Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]3[C:13](=[CH:14][N:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:6]=1)(=O)C.[OH-]>CO.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>[OH:4][C:5]1[CH:18]=[CH:17][C:16]2[C:7](=[C:8]3[C:13](=[CH:14][N:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:6]=1
Reactant: CC(=O)Oc1ccc2ncc3c(c2c1)CCCC3
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: Oc1ccc2ncc3c(c2c1)CCCC3
Temperature: 60 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
To a solution of Compound 274 (26.50 g, 110 mmol) in dry methanol (150 mL) was added Dowex 1x8-200 hydroxide form (0.40 g, catalytic), and tetra-n-butylammonium bromide (50 mg, catalytic), and the resulting mixutre was stirred at 60° C. for 24 hours. The reaction mixture was cooled, diluted with ethyl ether (100 mL) and filtered to give 21.47 g (98 percent) of Compound 275: white crystalline solid; mp 284°-286° C. (dec.); Rf =0.25 (silica, 50 percent ethyl acetate in dichloromethane); IR (CHCl3) νmax 2933, 2906, 2850, 2582, 1627, 1503, 1421 cm-1 ; 1H NMR (500 MHz, DMSO-d6) δ 9.92 (s, 1 H, OH), 8.34 (s, 1 H, H6), 7.77 (d, J=9.0 Hz, 1 H, H4), 7.19 (dd, J=9.0, 2.6 Hz, 1 H, H3), 7.12 (d, J=2.6 Hz, 1 H, H1), 2.88 (t, J=6.1 Hz, 2 H, H7 or H10), 2.78 (t, J=6.1 H, 2 H, H7 or H10), 1.87-1.74 (m, 4 H, H8 and H9); 13C NMR (125 MHz, DMSO -d6) δ 155.5, 148.8, 141.1, 138.5, 130.9, 129.4, 128.4, 120.0, 104.0, 26.5, 24.3, 22.1, 21.9; MS (FAB+) m/e (rel intensity) 200 (M+H, 100), 124 (8), 107 (14); HRMS for C13H14NO (M+H), calcd 200.1075, found 200.1079.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(-c2cccnc2)c1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(-c3cccnc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) (240 mg, 0.75 mmol) and 3-[2,3′]bipyridinyl-4-yl-3-oxo-propionic acid tert-butyl ester (Example K57) (224 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow foam (319 mg, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:31](=[O:32])[N:30]([CH3:33])[C:12]2[N:13]([CH:27]([F:29])[F:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=O)/[CH:21]=[CH:22]/[N:23](C)C)=[CH:16][CH:15]=3.C(O)(=O)C(O)=O.[CH2:40]([NH:42]N)[CH3:41]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:31](=[O:32])[N:30]([CH3:33])[C:12]2[N:13]([CH:27]([F:28])[F:29])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:42]([CH2:40][CH3:41])[N:23]=[CH:22][CH:21]=1)=[CH:16][CH:15]=3
Reactant: CCNN
Reactant: CN(C)/C=C/C(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C(F)F
Agent: O=C(O)C(=O)O
Product: CCn1nccc1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C(F)F

Procedure:
The process is carried out as indicated in Example 37 above, with compound B, 3-(2,4-dichlorophenyl)-9-difluoromethyl-6-((E)-3-dimethylaminoacryloyl)-1-methyl-1,9-dihydropyrido[2,3-b]indol-2-one, and ethylhydrazine oxalate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[S:21][C:20]2[C:19]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][CH:27]=[CH:26]4)=[N:18][CH:17]=[N:16][C:15]=2[CH:14]=1>>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([NH:22][C:19]3[C:20]4[S:21][C:13]([C:5]5[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=5)=[CH:14][C:15]=4[N:16]=[CH:17][N:18]=3)=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: COc1cccc(B(O)O)c1
Reactant: Brc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2s1
Product: COc1cccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)c1

Procedure:
The title compound was prepared from 3-methoxybenzeneboronic acid and (6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 2. M.P. 60-168° C.; LC-MS: 373 (MH+); HPLC RT: 4.75 minutes.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH2:11][OH:12])=[C:8]([I:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([I:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(I)c(CO)[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCc1nc(I)c(C=O)[nH]1
Yield: 84.2 %

