Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[CH2:14]([O:21][C:22]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(NCc1ccc(C(=O)O)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.3 %

Procedure:
To a solution of 4-(aminomethyl)benzoic acid (25 g) in a 2N aqueous solution of sodium hydroxide (100 ml), a solution of benzyloxycarbonyl chloride (33.8 g) in tetrahydrofuran (50 ml) was added drop by drop under ice cooling conditions, followed by stirring at room temperature for 2 hours. The resulting precipitate was collected by filtration, washed with water, 1N hydrochloric acid and ether and dried under reduced pressure to yield the title compound (10.5 g, yield 22%) as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:11](=[CH:14]/[C:15]2[S:16][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)/[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[CH3:28][N:29]([CH3:34])[CH2:30][C:31](O)=[O:32].O.[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42]([OH:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1>C1(C)C=CC=CC=1>[C:36]1([CH3:46])[CH:37]=[CH:38][C:39]([S:42]([OH:45])(=[O:43])=[O:44])=[CH:40][CH:41]=1.[CH3:28][N:29]([CH2:30][C:31]([O:26][CH:23]1[CH2:22][CH2:21][N:20]([C:17]2[S:16][C:15](/[CH:14]=[C:11](\[C:12]#[N:13])/[C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:19][CH:18]=2)[CH2:25][CH2:24]1)=[O:32])[CH3:34]
Reactant: COc1ccc(/C(C#N)=C/c2ccc(N3CCC(O)CC3)s2)cc1OC
Reactant: CN(C)CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(/C(C#N)=C/c2ccc(N3CCC(OC(=O)CN(C)C)CC3)s2)cc1OC
Yield: 6.1 %

Procedure:
Compound 6 (370 mg) was dissolved in toluene (80 mL), and N,N-dimethylglycin hydrochloride (140 mg) and p-toluenesulfonic acid monohydrate (380 mg) were added to the solution, followed by stirring under reflux for 5 hours. The solvent was evaporated to dryness, and the residue was purified by silica gel column chromatography (CHCl3-MeOH), to thereby yield the target product (yield: 38 mg, 7.7%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].B.CO>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH2:7][OH:8])[CH:10]=1
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1CO
Temperature: 20 °C
Reaction time: 72 h
Yield: 100.3 %

Procedure:
Dissolve 5-fluoro-2-nitrobenzoic acid (15 g, 81.08 mmol) in anhydrous tetrahydrofuran (200 mL) and add dropwise with stirring at 20° C. a 1 molar solution of borane in tetrahydrofuran (243 ml, 243 mmol). Stir the mixture at 20° C. for 72 hours then add methanol (200 ml). Concentrate under reduced pressure and purify the residue by flash column chromatography (silica gel, 10-30% ethyl acetate/hexane) to obtain 13.92 g (100%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].B.C1COCC1>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH2:7][OH:8])[CH:10]=1
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Agent: B
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1CO
Reaction time: 1 h

Procedure:
To a solution of 5-fluoro-2-nitrobenzoic acid (4.58 g) in THF (50 ml) was added a 1 M solution of BH3.THF in THF (62 ml) while cooling with an ice-bath. The cooling bath was removed and stirring was continued for 1 h at ambient temperature, followed by refluxing for 4 h. The reaction mixture was cooled and MeOH was added to destroy the excess of borane. The mixture was concentrated and water and ethyl acetate were added to the residue. The organic layer was washed with brine, dried and concentrated. Yield: 4.3 g.
Reaction SMILES: [OH:1]O.[CH:3]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=1>C(Cl)(Cl)Cl>[CH:3]12[O:1][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]2
Reactant: OO
Reactant: C1=CCCCCCC1
Solvent: ClC(Cl)Cl
Product: C1CCCC2OC2CC1
Temperature: 70 °C
Yield: 89.3 %

