Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:19](=[N:21]O)[CH3:20])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1>C(O)(=O)C.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]([NH2:21])[CH3:20])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1
Reactant: COc1ccc(COc2ccc(C(C)=NO)cc2OC)cn1
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(COc2ccc(C(C)N)cc2OC)cn1
Temperature: 65 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
To a stirred solution of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethan-1-one oxime (5.55 g, 18.36 mmol) in acetic acid (40 mL) was added zinc dust (6.00 g, 91.79 mmol). The resulting mixture was heated to 65° C. After 1 h, the mixture was allowed to cool to room temperature and was filtered through Celite. The filtercake was washed with methanol (100 mL). The filtrate was concentrated, and the residue dissolved in 5N ammonium hydroxide solution (75 mL). The mixture was extracted with chloroform (2×50 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 4.56 g (86%) of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethan-1-amine as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([Cl:11])[N:3]=1.[CH3:12][S-:13].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([S:13][CH3:12])[CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)nc(Cl)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc(Cl)nc(Cl)c1
Reaction time: 3 h
Yield: 74.7 %

Procedure:
To a solution of 2,6-dichloro-4-nitropyridine (3.8 g; 0.02 mol) in dimethylformamide (50 ml) cooled with an ice-bath was sodium thiomethoxide (1.4 g; 0.02 mol) slowly added. After stirring for 3 hours, the reaction mixture was quenched with water (300 ml) and extracted 3 times each with a hexane/ethyl acetate mixture (100 ml; 1/1). The combined extracts were dried with anhydrous magnesium sulphate and the solvent was removed in vacuo. Purification by silica gel flash column chromatography afforded 2,6-dichloro-4-methylthiopyridine (2.9 g; 74%) as a colorless oil.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([O:19][CH3:20])(=[O:18])[C:12]#[C:13][C:14]([O:16][CH3:17])=[O:15].CCN(CC)CC>CCOCC>[C:4]1([C:3]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([C:11]([O:19][CH3:20])=[O:18])[O:1][N:2]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O/N=C(\Cl)c1ccccc1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)c1onc(-c2ccccc2)c1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of (Z)-N-hydroxybenzimidoyl chloride (467 mg, 3 mmol) and dimethyl but-2-ynedioate (0.374 mL, 3.00 mmol) in Et2O (10 mL) at rt was added dropwise over 5 minutes Et3N (0.460 mL, 3.30 mmol). The reaction mixture became a thick suspension and was stirred at rt for 2 hr. After filtration, the filtrate was concentrated to an oil that was chromatographed on a 24 gm Isco silica gel cartridge, eluting with a 0-25% EtOAc/Hex gradient. The pure fractions were concentrated to afford dimethyl 3-phenylisoxazole-4,5-dicarboxylate (780 mg, 2.99 mmol, 100% yield) as a colorless oil. HPLC retention time=2.86 minutes (YMC Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=262.15. 1H NMR (500 MHz, CDCl3) d ppm 3.91 (s, 2H) 4.02 (s, 2H) 7.46-7.53 (m, 2H) 7.69 (d, J=6.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=2[F:20])=[C:10](Cl)[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:22]([NH2:25])([CH3:24])[CH3:23].C(N(C(C)C)C(C)C)C>CN(C=O)C>[Cl:1][C:2]1[C:11]([C:12]2[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=2[F:20])=[C:10]([NH:25][CH:22]([CH3:24])[CH3:23])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Fc1cc(F)c(-c2c(Cl)nc3ncccc3c2Cl)c(F)c1
Reactant: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Nc1c(-c2c(F)cc(F)cc2F)c(Cl)nc2ncccc12
Yield: 46 %

