Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][S:11][C:10]2[S:15][C:16]([C:18](=O)[NH2:19])=[CH:17][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(OCC)(=O)C.Cl>N1C=CC=CC=1.O>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][S:11][C:10]2[S:15][C:16]([C:18]#[N:19])=[CH:17][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc2c(s1)SCC(=O)N2Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc2c(s1)SCC(=O)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
A mixture of 1-benzyl-6-carbamoyl-2,3-dihydro-2-oxo-1H-thieno[2,3-b][1,4]thiazine (0.18 g) and p-toluenesulfonyl chloride (0.17 g) in pyridine (5 ml) was stirred for 24 hours at room temperature. The reaction mixture was poured into a mixture of ethyl acetate and water, and adjusted to pH 1.5 with concentrated hydrochloric acid. The organic layer was successively washed with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with chloroform. The fractions containing the object compound were collected and evaporated in vacuo to give 1-benzyl-6-cyano-2,3-dihydro-2-oxo-1H-thieno[2,3-b]-[1,4]thiazine (0.11 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([OH:15])[CH2:13][OH:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O.Cl>C1C=CC=CC=1>[Cl:16][C:17]1[CH:18]=[C:19]([CH:20]2[C:6]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[CH:7]=3)[CH2:11][CH:12]([CH2:13][OH:14])[O:15]2)[CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc(CC(O)CO)cc1OC
Reactant: O=Cc1cccc(Cl)c1
Agent: Cl
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)C(c1cccc(Cl)c1)OC(CO)C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 94 %

Procedure:
15.64 g (73.6 mmoles) of dl-3-(3,4-dimethoxyphenyl)-propane-1,2-diol (II) are dissolved in 200 ml of benzene. 8.03 ml (73.6 mmoles) of 3-chlorobenzaldehyde and 4.6 ml (56 mmoles) of concentrated hydrochloric acid are added to the solution and the reaction mixture is stirred for 5 hours at room temperature. The solution is then evaporated in vacuo, the oily residue is dissolved in 200 ml of 99.5% ethanol, clarified while hot, filtered and the filtrate is evaporated in vacuo. Thus 23.19 g (94%) of crude product are obtained in oily form, which can be used for the further reaction steps without purification (the purity of the product exceeds 95%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[CH2:14](I)[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:16]([O:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2)[CH:15]=[CH2:14]
Reactant: Cc1ccc(O)c2ccc(=O)[nH]c12
Reactant: C=CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(C)c2[nH]c(=O)ccc12
Temperature: 50 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
5-Hydroxy-8-methylcarbostyril (6.35 g, 36.3 mmol), allyl iodide (6.07 g, 36.1 mmol), n-tetrabutylammonium bromide (1.16 g, 36.1 mmol) were dissolved in dimethylformamide (108 ml). To the solution, potassium carbonate (10 g, 72.5 mmol) was added, and stirred in a bath of 50° C. for 2 hours. The solvent was evaporated, and the residue, dissolved in chloroform, was washed with water. The washed material was dried and condensed. The resultant residue was purified by silica gel column chromatography (eluent; chloroform). Recrystallization (chloroform-n-hexane) yielded 4.98 g of 5-allyloxy-8-methylcarbostyril as colorless flakes (63.8%).
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH2:3][O:4][CH2:5]2.[CH2:7]([OH:10])[CH:8]=[CH2:9].B(F)(F)F>ClCCl>[CH2:7]([O:10][C@H:6]1[C@H:2]([OH:1])[CH2:3][O:4][CH2:5]1)[CH:8]=[CH2:9]
Reactant: C1OCC2OC12
Reactant: C=CCO
Agent: FB(F)F
Solvent: ClCCl
Product: C=CCO[C@@H]1COC[C@H]1O
Temperature: 25 °C

