Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl.Cl.[CH3:26][N:27]([CH3:34])[CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(Cl)(Cl)Cl>[CH3:26][N:27]([CH3:34])[CH:28]1[CH2:33][CH2:32][N:31]([S:20]([C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:7]3[C:6]4[C:11](=[CH:12][C:3]([Cl:2])=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH2:30][CH2:29]1
Reactant: CN(C)C1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(C)C1CCN(S(=O)(=O)c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.3 Grams of 4-(7-chloro-4-quinolylamino)-benzenesulphonyl chloride hydrochloride [prepared as in Example 1(b)] were added in portions to a stirred mixture of 5.83 grams of 4-dimethylamino-piperidine dihydrochloride and 32 grams of sodium carbonate in 100 milliliters of water and 75 milliliters of chloroform. After stirring overnight at room temperature the mixture was filtered, the resultant solid washed with water, dried and recrystallised from ethanol/water to give 6.28 grams of the title compound. Melting point 230°--231°C.
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20].CCOCC>COCCOC>[CH2:17]([O:16][CH2:15][CH2:14][CH2:13][CH2:12][O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:8])[CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: OCCCCCCO
Reactant: CC(C)CCOCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: CC(C)CCOCCCCOCCCCCCO
Reaction time: 3 h

Procedure:
17.8 g (0.163 mol) of 1,6-hexandiol in 30 cc of absolute 1,2-dimethoxy ethane are added dropwise over the course of 15 minutes, under nitrogen and while stirring, to 4.85 g (0.117 mol) of 55% sodium hydride dispersion in oil, suspended in 140 cc of absolute 1,2-dimethoxy ethane. The mixture is stirred at 60° for 3 hours, 22.5 g (0.101 mol) of 1-bromo-4-isopentyloxy-butane are then added and then it is stirred at 60° for 40 hours. After cooling to 20°, 400 cc of ether are added to the reaction mixture. The ether solution is washed three times with water, subsequently with saturated sodium chloride solution, dried over sodium sulphate and evaporated. The residue is chromatographed with hexane/ethyl acetate (95:5) to (75:25) on silica gel. The almost pure fractions are fractionally distilled and 6-(4-isopentyloxy-butyloxy)-hexanol, having a B.P. of 134°-142°/0.5 mm Hg, is obtained as a colourless liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:19]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=2)[CH:20]=[O:21])[CH:5]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:7]=1.[Cl:30][C:31]1[CH:32]=[C:33]([N:38]=[C:39]=[S:40])[CH:34]=[C:35]([Cl:37])[CH:36]=1>CC(N(C)C)=O>[Cl:29][C:24]1[CH:23]=[C:22]([N:19]([C:4]2[CH:3]=[C:2]([NH:1][C:39]([NH:38][C:33]3[CH:34]=[C:35]([Cl:37])[CH:36]=[C:31]([Cl:30])[CH:32]=3)=[S:40])[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=3)[CH:5]=2)[CH:20]=[O:21])[CH:27]=[C:26]([Cl:28])[CH:25]=1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: Nc1cc(Nc2cccc(C(F)(F)F)c2)cc(N(C=O)c2cc(Cl)cc(Cl)c2)c1
Solvent: CC(=O)N(C)C
Product: O=CN(c1cc(Cl)cc(Cl)c1)c1cc(NC(=S)Nc2cc(Cl)cc(Cl)c2)cc(Nc2cccc(C(F)(F)F)c2)c1
Reaction time: 8 h