Procedure:
The product from Step 3 (0.12 g), isopropylamine (0.3 ml) and N-ethyl-diisopropylamine (0.10 g) were refluxed in DMF (8 ml) in a sealed tube at 50° C. for 17 hours. The dark coloured reaction mixture was evaporated to give an oil, which was purified by flash column chromatography on silica gel (40-60, ethyl acetate/hexane 1/3) to give [2-chloro-3-(2,4,6-trifluorophenyl)-[1,8]naphthyridin-4-yl]-isopropylamine as white crystals (0.059 g, 46%), m.p. 193° C.
Reaction SMILES: C[N:2]([CH3:36])[CH2:3][CH2:4][O:5][C:6]1C=C(N2C(=O)C3C(=CC=CC=3C)N=C2C(NC2N=CN=C3C=2N=CN3)C)C=CC=1.[NH2:37][C:38]1[N:46]=[C:45]2[C:41]([N:42]=[CH:43][NH:44]2)=[C:40]([NH:47][CH:48]([C:50]2[N:59]([C:60]3[CH:61]=[C:62]([CH:65]=[CH:66][CH:67]=3)C#N)[C:58](=[O:68])[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][C:56]=3[CH3:69])[N:51]=2)[CH3:49])[N:39]=1>>[NH2:37][C:38]1[N:46]=[C:45]2[C:41]([N:42]=[CH:43][NH:44]2)=[C:40]([NH:47][CH:48]([C:50]2[N:59]([C:60]3[CH:67]=[CH:66][CH:65]=[C:62]([N:2]4[CH2:3][CH2:4][O:5][CH2:6][CH2:36]4)[CH:61]=3)[C:58](=[O:68])[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][C:56]=3[CH3:69])[N:51]=2)[CH3:49])[N:39]=1
Reactant: Cc1cccc2nc(C(C)Nc3nc(N)nc4[nH]cnc34)n(-c3cccc(C#N)c3)c(=O)c12
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(OCCN(C)C)c3)c(=O)c12
Product: Cc1cccc2nc(C(C)Nc3nc(N)nc4[nH]cnc34)n(-c3cccc(N4CCOCC4)c3)c(=O)c12

Procedure:
Compound 158 was prepared in accordance with the procedure described for compound 129, but compound 133 was used in place of compound 126. m/z=498 (M+H). The structure of compound 153 is shown below.
Reaction SMILES: C(OC([N:8]1[C@H:17]([C:18]([OH:20])=[O:19])[CH2:16][C@@H:15]2[C@@H:10]([CH2:11][CH2:12][C@H:13]([O:21][C:22]3[CH:27]=[C:26]([N:28]4[CH:32]=[CH:31][CH:30]=[N:29]4)[CH:25]=[CH:24][C:23]=3[C:33]3[N:34]=[N:35][NH:36][N:37]=3)[CH2:14]2)[CH2:9]1)=O)(C)(C)C.[ClH:38]>C(Cl)Cl.C(OCC)C>[ClH:38].[N:28]1([C:26]2[CH:25]=[CH:24][C:23]([C:33]3[N:37]=[N:36][NH:35][N:34]=3)=[C:22]([CH:27]=2)[O:21][C@H:13]2[CH2:12][CH2:11][C@@H:10]3[C@@H:15]([CH2:16][C@@H:17]([C:18]([OH:20])=[O:19])[NH:8][CH2:9]3)[CH2:14]2)[CH:32]=[CH:31][CH:30]=[N:29]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CC[C@H](Oc3cc(-n4cccn4)ccc3-c3nn[nH]n3)C[C@@H]2C[C@H]1C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)[C@@H]1C[C@H]2C[C@@H](Oc3cc(-n4cccn4)ccc3-c3nn[nH]n3)CC[C@H]2CN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 0.040 g of the material from Step C, above, dissolved in 5 mL CH2Cl2, is added 3 mL 2M HCl in diethyl ether. After stirring four hours at ambient temperature, the reaction is concentrated in vacuo.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=C[C:14]([C:17]3[C:18](C(OC(C)(C)C)=O)=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].F[C:42](F)(F)[C:43]([OH:45])=[O:44]>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[C:42]([C:43]([OH:45])=[O:44])[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCc1nc2ccc(N(C)C(=O)OCC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Product: CCCCc1nc2ccc(N(C)C(=O)OCC)cc2n1Cc1ccc(-c2ccccc2)c(C(=O)O)c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-ethoxycarbonyl-methylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[NH:17][CH:18]=[CH:19][C:12]=23)[CH:7]=[CH:6][C:5]=1[OH:20])([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]3[NH:17][CH:18]=[CH:19][C:12]=23)[CH:7]=[CH:6][C:5]=1[OH:20]
Reactant: O=[N+]([O-])c1cc(Oc2ccnc3[nH]ccc23)ccc1O
Agent: [Pd]
Solvent: CO
Product: Nc1cc(Oc2ccnc3[nH]ccc23)ccc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Nitro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-phenol (Step c, 3 g, 11.1 mmol) was dissolved into MeOH (100 mL) and the atmosphere was replaced by argon. A catalytic amount of 10% Pd/C was added and the argon was replaced by a H2 atmosphere. The mixture was stirred for 16 h at RT at balloon pressure. The Pd/C was filtered and the obtained 2-amino-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-phenol was used crude in the next step.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH:2]=[CH2:3].[C:7]([NH:10][NH2:11])(=[O:9])[CH3:8]>C1C=CC=CC=1>[C:7]([NH:10][NH:11][C:5]([NH:4][CH2:1][CH:2]=[CH2:3])=[O:6])(=[O:9])[CH3:8]
Reactant: C=CCN=C=O
Reactant: CC(=O)NN
Solvent: c1ccccc1
Product: C=CCNC(=O)NNC(C)=O