Procedure:
To a 10-L flask fitted with a double surface condenser, overhead stirrer and nitrogen inlet was added 3,4-epoxytetrahydrofuran (750 g, 8.71 mol), dichloromethane (3750 ml, 5 vol) and allyl alcohol (2530 g, 43.56 mol, 5 eq.). The solution was cooled to between 0° and 5° C. and boron trifluoride diethyletherate (61.8 g, 0.436 mol, 0.05 eq.) was added dropwise whilst maintaining the temperature below 10° C. After addition was complete the solution was allowed to warm to room temperature at which point the reaction slowly exothermed to reflux. After 3 hours 1H NMR analysis showed that no epoxide remained and the reaction was quenched with saturated aqueous sodium hydrogen carbonate solution (1500 mL, 2 vol). The phases were separated and the organic phase was washed with a further portion of saturated aqueous sodium hydrogen carbonate solution (1500 mL, 2 vol). The combined aqueous washes were extracted with CH2Cl2 (5×750 ml, 1 vol). After drying the organic phases over MgSO4, filtering and concentrating in vacuo, the trans-3-allyloxy-4-hydroxytetrahydrofuran (I) was isolated by reduced pressure distillation (bp 94° C. @ 3 mbar) to give 1004.0 g (79.9% yield) of a clear colorless liquid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[CH:5][C:4]=1[F:17].C(=O)(O)[O-:19].[Na+]>CS(C)=O>[F:17][C:4]1[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH:7]=[CH:8][C:3]=1[CH:2]=[O:19]
Reactant: O=C([O-])O
Reactant: COc1cccc(-c2ccc(CBr)c(F)c2)c1
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc(-c2ccc(C=O)c(F)c2)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 4-bromomethyl-3-fluoro-3′-methoxy-biphenyl (0.45 g, 1.5 mmol) in dimethyl sulfoxide (10 mL) was added sodium bicarbonate (1.79 g, 21.3 mmol) and the resulting mixture was then stirred at 100° C. for 2 h. After the reaction was completed, it was cooled to room temperature and quenched with brine solution. The mixture was extracted with diethylether (50 mL×2) and the combined ether layers were washed with water, dried over anhydrous sodium sulphate and concentrated. The resulting residue was purified by column chromatography using 4% ethyl acetate in hexane to obtain the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1>Cl>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][O:13]1
Reactant: C1=COCCC1
Reactant: OCCCCCCCCCCCl
Agent: Cl
Product: ClCCCCCCCCCCOC1CCCCO1

Procedure:
The compounds in the composition are available commercially or can be prepared synthetically in accordance with the procedure described by S. Voerman in Agric. Ecosystems Environ. 21 31-41 (1988). The synthesis of I is shown in FIG. 1. In brief, 1,10-decanediol (III) is reacted with concentrated hydrochloric acid. Continuous extraction of the reaction mixture with petroleum ether (b.p. 100°-140° C.) gives 10-chlorodecan-1-ol (IV) free of dichloride. IV is reacted with an equimolar quantity of dihydropyran, catalysed by 1 drop of concentrated hydrochloric acid to produce 1-chloro-10-[(tetrahydro-2H-pyran-2-yl)oxy]decane (V). Butyne gas is bubbled into a solution of n-butyl lithium under nitrogen and then V is added dropwise to produce 14-[(tetrahydro-2H-pyran-2-yl)oxy]-3-tetradecyne (VI). VI is hydrogenated with a P2-nickel catalyst (H. C. Brown and V. K. Ahiya, J. Chem. Soc. Chem. Comm., pp. 553-554 (1973)) to produce the Z olefin, 14-[(tetrahydro-2H-pyran-2-yl)oxy]-(Z)-3-tetradecene (VII), with less than 1% of the E isomer. The pheromone component, I, is generated by heating VII for 15 minutes in methanol containing a few drops of hydrochloric acid. II is prepared according to the scheme shown in FIG. 2. The conversions of 1,8-octanediol (VIII) to (Z)-9-dodecen-1-ol (XIII) is carried out the same as III to I except that VIII is substituted for III. XIII is converted to the pheromone component, II, by reaction with acetic anhydride in pyridine.
Reaction SMILES: N(S([O-])(=O)=O)(S([O-])(=O)=[O:4])[O].[K+].[K+].[K].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1>O.CC(C)=O>[CH3:14][O:15][C:16]1[C:21](=[O:4])[CH:20]=[CH:19][C:18](=[O:22])[CH:17]=1
Reactant: COc1cccc(O)c1
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CC(C)=O
Product: COC1=CC(=O)C=CC1=O
Reaction time: 0.17 h
Yield: 117.5 %

