Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[CH2:23]([C:31]1[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=1)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:11][N:8]1[C:9]2[CH:10]=[C:2]([N:34]3[CH:35]=[CH:36][C:31]([CH2:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:32][C:33]3=[O:37])[CH:3]=[CH:4][C:5]=2[C:6]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(CCc2ccccc2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(CCc5ccccc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 47.5 %

Procedure:
The compound was prepared from tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (200 mg, 0.548 mmol) and 4-phenethylpyridin-2(1H)-one (109 mg, 0.548 mmol) according to the procedure in Example 1 (step c). Purification by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 to 25:75 then 0:100) provided the title compound (126 mg, 48%) as a yellow solid:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14](=[O:23])[NH:13][C:12]=12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:43]([N:45]1[C:49]([CH2:50]O)=[N:48][CH:47]=[N:46]1)[CH3:44].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:43]([N:45]1[C:49]([CH2:50][O:23][C:14]2[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:16][N:11]3[N:10]=[N:9][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[C:12]3[N:13]=2)=[N:48][CH:47]=[N:46]1)[CH3:44]
Reactant: O=c1[nH]c2c(-c3ccccc3F)nnn2cc1-c1ccccc1
Reactant: CCn1ncnc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCn1ncnc1COc1nc2c(-c3ccccc3F)nnn2cc1-c1ccccc1
Yield: 52 %

Procedure:
3-(2-Fluorophenyl)-6-phenyl-4H-1,2,3-triazolo[1,5-α]pyrimidin-5-one (95 mg, 0.31 mmol), triphenylphosphine (203 mg, 0.78 mmol) and (2-ethyl-2H-1,2,4-triazol-3-yl)methanol (110 mg, 0.78 mmol) were suspended in dry tetrahydrofuran (1,5 ml). Diethyl azodicarboxylate (123 μl, 0.78 mmol) was added and a solution resulted immediately. The reaction was stirred at room temperature for 16 hours before purification by preparative tlc (40% EtOAc/hexanes) to give a white solid which was recrystallised from ethyl acetate/hexanes and triturated with diethyl ether to afford 5-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-6-phenyl-1,2,3-triazolo[1,5-α]pyrimidine (67 mg, 52%) as white plates, m.p. 147-148° C.; δH (400 MHz, CDCl3) 1.22 (3H, t, J=7.3 Hz, NCH2CHH3), 4.13 (2H, q, J=7.3 Hz, NCH2CH3), 5.70 (2H, s, OCH2), 7.24 (1H, t, J=29.3 Hz, ArH), 7.31 (1H, t, J=7.5 Hz. ArH), 7.41-7.48 (4H, m, ArH, 7.54-7.56 (2H, m, ArH), 7.89 (1H, s, triazole CH), 8.02 (1H, td, J=7.5 and 1.7 Hz, ArH), 8.79 (1H, s, pyrimidine CH); m/z (ES+) 416 (M+H+).
Reaction SMILES: Cl[C:2](Cl)=[CH:3][C:4]([C:6]1[C:7]([Cl:14])=[N:8][C:9]([CH3:13])=[CH:10][C:11]=1[Cl:12])=[O:5].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1>[NH:16]([C:2]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:3][C:4]([C:6]1[C:7]([Cl:14])=[N:8][C:9]([CH3:13])=[CH:10][C:11]=1[Cl:12])=[O:5])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(Cl)c(C(=O)C=C(Cl)Cl)c(Cl)n1
Reactant: Nc1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Cl)c(C(=O)C=C(Nc2ccccc2)Nc2ccccc2)c(Cl)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A solution of 3,3-dichloro-1-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one (5.2 g, 18.0 mmol) in 1,4-dioxane (25 mL) was cooled to 0° C. and aniline (5.1 mL, 55.0 mmol) and TEA (7.7 mL, 55.0 mmol) were added dropwise. The reaction mixture was stirred at 0° C. for 1 h and at room temperature for 2 h. The solvents were removed in vacuo. The residue was purified by passing it through a pad of silica gel with EtOAc:Hex (1:5) as the eluent to provide 3,3-dianilino-1-(2,4-dichloro-6-methyl-3-pyridinyl)-2-propen-1-one (7.1 g, 99%): LCMS RT: 3.06 min, MH+: 398.7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:22]([NH2:24])=[O:23])[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH:25](OCC)(OCC)OCC>>[CH2:15]([N:12]1[CH2:13][CH2:14][C:9]2([N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:25]=[N:24][C:22]2=[O:23])[CH2:10][CH2:11]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NC(=O)C1(Nc2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Reactant: CCOC(OCC)OCC
Product: O=C1N=CN(c2ccc(Cl)cc2)C12CCN(Cc1ccccc1)CC2
Temperature: 150 °C
Reaction time: 240 h