Procedure:
A stirred mixture of 174.1 g (0.62 mol) of 2-n-butyl-5-hydroxymethyl-4-iodoimidazole and 360 g (4.14 mol) of manganese dioxide in 3 L of dichloromethane was refluxed for 24 hr using a trap to remove water. The hot reaction mixture was filtered through a Celite® pad which was then washed with 4.5 L of boiling methylene chloride. The combined filtrates were concentrated to dryness. The residue was dissolved twice in 150 ml of methanol and each time the solution was concentrated to dryness. The residue was dissolved in 130 ml of methanol and chilled. After crystallization stopped, 700 ml of water was added slowly. The mixture was chilled, and the solid was collected by filtration, washed with water and dried to give 145.2 g (84%) of product; mp 104°-105° C.
Reaction SMILES: N1CCCCC1.[CH2:7]([O:9][C:10](=[O:15])[CH2:11][C:12](O)=O)[CH3:8].[CH3:16][C:17]1[N:22]=[CH:21][C:20](C=O)=[CH:19][CH:18]=1.Cl>N1C=CC=CC=1>[CH2:7]([O:9][C:10](=[O:15])[CH:11]=[CH:12][C:20]1[CH:21]=[N:22][C:17]([CH3:16])=[CH:18][CH:19]=1)[CH3:8]
Reactant: CCOC(=O)CC(=O)O
Reactant: Cc1ccc(C=O)cn1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCOC(=O)C=Cc1ccc(C)nc1
Yield: 66.5 %

Procedure:
1.5 ml of piperidine are added to a solution of 25 g (0.19 mole) of malonic acid monoethyl ester in 50 ml of pyridine, followed by the dropwise addition of 17 g (0.14 mole) of 6-methyl-3-pyridine aldehyde. The mixture is refluxed for 5 hours and, after cooling, is poured onto a mixture of ice and concentrated hydrochloric acid. After extraction by shaking with diethyl ether, the organic phase is dried over sodium sulfate and concentrated by evaporation in vacuo, leaving 17.8 g (67%) of the title compound in the form of an oil which is further processed without purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[NH:4][C:5](=O)[C:6]2[NH:7][CH:8]=[N:9][C:10]=2[N:11]=1.O=S(Cl)[Cl:17].CN(C=O)C>C(Cl)(Cl)Cl>[Cl:17][C:5]1[N:4]=[C:3]([C:2]([F:14])([F:13])[F:1])[N:11]=[C:10]2[C:6]=1[NH:7][CH:8]=[N:9]2
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]c(C(F)(F)F)nc2nc[nH]c12
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1nc(Cl)c2[nH]cnc2n1
Temperature: 25 °C
Yield: 45.5 %

Procedure:
A mixture of 15 g (73 mmol) of 2-trifluoromethylhypoxanthine and 300 mL of CHCl3 was warmed to reflux and treated with a solution of 26.7 mL (366 mmol) SOCl2 and 28.3 mL (366 mmol) DMF. The reaction was maintained at reflux for 1.5 h, cooled to room temperature, and poured into 1.2 L of ice-water. The organic layer was separated and washed with 2×300 mL of H2O. The pH of the combined aqueous phases was adjusted to 7 with saturated NaHCO3 and extracted with 3×1.2 L of ether. The combined ether and chloroform extracts were dried (MgSO4) and concentrated to dryness to give 7.4 g of crude product. 1H NMR (DMSO-d6) δ 14.45 (bs, 1H), 8.95 (s, 1H). MS (ES+) 222.96 (100%, M+H).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:12])=[O:11])[CH:7]=[CH:6][C:5]=1[F:13].O>C(O)(=O)C>[Br:1][CH2:12][C:10]([C:8]1[CH:7]=[CH:6][C:5]([F:13])=[C:4]([CH3:3])[CH:9]=1)=[O:11]
Reactant: CC(=O)c1ccc(F)c(C)c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C(=O)CBr)ccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.1 mL bromine was added to 15 g 4-fluor-3-methylacetophenone in 80 mL concentrated acetic acid. The reaction was stirred 3 h at RT. The reaction was added to water. The precipitate was filtered and dried to give 20.6 g desired product. Rt: 1.37 min (method I), (M+H)+: 231
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]([CH3:8])([CH3:7])[CH2:5][OH:6].[Cl:9][C:10]1[N:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=1>C1C=CC=CC=1>[NH2:3][C:4]([CH3:8])([CH3:7])[CH2:5][O:6][C:13]1[N:12]=[N:11][C:10]([Cl:9])=[CH:15][CH:14]=1
Reactant: CC(C)(N)CO
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)(N)COc1ccc(Cl)nn1
Yield: 71.1 %

