Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][O:3]1.[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC.O>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:12][C:13]1[CH:19]=[CH:18][C:16]([N:17]2[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]2=[O:3])=[CH:15][CH:14]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)c1cccoc1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccn(-c2ccc(F)cc2)c1=O
Reaction time: 6 h

Procedure:
To a solution of methyl 2-oxo-2H-pyran-3-carboxylate (375 mg, 2.43 mmol) in dry N,N-dimethylformamide (DMF) under room temperature (rt) was added 4-fluoroaniline (0.23 mL, 2.44 mmol), and the reaction mixture was stirred for 6 hours. To the mixture was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 465 mg, 2.43 mmol) and 4-dimethylaminopyridine (DMAP, 75 mg, 0.61 mmol), and was stirred for additional 12 hours. Reaction mixture was dumped to water followed by ethyl acetate partition. Organic layers were combined, washed by 3N hydrochloric acid and water, and concentrated in vacuo to give crude methyl 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate. Crude methyl ester was saponificated by 10% sodium hydroxide solution (10 mL) in methanol (20 mL). Reaction mixture was heated at 65° C. for 3 hrs. Solid precipitated during acidic workup by 3N hydrochloric acid was collected by filter, washed by methanol (small amount), water and diethyl ether, dried to give an intermediate compound, 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1)=[O:6])#[N:2].[Br:16][C:17]1[C:18](I)=[N:19][C:20]([I:23])=[N:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[Br:16][C:17]1[C:18]([C:10]2[CH:11]=[CH:12][C:7]([C:5]([NH:4][CH2:3][C:1]#[N:2])=[O:6])=[CH:8][CH:9]=2)=[N:19][C:20]([I:23])=[N:21][CH:22]=1
Reactant: N#CCNC(=O)c1ccc(B(O)O)cc1
Reactant: Brc1cnc(I)nc1I
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: N#CCNC(=O)c1ccc(-c2nc(I)ncc2Br)cc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 50.2 %

Procedure:
To a mixture of 4-(cyanomethylcarbamoyl)phenylboronic acid (see example 3) (185 mg, 0.9 mmol) and 5-bromo-2,4-diiodopyrimidine (410 mg, 1.0 mmol) in 1,4-dioxane (10 mL), was added 2M aqueous potassium carbonate (100 μL). The resulting mixture was stirred under nitrogen for 5 minutes then tetrakis(triphenylphosphine)palladium(0) (52 mg, 0.045 mmol) was added under a nitrogen atmosphere. The mixture was heated at 80° C. overnight. The cooled reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with water then brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product as a brown solid. The crude material was purified by flash chromatography, eluting with 50% ethyl acetate/petroleum spirit to give 4-(5-bromo-2-iodopyrimidine-4-yl)-N-(cyanomethyl)benzamide (200 mg, 35% over 2 steps). LC-ESI-MS (method B): rt 6.2 min.; m/z 443.0/445.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[CH2:7][C:8](=[O:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[N:12]([O-])=[O:13].[Na+]>C(O)(=O)C>[C:1]([O:5][C:6](=[O:11])[C:7](=[N:12][OH:13])[C:8](=[O:10])[CH3:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=N[O-]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)C(=NO)C(=O)OC(C)(C)C
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl-3-oxobutyrate (158 g, 1 mol) was dissolved in 200 mL of acetic acid in a 500 mL 3-neck round bottom flask equipped with a thermometer, addition funnel and mechanical stirring. The mixture was cooled in an ice bath to about 10° C. Sodium nitrite (69 g, 1 mol) was added over 75 minutes keeping the temperature under 15° C. The cold bath was removed and the mixture stirred for 30 minutes and then allowed to stand for 3.5 hours to give t-butyl-2-hydroximino-3-oxobutyrate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]#[N:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]#[N:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CC#N)CC1
Reaction time: 6 h

