Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][C:18]3[CH:17]=[C:16]([OH:20])[CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:34]1[C:43]2[C:38](=[C:39]([O:44][CH3:45])[CH:40]=[CH:41][CH:42]=2)[N:37]=[CH:36][CH:35]=1>C(O)(C)C>[CH3:45][O:44][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]2[C:38]=1[N:37]=[CH:36][CH:35]=[C:34]2[N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][C:18]3[CH:17]=[C:16]([OH:20])[CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11]2)[CH2:2][CH2:3]1
Reactant: COc1cccc2c(Cl)ccnc12
Reactant: CCCN(CCN1CCNCC1)C1CCc2ccc(O)cc2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCCN(CCN1CCN(c2ccnc3c(OC)cccc23)CC1)C1CCc2ccc(O)cc2C1
Reaction time: 8 h
Yield: 73 %

Procedure:
To a mixture of 9a (0.6 g, 1.89 mmol) and diisopropylethylamine (0.4 mL, 2.08 mmol, 1.1 equiv) in 15 mL isopropanol was added 4-chloro-8-methoxyquinoline (17) (0.366 g, 1.89 mmol, 1 equiv). The mixture was refluxed with stirring for overnight. It was then evaporated and concentrate was dissolved in CH2Cl2 (50 mL) and the solution obtained was washed with 5% NaHCO3 (3×50 mL), brine (2×50 mL), and then dried over Na2SO4. The solution was filtered and evaporated to dryness. The residue was purified through column chromatography using 20% methanol in ethyl acetate to give 18a as white wax (0.66 g, 73% yield). 1H NMR (400 MHz, CDCl3) δ ppm 0.93-0.95 (t, 3H, 4 Hz), 1.75 (m, 3H), 2.11-2.21 (m, 2H), 2.69-3.07 (m, 13H), 3.23 (s, 4H), 3.47 (s, 1H), 4.02 (s, 3H), 6.60 (s, 1H), 6.66-6.68 (d, 1H, J=8 Hz), 6.82-6.84 (t, 2H, J=4 Hz), 6.98-7.00 (d, 1H, J=8 Hz), 7.36-7.42 (t, 1H, J=12 Hz), 7.50-7.52 (d, 1H, J=8 Hz), 8.67-8.68 (d, 1H, J=4 Hz).
Reaction SMILES: [C:1]([O:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([OH:20])=[C:12]([CH3:21])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC(C)=O>[CH2:28]([O:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:11][C:12]=1[CH3:21])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1cc(OC(=O)c2ccccc2)c2ccccc2c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(OC(=O)c2ccccc2)c2ccccc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.8 %

Procedure:
10.8 g (0.039 mol) of 4-benzoyloxy-2-methylnaphthol was dissolved in 100 ml of acetone, and to this was added 5.5 g (0.04 mol) of anhydrous potassium carbonate, and, while stirring at room temperature, 7.7 g (0.045 mol) of benzyl bromide was added dropwise over 30 minutes, and following completion of the addition, stirring was continued for 20 hours at room temperature. Then, inorganic salt was filtered out and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate, washed with water, and the solvent evaporated under reduced pressure. n-Hexane was added to the residue to cause crystallization. Recrystallization from ethyl acetate-n-hexane gave 11.9 g of white crystals, m.p. 179-180° C.
Reaction SMILES: CS[C:3]1[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>>[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH:17][C:3]1[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: CSc1ncnc2cnccc12
Product: Brc1cccc(Nc2ncnc3cnccc23)c1
Temperature: 100 °C
Yield: 52.7 %

