Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:21](=[O:22])[N:11]2[C:12]([C:18]([O-:20])=[O:19])=[C:13]([CH2:16][OH:17])[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na+].[C:24]([N:29]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[S:30]1(=[O:32])=[O:31])([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)CC)C.P(=O)(O)(O)O>CN(C)C=O.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:21](=[O:22])[N:11]2[C:12]([C:18]([OH:20])=[O:19])=[C:13]([CH2:16][O:17][C:39](=[O:40])[C:38]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[S:30](=[O:32])(=[O:31])[NH:29][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:14][S:15][C@H:10]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)N1C(=O)c2ccccc2S1(=O)=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)NS(=O)(=O)c1ccccc1C(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
In dimethylformamide (20 ml) is dissolved sodium 7β-(t-butoxycarbonyl)amino-3-hydroxymethyl-3-cephem-4-carboxylate (3.20 g), followed by the addition of N-carboethoxysaccharin (3.20 g) and triethylamine (2.0 ml). The solution is stirred for one hour at room temperature and, after the addition of triethylamine (2.0 ml), stirred further for one hour. The solution is poured into toleune (1 L) and the resultant precipitate is collected by filtration, washed with toleune and dried. The powder thus obtained is dissolved in water (30 ml). After the addition of ethyl acetate (200 ml), the solution is adjusted to pH 4.0 with diluted phosphoric acid. After separation, the ethyl acetate solution is washed with water, dried over anhydrous sodium sulfate and concentrated. To the concentrate (30 ml), ether (200 ml) is added under stirring and the resultant precipitate is filtered off. The filtrate is concentrated under reduced pressure and to the concentrate (30 ml) is added carbon tetrachloride (100 ml). The resultant precipitate is collected by filtration, washed with carbon tetrachloride and dried over phosphorus pentoxide. The procedure provides 7β-(t-butoxycarbonyl)amino-3-[2-(N-carboethoxysulfamoyl)benzoyloxy]methyl-3-cephem-4-carboxylic acid (2.50 g).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][SiH:10]([CH3:12])[Cl:11]>[Pt].C1(C)C=CC=CC=1>[CH2:1]([Si:10]([CH3:12])([CH3:9])[Cl:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[SiH](C)Cl
Reactant: C=Cc1ccccc1
Agent: [Pt]
Solvent: Cc1ccccc1
Product: C[Si](C)(Cl)CCc1ccccc1
Yield: 84 %

Procedure:
Reaction between styrene and dimethylchlorosilane with platinum catalyst (no substance acting as auxiliary catalyst). 526 mg Styrene and 408 mg dimethylchlorosilane were introduced into a glass tube, and 2.5 mg of a toluene solution of a 0-valent platinum complex of divinylsiloxane (0.04 wt % platinum content) were added. The tube was sealed with Teflon tape and a rubber septum and then placed in a 50° C. oil bath where it was heated for 30 minutes. After cooling, the tube contents were analyzed by gas chromatography revealing a styrene conversion of 98% and a phenethyldimethylchlorosilane yield of 84%. The ratio between the phenethyldimethylchlorosilane and (α-methylbenzyl)dimethylchlorosilane was 4.7:1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.[N+:8]([CH3:11])([O-:10])=[O:9].[OH-].[Na+].Cl>CO.O>[N+:8](/[CH:11]=[CH:6]/[C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)([O-:10])=[O:9]
Reactant: O=Cc1ccsc1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])/C=C/c1ccsc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-thiophenecarboxaldehyde (57.0 g, 502 mmol) and nitromethane (29.9 mL, 552 mmol) in methanol (100 mL) was added a solution of sodium hydroxide (22.1 g, 552 mmol) in water (45 mL) at a rate that kept the temperature at less than 5° C. The mixture was allowed to stand at about 0° C. for about 30 minutes. The precipitate was collected by filtration, dissolved in a minimum amount of ice-cold water and, poured into an ice-cold mixture of concentrated hydrochloric acid (96.7 mL, 1178 mmol) and water (152 mL). The precipitate was collected by filtration and was recrystallized from aqueous ethanol to provide the desired product. MS (DCI-NH3): m/z 173 (M+NH4)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].Cl[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19]>>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C=O)ccc1O
Reactant: OCCCCCCCl
Product: COc1cc(C=O)ccc1OCCCCCCO
Yield: 88 %