Procedure:
A solution of potassium nitrosodisulfonate (0.75 g) and potassium monobasic phosphate (0.75 g) in water (37.5 ml) was added to m-methoxyphenol (109 mg, 0.9 mmol) in acetone (12.5 ml) and the resulting mixture was stirred vigorously for 10 minutes. Potassium nitrosodisulfonate (0.75 g) was added to the reaction mixture in two portions at 30 minute intervals and the stirring was continued for an additional two hours. After removal of acetone under reduced pressure, the resulting aqueous solution was extracted with dichloromethane (four 10 ml aliquots). The combined organic layers were washed with 0.01 N sodium hydroxide (10 ml) and then with water (10 ml) and then dried over anhydrous magnesium sulfate. The dried solution was filtered and the solvents removed under reduced pressure to yield 146.1 mg of 2 -methoxy-p-benzoquinone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(O[C:18]([C:20]1(CI)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][CH3:34])[CH2:21]1)=O)C>>[CH2:33]([O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]([N:22]1[CH2:23][CH2:24][CH:20]([CH2:18][O:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)[CH2:21]1)=[O:35])[CH3:34]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OCC)C1
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Product: CCOc1ccccc1C(=O)N1CCC(COc2ccc(-c3ccc(F)cc3)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 4′-fluoro-biphenyl-4-ol and 1-(2-ethoxy-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 16) to afford the racemate as a white solid (191 mg, 70%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:30])[C:15]([C:20]2[CH:29]=[CH:28][C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=2)=[CH:16]N(C)C)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[O:32]1CCCC1>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:30])[C:15]([C:20]2[CH:29]=[CH:28][C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[CH:21]=2)=[CH:16][OH:32])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNC(=O)C(=CN(C)C)c2ccc3c(c2)CCCC3)cc1OC
Reactant: C1CCOC1
Agent: Cl
Solvent: O
Product: COc1ccc(CCNC(=O)C(=CO)c2ccc3c(c2)CCCC3)cc1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Three grams (3.00 g) of crude N-[2-(3,4-dimethoxyphenyl)ethyl]-3-dimethylamino-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (7.35 mmol), 30 ml of 5% hydrochloric acid and 30 ml of tetrahydrofuran were mixed and stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate twice, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with hexane and dried to give 2.20 g of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxy-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide.
Reaction SMILES: C([C:3]1([C:21]([O-:23])=[O:22])[CH:9](O)[CH2:8][CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:5][CH2:4]1)C.CS(Cl)(=O)=O.[CH2:29]1CCN2C(=NCCC2)C[CH2:30]1>C1COCC1>[N:6]1([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:7][CH2:8][CH:9]=[C:3]([C:21]([O:23][CH2:29][CH3:30])=[O:22])[CH2:4][CH2:5]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCC1(C(=O)[O-])CCN(C(=O)OCc2ccccc2)CCC1O
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)C1=CCCN(C(=O)OCc2ccccc2)CC1
Temperature: 80 °C
Yield: 50.5 %