Procedure:
4-(4-chloro-phenyl-amino)-1-(phenylmethyl)-4-piperidine-carboxamide (6.47 g) was dissolved in 31 ml triethyl orthoformate and stirred at 150° C. for 10 d. After cooling to 0° C., the reaction mixture was filtered and the light brown powder washed with ether to yield 8-benzyl-1-4-chloro-phenyl-1,3,8-triazaspiro[4,5]dec-2-en-4-one (3.90 g). M.p. 217-219° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:11]([NH2:13])=O>>[N:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[C:8]([OH:10])=[N:13][CH:11]=1
Reactant: NC=O
Reactant: Nc1cccnc1C(=O)O
Product: Oc1ncnc2cccnc12
Temperature: 170 °C
Reaction time: 1 h

Procedure:
3-Aminopicolinic acid (B-1) (30 g, 217 mmol, 1.0 eq) is suspended in formamide (75 mL, 1.88 mol, 8.66 eq). The resulting mixture is stirred at 140° C. for 1 h and at 170° C. for 1 h and then at 180° C. for an additional 1 h. The mixture is cooled to RT and filtered. The filter cake is washed with water, and dried in vacuo to afford the product, pyrido[3,2-d]pyrimidin-4-ol (B-2).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])[CH2:4][CH2:3]1.N1C=CN=C1.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O>[Si:23]([O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])[CH2:4][CH2:3]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CON(C)C(=O)[C@H]1CC[C@H](O)CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CON(C)C(=O)[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution in N,N-dimethylformamide (91 mL) of the compound (8.52 g) obtained in step (1) above, imidazole (4.03 g) and tert-butyldimethylchlorosilane (6.86 g) were added and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and water was added to the resulting residue. After extraction with ethyl acetate, the combined organic layers were washed with water and saturated brine. The washed organic layers were dried over anhydrous magnesium sulfate and after removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0-75:25) to give the titled compound as a colorless oil (10.5 g).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:5][N:6]=1.[NH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14]>>[OH:14][CH2:13][C:12]([NH:11][S:7]([C:4]1[S:3][C:2]([Cl:1])=[N:6][CH:5]=1)(=[O:9])=[O:8])([CH3:16])[CH3:15]
Reactant: CC(C)(N)CO
Reactant: O=S(=O)(Cl)c1cnc(Cl)s1
Product: CC(C)(CO)NS(=O)(=O)c1cnc(Cl)s1
Yield: 67.7 %