Procedure:
4-[(6-hydroxyhexyl)oxy]-3-methoxybenzaldehyde is prepared starting from 4-hydroxy-3-methoxybenzaldehyde and 6-chlorohexan-1-ol according the same procedure following for example 7 in 88% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH:23]4[C:28]([O:30]C)=[O:29])=[O:21])=[CH:14][C:13]=3[C:32]([F:35])([F:34])[F:33])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Cl[C:37]([O:39][CH3:40])=[O:38].N1C=CC=CC=1>C(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([N:22]4[CH2:27][CH2:26][N:25]([C:37]([O:39][CH3:40])=[O:38])[CH2:24][CH:23]4[C:28]([OH:30])=[O:29])=[O:21])=[CH:14][C:13]=3[C:32]([F:35])([F:33])[F:34])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1CNCCN1C(=O)/C=C/c1ccc(Sc2ccc3c(c2)OCCO3)c(C(F)(F)F)c1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3ccc4c(c3)OCCO4)c(C(F)(F)F)c2)C(C(=O)O)C1

Procedure:
The title compound was prepared by treating the compound of Example 255 with methyl chloroformate and pyridine in CH2Cl2 at room temperature, and followed by hydrolysis under basic conditions (aq. NaOHlEtOH), producing a white solid, mp 102° C. (dec.). 1H NMR (DMSO-d6, 300 MHz) δ 62.85 (m, 1H), 3.02 (m, 1H), 3.20 (m, 1H), 3.40 (m, 1H), 3.62 (s, 3H), 3.88 (m, 1H), 4.29 (s, 4H), 4.35 (m, 1H), 5.15 (m, 1H), 6.90-7.10 (m, 3H), 7.30 (d, J=15.0 Hz, 1. H), 7.40 (d, J=15.0 Hz, 1H), 7.54 (d, J=15.0 Hz, 1H), 7.82 (m, 1H), 8.15 (m, 1H). MS (ESI) m/z 553 (M+H)+. Anal. calcd. for C25H23F3N2O7S.0.25H2O: C, 53.91; H, 4.25; N, 5.03. Found: 53.91; H, 4.35; N, 5.05.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].O>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(I)ccc1OC
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(I)cc1C(=O)O
Temperature: 80 °C

Procedure:
Methyl 2-Methoxy-5-iodobenzoate obtained in step 1 in Example 27 was stirred in a solvent mixture (10 ml) of water and dioxane containing 4 N hydrogen chloride under heating at 80° C. for 3 hours. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:12]([O:29]2)[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(c3ccc(Cl)cc3)OC2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.5 %

Procedure:
To a cooled (0° C.) solution of 4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (7.10 g, approx. 24.1 mmol) in methylene chloride (150 mL) was added a solution of 3-chloroperbenzoic acid (75%, 8.34 g, 36.2 mmol) in methylene chloride (120 mL) over 40 min. The mixture was warmed to rt and allowed to stir over night (16 h). The solution was washed twice with a half-saturated aqueous solution of sodium bisfulfite to destroy excess oxidant. The mixture was then twice washed with half-saturated aqueous potassium carbonate, and brine. The extracts were dried over magnesium sulfate, filtered and concentrated to afford a crude oil which was purified by silica gel chromatography (100% hexanes—80% hexanes/20% ethyl acetate gradient) to afford pure 6-(4-Chloro-phenyl)-7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (5.34 g, 71%) as a clear, colorless oil which solidified on standing.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[N:14]1([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([NH2:26])=[CH:28][CH:29]=3)[N:3]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 83 %