Procedure:
To a stirred solution 1-benzyl 4-ethyl-5-hydroxyazepane-1,4-dicarboxylate (4.4 g, 13.7 mmol) in THF (100 ml) was added MsCl (2.58 ml, 33.6 mmol) and TEA (5.69 ml, 40.5 mmol) in three portions over 16 hours. The mixture was then concentrated, diluted with dichloromethane (100 ml), washed with saturated aqueous NaHCO3 (2×50 ml), dried (MgSO4), filtered and reconcentrated. The residue was dissolved in THF (100 ml) and DBU (3.1 ml, 20.6 mmol) was added and the resulting mixture was heated at 80° C. for 1 hour. The reaction was then concentrated, diluted with dichloromethane (100 ml), washed with saturated aqueous NaHCO3 (3×30 ml), dried (MgSO4), filtered and reconcentrated. The residue was purified via silica FCC (using a gradient of eluents; 9:1 to 7:3 Hexane/EtOAc) to give the title product as colourless oil (2.1 g, 51%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:31])[C@H:12]([CH2:28][CH:29]=O)[CH2:13][N:14]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[C:16]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH3:31])[C@@H:12]2[CH:28]=[CH:29][C:15]3[N:14]([C:18]4[N:19]=[CH:20][CH:21]=[CH:22][C:17]=4[C:16]=3[CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:13]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cn(C[C@@H](CC=O)N(C)S(=O)(=O)c2ccc(F)cc2)c2ncccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Product: COC(=O)Cc1c2n(c3ncccc13)C[C@H](N(C)S(=O)(=O)c1ccc(F)cc1)C=C2
Reaction time: 96 h

Procedure:
To a mixture of methyl [1-((2R)-2-{[(4-fluorophenyl)sulfonyl](methyl)amino}-4-oxobutyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]acetate (272 g, 589 mmol) in ethyl acetate (2.5 L) was added PPTS (326.33 g, 1299 mmol). After a period of 4 days at 65° C., the reaction mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The organic phase was separated, washed with brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by combiflash (10% ethyl acetate in hexane to 100% ethyl acetate) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([NH:11][NH2:12])[N:8]=[N+:9]([O-:10])[C:4]=2[CH:3]=1.[C:15]([CH2:18][C:19](=O)[CH3:20])(=O)[CH3:16]>C(O)C>[CH3:16][C:15]1[CH:18]=[C:19]([CH3:20])[N:11]([C:7]2[N:8]=[N+:9]([O-:10])[C:4]3[CH:3]=[C:2]([Cl:1])[CH:14]=[CH:13][C:5]=3[N:6]=2)[N:12]=1
Reactant: CC(=O)CC(C)=O
Reactant: NNc1nc2ccc(Cl)cc2[n+]([O-])n1
Solvent: CCO
Product: Cc1cc(C)n(-c2nc3ccc(Cl)cc3[n+]([O-])n2)n1
Yield: 73.3 %

Procedure:
21.2 g (0.1 mol) of 7-chloro-3-hydrazino-benzo-1,2,4-triazine 1-oxide were boiled under reflux with 10 g (0.1 mol) of acetylacetone in 200 ml of ethanol for 5 hours. After cooling, the reaction product which had precipitated was filtered off, washed with ethanol and dried. 20.2 g of 3-(3,5-dimethyl-pyrazol-1-yl)-7-chlorobenzo-1,2,4-triazine 1-oxide of melting point 198°-200° C. (from dimethylformamide) were obtained, that is to say 73% of theory.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:24][CH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[C:31](=[O:35])[N:30]([C@@:36]1([CH3:44])[CH2:41][CH2:40][C:39](=[O:42])[NH:38][C:37]1=[O:43])[C:29]2=[O:45].CC#N>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:24][CH2:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[C:31](=[O:35])[N:30]([C@@:36]2([CH3:44])[CH2:41][CH2:40][C:39](=[O:42])[NH:38][C:37]2=[O:43])[C:29]3=[O:45])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: C[C@]1(N2C(=O)c3ccc(CN)cc3C2=O)CCC(=O)NC1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: C[C@]1(N2C(=O)c3ccc(CNC(=O)c4ccc(Br)cn4)cc3C2=O)CCC(=O)NC1=O
Temperature: 40 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
A mixture of 5-bromopicolinic acid (0.40 g, 2.0 mmol) and CDI (0.36 g, 2.2 mmol) in DMF (20 mL) was stirred under nitrogen at 40° C. for 2 hours. Then, 5-aminomethyl-2-[(3S)-3-methyl-2,6-dioxo-piperidin-3-yl]-isoindole-1,3-dione hydrochloride (0.67 g, 2.0 mmol) was added, and the mixture was stirred at this temperature for an additional 2 hours. The mixture was cooled to room temperature, and the solvent was evaporated under vacuum. The residue was dissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (2×100 mL). The organic phase was evaporated. The residue was chromatographed on silica gel using methylene chloride as the mobile phase. A pale red solid was obtained; this material was triturated in 10 mL of acetonitrile for 16 hours. The solid was filtered and washed with an additional 7 mL of acetonitrile. The product was dried under vacuum, providing 0.55 g (57% yield) as a white solid; mp 260-262° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 45/55 CH3CN/0.1% H3PO4, 3.61 (96.62%); 1H NMR (DMSO-d6) δ 1.88 (s, 3H), 2.00-2.08 (m, 1H), 2.49-2.62 (m, 2H), 2.65-2.73 (m, 1H), 4.62 (d, J=6.3 Hz, 2H), 7.76-7.82 (m, 3H), 7.97 (dd, J=8.4 Hz, J=0.6 Hz, 1H), 8.26 (dd, J=8.4 Hz, J=2.3 Hz, 1H), 8.81 (dd, J=2.3 Hz, J=0.6 Hz, 1H), 9.63 (t, J=6.3 Hz, 1H), 11.00 (s, 1H); 13C NMR (DMSO-d6) δ 21.0, 28.5, 29.1, 42.4, 58.7, 121.8, 123.1, 123.5, 123.9, 129.6, 131.3, 133.6, 140.5, 147.1, 148.5, 149.3, 163.5, 167.7, 167.8, 172.0, 172.1; Anal. Calcd for C21H17BrN4O5: C, 51.97; H, 3.53; N, 11.55. Found: C, 52.05; H, 3.44; N, 11.39.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([CH3:23])=[N:21][CH:22]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>CN(C=O)C>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:16][C:17]3[CH:18]=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([CH3:23])=[N:21][CH:22]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[N:9]=1
Reactant: Cc1ncc(N)cc1NS(C)(=O)=O
Reactant: Cc1nc(N)nc(-c2cccnc2F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(-c2cccnc2Nc2cnc(C)c(NS(C)(=O)=O)c2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 41.4 %