Procedure:
Prepared by general procedure III from 2-chloro-thiazole-5-sulfonyl chloride (2.0 g, 9 mmol, example B.13, step 1) and 2-amino-2-methyl-1-propanol (0.95 g, 9 mmol) to give the title compound (1.65 g, 33%) as an off-white solid. MS (EI) 269.2 [(M)+] and 271.2 [(M+2)+].
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@H:19]3[CH3:24])=[O:17])=[CH:12][N:11]=2)=[CH:5][C:4](B(O)O)=[CH:3]1.[C:28]([C:32]1[CH:33]=[C:34]2[C:39](=[C:40]([F:42])[CH:41]=1)[C:38](=[O:43])[N:37]([C:44]1[N:51]=[CH:50][CH:49]=[C:48](Cl)[C:45]=1[CH:46]=[O:47])[N:36]=[CH:35]2)([CH3:31])([CH3:30])[CH3:29].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:28]([C:32]1[CH:33]=[C:34]2[C:39](=[C:40]([F:42])[CH:41]=1)[C:38](=[O:43])[N:37]([C:44]1[N:51]=[CH:50][CH:49]=[C:48]([C:4]3[CH:5]=[C:6]([NH:9][C:10]4[CH:15]=[CH:14][C:13]([C:16]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][C@H:19]5[CH3:24])=[O:17])=[CH:12][N:11]=4)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=3)[C:45]=1[CH:46]=[O:47])[N:36]=[CH:35]2)([CH3:31])([CH3:29])[CH3:30]
Reactant: C[C@@H]1COCCN1C(=O)c1ccc(Nc2cc(B(O)O)cn(C)c2=O)nc1
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3C=O)ncc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: C[C@@H]1COCCN1C(=O)c1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)nc1
Temperature: 100 °C
Yield: 36.8 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 132c (260 mg, 0.70 mmol), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotin-aldehyde 103b (180 mg, 0.50 mmol), K3PO4 (297 mg, 1.4 mmol), sodium acetate (114 mg, 1.4 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (57 mg, 0.070 mmol), and acetonitrile/water (10/0.2 mL). After three cycles of vacuum/N2 flush, the mixture was heated at 100° C. 1.5 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with dichloromethane (20 mL) and water (20 mL). The aqueous layer was separated and extracted with dichloromethane (3×20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with 60:1 dichloromethane/methanol to afford 132d (120 mg, 37%) as a yellow solid. MS-ESI: [M+H]+ 652.3
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].N.[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[CH2:7]([S:5][CH2:4][CH2:3][NH2:2])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrCc1ccccc1
Reactant: NCCS
Agent: Cl
Agent: N
Solvent: CO
Product: NCCSCc1ccccc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a suspension of 0.1 mole cysteamine hydrochloride in 20 mL methanol were added 13.6 mL of 25% ammonia solution, followed by dropwise addition of 0.12 mole benzyl bromide at room temperature. The mixture was stirred for 0.5 h, and the formed precipitate of S-dibenzylcysteamine was collected by filtration. The product was extracted with ether (3×100 mL) and the organic phase was successively washed with brine (2×100 mL), dried over MgSO4 and the solvent evaporated in vacuo. The crude product was essentially pure enough for the next step. It could, however be recrystallized from ethyl acetate. Yield 86%, of white solid. m.p. 85-6° C. NMR (CDCl3) in agreement with the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:30][OH:31].C([O-])(O)=O.[Na+]>>[OH:31][N:30]=[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)[CH2:9][CH:10]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1cc(C(=O)CC(c2ccc(CC(=O)O)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(CC(c2ccc(CC(=O)O)cc2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from {4-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-acetic acid and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (3.6:1) as a colorless oil, MS (ESI+): m/z=389.19 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1.CCCCCC.C([Li])CCC.[CH:23]1[N:27]=[CH:26][N:25]2[CH2:28][CH2:29][C:30](=[O:31])[C:24]=12>C1COCC1.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]2[S:7][C:8]([C:30]3([OH:31])[C:24]4[N:25]([CH:26]=[N:27][CH:23]=4)[CH2:28][CH2:29]3)=[CH:9][C:5]=2[CH:4]=1
Reactant: O=C1CCn2cncc21
Reactant: COc1ccc2sccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2sc(C3(O)CCn4cncc43)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
A solution of 5-methoxybenzo[b]thiophene (0.33 g) in THF (8 ml) was cooled to −78° C., and an n-butyl lithium hexane solution (1.6 M; 1.4 ml) was added dropwise to this solution. The mixture was stirred for 1 h at the same temperature, and a solution of 5,6-dihydro-7H-pyrrolo[1,2-c]imidazol-7-one (0.18 g) in THF (3 ml) was added to this solution. The reaction mixture was stirred for 1 h at the same temperature, and saturated brine was added. The mixture was warmed to room temperature and the organic layer was separated. The organic layer was diluted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was suspended in ethyl acetate and filtrated to give the title compound (0.24 g) as pale brown crystals. The crystals were recrystallized from THF to give the title compound (0.13 g) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16](C(OC(C)(C)C)=O)[CH3:17])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:7])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][NH:16][CH3:17])=[CH:13][CH:14]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CN(C)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(C)Oc1ccc(CNC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3.66 g (10 mmol) of the above prepared 2-{4-[(tert-butoxycarbonyl-methyl-amino)-methyl]-phenoxy}-2-methyl-propionic acid ethyl ester in 50 ml dichloromethane was treated at 0° C. with 3.98 ml TFA and stirred at room temperature for 16 h. The reaction was evaporated and treated with ice water, neutralized with NaHCO3 (pH=8) and extracted dichloromethane (two times). The organic phases were washed with water, dried (MgSO4), and evaporated to give 2.77 g of crude product. Purification by flash chromatography on SiO2 with CH2Cl2/MeOH (95:5) yielded 1.95 g of the title compound as brown-yellow oil.
Reaction SMILES: C([N:11]1[CH2:18][C@@H:17]([O:19][CH3:20])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.CO.[H][H]>[Pd].O>[CH3:20][O:19][C@@H:17]1[CH2:18][NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:16]1
Reactant: CO[C@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CO[C@@H]1CN[C@H](C(=O)O)C1