Procedure:
A mixture of 2-chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine (1.4 g, 4.9 mmoles), a catalytic amount of tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.061 mmoles), sodium carbonate solution 2 M (3 mL), 4-aminophenylboronic acid pinacol ester (1.6 g, 7.3 mmoles) and DME (100 mL) was refluxed for 24 hours. The solvent was evaporated, and the residue was dissolved in methylene chloride and filtered through Celite™. The filtrate was washed with water (200 mL) and the organic layer was dried with magnesium sulfate. This was filtered and the solvent was evaporated. The residue was purified by Silica gel column chromatography and eluted with Ethyl acetate/hexanes (1:1) to give 1.40 g, (83% yield) of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline as an amorphous solid. (M+H) 343.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>CN(C)C=O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCCCCCBr
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCBr
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3.70 g of potassium phthalimide was dissolved in 20 ml of N,N-dimethylformamide; 5.4 ml of 1,5-dibromopentane was added, followed by stirring at room temperature for 15 hours. Ice water was added to the reaction mixture, followed by extraction with ethyl acetate; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (4:1). The desired fraction was collected to yield 4.68 g of N-(5-bromopentyl)phthalimide as an oily substance. 4.68 g of N-(5-bromopentyl)phthalimide and 4.25 g of 4-(diphenylmethoxy)piperidine were dissolved in 30 ml of N,N-dimethylformamide; 2.42 g of potassium carbonate was added, followed by stirring at room temperature for 15 hours. Ice water was added to the reaction mixture, followed by extraction with ethyl acetate; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate-triethylamine (50:50:1). The desired fraction was collected to yield 6.67 g of N-[5-[4-(diphenylmethoxy)piperidino]pentyl]phthalimide as an oily substance. 6.6 g of N-[5-[4-(diphenylmethoxy)piperidino]pentyl]phthalimide was dissolved in 30 ml of ethanol; 0.694 ml of hydrazine monohydrate was added, followed by thermal refluxing for 3 hours. After cooling, the mixture was concentrated under reduced pressure; ethyl acetate was added to the residue; the crystal precipitated was collected, dissolved in 15 ml of a 1N aqueous solution of sodium hydroxide and 20 ml of water and extracted with ethyl acetate; the extract was washed with saline, dried over sodium sulfate and concentrated under reduced pressure; the crystal obtained was collected to yield 3.29 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:15][CH2:14][CH2:13][CH2:12][C:5]=2[C:6]=1[C:7](OCC)=[O:8].[CH:16]([NH2:18])=O>O>[C:5]12[CH2:12][CH2:13][CH2:14][CH2:15][C:4]=1[S:3][C:2]1[N:1]=[CH:16][N:18]=[C:7]([OH:8])[C:6]2=1
Reactant: NC=O
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Solvent: O
Product: Oc1ncnc2sc3c(c12)CCCC3
Temperature: 160 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
Into a 100-mL round-bottom flask containing a solution of ethyl 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate (4.06 g, 18.02 mmol, 1.00 equiv) in 100 mL of formamide was stirred for 8 h at 160° C. in an oil bath under nitrogen. The reaction mixture was cooled to 0° C. and diluted with water. The solids were filtered and precipitated with ethyl acetate to provide 8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-ol (3.0 g, 81%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11].[OH-].[Na+:26]>C(O)(C)C>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O-:12])=[O:11].[Na+:26]
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C([O-])c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 87.9 %