Procedure:
A mixture of 4-methylthiopyrido[3,4-d]pyrimidine (75 mg, 0.42 mmol) (see previous experimental), and 3-bromoaniline (1 mL) is heated to 100° C. under N2 for 2 h. The reaction mixture is then chromatographed on silica using MPLC and eluting with a gradient system (CHCl3 to 5% MeOH in CHCl3). The fractions are concentrated under reduced pressure, and the resulting solid is recrystallized from Et2O to yield 4-(3-bromoanilino)pyrido[3,4-d]pyrimidine (66 mg, 52.7%) as a light brown solid. 1H NMR (DMSO) δ 10.15 (1H, s), 9.21 (1H, s), 8.80 (1H, s), 8.76 (1H, d, J=5.8 Hz), 8.44 (1H, d, J=5.6 Hz), 8.25 (1H, s), 7.93 (1H, d, J=7.7 Hz), 7.45-7.37 (2H, m).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].CN(C=O)C.[Br:16][CH2:17][C:18](Br)=[O:19]>O1CCOCC1>[Br:16][CH2:17][C:18]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])=[O:19]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(Br)CBr
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(CBr)Nc1ccccc1C(=O)O
Temperature: 0 °C
Reaction time: 5 h
Yield: 87.8 %

Procedure:
A solution of anthranilic acid (50 g, 364.6 mmol) in a mixture of anhydrous DMF (125 mL) and dioxane (125 mL) in a 1 L morton flask equipped with a mechanical stirrer and a constant addition funnel was cooled with an ice-bath to 0° C. Distilled bromoacetyl bromide (73.6 g, 31.77 mL, 364.6 mmol) was added dropwise keeping the internal temperature between 0°-1.5° C. over a 2.5 h period. After the addition was completed, the ice-bath was removed and stirring was continued for 5 h at ft. The reaction mixture was cooled in an ice-bath and water (300 mL) was slowly added. A white precipitate formed, which was filtered, washed sequentially with 5% HBr solution (500 mL) and water (500 mL), and then dried in a vacuum desiccator. Further drying in a vacuum oven at 60° C. afforded 82.61 g (87.8%) of the title compound as a white powder: mp 164.6°-167.6° C. (lit. 165.5°-172° C. (Hoffman LaRoche U.S. Pat. No. 3,244,698)); 1H NMR (DMSO-d6) δ13.7 (bs, 1H), 11.60 (s, 1H), 8.44 (d, J=8.0, 1H), 8.00 (dd, J=8.0, J=1.6, 1H), 7.62 (dt, J=8.0, J=1.6, 1H), 7.21 (t, J=8.0, 1H); 4.26 (s, 2H); 13C NMR (DMSO-d6) δ169.20, 165.05, 139.95, 134.08, 131.13, 123.46, 120.02, 117.09, 30.67; MS (EI, m/z) 256.9 (M+), 258.9 (M+ 2+). HRMS (EI) calcd for C9H8NO3Br 256.9686, found 256.9695.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:31]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:32])[C:22]=2[N:21]=[C:20]1[CH2:33][CH2:34][CH2:35][CH3:36]>>[NH2:32][C:23]1[C:22]2[N:21]=[C:20]([CH2:33][CH2:34][CH2:35][CH3:36])[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][NH:14][S:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)(=[O:12])=[O:11])[C:31]=2[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:24]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1cccc([N+](=O)[O-])c1

Procedure:
According to the general method of Example 5, 3-nitrobenzenesulfonyl chloride and 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinoline-4-amine were combined. N1-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-3-nitro-1-benzenesulfonamide was isolated as the hydrochloride salt (white solid), m.p. 176.0-178.2° C. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (very broad s, 2H), 8.49-8.42 (m, 2H), 8.21-8.17 (m, 2H), 8.06 (t, J=5.7 Hz, 1H), 7.88-7.81 (m, 2H), 7.71 (t, J=7.7 Hz, 1H), 7.57 (t, J=7.7 Hz, 1H), 4.56 (t, J=7.3 Hz, 2H), 2.94 (t, J=7.7 Hz, 2H), 2.86 (m, 2H), 1.81 (m, 4H), 1.60-1.42 (m, 4H), 0.96 (t, J=7.3 Hz, 3H); IR (KBr) 3096, 2954, 2869, 2771, 1671, 1607, 1528, 1351, 1335, 1163, 1128, 1083, 879, 758, 735, 672, 661 cm−1; MS (EI) m/e 496.1897 (496.1893 calcd for C24H28N6O4S). Anal calcd for C24H28N6O4S*HCl*H2O: C, 52.31; H, 5.67; N, 15.25. Found: C, 52.26; H, 5.46; N, 15.09.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].[NH2:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([O:22][CH3:23])=[O:21].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10]([NH:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([O:22][CH3:23])=[O:21])(=[O:12])=[O:11]
Reactant: COC(=O)c1sccc1N
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sccc1NS(=O)(=O)c1cc(F)c(F)cc1Cl
Yield: 33.5 %

