Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([SH:5])[CH2:2][CH2:3][CH3:4].[CH:6]1([CH2:12][C@H:13]2[CH2:15][O:14]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[H-].[Na+]>CN(C=O)C>[CH2:1]([S:5][CH2:15][C@@H:13]([OH:14])[CH2:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: C1CCC(C[C@H]2CO2)CC1
Reactant: CCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCSC[C@@H](O)CC1CCCCC1
Yield: 77.3 %

Procedure:
Butanethiol (765 μL, 7.1 mmol), the product from Example 1308C (500 mg, 3.6 mmol) in DMF (3.0 mL), and NaH, 60% dispersion in mineral oil, (305 mg, 7.6 mmol) in DMF (40 mL) were allowed to react in a manner similar to that described in Example 1310A. The residue was chromatographed (silica gel; EtOAc/hexanes 1:40) to afford a clear oil (641 mg, 77%). 1H NMR (CDCl3, 300 MHz) δ0.80-1.00 (m, 2H), 0.92 (t, J=7 Hz, 3H), 1.08-1.34 (m, 4H), 1.37-1.75 (m, 10H), 1.81 (m, 1H), 2.42 (dd, J=9, 13.5 Hz, 1H), 2.53 (t, J=7 Hz, 2H), 2.72 (dd, J=3, 13.5 Hz, 1H), 3.76 (m, 1H); MS (CI/NH3) m/z: 231 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][N+:3]([O-:5])=[O:4].[N+:6]([N:9]([CH3:12])[CH2:10]O)([O-:8])=[O:7]>>[N+:3]([N:2]([CH2:10][N:9]([N+:6]([O-:8])=[O:7])[CH3:12])[CH3:1])([O-:5])=[O:4]
Reactant: CN(CO)[N+](=O)[O-]
Reactant: CN[N+](=O)[O-]
Product: CN(CN(C)[N+](=O)[O-])[N+](=O)[O-]

Procedure:
An additional mole of methylnitramine is reacted with the 2-nitro-2-aza-1-propanol to produce 2,4-dinitro-2,4-diazapentane. The reactants (in approximately 1:1 molar ratio) are dissolved in a suitable organic solvent and the resulting solution is added to concentrated sulfuric acid at a controlled rate. The reaction temperature is maintained at a temperature above the freezing point of the concentrated sulfuric acid up to 5° C., but preferably from -5° C. to 0° C. The product 2,4-dinitro-2,4-diazapentane is then isolated by extraction using a suitable organic solvent, washing to remove traces of the acid, evaporating off the solvent, and then recrystallizing the resulting solid. A suitable organic solvent is one that (1) is capable of holding the methylnitramine and 2-nitro-2-aza-1-propanol starting materials and the 2,4-dinitro-2,4-diazapentane product in solution, (2) chemically inert to concentrated sulfuric acid, and (3) essentially immiscible with concentrated sulfuric acid. Suitable solvents include methylene chloride, chloroform, 1,2-dichloroethane, and 1,1,2-trichloroethane. Methylene chloride is the most preferred solvent.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([N:14]([CH2:34][CH2:35][CH3:36])[CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C@H:24]([CH2:28][C:29]([O:31]CC)=[O:30])[CH2:23][CH2:22]4)=[N:12][CH:13]=2)[S:5][C:6]=1[CH3:7].CO.O.[Li+].[OH-]>C1COCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([N:14]([CH2:34][CH2:35][CH3:36])[CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C@H:24]([CH2:28][C:29]([OH:31])=[O:30])[CH2:23][CH2:22]4)=[N:12][CH:13]=2)[S:5][C:6]=1[CH3:7]
Reactant: CCCN(CCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC)c1ccc(-c2nc(C)c(C)s2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCN(CCCOc1ccc2c(c1)CC[C@H]2CC(=O)O)c1ccc(-c2nc(C)c(C)s2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.8 %