Procedure:
A mixture of 6.8 g. of N-carbobenzyloxy-cis-4-methoxy-L-proline, 210 ml. of 2:1 methanol and water, and 2.3 g. of 5% Pd-C is placed on a hydrogenator at 3 atmospheres of hydrogen for four hours. The mixture is filtered to remove the catalyst and the filtrate evaporated to give 3.15 g. of a grayish solid; m.p. 218°-220° (dec.). A sample is crystallized from methanol-ether to yield colorless cis-4-methoxy-L-proline, m.p. 224°-226° (dec.), [α]D25 -42° (c, 1% in methanol).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[O:14][C:13](=O)[C:12]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:7][CH:6]=1)(=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.Cl>C1(C)C=CC=CC=1.O1CCCC1>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[O:14][CH2:13][C:12]=2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc2c(-c3ccc(OC(C)=O)cc3)c(-c3ccccc3)c(=O)oc2c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)OCC(c1ccccc1)=C2c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(4-Acetoxyphenyl)-7-methoxy-3-phenyl-coumarin (180 g) was dissolved in toluene (2.1 l) at 70° C. and added to a suspension of lithiumaluminium hydride (35.4 g) in tetrahydrofuran (2.1 l). The reaction mixture was kept below 60° C. during the addition. The reaction mixture was cooled down to room temperature. Water (45 ml) was carefully added and then 5M hydrochloric acid (1.2 l). The mixture was heated to 60-65° C. and stirred for 3 hours. The organic phase was separated. The aqueous phase was extracted with toluene (250 ml). The combined organic phase was washed with water (250 ml) and evaporated to an oil. The oil was dissolved in boiling ethanol (600 ml). The solution was cooled and water was slowly added (400 ml) and the mixture was seeded. The crystals were filtered off, washed with water/ethanol; 25/75 (200 ml) and dried.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[CH2:12]([N+](CCCC)(CCCC)CCCC)CCC.CI>C(Cl)Cl.[OH-].[Na+]>[CH3:12][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: O=Cc1cccc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CI
Product: Cn1ccc2c(C=O)cccc21
Yield: 98.7 %

Procedure:
34 g of indol 4-carboxaldehyde in 800 ml of methylen chloride were mixed for 4 hours at ambient temperature with 79.5 g of tetrabutyl ammonium hydrogeno sulfate and 16.04 ml of methyl iodide in 400 ml of 5N sodium hydroxide and 300 ml of methylene chloride were added, followed by decanting and extraction was effected with methylene chloride. The organic phase was washed with a saturated aqueous solution of sodium chloride, dried and concentrated to dryness. The residue was chromatographed on silica (eluant: methylene chloride) to obtain 36.8 g of the expected product melting at <40° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[S:6](=[O:8])(=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[C:3]1=[O:13].[BH4-].[Na+]>C(O)C>[CH3:1][C:2]1([CH3:14])[S:6](=[O:8])(=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[CH:3]1[OH:13]
Reactant: CC1(C)C(=O)c2ccccc2S1(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1(C)C(O)c2ccccc2S1(=O)=O
Reaction time: 1 h

Procedure:
To a solution of 2,2-dimethyl-1,1-dioxo-1,2-dihydro-llambda*6*-benzo[b]thiophen-3-one (240 mg, 1.14 mmol) in ethanol (30 mL) at 0° C. is added NaBH4 (43 mg, 1.14 mmol). The reaction is placed at room temperature and permitted to stir for one hour. The reaction is quenched with saturated aqueous NH4Cl, and concentrated to near dryness. The resulting residue is diluted with ethyl acetate and washed with brine, dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 1:0) to provide 2,2-dimethyl-1,1-dioxo-2,3-dihydro-1H-1lambda*6*-benzo[b]thiophen-3-ol; MS: (ESI) m/z 213 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][C:10]([C:12]([O:14]C)=O)=[N:9][N:8]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:12]([C:10]2[O:11][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][N:9]=2)=[O:14])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1nnc(-c2ccccn2)o1
Reactant: BrCCCCCCCCc1ccccc1
Product: O=C(CCCCCCCCc1ccccc1)c1nnc(-c2ccccn2)o1
Yield: 43 %

