Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](Cl)[N:8]=[CH:7]2.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(OCC)(=O)C>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([F:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:17][CH:16]=1)[N:8]=[CH:7]2
Reactant: Fc1cc(Br)c2nc(Cl)ncc2c1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: NS(=O)(=O)c1ccc(Nc2ncc3cc(F)cc(Br)c3n2)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a 0.4M suspension of 8-bromo-2-chloro-6-fluoroquinazoline in isopropanol was added 4-aminobenzensulfonamide (1 eq). The reaction mixture was heated to 120° C. in an oil bath for 2 days. LCMS showed that reaction was complete under the condition. Ethyl acetate was added to the reaction flask and the suspension was stirred at ambient temperature for 30 min and was filtered. Filter cake was rinsed with hexane and dried in vacuum to give product in 81% yield. ES/MS m/z 397/399 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23](=[O:38])[CH2:24][Sn](CCCC)(CCCC)CCCC)[CH3:21]>CN(C=O)C.CCOC(C)=O.[Br-].[Zn+2].[Br-]>[CH2:20]([O:22][C:23](=[O:38])[CH2:24][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[CH3:21]
Reactant: Brc1cc(OCc2ccccc2)cc2ccccc12
Reactant: CCCC[Sn](CCCC)(CCCC)CC(=O)OCC
Agent: [Br-]
Agent: [Zn+2]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc(OCc2ccccc2)cc2ccccc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
3-Benzyloxy-1-bromo-naphthalene (5.64 g, 18.01 mmol) is dissolved under an atmosphere of argon in dry DMF (100 ml). Tributylstannanyl-acetic acid ethyl ester (7.47 g, 19.81 mmol) is added, as well as [bis(tri-ortho-tolyl-phosphine)]palladium (II) dichloride (2.83 g, 3.60 mmol) and zinc(II) bromide (5.27 g, 23.41 mmol). The reaction mixture is heated to 80° C. for 3 h. The reaction mixture is diluted with EtOAc and washed twice with diluted brine (back extracted). The combined organic layers are dried over Na2SO4, the solvent is removed, and the residue is purified by FCC (hexane/EtOAc 100:0 to 97.5:2.5 to 95:5 to 90:10). The resulting oil, still containing tin residues, is stirred in a 1:1 mixture of EtOAc/1N NaOH (200 ml) for 1 h. The mixture is extracted twice with EtOAc. The combined organic layers are washed twice with H2O (back extracted), dried over Na2SO4 and concentrated. The residue is purified by FCC (hexane/EtOAc 100:0 to 97:3 to 95:5 to 93:7 to 92:8 to 90:10) to yield the title compound. 1H NMR (DMSO, 400 MHz) δ 1.18 (t, J=7.2 Hz, 3H), 4.10 (q, J=7.2 Hz, 2H), 4.11 (s, 2H), 5.25 (s, 2H), 7.21 (d, J=3.0 Hz, 1H), 7.41 (m, 8H), 7.53 (d, J=6.6 Hz, 1H), 7.84 (dd, J=7.2 Hz, 1H); ES-MS: 320 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6](O)=O)[CH3:2].N1CCCCC1.C=O>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:16])[C:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH2:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)O
Agent: C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: C=C(Cc1ccccc1)C(=O)OCC
Temperature: 130 °C
Yield: 84.7 %

Procedure:
Benzylmalonic acid monoethyl ester (8.0 g, 36 mmol), 7 mL of pyridine, 0.36 mL (3.6 mmol) of piperidine, and 1.06 g (35 mmol) of paraformaldehyde is refluxed under nitrogen for 1.5 hours in an oil bath maintained at 130° C. After cooling for 0.5 hours the mixture is partitioned between 100 mL of water and 100 mL of hexane. The aqueous phase is re-extracted with 50 mL of hexane. The organic phase is washed with aqueous 10% HCl, water, 1M sodium bicarbonate, and brine. It is dried over anhydrous sodium sulfate and concentrated in vacuo, yielding 5.8 g of the title compound as a colorless oil.
