Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH2:6]([O:8][C:9]([C:11]1[N:12]([CH3:35])[C:13]([CH2:33][CH3:34])=[C:14]([C:31]#[N:32])[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:27]([N+:28]([O-])=O)=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:18][CH:17]=1)=[O:10])[CH3:7]>C(O)C>[CH2:6]([O:8][C:9]([C:11]1[N:12]([CH3:35])[C:13]([CH2:33][CH3:34])=[C:14]([C:31]#[N:32])[C:15]=1[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[C:27]([NH2:28])=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:20][CH:21]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1c(-c2ccc(-c3ncccc3[N+](=O)[O-])cc2)c(C#N)c(CC)n1C
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(-c3ncccc3N)cc2)c(C#N)c(CC)n1C
Temperature: 90 °C
Yield: 60.1 %

Procedure:
Add tin (II) chloride dihydrate (669 mg, 3.54 mmol) into a solution of 3-[4-(3-nitro-pyridin-2-yl)-phenyl]-4-cyano-5-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (275 mg, 0.681 mmol, prepared in example E-38) in ethanol. Heat the mixture at 90° C. for 3 hours. Concentrate the reaction to remove ethanol. Dilute the residue with methylene chloride and H2O. Adjust the pH to 8 by adding saturated aqueous NaHCO3 solution. Extract with methylene chloride (2×30 mL) and EtOAc (2×30 mL). Combine the organic extracts, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography (elution with 17% acetone in hexanes) to provide the title compound as yellow solid (153 mg, 0.409 mmol, 60%). Mass spectrum (m/e): 375.1 (M+1). Rf=0.1 (17% of acetone in hexanes).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])\[CH3:7])[CH3:2].[Br:17]N1C(=O)CCC1=O.O>ClCCl.N(C(C)(CC(C)C)C#N)=NC(C)(CC(C)C)C#N>[CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])\[CH2:7][Br:17])[CH3:2]
Reactant: CCOC(=O)/C=C(\C)Oc1ccccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)C
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)/C=C(\CBr)Oc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 113 %

Procedure:
To a solution of (E)-3-(2-chloro-phenoxy)-but-2-enoic acid ethyl ester (1880 g, 7.82 mol) in dichloromethane (18.6 L) was added N-bromosuccinimide (1490 g, 8.29 mol) and 2,2′-azobis(2,4-dimethylvaleronitrile) (47 g, 0.188 mol) and the resulting solution heated to reflux for 23 h. The light yellow solution was cooled to room temperature and transferred to an extractor before water (19 L) was added. The biphasic mixture was stirred at room temperature for 1 h. The mixture was separated and the organic phase washed with a 20% sodium chloride solution (19 L). The solution was evaporated to give (E)-4-bromo-3-(2-chloro-phenoxy)-but-2-enoic acid ethyl ester (87.8% pure by HPLC, 2824 g, 99%) as a red oil.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[CH:27][CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[CH:3]=1.CC1(C)C(C)(C)OB([C:46]2[CH:54]=[C:53]([NH:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH:52]=[C:51]3[C:47]=2[CH:48]=[CH:49][NH:50]3)O1.CS(N)(=O)=O.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:26]=[C:18]1[C:17]2=[CH:27][CH:28]=[CH:29][N:16]2[N:15]=[C:14]([C@@H:12]([NH:11][C:9]2[C:10]3[C:2]([C:46]4[CH:54]=[C:53]([NH:55][S:56]([CH3:59])(=[O:57])=[O:58])[CH:52]=[C:51]5[C:47]=4[CH:48]=[CH:49][NH:50]5)=[CH:3][N:4]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:5]=3[N:6]=[CH:7][N:8]=2)[CH3:13])[N:19]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@H](Nc1ncnc2c1c(Br)cn2COCC[Si](C)(C)C)c1nn2cccc2c(=O)n1-c1ccccc1
Reactant: CC1(C)OB(c2cc(NS(C)(=O)=O)cc3[nH]ccc23)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CS(N)(=O)=O
Product: C[C@H](Nc1ncnc2c1c(-c1cc(NS(C)(=O)=O)cc3[nH]ccc13)cn2COCC[Si](C)(C)C)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 97.3 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (125 mg, 0.22 mmol) was treated with N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-6-yl)methanesulfonamide (187 mg, 0.56 mmol, prepared from N-(4-bromo)-1H-indol-6-yl)methanesulfonamide, which is described at WO 2009147188 A1 20091210, and bis(pinacolato)diboron according to Preparation 119b), sodium carbonate (60 mg, 0.57 mmols) and bis(triphenylphosphine)palladium(II) dichloride (50 mg, 0.06 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 80%, hexane-ethyl acetate) to give 152 mg (98% yield) of the title compound. Purity 98%.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[C:17]([Cl:18])=[C:16]([O:19][CH3:20])[CH:15]=[C:14]([O:21][CH3:22])[C:13]=3[Cl:23])[CH:8]=2)[N:3]=1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]1[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:23][C:13]1[C:14]([O:21][CH3:22])=[CH:15][C:16]([O:19][CH3:20])=[C:17]([Cl:18])[C:12]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]1[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[N:11]=[CH:10]2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(Cl)ncc3c2)c1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)ncc3c2)c1Cl
Temperature: 70 °C
Yield: 77.3 %

