Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(C(F)(F)F)COC1N=C(C(O)=O)C=CC=1.[CH:19]1([C:22]2[CH:23]=[CH:24][C:25]([C:37]([OH:39])=O)=[N:26][C:27]=2[O:28][CH2:29][C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[CH2:21][CH2:20]1.[NH2:40][C:41]([CH2:48][CH3:49])([CH2:46][CH3:47])[C:42]([NH:44][CH3:45])=[O:43]>>[CH2:46]([C:41]([NH:40][C:37]([C:25]1[CH:24]=[CH:23][C:22]([CH:19]2[CH2:21][CH2:20]2)=[C:27]([O:28][CH2:29][C:30]([F:35])([F:36])[C:31]([F:34])([F:33])[F:32])[N:26]=1)=[O:39])([C:42](=[O:43])[NH:44][CH3:45])[CH2:48][CH3:49])[CH3:47]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC(F)(F)C(F)(F)F)n1
Reactant: CCC(N)(CC)C(=O)NC
Agent: O=C(O)c1cccc(OCC(F)(F)C(F)(F)F)n1
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC(F)(F)C(F)(F)F)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using the mixture of 6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid and 5-cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid (Example 297b) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70b) as starting materials, the product was isolated by preparative HPLC; LC-MS (UV peak area/ESI) 97%, 438.1810 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH:12]([CH2:17][CH2:18]Br)[C:13]([O:15][CH3:16])=[O:14].O>CN(C)C(=O)C>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:12]2([C:13]([O:15][CH3:16])=[O:14])[CH2:18][CH2:17]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: COC(=O)C(Br)CCBr
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)C1(n2cc([N+](=O)[O-])cn2)CC1
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
To a solution of 4-nitro-1H-pyrazole (3.0 g) in N,N-dimethylacetamide (30 mL) was added sodium hydride (60% in mineral oil, 1.2 g) in an ice bath, and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added methyl 2,4-dibromobutanoate (6.9 g) in an ice bath, and the mixture was stirred at room temperature for 10 hr. The reaction mixture was poured into water, and the reaction mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.4 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5](=[O:13])[CH:4]=1.[Cl:16][S:17](O)(=[O:19])=[O:18]>>[O:13]=[C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:17]([Cl:16])(=[O:19])=[O:18])[CH:11]=2)[NH:6]1
Reactant: O=c1cc(C(F)(F)F)c2ccccc2[nH]1
Reactant: O=S(=O)(O)Cl
Product: O=c1cc(C(F)(F)F)c2cc(S(=O)(=O)Cl)ccc2[nH]1
Temperature: 140 °C
Reaction time: 7 h
Yield: 40 %

Procedure:
4-Trifluoromethyl-1H-quinolin-2-one (5.00 g, 23.5 mmol) was treated with ClSO3H (3.1 mL, 47.0 mmol) at 0° C. The mixture was then heated with stirring to 140° C. for 7 hours. On cooling, ice-cold H2O (50 mL) was added. The solid produced was collected and dried to give the title compound (2.93 g, 41%): δH (CDCl3)=7.20 (s, 1H), 7.60 (d, 1H), 8.20 (dd, 1H), 8.50 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:15]=3)[C:10]([S:25]([CH3:27])=[O:26])=[CH:9]2)=[N:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH3:27][S:25]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)[N:8]([C:5]2[N:4]=[CH:3][C:2]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=3)=[CH:7][N:6]=2)[CH:9]=1)=[O:26]
Reactant: Brc1ccccn1
Reactant: CS(=O)c1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: C1COCCO1
Product: CS(=O)c1cn(-c2ncc(-c3ccccn3)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Temperature: 115 °C
Reaction time: 2.5 h