Procedure:
Add 4-cyanomethylenepiperidine-1-carboxylic acid t-butyl ester (5.39 g, 24.25 mmol) in ethanol (160 mL) to a suspension of 5% palladium on charcoal (0.69 g) in ethanol (20 mL) and hydrogenate at room temperature with agitation at 60 psi for 6 hr. Filter the mixture through celite and evaporate the solvent in vacuo to give 4-cyanomethylpiperidine-1-carboxylic acid t-butyl ester as an oil which solidifies on standing to give a solid (5.43 g, 99.8%). MS (m/z): 247 (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[OH-].[Na+].O.C(OCC)(=O)C.[CH3:20][C:21]([CH3:23])=[O:22]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[CH:20][C:21](=[O:22])[CH3:23]
Reactant: CC(C)=O
Reactant: COc1ccccc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccccc1C=CC(C)=O
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
In a 250 ml single neck flask was charged 13.6 g (100 mmoles,1.0 eq) of o-methoxybenzaldehyde dissolved in 30 ml of acetone. To this was added 5 g of 10% aqueous sodium hydroxide solution (12.5 mmoles, 0.125 eq), dropwise and during the course of addition, temperature was kept no higher than 25° C., while the mixture was agitated continuously for 30 minutes. To the mixture was added 50 ml of water, followed by 100 ml of ethyl acetate, the phases were separated and the organic phase was washed with water three times and then dried, and concentrated to obtain 14.5 g of 4-(2-methoxyphenyl)-3-buten-2-one as a faintly yellow oil in 82.3% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[F:15][C:16]([F:34])([F:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O.O>[F:15][C:16]([F:33])([F:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Reactant: FC(F)(F)CCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C=Cc1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Temperature: 60 °C

Procedure:
A mixture of ethyl 4-aminocinnamate, one equivalent of 15-(trifluoromethyl)pentadecyl bromide and one equivalent of anhydrous potassium carbonate in hexamethylphosphoramide is heated for 20 hours at 60° C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated to provide ethyl 4-[15-(trifluoromethyl)pentadecylamino]cinnamate. The ester is hydrolyzed with sodium hydroxide in a 1:9 water:ethanol solution at steam bath temperatures for 10 hours. The hot solution is then acidified with acetic acid, cooled and filtered and the solid is washed with water. Recrystallization from chloroform yields the product as a white solid.
Reaction SMILES: Cl.[CH:2]([C:5]1[S:14][C:13]2[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=[C:8]([NH2:19])[C:7]=2[CH:6]=1)([CH3:4])[CH3:3].[CH3:20][O:21][CH2:22][CH2:23][C@H:24]1[CH2:29]N[CH2:27][CH2:26][NH:25]1.C(N(C(C)C)CC)(C)C>CS(C)=O.C1(C)C=CC=CC=1>[CH3:20][O:21][CH2:22][CH2:23][C@@H:24]1[NH:25][CH2:26][CH2:27][N:19]([C:8]2[C:7]3[CH:6]=[C:5]([CH:2]([CH3:4])[CH3:3])[S:14][C:13]=3[NH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[N:9]=2)[CH2:29]1
Reactant: CC(C)c1cc2c(s1)Nc1ccccc1N=C2N
Reactant: COCC[C@H]1CNCCN1
Agent: Cl
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(C)C)cc32)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add 2-isopropyl-4H-3-thia-4,9-diaza-benzo[f]azulene-10-ylamine hydrochloride (0.32 g, 1.07 mmol) to a solution of (S)-2-(2-methoxy-ethyl)-piperazine (0.31 g, 2.15 mmol) in dimethyl sulfoxide: toluene (1:3, 4 mL). Add diisopropylethylamine (0.19 mL, 1.09 mmol), heat to 110° C. and stir. After an overnight period, cool to ambient temperature to give crude title compound.
Reaction SMILES: O.[OH-].[Li+:3].[CH3:4][C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH2:16][O:17][C:18]1[CH:38]=[CH:37][C:21]([CH2:22][O:23]/[N:24]=[C:25](/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)\[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:20][CH:19]=1>CO>[CH3:4][C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:7][C:6]=1[CH2:16][O:17][C:18]1[CH:38]=[CH:37][C:21]([CH2:22][O:23]/[N:24]=[C:25](/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)\[CH2:26][CH2:27][C:28]([O-:30])=[O:29])=[CH:20][CH:19]=1.[Li+:3]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)O)c2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCC(=O)[O-])c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
Lithium hydroxide monohydrate (44.6mg) was added to a solution of E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid (500 mg) in methanol (10 ml), which was stirred at room temperature for 30 minutes and concentrated. The remaining crystals were recrystallized from methanol-diethyl ether to obtain lithium E-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-4-phenylbutyrate (485 mg, yield 96%) as colorless crystals. m.p. 201-203° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])[N:10]=1.[CH3:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[CH2:33]>C(OCC)(=O)C.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([C:32]([CH3:33])([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:31])=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=2[CH3:30])[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:14]=1
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(O)cc3O)n2)c(C)c1
Reactant: C=C(C)c1ccccc1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3cc(C(C)(C)c4ccccc4)c(O)cc3O)n2)c(C)c1
Temperature: 175 °C
Yield: 67.7 %