Procedure:
A mixture of 2-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazoline (0.95 g, 2.6 mmol), tert-butyl ((1S,2R)-2-aminocyclohexyl)carbamate (1.1 g, 5.14 mmol), and DBU (0.77 mL, 5.14 mmol) in acetonitrile (9 mL) was degassed with N2 for 5 mins and heated at 70° C. for 16 h. The mixture was cooled to room temperature, concentrated and the residue was purified by silica gel column chromatography to afford tert-butyl ((1S,2R)-2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)cyclohexyl)carbamate (1.1 g, 81%). MS (ES+) C27H32Cl2N4O4 requires: 546, found: 547 [M+H]+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:24][N:25]1CCOC[CH2:26]1.C1C=CC2N(O)N=NC=2C=1.Cl.CNC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[Na+]>CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)([C:14](=[O:15])[N:25]([CH3:26])[CH3:24])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccc(Cl)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)C(=O)C1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Yield: 94 %

Procedure:
N-Boc-4-(4-chlorophenyl)-4-piperidine carboxylic acid Compound 2-1 (5.96 g, 18 mmol, Arch Chemical) was dissolved in DMF (175 mL) and chilled in an ice bath temp. To the solution was added N-methylmorpholine (5.76 mL, 53 mmol), HOBt (1.18 g, 8.8 mmol), dimethylamine hydrochloride (1.41 g, 18 mmol), and HBTU (10.0 g, 26 mmol). The solution was allowed to warm overnight to rt, poured into 1N sodium hydroxide solution (100 mL), and extracted with EtOAc (3×75 mL). The combined organic layers were washed with 1N NaOH (2×), 1N hydrochloric acid solution (2×), and brine (3×); and dried over Na2SO4 and concentrated to give Compound 2-2 (6.1 g, 17 mmol, 94%) as a white solid. 1H NMR (300 MHz, CDCl3,) δ 7.32 (d, J=9 Hz, 2H), 7.17 (d, J=9 Hz, 2H), 4.2-3.8 (br m, 2H), 3.0-2.6 (br m, 2H), 2.96 (s, 3H), 2.80 (s, 3H), 2.25 (m, 2H), 2.1-1.7 (br m, 2H), 1.45 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(Cl)ccc1C(=O)O
Agent: O=S(=O)(O)O
Product: Cc1c(C(=O)O)ccc(Cl)c1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with 4-chloro-2-methylbenzoic acid (200 mg, 0.001 mol) and sulfuric acid (1 mL, 0.02 mol). Fuming nitric acid (0.05 mL, 0.001 mol) was added at −20° C. and the reaction was stirred for 1 hour at 70° C. and poured into ice cold water wherein the mixture of 2- and 4-nitro compounds precipitated out. The precipitate was filtered and dissolved in ethylacetate (30 mL) and washed with saturated aqueous sodium bicarbonate solution, brine and dried over sodium sulfate. The solvent was reduced ¼ volume whereby the undesired isomer precipitated out. The precipitate was filtered and the filtrate was dried to obtain a 1:1 mixture of isomers as a white solid. MS m/z=214.5 (M−H).
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]([C:25]([O:27]C(C)(C)C)=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)[C:10]3[CH:32]=[CH:33][CH:34]=[CH:35][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>>[C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]([C:25]([OH:27])=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)[C:10]3[CH:32]=[CH:33][CH:34]=[CH:35][C:9]=3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(Cn2c(-c3ccccc3)nc3ccccc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccccc1-c1ccc(Cn2c(-c3ccccc3)nc3ccccc32)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-phenyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:20][NH2:21]>>[C:6]1([C:4]2[C:3]3[C:2](=[CH:15][CH:14]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:12]=3)[NH:21][N:20]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NN
Reactant: O=C(c1ccccc1)c1cc(C(F)(F)F)ccc1F
Product: FC(F)(F)c1ccc2[nH]nc(-c3ccccc3)c2c1
Reaction time: 8 h
Yield: 76 %