Procedure:
Allyl isocyanate (25 g, 0.30 mol) was added slowly to a boiling solution of acethydrazide (22.2 g, 0.30 mol) in dry benzene (300 ml). The mixture was heated for 1 hour whereupon 2 layers formed. The benzene was then evaporated off and the residue triturated with ether to yield the title compound as a white solid. (m.p. 71°-74° C.).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH3:10])=[CH:4][CH:3]=1.[CH3:12][C:13]([S@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14].O.S([O-])([O-])(=O)=O.[Mg+2]>ClC(Cl)C.ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:1][C:2]1[N:7]=[CH:6][C:5](/[C:8](=[N:18]/[S:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])/[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CCC(=O)c1ccc(Br)nc1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC/C(=N\S(=O)C(C)(C)C)c1ccc(Br)nc1
Reaction time: 0.17 h

Procedure:
A mixture of 1-(6-bromo-pyridin-3-yl)-propan-1-one (11.8 g, 55.1 mmol), (R)-(+)-2-methyl-2-propanesulfinamide (8.0 g, 66 mmol) and titanium isopropoxide (18.0 mL, 61.4 mmol) in dichloroethane (65 mL) was warmed at reflux for 2 days. The reaction was monitored by TLC (ethyl acetate-hexanes 2:8) indicating a new more polar product than starting ketone, however ketone was still evident. The mixture was diluted with first dichloromethane (600 mL) and then water (15 mL) was added. The mixture was stirred for 10 minutes and then magnesium sulfate added. The mixture was filtered through diatomaceous earth and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-40% ethyl acetate in hexanes and then a gradient of 0-40% ethyl acetate in dichloromethane to afford 2-methyl-propane-2-sulfinic acid [1-(6-bromo-pyridin-3-yl)-prop-(E)-ylidene]-amide.
Reaction SMILES: N#N.CCN=C=NCCCN(C)C.Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:27][C:28]([OH:30])=O)[CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24].[CH3:31][O:32][C:33]([C:35]1[CH:39]=[C:38]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][C:41]=2[N+:47]([O-:49])=[O:48])[O:37][C:36]=1[CH3:50])=[O:34]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCN(CC)CC>[CH3:31][O:32][C:33]([C:35]1[CH:39]=[C:38]([C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:28](=[O:30])[CH2:27][C:19]3[CH:20]=[C:21]([O:25][CH3:26])[C:22]([O:23][CH3:24])=[C:17]([O:16][CH3:15])[CH:18]=3)=[CH:42][C:41]=2[N+:47]([O-:49])=[O:48])[O:37][C:36]=1[CH3:50])=[O:34]
Reactant: COc1cc(CC(=O)O)cc(OC)c1OC