Reaction SMILES: [Cl-].[NH4+:2].[Al](C)(C)C.[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][N:9]=1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]([NH2:2])=[NH:13])=[CH:10][N:9]=1
Reactant: [NH4+]
Reactant: N#Cc1ccc(Cl)nc1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: N=C(N)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 40.8 %

Procedure:
Suspend ammonium chloride (1.16 g, 21.6 mmol) in toluene (10 mL). Cool to 0° C. and slowly add 2.0 M Al(CH3)3 in toluene (10.8 mL, 21.6 mmol) (see Tetrahedron Lett. 1990, 31(14), 1969-1972). After the gas stops evolving, add a solution of 6-chloronicotinonitrile (1.00 g, 7.22 mmol) in toluene (52 mL). Heat to 80° C. overnight. Cool the reaction mixture, then slowly pour into slurry of silica gel (40 g) in CHCl3 (200 mL). Stir for 10 minutes before filtering. Filter and wash the silica plug with methanol (2× 100 mL). Concentrate the filtrate and purify by 10 g SCX column washing with methanol and then eluting with 2.0 M NH3 in methanol to give the title compound (0.458 g, 40.8%): MS ES+ 155.9 (M+H)+: HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=1.2 min, 97.2% purity.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C@H:9]1[CH2:29][C@@:28]2([CH3:30])[C@@H:20]([CH2:21][C@H:22]([CH3:37])[C@:23]2([O:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[C:24](=[O:27])[CH2:25][OH:26])[C@H:19]2[C@H:10]1[C@:11]1([CH3:39])[C:16]([CH2:17][CH2:18]2)=[CH:15][C:14](=[O:38])[CH:13]=[CH:12]1.O.Cl>N1C=CC=CC=1>[C:1]([O:26][CH2:25][C:24](=[O:27])[C@:23]1([O:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[C@:28]2([CH3:30])[C@H:20]([C@H:19]3[C@H:10]([C@@H:9]([Cl:8])[CH2:29]2)[C@:11]2([CH3:39])[C:16](=[CH:15][C:14](=[O:38])[CH:13]=[CH:12]2)[CH2:17][CH2:18]3)[CH2:21][C@@H:22]1[CH3:37])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)C(=O)O[C@]1(C(=O)CO)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@@]21C
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)[C@@]1(OC(=O)C(C)C)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](Cl)C[C@@]21C
Reaction time: 3.5 h

Procedure:
Acetic anhydride (0.22 ml.) was added to a solution of 11β-chloro-21-hydroxy-17-isobutyryloxy-16β-methylpregna-1,4-diene-3,20 dione (71 mg.) in pyridine (1 ml.) at room temperature. After 3.5 hours, a little water was added and the solution was poured into dilute hydrochloric acid. Filtration of the precipitated solid and crystallization from methanol afforded the title compound, m.p. 204°-205° (K), [α]D + 95.2 (c 0.6 chloroform) λmax 240 nm (ε 15,450) (Found: C, 67.05; H, 7.4; Cl, 7.05, C28H37Cl O6 requires C, 66.6; H, 7.4; Cl, 7.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[C:12]1[CH:11]=[CH:10][C:9]([C:18](O)=[O:19])=[CH:8][C:7]=1[O:6]2.F[P-](F)(F)(F)(F)F.N1C2C=CC=C(OC(N(C)C)=[N+](C)C)C=2N=N1.[CH:45]([N:48](CC)[CH:49](C)[CH3:50])(C)[CH3:46].C(NCC)C>CN(C)C=O>[CH2:45]([N:48]([CH2:49][CH3:50])[C:18]([C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[O:17])[C:14]3[C:5]([O:6][C:7]=2[CH:8]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=3)=[O:19])[CH3:46]
Reactant: COc1ccc2c(=O)c3ccc(C(=O)O)cc3oc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(Oc1cccc2[nH]nnc12)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCN(CC)C(=O)c1ccc2c(=O)c3ccc(OC)cc3oc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.2 %

Procedure:
A mixture of compound 6i (0.707 g, 2.62 mmol) and O-benzotriazol-yl-N,N, N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 1.05 g, 2.74 mmol) in N,N-dimethylformamide (10 mL) was treated with N,N-diisopropylethylamine (DIEA, 0.685 mL, 3.92 mmol) and allowed to stir at rt for 15 min. Diethylamine (0.541 mL, 5.23 mL) was added and the resultant mixture was stirred for 2 h. The mixture was poured into ice water. A solid was collected by filtration, washed with water and air dried to give the title compound (0.445 g). MS: m/z 326.0 (MH+). 1H NMR (DMSO-d6): δ 1.07 (br t, 3 H), 1.19 (br t, 3 H), 3.20 (br q, 2 H), 3.48 (brt, 2 H), 3.95 (s, 3 H), 7.08 (m, 1 H), 7.17 (d, 1 H, J=2.1 Hz), 7.40 (d of d, 1H, J=1.3 &8.1 Hz), 7.59 (d, 1 H, J=1.2 Hz), 8.12 (d of d, 1 H, J=1.3 & 8.9 Hz) and 8.21 (d, 1 H, J=8.1 Hz).