Procedure:
A solution of 2-fluoro-5-trifluoromethylbenzophenone (0.828 g, 3.09 mmol) in hydrazine was heated at 130° C. for 3 hours. The reaction mixture stood at ambient temperature overnight and gave white needles. It was filtered and washed with hexane to provide the title compound (0.617 g, 76% yield): mp 152° C.; 1H NMR (CDCl3) δ 10.63 (br s, 1H), 8.33 (s, 1H), 7.96 (d, 2H), 7.48-7.67 (m, 5H); EI-MS (m/z) 262 [M]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Sb](Cl)(Cl)(Cl)(Cl)[Cl:12].II>>[Cl:12][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cl[Sb](Cl)(Cl)(Cl)Cl
Agent: II
Product: O=[N+]([O-])c1ccc(F)c(Cl)c1
Yield: 99 %

Procedure:
141 G of 4-fluoronitrobenzene, 7 g of antimony pentachloride and 0.5 g of iodine were charged. The same succeeding procedures as in Example 1 were repeated to obtain 173 g (yield: 99%) of 3-chloro-4-fluoronitrobenzene. Analytical value thereof by gas chromatography was as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5].[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][N:22]=1>CCO>[CH:13]1([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:1]=[C:25]3[C:24]3[CH:23]=[N:22][C:21]([CH3:20])=[CH:28][CH:27]=3)=[CH:8][CH:9]=2)[CH2:15][CH2:14]1
Reactant: Nc1ccccc1C(=O)Nc1ccc(C2CC2)cc1
Reactant: Cc1ccc(C=O)cn1
Solvent: CCO
Product: Cc1ccc(-c2nc3ccccc3c(=O)n2-c2ccc(C3CC3)cc2)cn1
Yield: 14.6 %