Procedure:
To a solution of ethyl ((1S)-5-{3-[[5-(4,5-dimethyl-1,3-thiazol-2-yl)-2-pyridinyl](propyl)amino]-propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 267) (70 mg, 0.15 mmol) in a mixture of THF (2 mL), methanol (2 mL), and water (1 mL) was added LiOH (40 mg, 1.74 mmol). The mixture was stirred at rt for 18 h and then concentrated under reduced pressure. The residue was taken up in water and acidified using H3PO4 (5% solution in water). The aqueous phase was extracted with ethyl acetate, and the combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure to provide the product (56 mg, 86%). 1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, 1H), 7.80 (d, 1H), 7.06 (d, 1H), 6.79 (d, 1H), 6.71 (dd, 1H), 6.56 (d, 1H), 3.95 (t, 2H), 3.62 (t, 2H), 3.44-3.25 (m, 3H), 2.81-2.62 (m, 3H), 2.30-2.23 (m, 8H), 1.99-1.96 (m, 2H), 1.65-1.53 (m, 3H), 0.87 (t, 3H); LC-MS: RT=2.73 min, (M+H)+ 480.2.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].N1C=CC=CC=1.[N:13]([CH2:16][CH2:17][CH2:18][OH:19])=[N+:14]=[N-:15]>C(Cl)Cl>[C:1]([O:19][CH2:18][CH2:17][CH2:16][N:13]=[N+:14]=[N-:15])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: [N-]=[N+]=NCCCO
Reactant: C=C(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCN=[N+]=[N-]
Reaction time: 1 h

Procedure:
29 mL (0.3 mol) of methacryloyl chloride was added to a mixture of 100 mL methylene chloride and 50 mL of pyridine (both solvents had been dried over sodium sulfate overnight). The suspension was cooled in an ice-water bath and 18.6 mL (0.2 mol) of 3-azidopropanol was added over a period of 10 minutes. A clear solution was formed, which was kept in the cooling bath for another 1 hour and then at room temperature for 24 h. 50 mL of methylene chloride were then added, and the mixture was extracted with a solution of 50 mL HCl in 300 mL water followed by four 200-milliliter portions of water (NaCl had to be added to break the stable emulsion). The methylene chloride layer was dried over sodium sulfate (5 grams of sodium carbonate were added to react with the excess of methacrylic acid potentially present), and the solvent was removed under vacuum. The obtained liquid was distilled under reduced pressure (0.1 g of hydroquinone was added to prevent polymerization). The yield was 8.55 g (25%). The procedure needs to be optimized, but the monomer obtained by this procedure was very pure (NMR) and was used to study polymerization reactions.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][C:5]1([CH2:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:23][C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][C:31]=4[CH3:33])[N:26]([CH3:34])[CH:25]=3)[C:13]2=[O:35])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.Cl>O1CCOCC1.O>[CH3:34][N:26]1[C:27]2[C:32](=[C:31]([CH3:33])[CH:30]=[CH:29][CH:28]=2)[C:24]([CH2:23][N:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21](=[O:22])[N:12]([CH2:11][C:5]3([CH2:4][C:3]([OH:36])=[O:2])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]3)[C:13]2=[O:35])=[CH:25]1
Reactant: COC(=O)CC1(Cn2c(=O)c3ccccc3n(Cc3cn(C)c4cccc(C)c34)c2=O)CCCCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc2c1c(Cn1c(=O)n(CC3(CC(=O)O)CCCCC3)c(=O)c3ccccc31)cn2C
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of {1-[1-(1,4-dimethyl-1H-indol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl]-cyclohexyl}-acetic acid methyl ester (63 mg, 0.13 mmol) in dioxane (2.5 ml) is added a solution of LiOH monohydrate (25 mg, 0.60 mmol) in H2O (2.5 mL). The solution is stirred at 60° C. for 16 hours. The reaction mixture is allowed to cool to room temperature, quenches with 4M HCl in dioxane (500 μL) and is concentrated. The resulting residue is purified by flash chromatography with 6% MeOH in dichloromethane as the eluent to afford the title compound. LCMS (ESMS): m/z 474.18 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.C(O)C.[S:12]([O-:15])([O-:14])=[O:13].[Na+:16].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:12]([O-:15])(=[O:14])=[O:13])[N:3]=1.[Na+:16]
Reactant: O=S([O-])[O-]
Reactant: Clc1cccc(Cl)n1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])c1cccc(Cl)n1
Temperature: 170 °C
Yield: 29.1 %