Reactant: COC(=O)c1cc(-c2ccc(N)cc2[N+](=O)[O-])oc1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(-c2ccc(NC(=O)Cc3cc(OC)c(OC)c(OC)c3)cc2[N+](=O)[O-])oc1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Suspend EDC HCl (138 mg, 0.72 mmol) and Et3N (101 μL, 0.72) in anhydrous DCM (4.5 mL) and stir the resulting solution for 5 min at rt. Add 2-(3,4,5-Trimethoxy-phenyl)-acetic acid (163 mg, 0.72 mmol) and DMAP (8 mg, 0.07 mmol) and stir the resulting solution for 10 min. Add 5-(4-Amino-2-nitro-phenyl)-2-methyl-furan-3-carboxylic acid methyl ester (40) (100 mg, to 0.36 mmol) and stir the reaction solution for 22 h at rt. Quench reaction solution with sat. aqu. NH4Cl and water, separate layers and extract aqu. layer with DCM (3 times). Wash the combined organic layer with water and brine and dry with Na2SO4. Purify the crude product by preparative radial chromatography (silica gel, EtOAc/CyH 1+1) to obtain 2-Methyl-5-{2-nitro-4-[2-(3,4,5-trimethoxy-phenyl)-acetylamino]-phenyl}-furan-3-carboxylic acid methyl ester (41) (96 mg, 55%) as an yellow solid. 1H NMR (400 MHz, CDCl3): 2.55 (s, 3H); 3.65 (s, 2H); 3.79 (s, 3H); 3.81 (s, 6H); 3.82 (s, 3H); 6.50 (s, 2H); 6.77 (s, 1H); 7.53 (d, 1H, J=8.6 Hz); 7.66 (dd, 1H, J1=8.6 Hz, J2=2.0 Hz); 7.93 (br.s, 1H); 7.96 (d, 1H, J=2.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CCN(CC)CC.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[CH:27]=[C:26]([C:33](Cl)=[O:34])[CH2:25][CH2:24]2>C(Cl)Cl>[CH3:32][O:31][C:30]1[CH:29]=[C:28]2[C:23](=[CH:22][C:21]=1[O:20][CH3:19])[CH2:24][CH2:25][C:26]([C:33]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:34])=[CH:27]2
Reactant: COC(=O)c1ccccc1N
Reactant: COc1cc2c(cc1OC)CCC(C(=O)Cl)=C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccccc1NC(=O)C1=Cc2cc(OC)c(OC)cc2CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
A mixture of 6,7-dimethoxy-3,4-dihydronaphthalene-2-carboxylic acid (476 mg, 2 mmol) and SOCl2 (1.5 mL, 20 mmol) in toluene (20 mL) was heated at 50° C. for 1 hour. The solvent was then removed under reduced pressure to give 6,7-dimethoxy-3,4-dihydronaphthalene-2-carbonyl chloride which was used directly in the next step without further purification. To a stirred solution of methyl 2-aminobenzoate (332 mg, 2.2 mmol) and Et3N (0.8 mL, 6 mmol) in anhydrous DCM (20 mL) was added 6,7-dimethoxy-3,4-dihydronaphthalene-2-carbonyl chloride in anhydrous DCM (2 mL) dropwise at 0° C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted with DCM. The combined organic phase was dried over sodium sulfate, the solvent was removed under reduced pressure and the residue was purified by flash column, eluting with petroleum ether/ethyl acetate (10:1) to give methyl 2-(6,7-dimethoxy-1,2-dihydronaphthalene-3-carboxamido)benzoate (330 mg, 45%). LC-MS (ES-API); rt 9.27 min; m/z calculated for C21H21NO5 [M+Na]+ 390.1, found 390.1.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH3:20])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=1>>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=2)[C:9]2[C:10]([CH3:20])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: Cc1nn(-c2ccccc2)cc1C(O)C1CCCCC1
Product: Cc1nn(-c2ccccc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 16.3 %