Procedure:
To a suspension of 1.5 g of 61% sodium hydride in 20 ml of benzene was added dropwise at room temperature 2.7 g of 2-amino-2-methylpropanol, and then a solution of 4.5 g of 3,6-dichloropyridazine in 20 ml of benzene was added. The mixture was refluxed for one hour. The reaction mixture was cooled, washed with water, and dried over magnesium sulfate. The solvent was evaporated to give 4.33 g of 3-(2-amino-2-methylpropoxy)-6-chloropyridazine.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:3]=1[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C@@H:17]([C:19]1[CH:30]=[CH:29][C:22]2[O:23][C:24]([CH3:28])(C)[O:25][CH2:26][C:21]=2[CH:20]=1)[OH:18].C(O)(=[O:38])C>O>[C:24]([O:23][C:22]1[CH:29]=[CH:30][C:19]([C@@H:17]([OH:18])[CH2:16][NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][C:3]2[C:2]([Cl:1])=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:35])=[CH:20][C:21]=1[CH2:26][OH:25])(=[O:38])[CH3:28]
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCOCc3c(Cl)cccc3Cl)ccc2O1
Reactant: CC(=O)O
Solvent: O
Product: CC(=O)Oc1ccc([C@@H](O)CNCCCCCCOCCOCc2c(Cl)cccc2Cl)cc1CO
Reaction time: 0.5 h

Procedure:
A solution of (1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (130 mg) in acetic acid (2 ml) and water (1 ml) was heated (oil bath temperature 80°) with stirring for 30 min. The mixture was cooled to 20° and the solvent was evaporated in vacuo. The residue was azeotroped in vacuo with MeOH (2×1 ml) to give the title compound (135 mg). LCMS RT=2.57 min, ES +ve 486 (MH)+, 488 (MH)+, 490 (MH)+.
Reaction SMILES: [CH3:1][O-:2].[Na+].[F:4][C:5]([F:13])([F:12])[C:6]([O:8][CH2:9][CH2:10]Cl)=[O:7]>O1CCCC1>[CH3:1][O:2][C:6]1([C:5]([F:13])([F:12])[F:4])[O:8][CH2:9][CH2:10][O:7]1
Reactant: O=C(OCCCl)C(F)(F)F
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(C(F)(F)F)OCCO1
Reaction time: 4 h
Yield: 43 %

Procedure:
A suspension of 5.4 g (0.10 mol) of sodium methoxide in 50 mL of tetrahydrofuran (THF) was stirred at -20° to -10° while 17.7 g (0.10 mol) of 2-chloroethyl trifluoroacetate were added dropwise. The resulting clear solution was allowed to warm with precipitation commencing at about 10° and a slow exotherm ensuing to 35°. The mixture was maintain below 35° until the exotherm subsided and then was stirred for 4 h. Filtration and fractionation of the filtrate gave 7.4 g (43% yield) of 2-methoxy-2-trifluoromethyl-1,3-dioxolane, b.p. 61°-62° at 3.3 kPa (25 mm). IR (neat): 3000, 2965, 2925, and 2680 (sat'd CH), 1250-1100 cm-1 (CF, C--O). NMR (CCl4): 1H 4.17 (m, 4H, ring CH2 and 3.33 ppm (s, 3H, OCH3); 19 F-85.0 ppm (s, CF3).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([CH:11]([CH3:17])[C:12]([O:14]CC)=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.Cl>[OH-].[Na+]>[CH:1]1[C:10]2[C:5](=[C:6]([CH:11]([CH3:17])[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CCOC(=O)C(C)c1cccc2cnccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)c1cccc2cnccc12
Temperature: 25 °C