Procedure:
To a solution of N-(3-amino-5-{[3-(trifluoromethyl)phenyl]amino}phenyl)(3,5-dichloro-phenyl)formamide (0.54 g, 1.2 mmol), in DMA (10 mL) was added 3,5-dichlorophenylisothiocyanate (0.30 g, 1.5 mmol) and the mixture stirred overnight.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:6]=2[O:5]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>C(Cl)Cl>[CH3:21][S:22]([O:1][CH2:2][CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:6]=2[O:5]1)(=[O:24])=[O:23]
Reactant: N#Cc1ccc(-c2ccc3c(c2)CC(CCO)O3)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC1Cc2cc(-c3ccc(C#N)cc3)ccc2O1
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To a solution of Example 67C (0.23 g, 0.87 mmol) and methanesulfonyl chloride (0.075 mL, 0.96 mmol) in CH2Cl2 (5 mL) at 0° C. was added triethylamine (0.13 mL, 9.4 mmol). The mixture was stirred for 30 minutes, diluted with CH2Cl2 (75 mL), washed with water (3×100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on silica using CH2Cl2 to provide the titled compound (0.278 g, 90%). 1HNMR (CDCl3): H NMR: 1.95 (m, 2H), 2.93 (m, 2H), 3.00 (s, 3H), 3.46 (m, 2H), 5.00 (m, 1H), 6.81 (d, J=7 Hz, 1H), 7.40 (m, 2H), 7.65 (m, 4H); MS (DCI) 343 (M+), 361 (M+NH4+).
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:34][C:35]1[C:40]([C:41]2[N:42]=[C:43]([N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)[S:44][C:45]=2[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([Cl:52])[N:47]=2)=[CH:39][CH:38]=[CH:37][C:36]=1[NH2:59].[O:60]1[CH:64]=[CH:63][CH:62]=[C:61]1[S:65](Cl)(=[O:67])=[O:66]>>[Cl:34][C:35]1[C:40]([C:41]2[N:42]=[C:43]([N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)[S:44][C:45]=2[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([Cl:52])[N:47]=2)=[CH:39][CH:38]=[CH:37][C:36]=1[NH:59][S:65]([C:61]1[O:60][CH:64]=[CH:63][CH:62]=1)(=[O:67])=[O:66]
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl
Reactant: O=S(=O)(Cl)c1ccco1
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1ccco1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using {2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}amine (1.03 g, 2.52 mmol) and 2-furansulfonyl chloride (0.588 g, 3.53 mmol) the title compound of Step E was obtained as an off-white solid (430 mg, 0.735 mmol, 29.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.53 (s, 1H), 8.38 (d, J=5.5 Hz, 1H), 7.91 (d, J=0.9 Hz, 1H), 7.43-7.58 (m, 2H), 7.31-7.43 (m, 1H), 7.08 (d, J=3.5 Hz, 1H), 6.55 (dd, J=3.5, 1.8 Hz, 1H), 6.18 (d, J=5.5 Hz, 1H), 3.71 (t, J=4.8 Hz, 4H), 3.55 (t, J=4.7 Hz, 4H). MS (ESI): 537.96 [M+H]+.
Reaction SMILES: CO[C:3](=[NH:34])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20](=[O:33])(=[O:32])[NH:21][CH2:22][C:23]3[C:28]([F:29])=[CH:27][CH:26]=[C:25]([F:30])[C:24]=3[F:31])=[CH:16][CH:15]=2)=[O:12])[CH:5]=1.[NH3:35].CO>>[F:31][C:24]1[C:25]([F:30])=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[CH2:22][NH:21][S:20]([C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[NH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([NH2:35])=[NH:34])=[CH:15][CH:16]=1)(=[O:32])=[O:33]
Reactant: N
Reactant: COC(=N)c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3c(F)ccc(F)c3F)cc2)c1
Solvent: CO
Product: N=C(N)c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3c(F)ccc(F)c3F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-{3-[4-(2,3,6-Trifluorobenzylsulfamoyl)-phenyl]-ureido}-benzimidic acid methyl ester (250 mg, 0.5 mmol) was dissolved in NH3/MeOH (15 ml, 7 M). The solution was stirred overnight at rt. Further 10 ml of NH3/MeOH (7 M) were added and the mixture stirred for 3 h at 65° C. The solvents were evaporated and the solid residue purified by flash chromatography on silica gel with a gradient of AcOEt and MeOH. The fractions with the desired product were collected, evaporated and the product crystallized from MeOH/Et2O. Yield 50%.
Reaction SMILES: [OH-].[Na+].[N+:3]([CH3:6])([O-:5])=[O:4].[CH2:7]([O:9][C:10]1[C:11]([B:19]2[O:23][C:22](C)(C)C(C)(C)[O:20]2)=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])C=O)[CH3:8].Cl>O.C1COCC1>[CH2:7]([O:9][C:10]1[C:11]2[B:19]([OH:20])[O:23][CH:22]([CH2:6][N+:3]([O-:5])=[O:4])[C:12]=2[CH:15]=[CH:16][C:17]=1[F:18])[CH3:8]
Reactant: CCOc1c(F)ccc(C=O)c1B1OC(C)(C)C(C)(C)O1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1c(F)ccc2c1B(O)OC2C[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 68.6 %