Procedure:
Into a 50 ml autoclave, 2.22 g (15 mmol) of 2,6-dichloropyridine and 4.5 ml of ethanol were introduced and dissolved. To the solution, 2.27 g (18 mmol) of sodium sulfite dissolved in 18 ml of water, was added, and after sealing, the mixture was heated in an oil bath of 170° C. for 12 hours. After completion of the reaction, the mixture was cooled, and after an addition of 30 ml of water, extracted with methylene chloride (30 ml×3 times). The aqueous layer was distilled under reduced pressure, and 200 ml of ethanol was added. The mixture was heated. After filtering off insoluble precipitates, the filtrate was distilled under reduced pressure to obtain 0.94 g (30%) of sodium 2-chloropyridine-6-sulfonate as crystalline solid. Purification was conducted by recrystallization from ethanol. The physical property values are shown below.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[F:10].CC1(C)N([O])C(C)(C)CCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.ClN1C(=O)CCC1=O>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[F:10]
Reactant: OCc1ccc(Br)c(F)c1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: O=Cc1ccc(Br)c(F)c1
Reaction time: 6 h

Procedure:
To a well-stirred mixture of 4-bromo-3-fluorobenzyl alcohol (as described in Example 1, Step B) (10.25 g, 0.05 mol), TEMPO (0.781 g, 0.005 mol) and tetrabutylammonium fluoride (1.39 g, 0.005 mol) in CH2Cl2 (200 mL) and a solution of 0.5M NaHCO2/0.05M K2CO3(200 mL) was added N-chlorosuccinimide (9.35 g, 0.07 mol). After 6 hrs, the layers were separated, the aqueous layer back-washed with CH2Cl2 (2×50 mL), the organics combined and dried (Na2SO4). The solution was filtered, concentrated to half its volume, then chromatographed (silica gel, CH2Cl2) to give the title compound.
Reaction SMILES: Br[C:2]1[C:3]([CH3:22])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:5]2[N:6]([N:8]=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.C([Sn](CCCC)(CCCC)[C:28]1[N:32]([C:33]2[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=2)[N:31]=[CH:30][CH:29]=1)CCC>>[CH3:11][C:9]1[N:10]=[C:5]2[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)=[C:3]([CH3:22])[C:2]([C:28]3[N:32]([C:33]4[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=4)[N:31]=[CH:30][CH:29]=3)=[CH:7][N:6]2[N:8]=1
Reactant: Cc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(Br)cn2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1-c1ccc(C#N)cc1
Product: Cc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(-c3ccnn3-c3ccc(C#N)cc3)cn2n1

Procedure:
The title compound was prepared from 6-bromo-2,7-dimethyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (Int. 7, 100 mg, 0.27 mmol) and 4-(5-tributylstannanyl-pyrazol-1-yl)-benzonitrile (Int. 3, 186 mg, 0.405 mmol) using a similar method to that used in Example 1 (Step 4) (91 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([O:24][CH3:25])[C:21]=1[O:22][CH3:23])[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14](OCC)=[O:15])[CH2:9][CH2:8]1.[NH2:26][NH2:27]>C(O)C>[CH3:25][O:24][C:20]1[CH:19]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:21]=1[O:22][CH3:23])[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:26][NH2:27])=[O:15])[CH2:9][CH2:8]1
Reactant: CCOC(=O)CN1CCN(Cc2cc(OC)c(OC)c(OC)c2)CC1
Reactant: NN
Solvent: CCO
Product: COc1cc(CN2CCN(CC(=O)NN)CC2)cc(OC)c1OC