Procedure:
Synthesized as described for 3 using 2-chloro-4,5,-difluorobenzenesulfonyl chloride (500 mg; 2.02 mmol), methyl 3-aminothiophene-2-carboxylate (382 mg; 2.43 mmol), 4-dimethylaminopyridine (62 mg; 0.51 mmol), pyridine (10 mL), and anhydrous dichloromethane (10 mL). The crude product was purified by automated silica gel chromatography (Biotage®) using ethyl acetate/hexanes as eluant system (0 to 20% v/v over 7 column volume gradient elution) to yield the title product as a white solid (249 mg).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][O:29][CH2:30][CH2:31][C:32]([CH2:45][CH2:46][O:47][CH3:48])([NH2:44])[C:33]([N:35]([CH3:43])[C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1)=[O:34]>>[CH3:28][O:29][CH2:30][CH2:31][C:32]([CH2:45][CH2:46][O:47][CH3:48])([NH2:44])[C:33]([N:35]([C:36]1[CH:37]=[CH:38][C:39]([NH:42]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:40][CH:41]=1)[CH3:43])=[O:34]
Reactant: COCCC(N)(CCOC)C(=O)N(C)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COCCC(N)(CCOC)C(=O)N(C)c1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-(di-(2-methoxyethyl)-amino-methylcarbonyl)-N-methyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C32H36N4O6
Reaction SMILES: Br[C:2]1[CH:36]=[CH:35][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:19]5[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:21][CH2:20]5)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:37][C:38]([OH:55])([CH3:54])[CH2:39][N:40]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[N:41]1>>[C:31]([Si:28]([CH3:29])([CH3:30])[O:27][CH2:26][CH2:25][N:22]1[CH2:21][CH2:20][CH:19]([N:15]2[C:14]([C:8]3[S:9][C:10]4[CH2:11][CH2:12][O:13][C:4]5[CH:3]=[C:2]([C:43]6[CH:42]=[N:41][N:40]([CH2:39][C:38]([CH3:54])([OH:55])[CH3:37])[CH:44]=6)[CH:36]=[CH:35][C:5]=5[C:6]=4[N:7]=3)=[N:18][CH:17]=[N:16]2)[CH2:24][CH2:23]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)[Si](C)(C)OCCN1CCC(n2ncnc2-c2nc3c(s2)CCOc2cc(Br)ccc2-3)CC1
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4C4CCN(CCO[Si](C)(C)C(C)(C)C)CC4)nc2-3)cn1

Procedure:
Following the procedure for 114, 8-Bromo-2-(2-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-piperidin-4-yl}-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 2-methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol to give 1-{4-[2-(2-{1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-piperidin-4-yl}-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-2-methyl-propan-2-ol. MS(ESI+) 650.3
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][O:5][C:4](=[O:7])[C@@H:3]1C(=C)C([O-])=O.[CH2:14]=[CH:15][C:16](=[CH2:18])[CH3:17]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:18][C:16]1[CH2:17][CH2:2][C@@H:3]([C:4]([O:7][C@H:3]2[C:2]([CH3:1])([CH3:13])[CH2:6][O:5][C:4]2=[O:7])=[O:5])[CH2:14][CH:15]=1
Reactant: C=CC(=C)C
Reactant: C=C(C(=O)[O-])[C@H]1C(=O)OCC1(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1=CC[C@H](C(=O)O[C@@H]2C(=O)OCC2(C)C)CC1
Reaction time: 0.25 h
Yield: 92.8 %