Procedure:
To a cooled solution of sodium hydroxide (80 mg, 2.0 mmol) in water (3.0 mL), nitromethane (244.0 mg, 4.0 mmol) was added at 0° C. and stirred for 10 min. Then 3-ethoxy-4-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (588.0 mg, 2.0 mmol) in THF (5.0 mL) was added. The reaction mixture was stirred at for 1 h at 0° C. and for 2 h at room temperature. The reaction mixture was acidified with 2.5 M HCl (1.0 mL) and the product was extracted with ethyl acetate (2×20 mL). The organic extracts were combined and washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and product was chromatographed on a column of silica gel(CH2Cl2:MeOH=95:5) to give the title compound as a solid (350 mg, 69%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.40 (dd, J=11.3, 8.2 Hz, 1H), 7.16 (dd, J=8.0, 3.3 Hz, 1H), 5.74 (d, J=9.0 Hz, 1H), 5.30 (dd, J=13.5, 2.2 Hz, 1H), 4.62 (dd, J=13.5, 9.2 Hz, 1H), 4.35 (q, J=6.8 Hz, 2H), 1.28 (t, J=6.8 Hz, 3H); MS (ESI) m/z=254 (M−1, negative).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][N:8]=1)=[O:6].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na+].[Cl-]>C1COCC1>[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]=1)=[O:6]
Reactant: COC(=O)c1n[nH]c2ccccc12
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1nn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
Sodium hydride (0.37 g. 60%, 9.3 mmol) was added to a solution of indazole-3-carboxylic acid methyl ester (1.5 g, 8.5 mmol) in dry THF (50 mL) at 0° C. Benzyl bromide (1.59 g, 9.3 mmol) was then added and the reaction mixture was warmed to 25° C. and stirred for 8 h The reaction mixture was poured onto saturated NaCl solution (100 mL) and extracted with 3×200 mL of diethyl ether. The combined extracts were dried (MgSO4) and concentrated under reduced pressure. The crude compound was purified by flash chromatography using cyclohexane/ethyl acetate (70:30) and recrystallised from cyclohexane/ethyl acetate to afford the title compound as a yellow solid (1.89 g, 84%). Mp 72-73° C. 1H NMR (300 MHz, CDCl3) ppm 4.07 (s, 3H), 5.72 (s, 2H), 7.22-7.40 (m, 8H), 8.24-8.27 (m, 1H). MS(EI) m/z 266 [M+]. Anal. Calcd. for C16H14N2O2: C, 72.17; H, 5.30; N, 10.52. Found: C, 72.12; H, 5.15; N, 10.85.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:4]=1[C:5]#[N:6].[CH3:13][O-:14].[Na+]>CO>[Cl:12][C:7]1[CH:8]=[C:9]([Cl:11])[CH:10]=[C:3]([CH2:2][O:14][CH3:13])[C:4]=1[C:5]#[N:6]
Reactant: C[O-]
Reactant: N#Cc1c(Cl)cc(Cl)cc1CBr
Agent: [Na+]
Solvent: CO
Product: COCc1cc(Cl)cc(Cl)c1C#N
Temperature: 50 °C