Procedure:
To a 15 mL round-bottom flask was added 4-(2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.045 g, 0.219 mmol), N-(5-amino-2-methylpyridin-3-yl)methanesulfonamide (0.049 g, 0.241 mmol), and DMF (2.0 mL). The mixture was cooled to 0° C. under N2. Sodium bis(trimethylsilyl)amide, 1.0 m in THF (Aldrich) (0.178 mL, 0.877 mmol) was then added to the solution in one portion. The now burgundy color mixture was stirred at 0° C. for 10 min then warmed up to rt and stirred for 1 h. The reaction mixture was quenched with sat. NH4Cl and partitioned between water and CHCl3. The aqueous layer was extracted with more CHCl3 (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (16 g, 5% to 10% MeOH in DCM) to afford the desired product as a yellow solid (35 mg). MS (ESI pos. ion) m/z: 387.0. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.46 (d, J=9.06 Hz, 6H) 3.06 (s, 3H) 3.33 (s, 3H) 6.96 (dd, J=7.60, 4.68 Hz, 1H) 7.75 (br. s., 1H) 7.87 (br. s., 1H) 8.27-8.41 (m, 2H) 8.67 (d, J=2.05 Hz, 1H) 8.79 (dd, J=7.82, 1.53 Hz, 1H) 9.30 (br. s., 1H) 12.03 (s, 1H).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC(C)([O-])C.[K+].[Si:18]([O:25][CH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH:30]=O)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].CCCCCCCCCCN>C1COCC1>[Si:18]([O:25][CH2:26][C:27]1[CH:28]=[C:29](/[CH:30]=[CH:3]/[C:1]#[N:2])[CH:32]=[CH:33][C:34]=1[Cl:35])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C=O)ccc1Cl
Agent: CC(C)(C)[O-]
Agent: CCCCCCCCCCN
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cc(/C=C/C#N)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of diethyl cyanomethylphosphonate (1.1 eq.) in THF (0.14 M) was added at 0° C. potassium tert-butoxide (1 M THF solution, 1.1 eq.). The resulting yellow solution was stirred at 0° C. for 1 h before 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-chlorobenzaldehyde from step 3 of Amine 10 synthesis (1 eq.) in THF (0.14 M) was added. The resulting mixture was stirred at RT 3 h. The reaction was quenched by the addition of sat. aq. NH4Cl and then extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO3, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded an orange oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→2:1 (v/v) Hex:EtOAc) afforded the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[CH2:5][N:6]=[C:7]=[S:8].[CH:13]([NH:15][NH2:16])=[O:14]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[CH2:5][NH:6][C:7](=[S:8])[NH:16][NH:15][CH:13]=[O:14]
Reactant: Fc1cc(F)cc(CN=C=S)c1
Reactant: NNC=O
Solvent: CCO
Product: O=CNNC(=S)NCc1cc(F)cc(F)c1
Yield: 56 %