Procedure:
Ethyl 2-(5-isoquinolinyl)propanoate (1.00 g, 4.36 mmol) was heated at 85° C. in NaOH (25%, 20 mL) for 1 hour. The mixture was allowed to cool to room temperature, acidified to around pH 1 with HCl, and concentrated to a dry residue. The solid was extracted with CHCl3:isopropyl alcohol (3:1, 50 mL×4). The extracts were combined, filtered, and the filtrate concentrated under reduced pressure to provide the title compound. MS (ESI+) m/z 202 (M+H)+; MS (ESI−) m/z 200 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.42 (d, J 7.1, 3H), 4.01 (q, J 7.1, 1H), 7.58 (t,J 8.1, 1H), 7.63 (d, J 7.5, 1H), 7.86 (d, J 8.1, 1H), 8.19 (d, J 6.8, 1H), 8.43 (d, J 6.8, 1H), 9.22 (s, 1H); Anal. Calcd for C12H10NO2Na+0.9 H2O: C, 60.20; H, 4.97; N, 5.85. Found: C, 60.45; H, 5.26; N, 5.46.
Reaction SMILES: Cl[CH2:2][C:3]1[N+:12]([O-:13])=[C:11]([C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]3[O:25][CH2:24][O:23][C:8]=3[CH:9]=2)[N:4]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.CN(C=O)C>CO>[N:26]1([CH2:2][C:3]2[N+:12]([O-:13])=[C:11]([C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)[C:10]3[C:5](=[CH:6][C:7]4[O:25][CH2:24][O:23][C:8]=4[CH:9]=3)[N:4]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: [O-][n+]1c(CCl)nc2cc3c(cc2c1-c1ccc2c(c1)OCO2)OCO3
Reactant: C1CCNC1
Solvent: CN(C)C=O
Solvent: CO
Product: [O-][n+]1c(CN2CCCC2)nc2cc3c(cc2c1-c1ccc2c(c1)OCO2)OCO3
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 2-chloromethyl-6,7-methylenedioxy-4-(3,4-methylenedioxyphenyl)quinazoline-3-oxide (200 mg, 0.55 mmol), in MeOH (5 mL), was added pyrrolidine (0.4 mL). The mixture was stirred at 65° C. for 1.5 h. DMF (6 mL) was added and the heating was continued at 60° C. for 15 h. After cooling, the separated solid was collected by filtration, washed with hexane, and air dried to give the title compound as off white solid (175 mg). The crude product was purified by column chromatography on silica gel (CH2Cl2:MeOH 95:5); mp 194-202° C. 1H NMR (CDCl3) 7.39 (s, 1H), 6.90-7.06 (m, 4H), 6.78 (s 1H), 6.11 (s, 2H), 6.08 (s, 2H), 4.25 (s, 2H), 2.87 (bs, 4H), 1.91 (bs, 4H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:9]=2[N:10]=1>C(OCC)(=O)C>[Cl:15][C:13]1[CH:12]=[CH:11][C:9]2[N:10]=[C:6]([N:5]=[C:1]=[O:2])[S:7][C:8]=2[CH:14]=1
Reactant: Nc1nc2ccc(Cl)cc2s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1nc2ccc(Cl)cc2s1

Procedure:
A saturated solution of phosgene in ethyl acetate (200 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Amino-6-chlorobenzothiazole (0.1 mole) is added with stirring. After the addition is completed, the reaction mixture is heated at reflux for a period of about 1 hour. After this time the mixture is cooled, and the solid product formed is recovered by filtration. The solid is then dried to yield the desired product 6-chlorobenzothiazol-2-yl isocyanate dimer.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[Br:6][CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1>>[Br:6][CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:14])=[CH:11][CH:10]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(Cl)c1ccc(CCBr)cc1
Product: CS(=O)(=O)NC(=O)c1ccc(CCBr)cc1

Procedure:
N-[4-(2-bromoethyl)benzoyl]methanesulfonamide was prepared according to Step 1 of Example 1 from methanesulfonamide and 4-(2-bromoethyl)-benzoyl chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[Cu][C:10]#[N:11]>CN(C=O)C>[C:10]([C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1)#[N:11]
Reactant: O=Cc1cc(Br)cs1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1csc(C=O)c1
Yield: 71.5 %

Procedure:
49.3 g (258.05 mmol) of 4-bromothiophene-2-carbaldehyde and 27.8 g (310.41 mmol) of copper(I) cyanide were suspended in 130 ml of absolute DMF and the suspension was refluxed for 8 hours. The solvent was evaporated in vacuo in a rotary evaporator at 400C, the residue was suspended in ethyl acetate and the suspension was transferred into a Soxleth apparatus. The residue was extracted overnight, the yellow solution was dried over sodium sulfate and evaporated in vacuo in a rotary evaporator, and the resulting yellow solid was recrystallized frome ether. 25.3 g of product resulted (80% of theory).
Reaction SMILES: [C:1]([C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1)#[N:2].N>C(O)C.O.[Ni]>[NH2:2][CH2:1][C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1
Reactant: CCOC(=O)C1(C#N)CC1
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(CN)CC1
Reaction time: 24 h
Yield: 67.1 %