Procedure:
To a suspension of 2-(bromomethyl)-4,6-dichlorobenzonitrile (1.04 mmol) (A.2.5.1) in 2.5 mL MeOH was added a solution of NaOMe (1.27 mmol, 0.5M in MeOH). The reaction mixture was heated to 50° C. for 1 h. The mixture was concentrated in vacuo, redissolved in EtOAc and it was then washed twice with an aqueous solution of KHSO4, twice with a sat. aq. NaHCO3 solution and once with brine. The organic layer was dried over MgSO4 and concentrated in vacuo to give the desired product as orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:9]([OH:12])(=O)=[O:10]>>[CH:4]1[C:5]([S:9]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:12])=[O:10])=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: Clc1ccccc1
Reactant: O=S(=O)(O)Cl
Product: O=S(=O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 22.3 %

Procedure:
To 112 g (1 mole) of chlorobenzene was added 123 g (1.1 moles) of chlorosulfonic acid at 10° to 20° C. After the addition, while being maintained at 20° to 30° C., the mixture was stirred for 3 hours to complete the reaction. A 0.1 mole quantity of the unreacted chlorobenzene was recovered in the same manner as in Example 1 and 32 g of 4,4'-dichlorodiphenylsulfone was obtained in 25% yield. M.P. 148.5° to 149.5° C. Purity of 99.8%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]2[N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:15][CH2:16][CH:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N+:46]([C:49]1[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=1)([O-:48])=[O:47].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][C:53](=[O:54])[C:52]2[CH:51]=[CH:50][C:49]([N+:46]([O-:48])=[O:47])=[CH:57][CH:56]=2)[CH:10]2[N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:15][CH2:16][CH:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CC(O)C2C1CCN2C(=O)OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)C2C1CCN2C(=O)OCc1ccccc1
Reaction time: 12 h

Procedure:
To a solution of bicyclic alcohol 11 (4.0 g, 11.0 mmol) in benzene (55 mL) at ambient temperature was added Ph3P (5.8 mg, 22.1 mmol) and p-nitrobenzoic acid (3.7 g, 22.1 mmol). DIAD (4.6 mL, 22.1 mmol) was added dropwise via syringe over 1 h, keeping the temperature below 25° C. After 12 h, the reaction mixture was concentrated in vacuo and the residue was purified by flash silica gel chromatography (3:1 to 1:1 hexanes/EtOAc). The partially-purified product (42) was used without further purification. Mass spectrum, m/z [511.9] (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]C(=O)N(C)C)=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>CO.O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([SH:19])=[CH:17][CH:18]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)Sc1ccc(CCCCNC(=O)OC(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCc1ccc(S)cc1
Temperature: 25 °C
Yield: 45.3 %

Procedure:
N-tert-Butoxycarbonyl-4-[4-(dimethylcarbamoylthio)phenyl]butylamine 37 (0.35 g, 1.02 mmol) was dissolved in MeOH (8 mL). KOH (0.19 g, 3.4 mmol) dissolved in water (2 ml) was added. The mixture was stirred under reflux for 6 h and cooled to room temperature. The solvent was removed under reduced pressure. The residue was dissolved in water and acidified with 5% aqueous HCl to pH ˜5. The solvent was removed again under reduced pressure and the residue was purified by flash chromatography over silica gel (hexane/ethyl acetate, 3:1, v/v) to give the desired thiophenol 38 (0.13 g, 45%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.43 (s, 9H), 1.49 (m, 2H) 1.59 (m, 2H), 2.57 (t, 2H), 3.12 (m, 2H), 3.38 (s, 1H), 4.47 (br s, 1H), 7.04 (d, 2H), 7.19 (d, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[N:10]1([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=2)[C:5]#[N:6])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: C1CNCCN1
Product: N#Cc1ccnc(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
2-Chloro-isonicotinonitrile (80 g, 0.58 mol) and piperazine (199 g, 2.32 mol, 5 equiv) were combined and heated at 70 DC for 2.5 hours. The resulting suspension was cooled to room temperature and partitioned between a solution of 50% ethyl acetate/dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were concentrated in vacuo to about half the initial volume and ether was added. The suspension was stirred overnight, then filtered. The solid was dried under vacuum to give the desired product (31 g). The mother liquors were concentrated in vacuo and the residue was triturated with ether and filtered. The solid collected in this second batch was dried under vacuum and combined with the first batch to give the total amount of desired product (46 g, 42%).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20]>CC(C)=O>[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:16][CH3:1])=[O:15])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reaction time: 16 h