Procedure:
To a 1L three-necked, round-bottomed flask equipped with a magnetic stirrer, condenser, dropping funnel, thermometer, and a nitrogen atmosphere are charged 15.0 g (37.8 mmol) of 2-(2,4-dihydroxyphenyl)-4,6-bis-(2,4-dimethylphenyl)-s-triazine and 390 mg of aluminum isopropoxide. The mixture is heated to 175° C. and 4.47 g (37.9 mmol) of α-methylstyrene are added dropwise at a rate of one drop every two seconds. A total of six equivalents of α-methyl styrene are added in this fashion over a 4.5 hour period. After cooling to room temperature, the mixture is diluted with ethyl acetate, washed twice with water and once with brine, and is dried over anhydrous magnesium sulfate. Following filtration, the solvent is removed under reduced pressure to yield a yellow solid. The crude product is purified with medium pressure chromatography with 12% ethyl acetate/heptane to afford 13.2 g of the title compound as a yellow solid; mp 168°-170° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][C:8]2=O.C[Si]([C:26]#[N:27])(C)C.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:26]([C:8]1[C:9]2[C:4](=[C:3]([O:2][CH3:1])[C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)[CH2:5][CH:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:7]=1)#[N:27]
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)CC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1OC)CC(c1ccccc1)C=C2C#N
Temperature: 60 °C
Yield: 83.4 %

Procedure:
To a suspension of 10 g (35 mmol) of 5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-one, the product of Example 1, was added 7.5 g (75.6 mmol) of trimethylsilyl cyanide (commercially available from Aldrich Chemical Company) and approximately 50 mg of anhydrous aluminum chloride (AlCl3). The reaction mixture was heated at 60° C. for 3 h then cooled to ambient temperature and diluted with 150 mL of toluene. The volume of the reaction mixture was reduced in vacuo to approximately 50 mL. The resultant trimethylsilyl adduct was dehydrated by treatment with 15 mL of trifluoroacetic acid and 100 mg of p-toluenesulfonic acid in 200 mL of toluene at reflux temperature for 1 h. The reaction mixture was cooled to ambient temperature, the layers separated and the organic layer washed with water, aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to a colorless oil. The oil was purified by column chromatography on silica gel eluted with 20% ethyl acetate in hexane to give 8.5 g (83% yield) of the title compound, m.p. 109°-110° C.
Reaction SMILES: [Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([OH:8])[CH2:4][C:5]([CH3:7])=[CH2:6].[C:11](OC(=O)C)(=[O:13])[CH3:12]>S(=O)(=O)(O)O>[Cl:1][C:2]([Cl:10])([Cl:9])[CH:3]([O:8][C:11](=[O:13])[CH3:12])[CH2:4][C:5]([CH3:7])=[CH2:6]
Reactant: C=C(C)CC(O)C(Cl)(Cl)Cl
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: C=C(C)CC(OC(C)=O)C(Cl)(Cl)Cl
Reaction time: 0.17 h

Procedure:
50.0 g. (0.246 moles) of 1,1,1-trichloro-2-hydroxy-4-methyl-4-pentene are admixed with 30.1 g. (0.295 moles) of acetic anhydride, whereupon 3 drops of a concentrated sulfuric acid solution are added to the mixture, which is then stirred for 10 minutes. 1,1,1-trichloro-2-acetoxy-4-methyl-4-pentene is obtained in the reaction which can be detected by t.l.c. measurement (Merck Art. No. 5715 analytical sheet, benzene; Rf for the starting material: 0.34, Rf for the acetylated product: 0.66). The reaction mixture obtained and 123 ml. of a 2 N aqueous sodium hydrogensulfate solution are simultaneously added to a suspension of 32.2 g. (0.492 moles) of zinc powder in 200 ml. of methanol in 10 minutes, under vigorous stirring, while keeping the reaction vessel on a water bath of 10°-15°C. When the addition is complete, the mixture is stirred for another 5 minutes, whereupon the solids are filtered off.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: Cc1cccc(C(=O)c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccccc1)c1cccc(CBr)c1
Temperature: 75 °C
Reaction time: 6.5 h
Yield: 76.8 %