Procedure:
Synthesized according to General Procedure C: 6{16} (5.99 g, 17.0 mmol, 1 equiv.), anhydrous hydrazine (1.6 mL, 51.0 mmol, 3 equiv.), ethanol (34.2 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{16} (4.93 g, 86%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 8.14 (br s, 1H), 6.47 (s, 2H), 3.83 (br s, 2H), 3.78 (s, 6H), 3.76 (s, 3H), 3.36 (s, 2H), 3.01 (s, 2H), 2.48 (br s, 4H), 2.39 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 170.2, 152.8, 136.6, 133.6, 105.4, 62.8, 60.6, 60.4, 55.9, 53.4, 52.8.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][Br:9])=[O:7].[BH4-].[Na+]>CO>[Br:9][CH2:8][CH:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[OH:7]
Reactant: O=C(CBr)c1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CBr)c1cccs1
Temperature: 0 °C

Procedure:
A solution of the haloketone, bromomethyl 2-thienyl ketone (6.0 g), described in Example 3, in 40 ml of methanol is cooled to 0° C. Sodium borohydride (1.11 g) in 10 ml of methanol is added rapidly to the solution. After 15 minutes the reaction mixture is diluted with ice-water and extracted with ether. The extract is washed with water and brine, dried (MgSO4) and concentrated to give α-(bromomethyl)-2-thiophenemethanol; γmaxCHCl3 3550, 3400, 1060, 1035 cm-1 (ArCHOHCHR2Y; Ar = 2-thienyl, R2 = H and Y = Br).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:21]([C:23]1[CH:24]([CH3:33])[CH:25]=[C:26]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:27]=1)=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:21][C:23]4[NH:27][C:26]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:25][C:24]=4[CH3:33])[C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN1C(=O)Cc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Reactant: CC1C=C(CCC(=O)O)N=C1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(CCC(=O)O)[nH]c1C=C1C(=O)N(C)c2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 80 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
4-(3-Chloro-4-fluoro-phenylamino)-7-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (100 mg, 0.34 mmol) was condensed with 3-(5-formyl-4-methyl-4H-pyrrol-2-yl)-propionic acid (62 mg, 0.41 mmol) and piperidine (2 drops) in ethanol (3 mL) stirred at 80° C. for 2 hours to give 31 mg (20%) of the title compound. 1H NMR (360 MHz, DMSO-d6) δ 13.14 (br s, 1H, NH), 9.14 (s, 1H), 8.34 (s, 1H), 7.69 (m, 1H), 7.30-7.40 (m, 3H), 6.08 (s, 1H), 3.32 (s, 3H, CH3), 2.89 (m, 2H, CH2), 2.53 (m, 2H, CH2), 2.16 (s, 3H, CH3).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]3[CH2:12][CH2:13][S:14][C:7]3=[N:6][C:5]=2[N:4]([CH3:15])[N:3]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:16]([NH:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]3[CH2:12][CH2:13][S:14][C:7]3=[N:6][C:5]=2[N:4]([CH3:15])[N:3]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cn1nc(N)c2c(=O)n3c(nc21)SCC3
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cn1nc(NC(=O)c2ccccc2)c2c(=O)n3c(nc21)SCC3
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
In 14 ml of pyridine was dissolved 1.40 g (6.27 mmol) of Compound 13 prepared in Example 10, and 0.80 ml (6.9 mmol) of benzoyl chloride was added to the solution, followed by stirring at 50° C. for 30 minutes. After evaporation of the solvent, the residue was subjected to partition between chloroform and water. The chloroform layer was washed with a dilute aqueous solution of hydrochloric acid and water, and concentrated to dryness under reduced pressure. The residue was recrystallized from chloroform/ethanol to give 1.81 g (80%) of Compound 21 in pure form.