Procedure:
Crosslinked polystyrene-divinylbenzene beads substituted in the phenyl rings by arsono groups (Polymer II of Example 2 (B) above, containing 0.25 mmole As) was added to a two phase system of 1.7 g of 30% aqueous H2O2 (15 mmoles of H2O2) and cyclooctene (7.5 mmoles) in chloroform (7 ml). The mixture was heated in a closed thick-walled tube at 70° C. for 45 hours. Cyclooctene oxide (6.7 mmol, 89% yield) was obtained after 45 hours. The polymer was then filtered and reused with no apparent loss of activity (90% yield after 55 hours at 70° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:9][C:10]1[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][C:11]=1[Br:19])[CH3:8])([CH3:4])([CH3:3])[CH3:2].NN>C1COCC1.CO>[C:1]([O:5][C:6](=[O:20])[N:7]([CH2:9][C:10]1[C:11]([Br:19])=[CH:12][CH:13]=[CH:14][C:15]=1[NH2:16])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(Cc1c(Br)cccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: CN(Cc1c(N)cccc1Br)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 69 %

Procedure:
To a warm solution of (2-bromo-6-nitro-benzyl)-methyl-carbamic acid tert-butyl ester from Preparation 2 (589 mg, 1.71 mmol), and a small (catalytic) amount of Ra(Ni) in THF/MeOH (8 ml/9 ml) was added H2NNH2 (110 μl, 3.5 mmol). With stirring, the solution was heated under reflux for an hour and was allowed to cool to room temperature. The reaction mixture was filtered through celite and washed with ethyl acetate. The concentrated filtrate was purified by flash chromatography to give (2-amino-6-bromo-benzyl)-methyl-carbamic acid tert-butyl ester (371 mg, 69%). 1H NMR (CDCl3, 300 MHz) δ:1.48(s, 9H), 2.80(s, 3H), 4.67(s, 2H), 6.56(m, 1H), 6.90(m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)c(Br)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)cc1Br
Temperature: 70 °C

Procedure:
To a solution of 2-bromo-4-methylbenzoic acid (10 g) in MeOH (50 ml) was added dropwise concentrated sulfuric acid (10 ml) at 0° C. The mixture was heated at 70° C. for 2 hours. After cooling to ambient temperature, the methanol was removed under reduced pressure. The residue was poured into ice-water (100 ml). The mixture was extracted with EtOAc (×2). The combined organic layers were washed with NaHCO3 (aq. sat. Note: gas evolution), brine, dried over MgSO4, filtered, and concentrated to give the product as a clear oil. Yield: 10.5 g, 99%. 1H NMR (400 MHz, Chloroform-d) δ 7.73 (d, 1H), 7.50 (d, 1H), 7.19-7.11 (m, 1H), 3.92 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].P(Cl)(Cl)(Cl)(Cl)[Cl:12]>C(Cl)(Cl)Cl.C(O)C>[Cl:12][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cnccc1Cl

Procedure:
4-Chloro-3-nitropyridine was prepared from 4-hydroxy-3-nitropyridine(25 g, 0.179M), phosphorus pentachloride(40 g, 0.192M) and 1 mL of phosphorous oxytrichloride. The mixture was heated at 120° for 1 hour. The reaction mixture was diluted with chlorform/ethanol mixture(9/1) and the precipitate was filtered to afford desired. (mp. 153-154° C.)
Reaction SMILES: C(=[C:8]1[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[O:18]=[O+][O-].CSC>C(Cl)Cl>[N:16]1[C:17]2[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: C(=C1CCCc2cccnc21)c1ccccc1
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CSC
Product: O=C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of 8-benzylidene-5,6,7,8-tetrahydro-quinoline (4.30 g, 19.4 mmole) in CH2Cl2 (150 mL) was reacted with ozone at −78° C. for 30 minutes. Dimethyl sulfide (5 mL) was added, and the reaction was warmed to RT and stirred overnight. The mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (EtOAc). The title compound (2.20 g, 79%) was obtained as an off-white solid after drying in vacuo: MS (ES) m/e 148 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[S:15]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16]1>>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][CH2:20][C:17]2[CH:18]=[CH:19][S:15][CH:16]=2)[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=Cc1ccsc1
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccsc2)CC1
Yield: 70.4 %