Procedure:
[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.014 g, 0.016 mmol) was added under an argon atmosphere at room temperature to a solution of [(1-(5-bromopyrimidin-2-yl)-3-(methylsulfinyl)-1H-indol-6-yl)(morpholino)methanone (0.15 g, 0.33 mmol), bis(pinacolato)diboron (0.093 g, 0.37 mmol) and potassium acetate (0.099 g, 0.99 mmol) in dioxane (6 mL). The reaction mixture was heated at 115° C. for 40 min and then cooled to ambient temperature. For the Suzuki coupling, which was also carried out under an inert atmosphere, 2-bromopyridine (0.078 g, 0.49 mmol), tetrakis(triphenylphosphine)palladium(0) (0.019 g, 0.016 mmol) and 2M potassium carbonate solution (0.5 mL) were added. The mixture was stirred at 100° C. for 2.5 h and then filtered through a plug of celite. The filtrate was concentrated and the resulting residue purified by flash column chromatography [methanol/dichloromethane=1:50] and a subsequent trituration with dichloromethane/hexane (1:2). White solid. Yield: 45 mg (30% of theory)
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]([NH2:20])=[O:19])[CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2].[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH:1]([C:3]1[CH:4]=[C:5]([S:21]([NH:24][C:32](=[O:33])[CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:23])=[O:22])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]([NH2:20])=[O:19])[CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2]
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc(NC(N)=O)c1
Reactant: O=C(Cl)Cc1ccccc1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)Cc2ccccc2)cc1-c1cccc(NC(N)=O)c1

Procedure:
Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-3′-ureido-biphenyl-3-sulfonamide and 2-phenylacetyl chloride, gave 5-formyl-6-methoxy-N-(2-phenylacetyl)-3′-ureido-biphenyl-3-sulfonamide.
Reaction SMILES: [S:1]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[O:12]1[CH:16]=[CH:15][C:14]([C:17](=O)[C:18](OCCCC)=[O:19])=[CH:13]1.C([O-])(C)(C)C.[K+].Cl>CO>[CH3:11][O:10][C:8]([C:7]1[S:1][C:2]([C:3]([O:5][CH3:6])=[O:4])=[C:18]([OH:19])[C:17]=1[C:14]1[CH:15]=[CH:16][O:12][CH:13]=1)=[O:9]
Reactant: COC(=O)CSCC(=O)OC
Reactant: CCCCOC(=O)C(=O)c1ccoc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: COC(=O)c1sc(C(=O)OC)c(-c2ccoc2)c1O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A mixture of 26 g of dimethyl thiodiacetate and 32 g of butyl 2-(fur-3-yl)-2-oxo-acetate is added dropwise, over 30 minutes at 64°-68° C., to a mixture of 100 ml of methyl alcohol and 39.9 g of potassium tert.-butanolate. The reaction mixture is kept at this temperature for a further 3 hours, and then poured into a mixture of 179 g of ice and 58 g of concentrated hydrochloric acid. The resultant crystals are separated off, washed with ice water until free of chloride, and dried at 60 C./0.1 mbar. Yield: 27.9 g. The product is recrystallized from 250 ml of methyl alcohol, and 22 g of 2,5-bis-(methoxycarbonyl)-3-fur-3-yl-4-hydroxythiophene having a melting point of 102° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:29]=[CH:28][C:9]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([O:22]CC=C)=[O:21])=[CH:17][CH:18]=3)[C:13]([CH3:26])=[C:12]2[CH3:27])=[CH:8][CH:7]=1.N1CCOCC1>C1COCC1.C(OCC)(=O)C.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>[CH3:1][O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:29]=[CH:28][C:9]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH:18]=3)[C:13]([CH3:26])=[C:12]2[CH3:27])=[CH:8][CH:7]=1
Reactant: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(OCC(=O)OC)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)cc1
Reaction time: 1.5 h

Procedure:
A solution of the allyl 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylate (536 mg, 1.3 mmol) and morpholine (1.14 mL, 13.2 mmol) in anhydrous THF was degassed with argon. Then Pd(PPh3)4 (152 mg, 0.13 mmol) was added and the reaction stirred under argon protection for 1.5 h. The reaction mixture was diluted with ethyl acetate, washed with brine, concentrated. The title compound was precipitated in ethyl ether as a beige powder (430 mg, 89%). ESI-MS (m/z): 368 [M+H]+.
Reaction SMILES: C(Cl)Cl.C[C@@:5]12[C@H:14]3[CH2:15][CH2:16][C@:17]4(C)[C:21]([C:22]5[CH:23]=[CH:24]C=NC=5)=C[CH2:19][C@H:18]4[C@@H:13]3[CH2:12][CH:11]=[C:10]1[CH2:9][C@@H:8]([OH:29])[CH2:7][CH2:6]2.C[OH:31]>>[CH3:9][C@@:10]12[C:8](=[O:29])[CH2:7][CH2:6][C@H:5]1[C@@H:14]1[CH2:15][CH:16]=[C:17]3[CH2:21][C@@H:22]([OH:31])[CH2:23][CH2:24][C@:18]3([CH3:19])[C@H:13]1[CH2:12][CH2:11]2
Reactant: CO
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Solvent: ClCCl
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 42.5 °C