Procedure:
Using cyclohexyl(3-methyl-1-phenyl-1H-pyrazol-4-yl)methanol (0.14 g) synthesized in Example 17(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.15 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.04 g, 23%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[Br:10]Br>C(=S)=S.C(OCC)C>[Br:10][C:3]1[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=1[OH:9]
Reactant: Oc1cc(F)cc(F)c1
Reactant: BrBr
Solvent: S=C=S
Solvent: CCOCC
Product: Oc1cc(F)cc(F)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
A solution of 2.6 gm (20 mmol) 3,5-difluorophenol in 20 mL carbon disulfide was cooled to 0° C. and then a solution of 1.02 mL (20 mMol) bromine in 10 mL carbon disulfide was added dropwise over 30 minutes. After stirring for an additional 30 minutes, the reaction mixture was warmed to room temperature and stirred for 1.5 hours. The reaction mixture was diluted with 200 mL diethyl ether and was washed sequentially with aqueous sodium metabisulfite and saturated aqueous sodium chloride. The organic phase was then dried over sodium sulfate and concentrated under reduced pressure. The residue was vacuum distilled to provide 2.5 gm (60%) of 2-bromo-3,5-difluorophenol (b.p.=65° C. (5 mm Hg)).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([S:20]([NH:23]C(C)(C)C)(=[O:22])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:10]([F:28])[C:9]=2[F:29])=[N:6][CH:7]=1>C(O)(C(F)(F)F)=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([S:20]([NH2:23])(=[O:21])=[O:22])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[C:10]([F:28])[C:9]=2[F:29])=[N:6][CH:7]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Product: Nc1cnc(-c2ccc(-c3ccccc3S(N)(=O)=O)c(F)c2F)cn1
Temperature: 50 °C
Yield: 96.6 %

Procedure:
A suspension of 4′-(5-aminopyrazin-2-yl)-N-tert-butyl-2′,3′-difluorobiphenyl-2-sulfonamide (168 mg, 0.40 mmol) in TFA (3 mL) was heated at 50° Celsius for 3 hours. The reaction was then cooled to rt and carefully partitioned between NaHCO3 and EtOAc. The organic layer was isolated, dried over MgSO4, and concentrated to dryness. Purification by FCC afforded the title compound (140 mg, 96%). MS (ESI): mass calcd. for C16H12F2N4O2S, 362.06; m/z found, 363.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.12-8.01 (m, 2H), 7.72-7.61 (m, 3H), 7.45-7.36 (m, 3H), 7.19 (m, 1H), 6.81 (s, 2H).
Reaction SMILES: [O-]CC.[Na+].[Na].[OH:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[N:11][CH:12]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH2:14]([O:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[N:11][CH:12]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccc(O)cn1
Reactant: BrCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: Cc1ccc(OCc2ccccc2)cn1

Procedure:
To a solution of sodium ethoxide prepared from 1.3 g. (0.0565 g. -atom) of sodium and 30 ml. of absolute ethanol is added a solution of 5-hydroxy-2-methylpyridine (5.0 g., 0.0458 mol) in 15 ml. of ethanol, followed by 8.6 g. (0.05 mol) of benzyl bromide. The mixture is refluxed for three hours, poured into 150 ml. of water and extracted with ether. The extract is dried and then treated with ethereal hydrogen chloride. The hydrochloride salt is dissolved in water and the aqueous solution is washed with ether, basified and extracted with ether. The dried extract is treated with charcoal and evaporated to give 5-benzyloxy-2-methylpyridine as a pale yellow oil.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([NH:19]C(=O)C)[CH2:15][CH2:14]2)[CH2:3][CH2:2]1.[OH-].[Na+]>Cl>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]2)[CH2:3][CH2:2]1
Reactant: CC(=O)NC1CCN(CCC2CCOc3ccccc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC1CCN(CCC2CCOc3ccccc32)CC1
Yield: 100.4 %

Procedure:
A solution of N-[1-[2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]-4-piperidinyl]acetamide (3.3 g, 10.9 mmol) in 1.2N hydrochloric acid (35 ml) was heated on a steam bath for 16 h. The reaction mixture was cooled and neutralized with 50% sodium hydroxide solution (pH 12). The basic aqueous solution was extracted with ethyl acetate. The organic extracts were washed with distilled water, dried (Na2SO4), filtered and evaporated in vacuo to afford the title compound (2.85 g, 100%) as an oily gum.
Reaction SMILES: [K].[SH:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[C:25]([O:26][CH3:27])=[C:24]([O:28][CH2:29][CH3:30])[CH:23]=[CH:22][N:21]=1>CN(C)C=O.C(Cl)(Cl)Cl>[CH2:29]([O:28][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([CH2:19][S:2][C:3]2[NH:4][C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=3[N:7]=2)[C:25]=1[O:26][CH3:27])[CH3:30]
Reactant: CCOc1ccnc(CBr)c1OC
Reactant: Sc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOc1ccnc(CSc2nc3ccccc3[nH]2)c1OC
Yield: 68.3 %