Procedure:
2-amino-N-(4-cyclopropylphenyl)benzamide (0.342 g, 1.36 mmol), 6-methylnicotinaldehyde (0.197 g, 1.63 mmol), and anyhydrous CuCl2 (0.547 g, 4.08 mmol) were combined in anyhydrous EtOH (30 mL) and heated at reflux for 2.5 hours. After concentration, ethyl acetate (200 mL) was added, and the mixture was washed with water (2×100 mL), dried (MgSO4), filtered, and concentrated. Purification by flash chromatography on silica gel, eluting with 20% ethyl acetate/hexanes to 30% ethyl acetate/hexanes to 100% ethyl acetate, plus further purification by flash chromatography on silica gel, eluting with 1:1 ethyl acetate/CH2Cl2, afford the title compound as a white solid (0.070 g, 15%). 1H-NMR (300 MHz, DMSO-6): δ8.44 (d, J=2.0 Hz, 1H), 8.18-8.20 (m, 1H), 7.88-7.94 (m, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.58-7.65 (m, 2H), 7.22 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.1 Hz, 1H), 7.04 (d, J=8.4 Hz, 2H), 2.40 (s, 3H), 1.84-1.91 (m, 1H), 0.91-0.99 (m, 2H), 0.63-0.68 (m, 2H). MS (APCI) m/z: 354 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14]([CH:15]=[CH:16][C:17]2([O:26][CH2:25][CH2:24][O:23]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12]C1=O.CO[CH:31]([O:34][CH3:35])[O:32][CH3:33]>>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[C@@H:14]([CH:15]=[CH:16][C:17]2([O:26][CH2:25][CH2:24][O:23]2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12][C:31]1([O:32][CH3:33])[O:34][CH3:35]
Reactant: CCCCCC1(C=C[C@H]2CCC(=O)[C@@H]2CCCCCCC(=O)OC)OCCO1
Reactant: COC(OC)OC
Product: CCCCCC1(C=C[C@H]2CCC(OC)(OC)[C@@H]2CCCCCCC(=O)OC)OCCO1
Reaction time: 6 h

Procedure:
A mixture of 1.5 g of 9-oxo-15,15-ethylenedioxy-13-prostenoic acid methyl ester, 20 ml of trimethoxy-methane and 3 drops of concentrated H2SO3 is boiled for 6 hours. 15 ml of the solvent is distilled within 2 hours. The residue is diluted with 30 ml of diethyl ether, washed with aqueous saturated NaHCO3 solution and H2O and dried over MgSO4. The solvent is distilled. After chromatographic purification of the residue (silica gel/diisopropyl ether), 9,9-dimethoxy-15,15-ethylenedioxy-13-prostenoic acid methyl ester is obtained.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:14]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=3[NH:12][C:10](=[O:11])[CH:9](O)[N:8]=2)=[CH:5][CH:6]=1.S(Cl)([Cl:23])=O>CN(C=O)C>[Cl:23][CH:9]1[N:8]=[C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:10]1=[O:11]
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1Cl
Reaction time: 24 h

Procedure:
Oxazepam (1.0 g) was added in portions to 1.0 ml of freshly distilled thionyl chloride that contained ~50μl of DMF with stirring under N2 atmosphere at ice-bath temperature. As soon as the oxazepam was added to the thionyl chloride, the color turned bright yellow and remained unchanged. After complete addition, the heterogeneous reaction mixture was stirred at 0° for 1 hour and then left in the cold room at ~4° for 24 hours. Excess thionyl chloride was removed on a rotary evaporator. The resulting bright yellow solid was thoroughly mixed with a small amount of anhydrous benzene and then benzene was removed on a rotary evaporator, this was repeated several times to remove thionyl chloride. The residue was then triturated with 3 ml of anhydrous benzene and filtered with suction. The product was dried under vacuum to give 1.1 g of bright yellow solid, m.p. 139°-140° C. decomposition (lit. m.p. 151°-153° dec. and 120°-122° C.).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C)(=O)=O)=[CH:13][CH:12]=[N:11][C:10]=2[O:21][CH2:22][CH3:23])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:24][C:25]1[C:26]([CH3:31])=[CH:27][CH:28]=[CH:29][CH:30]=1>C(#N)C>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])=[CH:13][CH:12]=[N:11][C:10]=2[O:21][CH2:22][CH3:23])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccccc1N
Reactant: CCCC(=O)c1cnc2c(OCC)nccc2c1OS(C)(=O)=O
Solvent: CC#N
Product: CCCC(=O)c1cnc2c(OCC)nccc2c1Nc1ccccc1C
Yield: 86 %