Procedure:
34.8 ml of CH2Cl2 and 26.1 ml of methanol were added to 8.7 g (24.9 mmol) of crude stage 3 (abiraterone). The mixture was heated to 40-45° C. (reflux), to have a solution. The CH2Cl2 was then removed by distillation at atmospheric pressure. The mixture was cooled to 0-5° C., and then maintained 1 hour at 0-5° C. The suspension was filtered (fast filtration) and the cake was washed twice with 4.4 ml of methanol cooled to 0-5° C. The wet solid was dried at 40-45° C. under vacuum for 5 hours to give 7.2 g (yield of purification 82.8%) of pure stage 3 (abiraterone). The overall yield from DHEA was around 50%.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].CN1CCCC1=O>C(OCC)(=O)C>[Br:8][C:6]1[N:7]=[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([F:11])=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cn1cc(Br)nc(Nc2ccc(F)c([N+](=O)[O-])c2)c1=O
Temperature: 25 °C
Yield: 69.2 %

Procedure:
A mixture of 3,5-dibromo-1-methyl-2(1H)pyrazinone (10 g; 37.5 mmol), 4-fluoro-3-nitroaniline (5.9 g; 37.5 mmol), and 1-methyl-2-pyrollidinone (30 mL) was heated at 140 degrees for 1 hr. The mixture was cooled to room temperature, diluted with ethyl acetate (100 mL) and filtered to give 5-bromo-3-(4-fluoro-3-nitro-phenylamino)-1-methyl-1H-pyrazin-2-one (1) as a yellow solid (8.9 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]2=1.C([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#N>>[CH2:15]([C:11]1([CH2:17][CH2:18][OH:19])[C:8]2[NH:9][C:10]3[C:6]([C:7]=2[CH2:14][CH2:13][O:12]1)=[CH:5][C:4]([CH:20]([CH3:22])[CH3:21])=[CH:3][C:2]=3[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH3:16]
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(Br)cc(C(C)C)cc21
Reactant: N#Cc1cccc(B(O)O)c1
Product: CCC1(CCO)OCCc2c1[nH]c1c(-c3ccccc3)cc(C(C)C)cc21

Procedure:
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 3-cyanophenylboronic acid in step 1.F.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24](=[O:28])[N:25]([CH3:27])[CH3:26])=[CH:20][C:19]=4[Cl:29])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:30]=1.[C:31]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:18]4[CH:23]=[CH:22][C:21]([C:24](=[O:28])[N:25]([CH3:27])[CH3:26])=[CH:20][C:19]=4[Cl:29])[CH3:31])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:30]=1
Reactant: CN(C)C(=O)c1ccc(NC(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To solution of 8-bromo-N-(2-chloro-4-(dimethylcarbamoyl)phenyl)-4,5-dihydro-benzo[b]thieno[2,3-d]oxepine-2-carboxamide (29.0 g, 57.3 mmol), Cs2CO3 (37.40 g, 114.7 mmol) in DMF (600 mL), CH3I (30 mL, 479.8 mmol) was slowly added. The reaction mixture was stirred at room temperature overnight. Concentration removed about 200 mL of DMF, and then water (100 mL) was added to the mixture. The resulting precipitate was filtered, washed with water, dried to give 8-bromo-N-(2-chloro-4-(dimethylcarbamoyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (29.50 g, yield: 99%). ESI-MS: 519.4. 1H NMR (DMSO-d6, 400 MHz): δ7.72-7.68 (m, 2H, ArH), 7.52-7.49 (m, 1H, ArH), 7.30-7.20 (m, 3H, ArH), 6.76 (s, 1H, ═CH), 4.19 (s, 2H, CH2), 3.29 (s, 3H, CH3), 3.00 (s, 3H, CH3), 2.96 (s, 2H, CH2), 2.93 (s, 3H, CH3).
Reaction SMILES: [H-].[Na+].[N:3]1([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH3:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25].O>CN(C)C=O>[CH3:27][O:26][C:24]([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]([CH3:17])=[C:8]1[N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[O:25]
Reactant: Cc1c(-n2ccnc2)[nH]c2ccccc12
Reactant: COC(=O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCn1c(-n2ccnc2)c(C)c2ccccc21
Reaction time: 48 h