Procedure:
To a suspension of potassium salt of 2-mercaptobenzimidazole (1.3 g) and potassium carbonate (1.0 g) in dimethylformamide (15 ml) was added with stirring, a solution of 2-bromomethyl-4-ethoxy-3-methoxy-pyridine (1.6 g) in dimethylformamide (5 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with chloroform (50 ml), washed with water, 1N-sodium hydroxide, and water in this order, dried, and evaporated. The residue was purified by column chromatography on silica gel (chloroform-methanol (50:1)), to give 2-[(4-ethoxy-3-methoxypyrid-2-yl)methylthio]benzimidazole (1.4 g) as a light yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[C:5]([CH3:16])[CH:4]=1)#[N:2].C1C(=O)N([Br:24])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:16][C:5]1[CH:4]=[C:3]([C:1]#[N:2])[CH:8]=[CH:7][C:6]=1[NH:9][C:10](=[O:15])[C:11]([F:13])([F:12])[F:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C#N)ccc1NC(=O)C(F)(F)F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(NC(=O)C(F)(F)F)c(CBr)c1
Temperature: 25 °C

Procedure:
In a 500 mL round-bottomed flask N-(4-cyano-2-methylphenyl)-2,2,2-trifluoroacetamide (Intermediate 1; 7.3 g, 32.0 mmol), NBS (5.98 g, 33.6 mmol), and benzoyl peroxide (70%) (1.162 g, 4.80 mmol) were added to carbon tetrachloride (150 mL). The reaction mixture was then heated to reflux under argon for 4 days. The reaction mixture was cooled to room temperature then NBS (0.5 eq, 3 g) and benzoyl peroxide (0.075 eq, 0.581 g) were added. The reaction mixture was then heated to reflux for a further 18 hrs. The reaction mixture was allowed to cool to room temperature then poured into 2M NaOH (100 mL). The organic layer was collected then washed with a solution of sodium metabisulfite (10 g in 100 mL water), dried (MgSO4), filtered and the solvent removed. The resulting orange oil was then purified through a plug of silica gel eluting with 1-10% EtOAc:isoHexane. The desired fractions were then combined and evaporated to dryness to give a 1:1 mixture of the title compound and the starting material as an orange solid (9 g) which was then used in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[N:5]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:4]1.[N+:26]([O-])([O-:28])=[O:27].[K+]>OS(O)(=O)=O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:15][C:9]=3[C:8]([N+:26]([O-:28])=[O:27])=[CH:7][C:6]=2[N:5]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:4]1
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(N1CC(CCl)c2c1ccc1cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(N1CC(CCl)c2c1cc([N+](=O)[O-])c1cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Yield: 66.7 %

Procedure:
A solution of 113(250 mg, 0.63 mmol) in conc. H2SO4 (10 mL) was nitrated with KNO3 (65 mg, 0.65 mmol) in H2SO4 (5 mL) as above, to give 1-(chloromethyl)-5-nitro-3-(trifluoroacetyl)-1,2-dihydro-3H-benzo[e]indole-7-sulfonyl chloride (116) (192 mg, 67%) as a red solid: mp (EtOAc/petroleum ether) 184-189° C.; 1H NMR [(CDCl3)] a 9.34 (s, 1H), 9.28 (d, J=1.8 Hz, 1H), 8.22 (dd, J=9.0, 1.9 Hz, 1H), 8.11 (d, J=9.0 Hz, 1H), 4.77-4.71 (m, 1H), 4.58 (dd, J=11.5, 8.8 Hz, 1H), 4.42-4.33 (m, 1H), 3.95 (dd, J=11.7, 3.5 Hz, 1H 3.73 (dd, J=11.7, 7.7 Hz, 1H); 13C NMR δ 153.4 (q, JC-F 38 Hz), 153.0, 148.2, 147.0, 138.7, 133.2, 129.1, 126.7, 124.5, 122.0, 119.3, 115.9 (q, JC-F 288 Hz), 52.6, 47.3, 41.2. Anal. (C15H9Cl2F3N2O5S) C, H, N, Cl.