Procedure:
(S)-4,4-dimethyl-2-oxotetrahydrofuran-3-ylacrylate 501 (2.05 g, 11.1 mmol) in dichloromethane (17.5 mL) and hexanes (2.5 mL) was cooled to −10° C. and treated with titanium tetrachloride (2.2 mL, 1 M in dichloromethane, 2.2 mmol). The yellow solution was stirred for 15 minutes and treated with isoprene (1.67 mL, 16.7 mmol) dropwise over 5 minutes. After stirring for 2 hours, an additional portion of isoprene (1.67 mL, 16.7 mmol) was added and the reaction mixture was stirred at −10 to 0° C. for 3.5 hours. The reaction mixture was quenched with ammonium chloride (sat. aq.). Water and ethyl acetate:hexanes (1:1) were added. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate:hexanes (1:1). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (10-50% EtOAc:Hex, 80 g column) to afford 1.30 g (46% yield) of (R)—((S)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl) 4-methylcyclohex-3-enecarboxylate 502 as a clear oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)=O.C(OC([N:26]1[CH2:31][CH2:30][CH:29]([C:32](=[S:34])[NH2:33])[CH2:28][CH2:27]1)=O)(C)(C)C>C(O)C>[CH3:15][C:11]1([CH3:16])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]2[CH:6]=[C:5]([C:3]3[N:33]=[C:32]([CH:29]4[CH2:30][CH2:31][NH:26][CH2:27][CH2:28]4)[S:34][CH:2]=3)[CH:14]=[CH:13][C:12]1=2
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CBr)ccc21
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCNCC4)n3)ccc21

Procedure:
6.12 g (12.28 mmol) of 2-bromo-1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethanone and 3 g (12.28 mmol) of 4-thiocarbamoylpiperidine-1-carboxylic acid tert-butyl ester were suspended in 50 ml of ethanol and refluxed overnight. The reaction mixture was cooled and evaporated. The residue was slurried using a little EA and PE, digested and filtered off with suction. The solid was suspended in 180 ml of EA, washed with 60 ml of a saturated sodium hydrogencarbonate solution. The organic phase was dried over sodium sulfate, filtered and evaporated.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:7]=[CH:8][C:9]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:13]=[CH:12][C:10]=2[N:11]=1)[CH2:2][CH2:3][CH3:4].C1C(=O)N([Br:29])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:29][C:12]1[C:10]2[N:11]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:7]=[CH:8][C:9]=2[N:14]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH:13]=1
Reactant: CCCCNc1ncc2c(ccn2-c2ccc(F)cc2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCNc1ncc2c(n1)c(Br)cn2-c1ccc(F)cc1
Reaction time: 1 h
Yield: 80.1 %