Procedure:
To a suspension of 60% sodium hydride (0.34 g) in dimethylformamide (10 ml), while stirring under nitrogen at 0°-5°, is added dropwise a solution of 2-(1-imidazolyl)-3-methyl-indole (1.50 g) in dimethylformamide (15 ml). Upon complete addition the mixture is stirred at 0°-5° for 1 hr. To the nearly complete solution is added methyl 6-bromohexanoate (1.67 g) dropwise. The mixture is stirred at 0°-5° for 0.5 hr, then for two days at room temperature. The solution is poured into water (100 ml) and extracted with ethyl acetate (3×50 ml), dried (MgSO4), filtered, and concentrated in vacuo to give an amber oil which is stirred with 100 ml of petroleum ether for 15 minutes. The mixture is placed in a separatory funnel and the insoluble amber oil separated and removed. The oil is dried in vacuo to give 1-(5-methoxycarbonylpentyl)-2-(1-imidazolyl)-3-methylindole as an oil; NMR (CDCl3): δ3.60(3H), 3.90(2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClCCl.[CH2:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34]>C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([S:35]([CH2:33][CH3:34])(=[O:37])=[O:36])[CH2:26][CH2:25]3)=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CCNCC3)cn2)c2ccccc21
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCN(c2ccc(N3CCN(C(=O)OC(C)(C)C)c4ccccc43)nc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.8 g of 4-(5-(piperazin-1-yl)pyridin-2-yl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester is placed in a 25 ml round-bottomed flask. ml of dichloromethane are added, followed by 0.37 ml of triethylamine and finally 0.23 ml of ethylsulphonyl chloride. The reaction mixture is stirred at ambient temperature for 3 h, then washed twice with water and once with a saturated sodium chloride solution and then evaporated under reduced pressure. 0.98 g of 4-[5-(4-(ethanesulphonyl)piperazin-1-yl)pyridin-2-yl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid tert-butyl ester is obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[F:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: O=S(=O)(Nc1cccc(CO)c1F)c1ccc(C(F)(F)F)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Product: O=Cc1cccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To N-(2-fluoro-3-hydroxymethyl-phenyl)-4-trifluoromethyl-benzenesulfonamide (25, 634 mg, 1.82 mmol) in 7 mL of tetrahydrofuran, Dess-Martin periodane (847 mg, 2.00 mmol) and sodium bicarbonate (2 g) were added. The reaction was stirred at room temperature for one hour, then poured into saturated aqueous sodium thiosulfate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 15% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (26, 607 mg, 96%). MS (ESI) [M−H+]−=346.4.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH3:22])[CH2:6][CH2:5][CH2:4]1>CO.C(OCC)C>[CH3:24][N:2]([CH3:1])[CH:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:14](=[O:23])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:22])=[CH:17][C:16]=2[CH3:22])[CH2:6][CH2:5][CH2:4]1
Reactant: Cc1cc(N)ccc1C(=O)N1CCCC(N(C)C)c2ccccc21
Solvent: CO
Solvent: CCOCC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)C)c3ccccc32)c(C)c1
Yield: 70.3 %

Procedure:
Using 5-dimethylamino-1-(2-methyl-4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (G) (1.00 g), 5-dimethylamino-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.48 g) is obtained in the same manner as in Example 978 except that methanol/diethyl ether is used instead of ethyl acetate as recrystallization solvent, as white powder, m.p. 183°-185° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[O:21]1[CH:25]=[CH:24][C:23]([NH2:26])=[N:22]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][C:23]2[CH:24]=[CH:25][O:21][N:22]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: Nc1ccon1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(Nc1ccon1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (150 mg, 0.43 mmol) and isoxazol-3-amine (43 mg, 0.51 mmol). The title compound was obtained as a brown solid (20.0 mg, 11% yield). 1H NMR (400 MHz, d6-DMSO) δ: 11.90 (1H, s), 9.03 (2H, s), 8.86 (1H, m), 6.89 (1H, s). MS m/z: 415.18, 417.16 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:16])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[Cl:16][C:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:25]([CH2:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[Cl:17])(=[O:26])=[O:27])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Solvent: c1ccncc1
Product: N#Cc1ccc(-c2cncc(NS(=O)(=O)Cc3ccccc3Cl)c2)cc1Cl
Yield: 41.5 %