Procedure:
Commercially available 3-methylbenzophenone (4.00 g, 20.4 mmol) was dissolved in carbon tetrachloride (100 mL), and N-bromosuccinimide (4.71 g, 26.5 mmol) and 2,2′-azobisisobutyronitrile (1.00 g, 6.09 mmol) was added to the solution, followed by stirring at 75° C. for 6.5 hours. After the reaction mixture was cooled, the precipitates were filterd out. The filtrate was combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:20) to obtain 3-bromomethylbenzophenone (4.31 g, yield 77%).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[O:5][CH2:6][CH3:7])\[CH3:4].C(N(CC)CC)C.[C:15]1([CH3:27])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23](Cl)(=[O:25])=[O:24]>CN(C)C=O.C(Cl)Cl>[C:15]1([CH3:27])[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:16]=1[S:23]([O:1]/[N:2]=[C:3](/[O:5][CH2:6][CH3:7])\[CH3:4])(=[O:24])=[O:25]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CCO/C(C)=N/O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCO/C(C)=N/OS(=O)(=O)c1c(C)cc(C)cc1C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
The ethyl (1E)-N-hydroxyethanimidoate (4.72 g, 45.7 mmol) was dissolved in N,N-dimethylformamide (12.0 mL) and triethylamine (6.37 mL, 45.7 mmol) and cooled in an ice bath. The mesitylenesulfonyl chloride (10.0 g, 45.7 mmol) was added portion wise over 5 minutes and the reaction was stirred vigorously for 30 minutes. The reaction mixture became a thick syrup. The reaction was diluted with methylene chloride (100 mL) and was washed with water 3×, brine, dried over magnesium sulfate and concentrated to give ethyl (1E)-N-[(mesitylsulfonyl)oxy]ethanimidoate (11.2 g, 86%) as a semi-solid residue. LCMS calculated for C13H20NO4S (M+H)+: m/z=286.1. found: 285.9.
Reaction SMILES: [Li+].[BH4-].C([O:5][C:6]([C:8]1[C:9]2[C:17]([NH2:18])=[C:16]([C:19](=[O:21])[NH2:20])[S:15][C:10]=2[N:11]=[C:12]([CH3:14])[CH:13]=1)=O)C.C1COCC1>CO>[NH2:18][C:17]1[C:9]2[C:10](=[N:11][C:12]([CH3:14])=[CH:13][C:8]=2[CH2:6][OH:5])[S:15][C:16]=1[C:19]([NH2:20])=[O:21]
Reactant: CCOC(=O)c1cc(C)nc2sc(C(N)=O)c(N)c12
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(CO)c2c(N)c(C(N)=O)sc2n1
Reaction time: 2 h
Yield: 71 %

Procedure:
LiBH4 (62 mg, 2.04 mmol) was added to a solution of 3-Amino-2-carbamoyl-6-methyl-thieno[2,3-b]pyridine-4-carboxylic acid ethyl ester (205 mg, 0.73 mmol) in 10:1 THF:MeOH (15 mL) at room temperature. After stirring for 2 h, the reaction was quenched by addition of 1M HCl. The mixture was buffered to a pH ≈7, diluted with EtOAc, washed sequentially with H2O, brine, dried over Na2SO4, concentrated, and triturated with 50% EtOAc/hexane giving 3-amino-4-hydroxymethyl-6-methyl-thieno[2,3-b]pyridine-2-carboxylic acid amide (123 mg, 71%) as a yellow solid, m.p. >210° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[OH:19].C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[NH2:1][C:2]1[CH:7]=[C:6]([O:19][C:11]2[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]=2[F:9])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1
Temperature: 160 °C
Reaction time: 41 h
Yield: 19.5 %