Procedure:
A solution of N-butyl-5-(4-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-2-amine (1.03 g, 3.61 mmol) in DMF (10 mL) was added NBS (0.71 g, 3.97 mmol) at room temperature. The resulting solution was stirred for 1 h and diluted with EtOAc. The resulting solution was washed with a sat. aq. solution of NaHCO3, H2O and brine. The EtOAc layer was dried (Na2SO4), concentrated and purified by ISCO to provide the desired product (1.05 g, 80%). 1H NMR (400 MHz, CD3OD) δ 8.46 (s, 1H), 7.68 (s, 1H), 7.52-7.42 (m, 2H), 7.32-7.21 (m, 2H), 3.44 (t, J=7.1 Hz, 2H), 1.68-1.54 (m, 2H), 1.49-1.36 (m, 2H), 0.95 (t, J=7.3 Hz, 3H); MS m/z 363.1 [M+H]+.
Reaction SMILES: C(N1CCN(C2C=[C:11]([NH:15][C:16]([C:18]3[C:19]4[N:20]=[CH:21][CH:22]=[N:23][C:24]=4[C:25]([C:28]4[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30]C=4Cl)=[CH:26][CH:27]=3)=[O:17])C=CC=2)CC1)C.[CH2:37]([Cl:39])Cl.CO>>[NH:20]1[CH:19]=[CH:24][N:23]=[C:11]1[NH:15][C:16]([C:18]1[C:19]2[N:20]=[CH:21][CH:22]=[N:23][C:24]=2[C:25]([C:28]2[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:37]=2[Cl:39])=[CH:26][CH:27]=1)=[O:17]
Reactant: ClCCl
Reactant: CCN1CCN(c2cccc(NC(=O)c3ccc(-c4cc(OC)ccc4Cl)c4nccnc34)c2)CC1
Solvent: CO
Product: COc1ccc(Cl)c(-c2ccc(C(=O)Nc3ncc[nH]3)c3nccnc23)c1

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 8-(2-chloro-5-methoxy-phenyl)-quinoxaline-5-carboxylic acid (Example 63) in Step 14.1. Title compound: ESI-MS: 380.0 [M+H]+; tR=3.61 min (System 1); TLC: Rf=0.36 (DCM/MeOH, 95:5).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[CH:17]=4)[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]4[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=4)[NH2:22])[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: Cc1cc2c(ccc3nnc(C)n32)n1Cc1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1cccc(N)c1

Procedure:
1,7-Dimethyl-6-(3-nitrobenzyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (0.16 g, 0.50 mmol, from Example 25, Step 1) in methanol (100 mL) was hydrogenated for 6.5 hours under 1 atmosphere of hydrogen provided by a balloon, over 10% palladium on activated carbon (100 mg, 0.10 mmol, Degussa type, Aldrich). The reaction mixture was filtered through celite and concentrated to afford product as light yellow solid, which was used without further purification (0.14 g, 96%).
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][S:14]([O-:17])(=O)=[O:15])=[CH:8][CH:7]=1.[Na+].C1C=CC=CC=1>CN(C)C=O>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][S:14]([Cl:3])(=[O:17])=[O:15])=[CH:8][CH:7]=1
Reactant: O=S(=O)([O-])CCc1ccc(Br)cc1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=S(=O)(Cl)CCc1ccc(Br)cc1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
Thionyl chloride (1.51 mL, 20.8 mmol) was added dropwise at 0° C. to a suspension of sodium 2-(4-bromo-phenyl)-ethanesulfonate (4.33 g, 15.08 mmol) in a mixture of anhydrous benzene (50 mL) and N,N-dimethylformamide (1 mL). The reaction mixture was allowed to warm to room temperature and was then heated at 80° C. for 18 hours. The reaction mixture was cooled to room temperature and filtered through a pad of Celite. The solids were washed with benzene and the combined filtrates were concentrated in vacuo. The residue was taken up in hexane (30 mL) and the resulting suspension was heated at 50° C. for 30 min. After cooling to room temperature, the formed precipitate was collected by filtration to give 4.06 g (95% yield) of the title compound.
Reaction SMILES: C([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[C:11]([S:18][C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)=[CH:10][C:9]1=[O:26])C1C=CC=CC=1.Br.[OH-].[Na+]>O>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([S:18][C:11]2[C:12]3[C:17](=[N:16][CH:15]=[CH:14][CH:13]=3)[NH:8][C:9](=[O:26])[CH:10]=2)=[CH:20][CH:21]=1
Reactant: O=c1cc(Sc2ccc(Br)cc2)c2cccnc2n1Cc1ccccc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1cc(Sc2ccc(Br)cc2)c2cccnc2[nH]1
Yield: 19.2 %