Procedure:
Potassium carbonate (149 g, 1.08 mol) and iodomethane (252 mL, 4.05 mol) were added to a solution of 4-fluoro-3-nitrobenzoic acid (50 g, 0.27 mol) in dry acetone (700 mL) under argon. Overhead mechanical stirring was carried out for 16 hours. The reaction mixture was filtered, and acetone was removed under vacuum. The residue was partitioned between ethyl acetate and saturated potassium carbonate solution, the aqueous layer was washed with ethyl acetate, the combined organic layers were washed with saturated potassium carbonate solution, brine, dried over sodium sulfate, and concentrated to yield the title compound as a light yellow solid; m.p. 58.5°-59.50° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11].Br[CH2:14][C:15]#[CH:16].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:16][C:15]#[CH:14])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11]
Reactant: C#CCBr
Reactant: CCC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1ccc(C(=O)CC)c(O)c1
Yield: 85.5 %

Procedure:
A mixture of 2′,4′-dihydroxy-propiophenone (24.9 g, 0.15 mol), 3-bromo-propyne (24.2 g, 0.20 mol) and K2CO3 (20.7 g, 0.15 mol) in acetone (500 mL) was refluxed for 12 h. The reaction mixture was allowed assume room temperature and the precipitate was removed by filtration. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 0→2% MeOH in H2O), to give 26.2 g (85%) of 1-(2-hydroxy-4-prop-2-ynyloxy-phenyl)-propan-1-one.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][C:9](=O)[CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:14][OH:15].C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:15][NH:14][CH:9]1[CH2:8][CH2:7][C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:11][CH2:10]1
Reactant: NO
Reactant: O=C1CCc2ccccc2CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: ONC1CCc2ccccc2CC1
Reaction time: 8 h

Procedure:
To 6,7,8,9-tetrahydro-5H-benzocyclohepten-7-one (2.56 g, 16 mmol) and hydroxylamine hydrochloride (2.2 g, 32 mmol) in 27 mL of water is slowly added a solution of sodium carbonate (1.69 g, 16 mmol) in 14 mL of water. The mixture is stirred overnight. The solid is then filtered off, washed with water, and dried at 50° C. under reduced pressure to give 6,7,8,9-tetrahydro-N-hydroxy-5H-benzocyclohepten-7-amine as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([N+:12]([O-])=O)=[CH:11][C:6]=2[S:5][CH2:4][C:3]1=[O:15].[Cl-].[NH4+]>CCO.O.[Fe]>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([NH2:12])=[CH:11][C:6]=2[S:5][CH2:4][C:3]1=[O:15]
Reactant: CN1C(=O)CSc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CN1C(=O)CSc2cc(N)ccc21
Temperature: 80 °C
Yield: 92.3 %