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH:10]=2)O1.Br[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1.C(Cl)Cl>COCCOC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[O:13]1[C:12]2([CH2:17][CH2:18][C:9]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=3)=[CH:10][CH2:11]2)[O:16][CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(C2=CCC3(CC2)OCCO3)nc1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dioxaspiro[4.5]dec-7-ene prepared as above (8.40 g, 31.56 mmol), 2-bromo-5-nitropyridine (6.0 g, 29.55 mmol) in DME (200 mL), degassed 2M potassium carbonate (40 mL) was added palladium tetrakis(triphenylphosphine) (Pd(PPh3)4; 1.8 g, 1.58 mmol). The reaction mixture was evacuated with nitrogen (3 cycles) and allowed to stir under vacuum for 5 minutes, then heated to 80° C. overnight. The reaction mixture was allowed to cool to ambient temperature, EtOAc (200 mL) was added followed by water (200 mL), the suspension was filtered and the organic phase was separated and the aqueous layer re-extracted into EtOAc (200 mL). The organic extracts were combined, washed with brine (200 mL), dried (MgSO4) and concentrated to leave crude product. DCM was added and the suspension was filtered and dried to leave the title compound (1.64 g). The filtrate was concentrated after the addition of DCM a further 1.51 g of product was obtained, the filtrate was purified on a 120 g SiliCycle cartridge eluting 20-50-70% EtOAc in isohexane to provide 1.72 g of product. Total yield is 4.85 g (18.51 mmol, 58%);
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[CH:10]1[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[O:13][C:12]([CH3:20])([CH3:19])[C:11]1=[O:21])[CH3:2].F[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.ClCCl>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]=2)=[CH:5][C:4]=1[CH:10]1[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[O:13][C:12]([CH3:20])([CH3:19])[C:11]1=[O:21])[CH3:2]
Reactant: CCc1ccc(O)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Reactant: Fc1cccc(C(F)(F)F)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1ccc(Oc2cccc(C(F)(F)F)n2)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 140 °C

Procedure:
A mixture of 4-(2-ethyl-5-hydroxyphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (100 mg, 0.34 mmol), 2-fluoro-6-trifluoromethylpyridine (68 mg, 0.41 mmol), and potassium carbonate (110 mg, 0.69 mmol) in N,N-dimethylformamide (3 ml) is heated to 140° C. under microwave irradiation for 40 minutes. The mixture is cooled to room temperature, poured into 2M aqueous hydrochloric acid, diluted with dichloromethane and filtered through a phase separation cartridge. The organic phase is collected. The solvent is evaporated under reduced pressure and the residue is purified by column chromatography on silica gel to give 4-[2-ethyl-5-(6-trifluoromethylpyridin-2-yloxy)phenyl]-2,2,6,6-tetramethylpyran-3,5-dione.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:26]4[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=4)=[N:15][N:16]4[C:21]([NH:22][CH:23]5[CH2:25][CH2:24]5)=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:40][CH:41]1[CH2:43][CH2:42]1>CN(C)C=O>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([C:26]4[CH:27]=[CH:28][C:29]([O:32][CH2:40][CH:41]5[CH2:43][CH2:42]5)=[CH:30][CH:31]=4)=[N:15][N:16]4[C:21]([NH:22][CH:23]5[CH2:24][CH2:25]5)=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccc(-c2nn3c(NC4CC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1cc(NC2CC2)n2nc(-c3ccc(OCC4CC4)cc3)c(-c3ccnc(NC4CCCC4)n3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To a solution of 4-[3-[2-(cyclopentylamino)-4-pyrimidinyl]-7-(cyclopropylamino)pyrazolo[1,5-a]pyridin-2-yl]phenol (146 mg, 0.34 mmol) in N,N-dimethylformamide (3 mL) was added cesium carbonate (0.22 g, 0.68 mmol) and (bromomethyl)cyclopropane (66 μL, 0.68 mmol). The reaction was stirred for 1 hour at room temperature, then partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (3:1 to 1:1 hexanes-ethyl acetate) provided 3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-[4-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-a]pyridin-7-amine (90.4 mg, 55%) as an off-white solid. 