Procedure:
3-Butyryl-8-ethoxy-4-methanesulfonyloxy-1,7-naphthyridine (338 mg) and o-toluidine (214 mg) were dissolved into 7 ml of acetonitrile, and the solution was heated to reflux for 30 minutes and concentrated to evaporate solvent under reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform, and the organic phase was washed with water and then saturated sodium bicarbonate. After dying, and concentration under reduced pressure, the resulting residue was subjected to silica gel column chromatography using a mixture of hexane:ethyl acetate (2:1) as an eluant to give yellow titled compound (300 mg, 86%)
Reaction SMILES: [S:1]1[C:5]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)=[CH:4][N:3]=[CH:2]1.O1CCOCC1>Cl>[N:21]1([C:19]2[N:20]=[C:15]([N:14]3[C:8]4[CH:7]=[C:6]([C:5]5[S:1][CH:2]=[N:3][CH:4]=5)[N:11]=[CH:10][C:9]=4[CH:12]=[N:13]3)[CH:16]=[CH:17][CH:18]=2)[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(-c5cncs5)cc43)n2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1cc(N2CCNCC2)nc(-n2ncc3cnc(-c4cncs4)cc32)c1
Yield: 72 %

Procedure:
A mixture of tert-butyl 4-[6-(6-thiazol-5-ylpyrazolo[4,3-c]pyridin-1-yl)-2-pyridyl]piperazine-1-carboxylate in hydrogen chloride (4 mol/l) in dioxane (1.5 mL, 6.0 mmol) and dioxane 1.0 mL was stirred at RT 14 h. The reaction was concentrated. The crude product was submitted for reverse phase HPLC to give 109 (44 mg) in 72% yield. MS (ESI) m/z: 364.1. 1H NMR (400 MHz, DMSO) δ 9.20 (d, J=8.2 Hz, 2H), 8.94 (s, 1H), 8.64-8.59 (m, 1H), 8.43 (s, 1H), 7.77 (t, J=8.1 Hz, 1H), 7.23 (d, J=7.7 Hz, 1H), 6.81 (d, J=8.4 Hz, 1H), 3.65-3.57 (m, 4H), 2.96-2.88 (m, 4H)
Reaction SMILES: [CH3:1][CH:2]([NH:11][C:12]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1)=[O:13])[CH2:3][CH2:4][CH2:5][N:6]([CH2:9][CH3:10])[CH2:7][CH3:8].[P:24](=[O:28])([OH:27])([OH:26])[OH:25]>>[OH:28][P:24]([O:27][P:24]([OH:27])([OH:26])=[O:25])(=[O:26])[OH:25].[CH3:1][CH:2]([NH:11][C:12]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1)=[O:13])[CH2:3][CH2:4][CH2:5][N:6]([CH2:9][CH3:10])[CH2:7][CH3:8]
Reactant: O=P(O)(O)O
Agent: CCN(CC)CCCC(C)NC(=O)c1ccnc2ccccc12
Product: O=P(O)(O)OP(=O)(O)O

Procedure:
2-[4'-(5"-nitrofuryl-2")-1,3-butadienyl]quinoline-4-carboxylic acid (α-methyl-δ-diethylaminobutyl)amide diphosphate was prepared as described in Example 9 from 2-[2'-(5"-nitrofuryl-2")vinyl]quinoline-4-carboxylic acid (α-methyl-δ-diethylaminobutyl)amide and ortho-phosphoric acid. The yield was 68.1%, m.p. 176°-178° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)[N:14]=1)[N:11]([C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])[C:10](=[O:24])[C:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2[C@H](C)c2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2[C@H](C)c2ccccc2)c1O
Temperature: 120 °C
Yield: 41.9 %