Procedure:
Starting with methyl 5-(pyridin-2-yl)-[1,3,4]-oxadiazole-2-carboxylate and 8-bromooctylbenzene, the title compound (28 mg, 43%) was obtained as a white solid using a procedure similar to Example 1. 1H NMR (400 MHz, CDCl3) 1.34 (m, 8H), 1.62 (quintet, J=7.3 Hz, 2H), 1.81 (quintet, J=7.3 Hz, 2H), 2.61 (dd, J=7.9, 7.6 Hz, 2H), 3.21 (t, J=7.5 Hz, 2H), 7.16-7.19 (m, 3H), 7.26-7.30 (m, 2H), 7.54 (dd, J=7.6, 4.7, Hz, 1H), 7.93 (td, J=7.6, 1.5 Hz, 1H), 8.30 (d, J=7.9 Hz, 1H), 8.85 (d, J=4.7 Hz, 1H); 13C NMR (CDCl3, 100 MHz) 23.6, 28.9, 29.00, 29.02, 29.2, 31.4, 35.90, 35.92, 40.1, 124.0, 125.5, 126.7, 128.2, 128.4, 137.3, 142.6, 142.8, 150.8, 161.2, 165.0, 187.2; MALDI-FTMS m/z 364.2024 (C22H25N3O2+H+ requires 364.2019).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][C:8]#[N:9])([O-:3])=[O:2].O.[C:14]([OH:18])(=[O:17])[CH:15]=O.C(=O)([O-])[O-].[K+:23].[K+]>CO>[K+:23].[C:8]([C:7]([C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[CH:15][C:14]([O-:18])=[O:17])#[N:9]
Reactant: O=CC(=O)O
Reactant: N#CCc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#CC(=CC(=O)[O-])c1cccc([N+](=O)[O-])c1
Reaction time: 5 h
Yield: 85.1 %

Procedure:
A suspension of 3-nitrobenzyl cyanide (1.62 g), glyoxylic acid monohydrate (1.38 g) and potassium carbonate (3.59 g) in methanol (20 ml) was stirred for 5 hours. The precipitate was collected by filtration, washed with dichloromethane and dried. The precipitate was suspended in water and stirred for an hour. The insoluble material was collected by filtration and dried to give 3-cyano-3-(3-nitro-phenyl)-acrylic acid potassium salt (2.18 g, 85.2%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][NH:7]1.Cl[C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:28])[C:18]([C:25]([OH:27])=[O:26])=[CH:19][N:20]2[CH2:23][CH3:24])=[CH:15][C:14]=1[F:29]>N1C=CC=CC=1>[CH2:23]([N:20]1[C:21]2[C:16](=[CH:15][C:14]([F:29])=[C:13]([N:10]3[CH2:9][CH2:8][NH:7][CH:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[CH2:11]3)[CH:22]=2)[C:17](=[O:28])[C:18]([C:25]([OH:27])=[O:26])=[CH:19]1)[CH3:24]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: c1csc(C2CNCCN2)c1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cccs4)C3)cc21
Yield: 27.5 %

Procedure:
A mixture of 504 mg of the above piperazine, 269 mg of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 10 ml of pyridine was refluxed under argon for 24 hours, then cooled and evaporated under reduced pressure. The residue was triturated with ether, the solid collected, dissolved in 40% acetic acid and neutralized with 1N sodium hydroxide. The solid was collected, washed with methanol, ether and dried, giving 110 mg of the desired product, mp 232°-234° C.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][N+:6]([O-])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].OS([O-])(=O)=O.[K+]>C1COCC1>[Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][NH2:6]
Reactant: O=[N+]([O-])C=Cc1ccccc1Br
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCCc1ccccc1Br
Reaction time: 1 h

Procedure:
To the styrene of Step 1 (0.310 g, 1.3 mmol) in 5 mL of THF was added 1 M LiAlH4 solution in THF (5.2 mL, 5.2 mmol) at 0° C. The solution was stirred for 1 hour. A concentrated KHSO4 solution was added dropwise to destroy the excess of LiAlH4. The solution was filtered over celite and the filtrate concentrated in vacuo to give a yellow oil; 150 mg (58%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][CH:13]=[CH:12][C:11]=1[CH:25]([OH:29])[C:26]([OH:28])=[O:27].C(OC(=O)C)(=O)C>CS(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][CH:13]=[CH:12][C:11]=1[C:25](=[O:29])[C:26]([OH:28])=[O:27]
Reactant: O=C(O)C(O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)C(=O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Reaction time: 3 h
Yield: 96 %

Procedure:
To a stirred solution of Example 1 Part B compound (400 mg, 0.867 mmol) in DMSO (1 mL) at 90° C. was added acetic anhydride (0.1 mL, 1 mmol) over 1 h. After an additional 3 h, the reaction mixture was cooled, diluted with water and extracted three times with ether. The organic extracts were combined, washed with brine, dried (Na2SO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound, 382 mg (96% yield). LC/MS gave the correct molecular ion [(M+Na)+=481] for the desired compound.