Procedure:
A mixture of 1-benzyl-4-(4-bromo-phenylsulfanyl)-1H-[1,8]naphthyridin-2-one (200 mg, 0.47 mmol) and HBr (5 mL, 48%) was heated under reflux for 4 h. After cooling, water was added and the mixture was neutralized with NaOH. The mixture was extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4. After removal of solvent, the solid was recrystallized with EtOAc and hexane to give 30 mg of product (Yield: 19%). Note: the solubility of the product in organic solvent is poor. 1H NMR (500 MHz, DMSO-d6) δ 12.12 (s, 1H), 8.58 (d, J=4.0 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.76 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.29 (dd, J=8.0, 5.0 Hz, 1H), 5.74 (s, 1H); LCMS (EI) m/z 332.8 (M+), 334.9.
Reaction SMILES: CN(OC)[C:3]([C:5]1[CH:9]=[CH:8][O:7][CH:6]=1)=[O:4].C[Mg]Br.Cl.[CH2:16]1COC[CH2:17]1>CCOCC>[O:7]1[CH:8]=[CH:9][C:5]([C:3](=[O:4])[CH2:16][CH3:17])=[CH:6]1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)c1ccoc1
Agent: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: CCC(=O)c1ccoc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a solution of 3-(N-methyl-N-methoxycarbamoyl)furan (14 g, 0.09 mol) in 150 ml of THF cooled to -78° C. was added in portions 36.1 ml (0.108 mol) of 3M methylmagnesium bromide in ether and the mixture was allowed to warm to room temperature, and then stirred for 30 min. To the above mixture was added a cold 2N HCl (100 ml) and the aqueous layer was extracted with ether (3×100 ml), the combined organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to yield a pale-yellow oil. The above oil was chromatographed on silica (methylene chloride/hexane 2:1) to afford 6.95 g (70.2%) of 1-(3-furyl)-1-propanone as a colorless oil which crystallized as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](N(C)C)=[O:4].O=P(Cl)(Cl)Cl.[CH:13]1[C:23]2=[C:24]3[C:19](=[CH:20][CH:21]=[CH:22]2)[CH2:18][CH2:17][CH2:16][N:15]3[CH:14]=1.[OH-].[Na+]>C(Cl)Cl>[Cl:1][CH2:2][C:3]([C:13]1[C:23]2=[C:24]3[C:19](=[CH:20][CH:21]=[CH:22]2)[CH2:18][CH2:17][CH2:16][N:15]3[CH:14]=1)=[O:4]
Reactant: CN(C)C(=O)CCl
Reactant: c1cc2c3c(c1)ccn3CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(CCl)c1cn2c3c(cccc13)CCC2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of 2-chloro-N,N-dimethyl-acetamide (10 mL, 97.5 mmol) was added POCl3 (14 mL, 149.5 mmol). The clear mixture was stirred at room temperature for 20 min 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline (10.20 g, 65.0 mmol, for preparation see WO06086486A1) was added. The mixture was stirred at 80° C. for two hours. The mixture was poured on to ice (200 mL) and dichloromethane (300 mL). Aqueous sodium hydroxide was added to adjust to pH>12. The dichloromethane layer was separated, washed with water (300 mL), dried over Na2SO4, filtered and evaporated to give a dark solid. The solid was dissolved into DCM and purified by silica gel column chromatography (eluent: 0% to 1% EtOAc in DCM). 2-Chloro-1-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-ethanone was obtained as an off-white solid (10.82 g, 71%) after tituration with EtOAc. M.p.=118-119° C.; 1H NMR (400 MHz, CDCl3) δ: 8.00 (d, J=8.0 Hz, 1H), 7.82 (s, 1H), 7.23 (m, 1H), 7.03 (d, J=7.2 Hz, 1H), 4.51 (s, 2H), 4.21 (t, J=6.0 Hz, 2H), 3.01 (t, J=6.0 Hz, 2H), 2.27 (m, 2H). LCMS: m/e 234.03 [M+H].