1H NMR (CDCl3): δ 7.99 (d, 1 H), 7.84 (d, 1 H), 7.55 (d, 2 H), 7.34 (t, 1 H), 6.98 (d, 2 H), 6.39–6.32 (m, 3 H), 5.08 (broad, 1 H), 4.37 (m, 1 H), 3.87 (d, 2 H), 2.68 (m, 1 H), 2.10 (m, 2 H), 1.80–1.27 (m, 6 H), 0.89 (m, 2 H), 0.78–0.65 (m, 4 H), 0.39 (m, 2 H); MS m/z 481 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:30]=[CH:29][C:6]([C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=2[CH2:27][CH3:28])=[O:8])=[CH:5][CH:4]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>O1CCCC1.O>[C:31]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([C:17]([F:26])([C:18]([F:19])([F:20])[F:21])[C:22]([F:23])([F:24])[F:25])=[CH:12][C:11]=2[CH2:27][CH3:28])=[O:8])=[CH:29][CH:30]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(CN)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(CNC(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
The crude product of 4-(aminomethyl)-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoro-propan-2-yl)-6-methylphenyl]benzamide (0.30 g) was dissolved in tetrahydrofuran (5 ml). To the solution, acetic anhydride (0.07 g) was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed with 2N hydrochloric acid and dried over magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography to obtain 4-(acetamidomethyl)-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methyl-phenyl]benzamide (0.27 g, yield 77%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C(S)C.[CH:8]([C:11]1[CH:21]=[C:20]([O:22]C)[CH:19]=[C:18]2[C:12]=1[C:13](=[O:24])[NH:14][S:15]2(=[O:17])=[O:16])([CH3:10])[CH3:9].Cl>C(Cl)(Cl)Cl>[OH:22][C:20]1[CH:19]=[C:18]2[C:12]([C:13](=[O:24])[NH:14][S:15]2(=[O:17])=[O:16])=[C:11]([CH:8]([CH3:10])[CH3:9])[CH:21]=1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)NC2=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CCS
Product: CC(C)c1cc(O)cc2c1C(=O)NS2(=O)=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.8 %

Procedure:
An alternative procedure was also used. To a stirred suspension of 62.74 g (0.47 mol) of AlCl3 in 500 mL of chloroform at 0° was added 43.9 g (0.7 mol) of ethanethiol. Within minutes a clear solution formed. To this a solution of 20.0 g (0.078 mol) of 4-isopropyl-6-methoxysaccharin in 550 mL of chloroform was added over a 30-min period. This solution was allowed to warm to RT and stirred for 3-4 hr at 60°. After cooling, the mixture was poured into ice-water and acidified with dilute HCl. The solid which separated was collected by filtration, washed with water and dried to give 18.4 g (97%) of 6-hydroxy-4-isopropylsaccharin.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH2:11][CH3:12])[C:8](O)=[O:9])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].S(Cl)([Cl:21])=O>C(Cl)Cl.N1C=CC=CC=1>[F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH2:11][CH3:12])[C:8]([Cl:21])=[O:9])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16]
Reactant: O=S(Cl)Cl
Reactant: CCC(Oc1ccc(F)c(C(F)(F)F)c1)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(Oc1ccc(F)c(C(F)(F)F)c1)C(=O)Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
To 1.2 g (4.5 mmole) of (-)-2-(4-fluoro-3-trifluoromethylphenoxy)butanoic acid dissolved in 15 ml methylene chloride was added one drop of pyridine and further added dropwise 0.6 g of thionyl chloride. The reaction mixture was further stirred at room temperature for 4 hours and then thionyl chloride and methylene chloride were removed under reduced pressure to obtain 1.2 g of (-)-2-(4-fluoro3-trifluoromethylphenoxy)butanoic acid chloride. The resulting mixture was applied for the next reaction without purification.
Reaction SMILES: [NH2:1][C:2]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:22](Cl)(=[O:26])[O:23][CH2:24][CH3:25]>ClCCl>[CH2:24]([O:23][C:22]([NH:1][C:2]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1)=[O:26])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NC1(c2ccc(C(=O)OC)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 4-(1-aminocyclopropyl)benzoate (1.84 g) and triethylamine (2.82 mL) were dissolved in dichloromethane (40 mL), ethyl chlorocarbonate (1.01 mL) was added under ice-cooling, and the mixture was stirred at the same temperature for 30 min and at room temperature for 1 hr. After completion of the reaction, the solvent was evaporated, to the residue was added 0.5N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (0.86 g).