Procedure:
To a stirred solution of 3,4-dihydro-4-methyl-7-nitro-2H-1,4-benzothiazin-3-one (4.50 g, 20.07 mmol) in EtOH (100 mL) and water (50 mL) is added ammonium chloride (10.76 g, 200.7 mmol). To this mixture is added iron (3.37 g, 60.21 mmol) in 3 equal portions. The resulting mixture is heated to 80° C. for 2 h at which time the reaction is cooled to room temperature. This mixture is filtered and the filtrate is concentrated under reduced pressure and extracted with EtOAc (3×50 mL). The organic phase is washed with water and saline, dried over MgSO4, and concentrated under reduced pressure to give the title compound (for reference see DE 19802239) as a dark brown oil (3.60 g, 93%), MS m/z 195.5 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]Cl)=[CH:9][CH:8]=1.O>[Au].C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:1][CH2:2][CH:3]([OH:5])[CH3:4])=[CH:9][CH:8]=1
Reactant: ClCCc1ccc(Cl)cc1
Reactant: CC(O)CN
Agent: [Au]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(O)CNCCc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Into a 5-L jacketed reactor equipped with a chiller, overhead stirring, an anchor impeller, a thermocouple, a glycol condenser, and a nitrogen inlet vented to a caustic scrubber, was charged 1-aminopropan-2-ol (1102 mL, 14.3 mol). The reactor contents were heated to 80° C. and 1-chloro-4-(2-chloroethyl)benzene (Method 4, Step A, 500 g, 2856 mmol) was slowly charged over 40 min. The temperature of the gold-colored reaction mixture reached 97° C. during the addition and 101° C. approximately 1 min after addition was complete. The mixture was then allowed to cool to 90 to 95° C. and stirring was continued at that temperature for 2 h. Water (500 mL) and toluene (1000 mL) were added and the mixture was stirred at 75 to 80° C. for 15 min. The layers were allowed to separate at 70 to 75° C. The organic phase was removed and the aqueous phase was extracted with toluene at 70 to 75° C. for 15 min (2×500 mL). The combined organic phases were washed with water at 70 to 75° C. for 15 min (2×500 mL) and stirred overnight under nitrogen at 50° C. The solution was concentrated by distillation at 60° C. (jacket) under reduced pressure, and the residue was diluted with toluene to a total volume of about 800 mL. This solution was distilled a second time at 65° C. (jacket) under reduced pressure and the residue was diluted with toluene to a total volume of about 400 mL. The water content of the solution was 0.03% by Karl Fisher titration.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Cl.Br[C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[CH2:40][NH:39][CH2:38]2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH2:38]1[C:37]2[C:41](=[CH:42][C:43]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]3)=[CH:35][CH:36]=2)[CH2:40][NH:39]1
Reactant: Brc1ccc2c(c1)CNC2
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)CNC5)cc23)CC1
Yield: 7.5 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (150 mg, 0.325 mmol) in dioxane (0.75 mL) and water (0.25 mL), was added 5-bromo-2,3-dihydro-1H-isoindole hydrochloride (130 mg, 0.651 mmol), and cesium carbonate (636 mg, 1.952 mmol). The reaction mixture was kept under argon for 10 min before addition of tetrakis(tripehnylphosphine)palladium(0) (19 mg, 0.016 mmol). The resultant mixture was heated in a microwave for 20 min at 150° C. Mixture was then purified by HPLC to give 11 mg of the title compound.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:19])[C:13]3[S:20][CH:21]=[CH:22][C:12]=3[C:11]=2[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:23]N1C(=O)CCC1=O>>[Br:23][C:10]1[C:11]2[C:12]3[CH:22]=[CH:21][S:20][C:13]=3[C:14](=[O:19])[NH:15][C:16]=2[CH:17]=[CH:18][C:9]=1[O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c(=O)c3sccc3c2c1
Reactant: O=C1CCC(=O)N1Br
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c(=O)c3sccc3c2c1Br
Yield: 37.7 %

Procedure:
Following Step 4 from General Procedure A, 8-(tert-butyldimethylsilyloxy)thieno[2,3-c]quinolin-4(5H)-one (740 mg, 2.2 mmol) was reacted with N-bromosuccinimide (480 mg, 2.7 mmol) to afford the desired product (340 mg, 37%) as a brown solid: ESI MS m/z 411 [C17H20BrNO2SSi+H]+.