Procedure:
Using general procedure A, 4-amino-1-Boc-piperidine (481 mg, 2.40 mmol) and 3-thiophenecarboxaldehyde (228 mg, 2.03 mmol) gave 4-[(thiophen-3-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil (425 mg, 1.43 mmol, 71%). 1H NMR (CDCl3) δ 1.22-1.36 (m, 3H), 1.45 (s, 9H), 1.80-1.90 (m, 2H), 2.67 (tt, 1H, J=10.1, 3.9 Hz), 2.74-2.86 (m, 2H), 3.85 (s, 2H), 3.95-4.10 (m, 2H), 7.04 (dd, 1H, J=4.8, 1.5 Hz), 7.11-7.14 (m, 1H), 7.29 (dd, 1H, J=5.0, 2.9 Hz).
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[CH:2].[C:10]([C:13]1[CH:14]=[C:15](/[CH:18]=[C:19]2\[C:20](=[O:30])[NH:21][C:22]3[C:27]\2=[C:26](I)[C:25]([F:29])=[CH:24][CH:23]=3)[NH:16][CH:17]=1)(=[O:12])[CH3:11]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[C:10]([C:13]1[CH:14]=[C:15](/[CH:18]=[C:19]2\[C:20](=[O:30])[NH:21][C:22]3[C:27]\2=[C:26]([C:2]#[C:1][C:3]2([OH:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[C:25]([F:29])=[CH:24][CH:23]=3)[NH:16][CH:17]=1)(=[O:12])[CH3:11]
Reactant: C#CC1(O)CCOCC1
Reactant: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(C#CC4(O)CCOCC4)c32)c1

Procedure:
Using Method C above, 4-Ethynyl-tetrahydro-pyran-4-ol (0.16 g, 1.26 mmol) (Example 85A) was coupled with (Z)-3-[(4-acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (0.2 g, 0.50 mmol) (Example 90B above) using (Ph3P)4Pd (58.4 mg) and CuI (9.6 mg) as catalyst in DMF (15 mL) and Et3N (15 mL) as solvent at 85° C. for 18 h. (Yield 102 mg, 52%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[CH:12]([Mg]Br)=[CH2:13].[NH4+].[Cl-]>C1COCC1.COCCOC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]2[C:3]=1[NH:9][CH:13]=[CH:12]2
Reactant: O=[N+]([O-])c1cc(F)ccc1Br
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: Fc1ccc(Br)c2[nH]ccc12
Temperature: -78 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
A solution of 1-bromo-4-fluoro-2-nitrobenzene (3.6 g, 16.4 mmol) in THF (100 mL) was added to a solution of 1 M vinylmagnesium bromide in THF (100 mL, 100 mmol) and DME (100 mL) at −78° C. (bath temp). The reaction was stirred at −78° C. for 4 h, and saturated aqueous NH4Cl was added. The layers were separated, and the organic layer was evaporated. The crude product was purified flash chromatography, giving 2 g (57%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([OH:11])=[O:10])([O-])=O.[H][H]>C(O)C.O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Nc1cccc(CCC(=O)O)c1

Procedure:
3-Nitrocinnamic acid (1.5 g, 7.77 mM) was suspended in a mixture of ethanol (80 ml) and water (20 ml), and palladium on charcoal (10%, 100 mg) added. The mixture was shaken in an atmosphere of hydrogen for 4.5 hours, when uptake of gas complete. After filtration through diatomaceous earth, the solvent was removed to give title compound.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18](OC)=[O:19])=[CH:16][C:3]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][OH:19])=[CH:16][C:3]1=2
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCc1ccc2c(c1)C(O)c1ccccc1CO2
Temperature: 0 °C

Procedure:
A solution of 3.5 g. of methyl 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetate in 150 ml. of dry ether is added dropwise to a stirred suspension of 2.5 g. of lithium aluminum hydride in 50 ml. of dry ether. The mixture is refluxed for three hours, cooled to 0° C., and hydrolyzed. The mixture is extracted with ether, dried over sodium sulfate, and evaporated to a crude crystalline product. Recrystallization from acetonitrile provides colorless crystals, m.p. 135°-137° C. of 6,11-dihydro-11-hydroxydibenz[b,e]oxepin-2-ethanol.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O>[F:1][C:2]1[C:3]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[C:4]2[O:9][CH2:8][C@H:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CN1CCNCC1
Solvent: CS(C)=O
Product: C[C@H]1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 135 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
(S)-(−)-9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid (21 mg) and N-methylpiperazine (30 mg) were dissolved in anhydrous dimethyl sulfoxide (3 ml) and stirred at 130 to 140° C. for 1 hour. After evaporating the solvent, ethanol (2 ml) was added to the residue. The solid thus precipitated was collected by filtration and washed successively with a small amount of ethanol and ether. 14 mg of the obtained powder was subjected to silica gel column chromatography with the use of 5 g of silica gel and eluted with a lower layer solution of chloroform-methanol-water (7:3:1) to thereby give (S)-(−)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid. The above-described filtration mother liquor was fractioned and subjected to thin layer chromatography (silica gel, 20×20 cm, 0.5 mm), thereby purifying by developing with a lower layer solution of chloroform-methanol-water (15:3:1). The products were combined to thereby give 14 mg of crystals of the target compound. Melting point: 220 to 228° C. (decomposition).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:15][NH2:16]>>[CH3:15][NH:16][S:11]([C:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=1)(=[O:13])=[O:12]
Reactant: CN
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Product: CNS(=O)(=O)c1ccc(NC(C)=O)cc1