Procedure:
According to General Sulfonylation Procedure 2 in Example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, 1 eq) in anhydrous pyridine (500 μl) was added (2-chloro-phenyl)-methanesulfonyl chloride (21.6 mg, 96 μmol, 1.1 eq). The crude product was purified by Isco Cornbiflash® Companion™ flash chromatography system on normal phase (4 g SiO2, flow rate 18 mL/min), eluting with mixtures of dichloromethane/methanol, to give N-[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-1-(2-chloro-phenyl)-methanesulfonamide (15.1 mg, >95% purity, yield: 41.5%). The isolated product was lyophilized and identified by LC-MS (system 1) and NMR (system 2): ESI-MS m/z: 418 [M+H]+, retention time=2.34 min, 1H NMR (400 MHz, DMSO-d6) δ ppm 4.80 (s, 2H) 7.30-7.32 (m, 2H) 7.37-7.39 (m, 1H) 7.47-7.49 (m, 1H) 7.69 (t, J=2.27 Hz, 1H) 7.75 (dd, J=8.08, 1.77 Hz, 1H) 7.98 (d, J=1.77 Hz, 1H) 8.09 (d, J=8.08 Hz, 1H) 8.37 (d, J=2.53 Hz, 1H) 8.61 (d, J=1.89 Hz, 1H) 10.50 (br. s., 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.C(N(CC)C(C)C)(C)C.[CH3:22][O:23][CH2:24]Cl>C(#N)C>[CH3:22][O:23][CH2:24][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: COCCl
Reactant: O=c1ccc2cc(O)ccc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COCOc1ccc2oc(=O)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
Equip a 3-L, three-neck, round-bottom flask equipped with a large blade mechanical stirrer, a thermocouple, a Claisen adapter, an addition funnel, and a reflux condenser. Add 2,5-dimethoxycinnamic acid (102.8 g, 493 mmol, 1.0 equiv) and dichloroethane (1.5 L). Add boron tribromide (247.4 g, 987 mmol, 2.0 equiv) dropwise over 45 min while keeping the temperature below 40° C. Rapidly stir the resulting mixture and heat gradually to 83° C. over 45 min, monitoring the temperature increase and gas evolution, Stir for 6 h at reflux then for 15 h at 76° C. Cool the resulting mixture to room temperature and quenched carefully with water (450 mL). Filter the solid, wash with heptane and dry under vacuum to afford 6-hydroxy coumarin (95 g) as a light brown solid which is used without further purification. Equip a 2-L, three-neck, round-bottom flask with a magnetic stir bar and a thermocouple. Add 6-hydroxy coumarin (39.8 g, 245 mmol, 1.0 equiv), anhydrous acetonitrile (700 mL) and N,N-diisopropylethylamine (200 mL, 1.15 mol, 4.7 equiv). Add chloromethyl methyl ether (40.0 mL, 527 mmol, 2.1 equiv) dropwise over 30 min while keeping the temperature below 40° C. Stir the resulting mixture at room temperature for 3 h, then add an additional equiv of chloromethyl methyl ether. Stir at room temperature for 15 h, then quench the reaction mixture with saturated aqueous ammonium chloride (500 mL) and extracted with ethyl acetate. Combine the organic extracts and dry over anhydrous magnesium sulfate, filter and concentrate under reduced pressure. Purify the residue by column chromatography on silica gel (30-50% ethyl acetate/heptane) to afford a light yellow solid. Suspend the solid in a mixture of ethyl acetatefleptane (150 mL, 10:90), filter and dry to afford 6-methoxymethoxy coumarin 17a (25.6 g, 50%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J=7.8 Hz, 1H), 7.30-7.12 (m, 3H), 6.41 (d, J=7.8 Hz, 1H), 5.20 (s, 2H), 3.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.2, 154.0, 149.5, 143.5, 121.6, 119.6, 118.1, 117.3, 113.8, 95.3, 56.4; IR (KBr) 1714 (s), 1570 (s), 1491 (m), 1447 (m), 1266 (s), 1154 (s), 1070 (s), 1017 (s) cm−1; ESI MS m/z 207 [C11H10O4+H]+.