Procedure:
3,5-Difluorobenzyl isothiocyanate (9.9 g, 25.5 mmole) and formyl hydrazine (1.7 g, 28.7 mole) were refluxed in ethanol (30 ml) for one hour. The reaction was evaporated to dryness, triturated with hexane:ethyl acetate (1:1), filtered, and recrystallized from ethanol-hexane to yield 3.5 g (35%) of crude 4-(3',5'-difluorobenzyl)-1-formyl-3-thiosemicarbazide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.Cl[Sn]Cl.[OH2:16]>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:9])=[O:16])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1
Reactant: O
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Product: NC(=O)c1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 85 °C

Procedure:
A mixture of 6-chloro-3-nitropicolinonitrile (12 g, 65.4 mmol) and SnCl2.H2O (59 g, 262 mmol) in ethanol (144 ml) was heated to 85° C. for 3 hours. The solution was concentrated under reduced pressure, water was added and a saturated aqueous solution of sodium bicarbonate was added until pH=8. The mixture was extracted with ethyl acetate several times. The combined organic layers were dried (Na2SO4), and concentrated under reduce pressure to afford 6-chloro-3-nitropicolinamide in quantitative yield.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[C:15]([CH3:23])[C:3]=1[O:4][Si:5]([CH:12]([CH3:14])[CH3:13])([CH:9]([CH3:11])[CH3:10])[CH:6]([CH3:8])[CH3:7].[Li]CCCC.[P:29](Cl)(=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32]>C1COCC1>[CH3:23][C:15]1[CH:16]=[C:17]([S:19]([CH2:22][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])(=[O:21])=[O:20])[CH:18]=[C:2]([CH3:1])[C:3]=1[O:4][Si:5]([CH:6]([CH3:7])[CH3:8])([CH:9]([CH3:10])[CH3:11])[CH:12]([CH3:14])[CH3:13]
Reactant: CCOP(=O)(Cl)OCC
Reactant: Cc1cc(S(C)(=O)=O)cc(C)c1O[Si](C(C)C)(C(C)C)C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOP(=O)(CS(=O)(=O)c1cc(C)c(O[Si](C(C)C)(C(C)C)C(C)C)c(C)c1)OCC
Temperature: -78 °C
Reaction time: 1 h
Yield: 15.4 %

Procedure:
To a stirring solution of (2,6-dimethyl-4-methanesulfonylphenoxy)triisopropylsilane (0.47 g, 1.32 mmol) in THF (15 mL) at −78° C. was added n-BuLi (2.5 M in hexanes, 0.58 mL), the reaction mixture was stirred at −78° C. for 1 hr, then diethyl phosphorochloridate (0.25 mL, 1.72 mmol) was added at −78° C. The reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was quenched with saturated NH4Cl and diluted with diethyl ether. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1:1) to afford diethyl (3,5-dimethyl-4-triisopropylsilanyloxy-benzenesulfonyl)methylphosphonate as a colorless oil (0.1 g, 15%): 1H NMR (200 MHz, CDCl3-d6): δ 7.57 (s, 2 H), 4.17 (m, 4 H), 3.71 (d, J=17.2 Hz, 2 H), 2.29 (s, 6 H), 1.33 (m, 9 H), 1.10 (d, J=7.2 Hz, 18 H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:1); Rf=0.45.