Procedure:
10.5 g (45 mmol) of 4-acetylaminobenzenesulfonyl chloride are stirred at 50° C. for 3 hours in 100 ml of 40% strength methylamine solution. The solution is then extracted three times with ethyl acetate. The organic phases are dried using Na2SO4 and concentrated. The residue is stirred with dichloromethane and the insoluble constituents are filtered off. Concentration of the filtrate gives the desired sulfonamide in adequate purity and almost quantitative yield. (MS-CI+: 229.1; LCMS Rt=3.249 min)
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH-].[Na+].[CH2:12](I)[CH2:13][CH3:14].Cl>O.CO>[CH2:12]([S:3][C:2]1[N:4]=[C:5]([OH:6])[CH:7]=[C:8]([OH:9])[N:1]=1)[CH2:13][CH3:14]
Reactant: CCCI
Reactant: O=C1CC(=O)NC(=S)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCSc1nc(O)cc(O)n1
Temperature: 32.5 °C
Yield: 61.9 %

Procedure:
2-Thiobarbituric acid (100 g) was added to water (250 ml) under stirring. A solution of sodium hydroxide pellets or flakes (63.13 g) in water (147.35 ml) was added to the resulting mixture over a period of 15 to 20 minutes at 20-25° C. The resulting mass was stirred for 40 minutes at 20-25° C., followed by the addition of water (200 ml). The reaction temperature was raised to 30-35° C., followed by the addition of methanol (200 ml) and propyl iodide (123.36 g) under stirring at 30-35° C. The resulting reaction mixture was stirred for 30 hours at 30-35° C. The reaction was monitored by thin layer chromatography. After completion of reaction, the pH of the reaction mixture was then adjusted to less than 2.0 by the addition of dilute hydrochloric acid (prepared by mixing of 60 ml of concentrated hydrochloric acid with 140 ml of water). The resulting slurry was stirred for 15 hours and the product was isolated by filtration and washed successively with water (4×200 ml). The wet cake was slurried in cyclohexane (500 ml) at boiling temperature for 30 minutes, followed by cooling to 25-30° C. The product was isolated by filtration and washed with cyclohexane (200 ml). The wet product was dried under reduced pressure at 40-45° C. to produce 80 g of 2-propylthio-pyrimidine-4,6-diol as a white powder (Yield: 61.9%).
Reaction SMILES: [I-:1].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:14]=[C:13]([CH2:24]OS(C)(=O)=O)[CH:12]=2)[CH:7]=[CH:8][C:9]=1[Cl:10]>C1COCC1.C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[N:14]=[C:13]([CH2:24][I:1])[CH:12]=2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: [I-]
Reactant: COc1ccc(-n2nc(COS(C)(=O)=O)cc2-c2ccc(Cl)c(Cl)c2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(-n2nc(CI)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 40 °C

Procedure:
Sodium iodide (4.06 kg, 27.1 mol) was added to the THF/toluene solution of methanesulfonic acid 5-(3,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-ylmethyl ester (Example 517, 6.32 kg, 14.8 mol). The resulting reaction mixture was heated at 40° C. for 6 h and then allowed to cool to rt overnight. When HPLC analysis indicated the disappearance of the starting material, the reaction was quenched with 28% aq. sodium thiosulfate (6.3 L). The organic layer was washed with sat. aq. NaHCO3 (6.3 L), brine (6.3 L), then dried (MgSO4). After filtration to remove the drying agent, the desired product was obtained in a solution, which was used in the next synthetic step without isolation. Chemical characterization data obtained herein for the title compound is not duplicated in this Example in light of the same data given in Example 1, Step E.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-])=O)[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10])[CH3:2]
Reactant: CCNc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCNc1ccccc1N
Reaction time: 2 h
Yield: 100 %