Reaction SMILES: ClC1C=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24])(=[O:14])=[O:13].C[O-].[Na+].O1[CH2:41][CH2:40][O:39][CH2:38]C1>CCOC(C)=O>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([S:23]([NH:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][S:12]([C:3]2[CH:4]=[C:5]([C:8]([F:10])([F:9])[F:11])[CH:6]=[CH:41][C:40]=2[O:39][CH3:38])(=[O:13])=[O:14])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: C1COCCO1
Reactant: O=S(=O)(Nc1ccccc1NS(=O)(=O)c1cc(C(F)(F)F)ccc1Cl)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(C(F)(F)F)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-N-[2-(4-chloro-benzenesulfonylamino)phenyl]-5-trifluoromethylbenzenesulfonamide (0.5 mmol) in dioxane (5 mL), solid sodium methoxide (2 mmol) was added in one portion and the resulting reaction mixture was then heated to reflux for ca. 4 h. After the completion of the reaction, the reaction mixture was cooled to RT and concentrated in vacuo. The residue obtained was redissolved in EtOAc (10 mL) and washed with water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 160 mg of N-[2-(4-chlorobenzenesulfonylamino)phenyl]-2-methoxy-5-trifluoromethylbenzenesulfonamide. LC: Tr 1.22 min; MS: 521.8 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([Cl:12])(=[O:11])=[O:10])#[N:2].[NH:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.Cl.NCC1C=CC=CC=1S(N(C(C)(C)C)C)(=O)=O>>[ClH:12].[N:13]1([S:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][NH2:2])(=[O:11])=[O:10])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: C1CCCNCC1
Agent: CN(C(C)(C)C)S(=O)(=O)c1ccccc1CN
Agent: Cl
Product: NCc1ccccc1S(=O)(=O)N1CCCCCC1

Procedure:
A (125 mg) was prepared in two steps from 2-cyanobenzene-1-sulfonyl chloride (100 mg) and azepane in 82% overall yield following procedures analogous to those used in the preparation of 2-(aminomethyl)-N-tert-butyl-N-methylbenzenesulfonamide hydrochloride salt. LC-MS: 269.25 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([C:18]3[N:26]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:21]4=[N:22][CH:23]=[CH:24][CH:25]=[C:20]4[CH:19]=3)=[CH:14][NH:15]2)=[CH:11][C:10]=1[O:37][CH3:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:41]I.O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([C:18]3[N:26]([S:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=4)(=[O:29])=[O:28])[C:21]4=[N:22][CH:23]=[CH:24][CH:25]=[C:20]4[CH:19]=3)=[CH:14][N:15]2[CH3:41])=[CH:11][C:10]=1[O:37][CH3:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)c[nH]c2cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCc1ccccc1
Reaction time: 0.25 h
Yield: 86.9 %

Procedure:
A solution of 2-(6-benzyloxy-5-methoxy-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (1 g, 1.9 mmol) in dimethylformamide (10 ml) is placed in a 25 ml three-necked flask placed under argon, then sodium hydride (0.063 g; 2.101 mmol) is added and the mixture is left to agitate for 15 minutes. When there is no longer any gas being given off, methyl iodide (0.131 ml, 2.101 mmol) is added dropwise and the mixture is left to react at 21° C. for 2 hours. The reaction medium is run into 100 ml of distilled water, and then extracted with 2 times 100 ml of dichloromethane. The organic extracts are combined, dried over magnesium sulfate, filtered, and evaporated to dryness under reduced pressure. The evaporation compound is triturated in diisopropyl ether. The pulverulent solid compound thus obtained is filtered off and rinsed. 2-(6-Benzyloxy-5-methoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.888 g; 86%) is isolated in the form of a beige-colored solid, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([N+:10]([O-])=O)=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.[C:13](O)(=O)C>C(OC)(OC)OC.[Zn]>[CH3:1][S:2][C:3]1[C:4]2[N:10]=[CH:13][NH:9][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: CSc1cccc(N)c1[N+](=O)[O-]
Reactant: CC(=O)O
Agent: [Zn]
Solvent: COC(OC)OC
Product: CSc1cccc2[nH]cnc12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
6 g of 3-methylsulfanyl-2-nitrophenylamine were dissolved in 150 ml of glacial acetic acid and 60 ml of trimethyl orthoformate. Zinc powder (7 g) was added and the mixture was stirred for 2 h at 60° C. The solids were removed by filtration, the solvent was evaporated in vacuo and the residue was taken up in water and EA (200 ml each) and made basic with potassium carbonate. The precipitate was filtered off and the filtrate was extracted with EA, the combined organic phases were washed with brine, dried over sodium sulfate and the solvent removed in vacuo. The crude product was purified by flash chromatography (200 g silica gel; DCM/MOH, gradient from 100:0 to 90:10). 2 g of the title compound were obtained as an off-white solid.