Procedure:
To a solution of ethyl 1-cyanocyclopropanecarboxylate (1 g, 7.18 mmol) in ethanol-water-conc. ammonia solution (7 ml-350 μl-1 ml) was added raney nickel (ca. 350 μl) and the mixture was sittred for 24 hr at 50° C. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo to obtain the title compound (690 mg, 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:15]([O-:17])=[O:16])=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]=[CH:8][C:7]=2[CH:14]=1.CN1C=CN=C1.I(C1C=CC=CC=1)=[O:25].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[O:25]1[C@H:8]2[C@@H:9]1[C:10]([CH3:13])([CH3:12])[O:11][C:6]1[CH:5]=[C:4]([N+:15]([O-:17])=[O:16])[C:3]([O:2][CH3:1])=[CH:14][C:7]=12
Reactant: O=Ic1ccccc1
Reactant: COc1cc2c(cc1[N+](=O)[O-])OC(C)(C)C=C2
Agent: Cn1ccnc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: COc1cc2c(cc1[N+](=O)[O-])OC(C)(C)[C@@H]1O[C@H]21
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution (300 mL) of acetonitrile containing 6-methoxy-2,2-dimethyl-7-nitro-2H-1-benzopyran (10.0 g, 42.5 mmol), N-methyl imidazole (0.678 mL, 8.50 mmol), (R,R,S,S)-Ph,Ph salen manganese complex (XY) (880 mg, 0.850 mmol) and iodosobenzene (18.7 mg, 85.0 mmol) were added at room temperature and the mixture was stirred for 2 hours. Upon the completion of the reaction, an aqueous solution of sodium thiosulfate was added to the reaction solution, the resulting solution was filtered through celite. The resulting filtrate extracted with ethyl acetate. The organic phase was washed with water and sodium chloride solution, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=4/1) and the aimed product was obtained as yellow crystals (yield: 75%, optical purity: 99.7% ee).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[CH:8]=[C:9]([SH:13])[CH:10]=[CH:11][CH:12]=1>CCOCC>[Cl:6][C:7]1[CH:8]=[C:9]([S:13][CH2:3][CH2:2][C:1]([OH:5])=[O:4])[CH:10]=[CH:11][CH:12]=1
Reactant: C=CC(=O)O
Reactant: Sc1cccc(Cl)c1
Solvent: CCOCC
Product: O=C(O)CCSc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 88 h
Yield: 29.9 %

Procedure:
Acrylic acid (2.66 g, 37 mmol) and 3-chlorothiophenol (4.85 g, 34 mmol) were dissolved in ether (15 mL) and stirred at room temperature for 88.0 hours. The reaction mixture solidified, was dissolved in ether and extracted with 5% NaOH. The aqueous layer was acidified with concentrated hydrochloric acid, extracted with ether, washed with brine, dried over MgSO4, and concentrated in vacuo to give the 3-(3-chlorophenylthio)propanoic acid (2.20 g, 34%): 1H NMR (acetone-d6) 300 MHz 7.33-7.40 (m, 3H) 7.24 (m, 1H) 3.25 (t, J=7.1 Hz, 2H) 2.67 (t, J=7.1 Hz, 2H). Mass spectrum: M+H=217.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:12])=[O:11])=[C:6]([O:22][CH3:23])[CH:5]=1)([O-])=O.C>C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:11])=[O:12])=[C:6]([O:22][CH3:23])[CH:5]=1
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)NCCCCCC(=O)O
Solvent: CCOC(C)=O
Product: COc1cc(N)ccc1S(=O)(=O)NCCCCCC(=O)O
Reaction time: 4 h
Yield: 98 %