Procedure:
2-Amino-4-chloropyridine (8.00 g) was dissolved in N-methylpyrrolidone (65 ml), and 2-fluoro-4-nitrophenol (19.55 g) and N,N-diisopropylethylamine (43.36 ml) were added thereto, followed by stirring at 160° C. for 41 hr. The reaction mixture was allowed to cool down to room temperature, and was partitioned between ethyl acetate-tetrahydrofuran (1:1) and a 2N aqueous solution of sodium hydroxide. The organic layer was washed with water and brine in this order. The aqueous layer was re-extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=1:2, then ethyl acetate). Fractions containing the target compound were concentrated, and crystals were precipitated by addition of ethyl acetate to the residue. The crystals were collected by filtration and dried under aeration to provide the titled compound as opalescent crystals (3.02 g, 20%).
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.O.Cl.C(N=C=NCCCN(C)C)C.Cl.[NH2:40][CH2:41][C:42]([C:44]1[CH:49]=[CH:48][C:47]([Br:50])=[CH:46][CH:45]=1)=[O:43].C(N(CC)C(C)C)(C)C>ClCCl>[Br:50][C:47]1[CH:46]=[CH:45][C:44]([C:42](=[O:43])[CH2:41][NH:40][C:10]([C@@H:9]2[CH2:13][CH2:14][CH2:15][N:8]2[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[O:12])=[CH:49][CH:48]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: NCC(=O)c1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A solution of N-Boc-L-Proline (5.16 g, 24.0 mmol) and HOBt.H2O (3.67 g, 24.0 mmol) was stirred at room temperature for 10 min and then treated with N-ethyl-N′-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl, 4.60 g, 24.0 mmol). The resulting mixture was stirred at room temperature for 30 min and then treated with a yellow solution formed by stirring 2-amino-4′-bromoacetophenone hydrochloride (5.0 g, 20.0 mmol) and N,N-diisopropylethylamine (DIPEA, 2.58 g, 20 mmol) in dichloromethane (DCM, 150 ml) at room temperature for 10 min. The resulting mixture was stirred at room temperature overnight and then filtered through Celite® to remove the precipitate. The filtrate was extracted with DCM and H2O. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified with column chromatography (ethyl acetate:hexanes=2:5) to yield pure product 1a as a yellow gel (7.39 g, 90%).
Reaction SMILES: Cl.C(O)C.[N+:5]([C:8]1[CH:19]=[CH:18][C:11]([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[CH:10][CH:9]=1)([O-])=O>[Pd].O>[NH2:5][C:8]1[CH:19]=[CH:18][C:11]([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Cn2cncn2)cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(Cn2cncn2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A stainless steel vessel was inetted with nitrogen and connected via its vent to a mobile scrubber unit. The scrubber was charged with very dilute hydrochloric acid. The vessel was charged with 96% ethanol (40 kg) followed by 1-(4-nitrobenzyl)-1,2,4-triazole (9.62 kg). The vessel was re-inerted with nitrogen and a slurry of 10% Pd/C catalyst (Engelhardt type 4505, 192 g) in water added to the stirred batch via the addition funnel. The vessel, funnel and line were rinsed with water. Total water used was 16 l. The batch was well stirred and heated to 60° C. A solution of ammonium formate (13.95 kg) in water (30 l) was metered into the reactor over 1 hour. Batch temperature settled at 65° C. At the end of this addition, the batch was heated at 70°-75° C. for a further 1 hour. Tlc showed complete reaction and single spot formation. The batch was cooled to 60° C. and passed through a pressure filter coated with hyflo (1.5 kg) to another vessel. The reaction vessel, filter and lines were washed with water (10 l). A further batch of 1-(4-nitrobenzyl)-1,2,4-triazole (9.585 kg) was then reduced in the same way. This batch was filtered and added to the previously filtered batch together with a 10 l water wash of the vessel, filter and lines. The combined, filtered batch (215 l) was distilled at atmospheric pressure until 70 l of distillate had been removed (vapour temperature was 83° C. at this point). Water (30 l) was added and the distillation continued until the vapour temperature reached 95° C. (106 l total distillate). The pressure in the distillation vessel was then reduced to allow distillation at a boiling point of ≤70° C. A further 70 l of distillate was removed to leave a residual volume of 69 l. The batch had crystallised at this point and the slurry was cooled to ≤20° C. over 1 hour. The batch was gently stirred and aged overnight. The batch was cooled to 0° C., aged for 1 hour and then filtered. The solid was washed with water at 0°-5° C. (10 l). The batch was dried overnight at 50° C., in vacuo, with a nitrogen bleed to give 1-(4-aminobenzyl)-1,2,4-triazole in 96% yield.