Procedure:
N-Ethyl-2-nitroaniline (0.97 g, 5.8 mmol) was dissolved in EtOAc (60 mL) and placed in a closed vessel. 10% Pd/C (0.4 g, 7 mol %) was added and the mixture was hydrogenated under 50 psi H2 for 2 h. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure to yield the title product (0.79 g, 99%) as a brown liquid, which was used without further purification. 1H-NMR (CDCl3): δ 6.83 (1H, m), 6.64-6.74 (3H, m), 3.29 (3H, br s), 3.15 (2H, q), 1.30 (3H, t); TLC (2:98 MeOH/DCM Rf 0.24).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]#[N:7])[N:3]=[CH:2]1.[CH3:8][Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][O:12][CH2:13]Cl.C([O-])([O-])=O.[K+].[K+].CC(C)=O>CCOC(C)=O>[CH3:8][Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][O:12][CH2:13][N:1]1[CH:5]=[C:4]([C:6]#[N:7])[N:3]=[CH:2]1
Reactant: N#Cc1c[nH]cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: C[Si](C)(C)CCOCn1cnc(C#N)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 68.9 %

Procedure:
A flask charged with imidazole-4-carbonitrile (0.5 g, 5.2 mmol) (Synthesis, 677, 2003), 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) (0.95 mL, 5.3 mmol), K2CO3 (1.40 g, 10.4 mmol), and acetone (5 mL) was stirred for 10 h at RT. The mixture was diluted with EtOAc (20 mL) and washed with water (20 mL) and brine (20 mL) and the organic layer dried over MgSO4. The crude product was eluted from a 20-g SPE cartridge (silica) with 30% EtOAc/hexane to give 0.80 g (70%) of the title compound as a colorless oil. Mass spectrum (CI (CH4), m/z) Calcd. for C10H17N3OSi, 224.1 (M+H). found 224.1.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1.[CH3:16][NH:17][C@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19].O>CS(C)=O>[CH3:11][C:8]1[N:6]2[N:7]=[C:2]([N:17]([CH3:16])[C@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5]2=[N:10][N:9]=1
Reactant: COC(=O)c1cc(Cl)nn2c(C)nnc12
Reactant: CN[C@@H](C)c1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc(N(C)[C@@H](C)c2ccccc2)nn2c(C)nnc12
Yield: 15 %

Procedure:
A solution of methyl 6-chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate (2.0 g, 8.85 mmol) and (S)-N-methyl-1-phenylethanamine (2.39 g, 17.7 mmol; commercially available from Aldrich) in DMSO (20 mL) was heated at 130° C. in a microwave tube for 30 min. Water (100 mL) was added to the reaction mixture, and the product was extracted with EtOAc (3×100 mL). The combined EtOAc layers were concentrated and the residue was purified by flash chromatography (silica gel, 1% to 10% MeOH in CH2Cl2) to give the (S)-methyl 3-methyl-6-(methyl(1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylate (400 mg, 15% yield). LRMS [M+H]+: 325 m/z.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[C:8]([CH2:10][CH2:11][O:12][P:13](Cl)[Cl:14])#[N:9]>C(OCC)C>[C:8]([CH2:10][CH2:11][O:12][P:13]([Cl:14])[N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])#[N:9]
Reactant: CC(C)NC(C)C
Reactant: N#CCCOP(Cl)Cl
Solvent: CCOCC
Product: CC(C)N(C(C)C)P(Cl)OCCC#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Diisopropylamine (156 millimoles) was dissolved in 80 ml of diethyl ether, and then 34.7 millimoles of beta-cyanoethoxydichlorophosphine was added. The mixture was stirred at room temperature for 12 hours. After the reaction, the resulting diisopropyl ammonium chloride was separated by filtration. The ether solution was distilled to give beta-cyanoethoxymonochloro(N,N-diisopropylamino) phosphine as an oil. The yield was 73 mole%, and the product had a boiling point of 102 to 104° C. (0.08 mmHg).