Procedure:
5-(2-Chloro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid (3.0 g, 0.0083 mole) is dissolved in isopropyl alcohol (20 ml) and a solution of 50% aqueous sodium hydroxide (0.644 g, 0.0083 mole) is added dropwise and the reaction mixture stirred for 1 hour before removing the solvent and water under vacuum at 0.2 mm overnight to afford 2.8 g of sodium 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoate.
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.C(O)=O.CCN(CC)CC.C([O:36][C:37]([C@@H:39]1[CH2:44][C@@H:43]2[C@@H:41]([CH2:42]2)[N:40]1[C:45](=[O:59])[CH2:46][N:47]1[C:51]2=[N:52][CH:53]=[CH:54][CH:55]=[C:50]2[C:49]([C:56](=[O:58])[CH3:57])=[N:48]1)=[O:38])C=C>CN(C=O)C.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+]>[C:56]([C:49]1[C:50]2[C:51](=[N:52][CH:53]=[CH:54][CH:55]=2)[N:47]([CH2:46][C:45]([N:40]2[C@H:39]([C:37]([OH:38])=[O:36])[CH2:44][C@@H:43]3[C@H:41]2[CH2:42]3)=[O:59])[N:48]=1)(=[O:58])[CH3:57]
Reactant: C=CCOC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)Cn1nc(C(C)=O)c2cccnc21
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)O)c2ncccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Allyl palladium chloride dimer (0.084 g, 0.231 mmol) and 2-di-tert-butylphosphino-2′-methylbiphenyl (0.288 g, 0.923 mmol) were dissolved in DMF (7.69 mL) under an argon atmosphere. The reaction mixture was stirred at RT for 10 min. After cooling the reaction mixture to 10° C., formic acid (0.513 mL, 13.38 mmol) was added followed by Et3N (1.86 mL, 13.38 mmol) and a solution of (1R,3S,5R)-2-[2-(3-acetyl-pyrazolo[3,4-b]pyridin-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxylic acid allyl ester (1 g, 2.3 mmol) in DMF (15.4 mL). The reaction mixture was stirred at 10° C. for 1 h. DMF was evaporated. The residue was poured into NH4Cl (sat. aq. solution) and extracted with EtOAc (3×50 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was dissolved in MeOH and filtered over a PL-Thiol cartridge. The filtrate was concentrated and the crude residue was purified by preparative HPLC (Waters Sunfire C18-OBD, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 5% to 80% CH3CN in H2O in 20 min, CH3CN and H2O containing 0.1% TFA) and the pure fractions were combined and lyophilized. White solid. MS (LCMS): 328.9 [M+H]+, 351.0 [MH+Na]; tR (HPLC conditions c): 1.84 min. 1H NMR (400 MHz, DMSO-d6): δ (ppm) 8.66 (dd, J=4.52, 1.59 Hz, 1H), 8.58 (m, J=6.36 Hz, 1H), 7.35-7.50 (m, 1H), 8.54-8.61 (m, 1H), 5.88 (d, J=16.87 Hz, 1H), 5.55 (d, J=17.12 Hz, 1H), 4.14-4.24 (m, 1H), 3.75-3.83 (m, 1H), 2.64 (s, 3H), 2.26-2.36 (m, 1H), 2.10-2.23 (m, 1H), 1.80-1.95 (m, 1H), 0.95-1.07 (m, 1H), 0.67-0.81 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]([O:5][C:6]1(O)[CH:15]=[CH:14][C:13]2[CH:12]([CH2:16][C:17](OCC)=[O:18])[N:11]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10][CH2:9][C:8]=2[CH2:7]1)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:30][N:2]([CH3:1])[C:3]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]([CH2:16][CH2:17][OH:18])[N:11]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:10][CH2:9]2)=[O:4]
Reactant: CCOC(=O)CC1C2=C(CCN1C(=O)OC(C)(C)C)CC(O)(OC(=O)N(C)C)C=C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)Oc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2CCO
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 78.2 %

Procedure:
To a solution of t-butyl 6-dimethylcarbamoyloxy-1-ethoxycarbonylmethyl-6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.97 g, 4.84 mmol) synthesized in step (e) of Example 187 in tetrahydrofuran (30 ml) was added lithium aluminum hydride (270 mg, 7.2 mmol) at −78° C., and the resulting mixture was stirred for 20 minutes at −78° C. and for 20 minutes at 0° C. successively under a nitrogen atmosphere. After stirring, to the reaction mixture were added water (0.3 ml), 15% aqueous sodium hydroxide solution (0.3 ml) and water (0.9 ml) in this order with stirring, and the resulting mixture was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and. ethyl acetate (1:1-0:1) as the eluent to afford the title compound (1.38 g, yield: 78%) as a colorless oil.
Reaction SMILES: [H-].[Na+].[S:3]1([C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=[O:8])[NH:6]1)(=[O:5])=[O:4].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>CN(C)C=O>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][N:6]1[C:7](=[O:8])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[S:3]1(=[O:4])=[O:5]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCBr
Reaction time: 5 h
Yield: 91.9 %