Procedure:
A solution of ε(4-nitro 2-methoxy-benzenesulfonamido) caproic acid (1.4 g) in solution in ethyl acetate (150 cm3) is stirred magnetically under a hydrogen atmosphere in the presence of 5% palladized charcoal (120 mg). After four hours, the hydrogen absorption being terminated, the catalyst is filtered and the filtrate concentrated under reduced pressure. Pure ε(4-amino 2-methoxy-benzenesulfonamido) caproic acid is obtained, with a yield of 98%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[NH2:26]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:11]([NH:26][C:22]2[S:21][CH:25]=[CH:24][N:23]=2)=[O:13])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCOCC1)c1ccc([N+](=O)[O-])cc1
Product: O=C(Nc1nccs1)C(CC1CCOCC1)c1ccc([N+](=O)[O-])cc1

Procedure:
2-(4-Nitrophenyl)-3-(tetrahydropyran-4-yl)propionic acid (Preparation 46, 10.40 g, 37.2 mmol) was condensed with thiazol-2-ylamine employing the procedure described in EXAMPLE 65 to afford 2-(4-nitrophenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylpropionamide: m/z (ES+)=362.1 [M+H]+. The nitro group of this compound (6.55 g, 18.1 mmol) was reduced utilising the procedure described in EXAMPLE 145 to give 2-(4-aminophenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-yl-propionamide: m/z (ES+)=332.1 [M+H]+. A solution of NaNO2 (2.11 g, 30.5 mmol) in H2O (20 mL) was added slowly to a stirred mixture of the above aniline (9.40 g, 28.4 mmol), 12M HCl (30 mL), and H2O (30 mL) at 0° C. After 1 h, the resulting diazonium salt solution was added over 15 min to a mixture of CuCl2.2H2O (1.29 g, 7.6 mmol) in AcOH (64.5 mL) and H2O (3.2 mL) which had been saturated previously with SO2. The mixture was stirred for 1.5 h, treated with H2O (200 mL) and extracted with EtOAc (300+150 mL). The combined EtOAc extracts were washed with H2O (2×200 mL), filtered, and dried (MgSO4). Filtration and solvent evaporation provided the title compound: m/z (ES+)=466.1 [M+MeCN+H]+.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[N+:6]([O-])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:12]([OH:15])(=[O:14])[CH3:13]>N1C=CC=CC=1.[Fe]>[C:12]([OH:15])(=[O:14])[CH3:13].[N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[C:4]([OH:14])=[CH:3][CH:2]=1
Reactant: [O-][n+]1cccc2ncccc21
Agent: [Fe]
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: Oc1ccnc2cccnc12
Reaction time: 2 h

Procedure:
To a solution of 1,5-naphthyridin-5-oxide 4-01 (D-5) (330 mg, 2.0 mmol, 1.0 eq) in acetic acid (12 mL) and pyridine (2.5 mL) at RT, iron powder (456 mg, 8.15 mmol, 4.0 eq) is added in portions (over 10 min) and the resulting mixture is stirred for 2 h. The mixture is filtered and the solid is rinsed with acetic acid. The filtrate is concentrated in vacuo. The residue is triturated with acetone and then filtered. The filter cake is rinsed with acetone and dried in vacuo to afford the product, 1,5-naphthyridin-4-ol acetic acid salt (D-6).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[CH3:19]I.[H-].[Na+]>CS(C)=O.CCCCC>[Br:1][C:2]1[CH:3]=[C:4]([N+:16]([O-:18])=[O:17])[C:5]2[N:6]([CH3:19])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3
Reactant: O=[N+]([O-])c1cc(Br)cc2c1[nH]c1ccc(Br)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCC
Product: Cn1c2ccc(Br)cc2c2cc(Br)cc([N+](=O)[O-])c21
Reaction time: 0.03 h

Procedure:
3,6-dibromo-1-nitrocarbazole (3.56 g, 0.01 mole) was dissolved in 30 ml of warm DMSO followed by the addition of 30 ml of CH3I. Then 2.0 g of 50% NaH dispersion in mineral oil (0.02 mole) was washed under N2 with 2×50 ml of pentane, dried under N2 and added rapidly to the DMSO solution. The solution turned purple immediately with H2 evolution and became yellow in two minutes. Addition of 0.25 g of NaH did not cause the yellow slurrY to turn purple indicating that the reaction was complete. Methanol (200 ml) was added cautiously to precipitate the product. The product was recovered by filtration, washed with 25 ml of methanol, 10×25 ml of water, 25 ml of methanol and air dried to give 3.40 g of product, m.p. 225°-226° C. (corrected). [H. Lindemann & F. Muhlhaus, Ber., 58, 2371 (1925) report a m.p. of 221° C. for the product].