solid was filtered off to obtain the first crop of crude product (1.09 g). Half of the solvent was removed from the filtrate and after chilling, a second crop of crystals was obtained (33 mg). The solids were combined, dissolved in CH2Cl2, and washed with water several times. The organic layer was dried and evaporated to give 7-(beta-chloroallyloxy)-4,8-dimethyl-3-phthalimidomethylcoumarin, a white solid (690 mg, 87%). 1H NMR (CDCl3): δ 7.66-7.83 (m, 4H), 7.49 (d, J=9.1 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 5.56 (s, 1H), 5.47 (s, 1H), 4.91 (s, 2H), 4.67 (s, 2H), 2.59 (s, 3H), 2.32 (s, 3H).