Procedure:
A 60% sodium hydride in mineral oil (1.1 g) was added to dry dimethylformamide (50 ml) at room temperature while stirring. Saccharin (5 g) was gradually added to the suspension at room temperature, followed by stirring for 30 minutes. To the resultant mixture, 1,4-dibromobutane (29.5 g) was dropwise added, and the mixture was kept at an inner temperature of 90° to 100° C. for 5 hours. After completion of the reaction, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using chloroform as an eluent to give the objective compound (7.98 g). IR νmaxfilm (cm-1): 1730, 1595, 1460, 1440, 1330.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([F:10])=[C:4]([Cl:11])[N:3]=1.C(C1C=CC=CN=1)#N.S(=O)(=O)(O)[OH:21]>>[Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]([F:10])=[CH:6][C:7]=1[C:8]([NH2:9])=[O:21]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: N#Cc1ccccn1
Product: NC(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 10 °C

Procedure:
The amide was prepared from the 2,6-dichloro-5-fluoro-3-cyanopyridine described in Example 1b. The cyanopyridine was placed in 12 L flask, cooled to 5°-10° C. in an ice bath, and 2300 mL of concentrated sulfuric acid was added. The residual DCE was then removed under vacuum at room temperature. After removal of the DCE the mixture was heated at 65°-70° C. for 1-2 hours and monitored by HPLC. After about 2 hours the mixture was cooled to about 10° C. in an ice bath. The amide product (3) formed was used directly for the next step without isolation or purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[N-:10]=[N+:11]=[N-:12].[Na+].O>CO>[N:10]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH3:9])=[O:7])=[N+:11]=[N-:12]
Reactant: COC(=O)CCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CCCCN=[N+]=[N-]
Yield: 99.7 %

Procedure:
A solution of methyl 5-bromovalerate (5.00 g, 25.6 mmol), NaN3 (3.33 g, 51.2 mmol) and 15 ml of water in 40 ml of MeOH was refluxed for 3.5 hrs. The MeOH was removed in vacuo and residue was partitioned between CHCl3 (200 ml) and water (50 ml). The organic layer was separated and washed with water. After drying and removal of solvent, methyl 5-azidovalerate (4.01 g, 99.7%) was obtained as a colorless oil.
Reaction SMILES: O[C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].O=P(Cl)(Cl)[Cl:16]>CN(C=O)C>[Cl:16][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(O)c(C(=O)O)nn(C)c1=O
Solvent: CN(C)C=O
Product: Cc1c(Cl)c(C(=O)O)nn(C)c1=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 30.1 %

Procedure:
A mixture of 4-hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (35.4 g, 192 mmol), catalytic amount of DMF (3 drop), and POCl3 (178 mL, 1.92 mol) was heated for 2 days at 90° C., and then the POCl3 was removed under reduced pressure. The crude material was quenched with ice, and the reaction mixture was stirred for 2 hours at room temperature. The precipitates formed out of the solution was filtered off and washed with ether. The precipitates collected were triturated with ether to afford 11.7 g (30%) of the desired product. The filtrate was extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude product that was triturated with ether and dried under reduced pressure to afford additional 9.56 g (24%) of the desired product. A total of 21.29 g (55%) of the desired product was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]([NH2:13])=O>>[N:1]1[C:2]2[CH:10]=[N:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:6])[NH:13][CH:11]=1
Reactant: NC=O
Reactant: Nc1cnccc1C(=O)O
Product: O=c1[nH]cnc2cnccc12
Temperature: 160 °C
Yield: 72 %

Procedure:
A mixture of 3-amino isonicotinic acid (485 mg, 3.51 mmol) in formamide (3 mL) is heated to 160° C. for 12 h. Upon cooling, the resulting solid is filtered and washed with H2O and dried in a vacuum oven to yield 3H-pyrido[3,4-d]pyrimid-4-one (373 mg, 72%). 1H NMR (DMSO) δ 12.60 (1H, brs), 9.06 (1H, s), 8.68 (1H, d, J=5.3 Hz), 8.23 (1H, s), 7.96 (1H, d, J=5.1 Hz).