Procedure:
A mixture of (R)-8-bromo-5-hydroxy-2-oxo-3-phenyl-1-(1-phenyl-ethyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (73 mg, 0.15 mmol), 3-tributylstannanyl-pyridine (0.073 mL, 0.23 mmol) and PdCl2(PPh3)2 (21 mg, 0.030 mmol) in 4 mL of DMF was heated at 120° C. for 3 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by silica gel chromatography (5-90% EtOAc/hexanes+1% AcOH) to give 30 mg of the title compound as a brown oil. MS: (+) m/z 478.39 (M+1).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([NH:7][C:8]([C:10]1[C:18]2[S:17][C:16]([NH:19][C:20](=[O:24])[NH:21][CH2:22][CH3:23])=[N:15][C:14]=2[CH:13]=[C:12]([O:25]C)[CH:11]=1)=[O:9])[CH3:6]>C(Cl)Cl.CCOC(C)=O>[CH2:5]([NH:7][C:8]([C:10]1[C:18]2[S:17][C:16]([NH:19][C:20](=[O:24])[NH:21][CH2:22][CH3:23])=[N:15][C:14]=2[CH:13]=[C:12]([OH:25])[CH:11]=1)=[O:9])[CH3:6]
Reactant: CCNC(=O)Nc1nc2cc(OC)cc(C(=O)NCC)c2s1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCNC(=O)Nc1nc2cc(O)cc(C(=O)NCC)c2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
Boron tribromide (8.72 mL, 8.72 mmol, 4M solution in DCM was added to a suspension of N-ethyl-2-(ethylcarbamoylamino)-5-methoxy-1,3-benzothiazole-7-carboxamide in dichloromethane (10 mL). The reaction was stirred at ambient temperature overnight then diluted with EtOAc, washed with saturated aqueous sodium hydrogen carbonate and brine and the organic layer dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel using DCM:MeOH 95:5. The product was obtained as a white solid, 212 mg, 31% yield.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][N:5]([CH3:17])[C:6](=[O:16])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1>CO.[Pd]>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:18])[CH3:17])=[O:16])=[CH:8][CH:9]=1
Reactant: CN(C)CCN(C)C(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCN(C)C(=O)c1ccc(N)cc1
Reaction time: 3 h
Yield: 101 %

Procedure:
To a solution of N-(2-dimethylamino-ethyl)-N-methyl-4-nitro benzamide (4.5 g, 0.0179 mol) in MeOH (100 mL) was added Pd/C 10% (0.5 g) in portions and the Parr reaction vessel was purged with nitrogen for 10 min. The reaction vessel was fixed in Parr shaker at 60 psi pressure for 3 h. The reaction mixture was filtered through the Celite® pad and the filtrate was concentrated under reduced pressure to afford the title compound [4.0 g, 100%]; LC-MS (ESI): Calculated mass: 221.2; Observed mass: 222.1 [M+H]+ (RT: 0.17 min).
Reaction SMILES: [C:1]([Sn:5]([Cl:11])(F)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].CCCCC.[C:17]([Li])([CH3:20])([CH3:19])[CH3:18]>CCCCCCC>[C:1]([Sn:5]([Cl:11])([C:17]([CH3:20])([CH3:19])[CH3:18])[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Sn](F)(Cl)C(C)(C)C
Reactant: [Li]C(C)(C)C
Solvent: CCCCCCC
Solvent: CCCCC
Product: CC(C)(C)[Sn](Cl)(C(C)(C)C)C(C)(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A suspension of di-t-butyltin chloride fluoride (5.0 g., 0.017 mole) in heptane (100 ml.) was cooled to -78° C., and a pentane solution of t-butyl-lithium (20 ml., 1.95 M) was added dropwise. After the addition was completed, stirring was continued for 2 hrs., the cooling bath was removed, and the mixture was allowed to warm to room temperature with stirring for 6 more hrs. The resulting pale yellow mixture was worked up to give a thick, pale yellow oil which was chromatographed with pentane. Evaporation of the solvent left a clear oil which solidified spontaneously (5.0 g., 88.3%), m.p. 31-32; (b.p. 122°-123°/5 mm. (Found: C, 44.15; H, 8.15; Cl, 10.95. C12H27ClSn requires C, 44.3; H, 8.35; Cl, 10.9%); n.m.r. 61.35 (s).