Reaction SMILES: [C:1](Cl)(C(Cl)=O)=[O:2].[Cl:7][C:8]1[CH:9]=[C:10]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:31]=[C:30]4[C:26]([CH:27]=[CH:28][NH:29]4)=[CH:25][CH:24]=3)[N:19]=2)[CH:11]=[N:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16].Cl.[OH-].[Na+]>C(Cl)Cl.O.CN(C=O)C>[Cl:7][C:8]1[CH:9]=[C:10]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:31]=[C:30]4[C:26]([C:27]([CH:1]=[O:2])=[CH:28][NH:29]4)=[CH:25][CH:24]=3)[N:19]=2)[CH:11]=[N:12][C:13]=1[O:14][CH:15]([CH3:17])[CH3:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)Oc1ncc(-c2nc(-c3ccc4cc[nH]c4c3)no2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1ncc(-c2nc(-c3ccc4c(C=O)c[nH]c4c3)no2)cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
DMF (0.28 mL) was added dropwise to a solution of (COCl)2 (0.31 mL) in DCM (9 mL) at 0° C. The resulting mixture was stirred at 0° C. for 1 hour. Then a solution of 6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole (D101) (1.06 g) in DCM (30 mL) was added. The reaction mixture was warmed to RT and stirred overnight. Then water and 2 M HCl was added. After stirred for 2 hours, the mixture was neutralized with 2 M aqueous NaOH solution until pH was between 8 and 9. The organic layer was separated and washed with brine, dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography to afford 6-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-oxadiazol-3-yl)-1H-indole-3-carbaldehyde (D102) (620 mg) as a yellow solid. δH (DMSO-d6, 400 MHz): 1.46 (6H, d), 5.51 (1H, m), 7.99 (1H, d), 8.14 (1H, d), 8.30 (1H, s), 8.42 (1H, d), 8.46 (1H, d), 8.90 (1H, d), 8.98 (1H, br s), 10.12 (1H, d).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:42])([F:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].I[CH2:44][C:45]1([CH3:49])[CH2:48][O:47][CH2:46]1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C:38]([F:41])([F:42])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:44][C:45]3([CH3:49])[CH2:48][O:47][CH2:46]3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: CC1(CI)COC1
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: CC1(Cn2nnc3c(N4CCC(F)(F)C4)nc(C(C)(C)C)nc32)COC1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(iodomethyl)-3-methyloxetane and isolated as white solid. MS (m/e): 367.3 (MH+).
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].C([O:10][C:11](=O)[CH:12]([CH2:18][CH3:19])[C:13](OCC)=[O:14])C.[O-]CC.[Na+]>C(O)C>[CH2:18]([C:12]1[C:13]([OH:14])=[N:6][CH:5]=[N:7][C:11]=1[OH:10])[CH3:19]
Reactant: N=CN
Reactant: CCOC(=O)C(CC)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1c(O)ncnc1O

Procedure:
Formamidine acetate was reacted with diethyl-ethylmalonate in the presence of sodium ethoxide in dry ethanol to yield 5-ethylpyrimidine-4,6-diol, which was converted to 4,6-Dichloro-5-ethylpyrimidine by POCl3 in the presence of TEA in toluene. 4,6-Dichloro-5-ethylpyrimidine was then reacted with aqueous ammonia in n-butanol at 100° C. to afford 4-amino-5-ethyl-6-chloropyrimidine.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:25][N:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[NH2:27].CCOC(C)=O.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:27][N:26]([CH3:25])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:8]=1
Reactant: CN(N)c1ccccn1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CN(NC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)c1ccccn1
Yield: 16.2 %

Procedure:
A 50-mL, 3-necked, round-bottomed flask was charged with (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.43 g), 2-(1-methylhydrazinyl)pyridine (0.15 g, 1.0 eq.) in EtOAc (10 mL) T3P (50% in EtOAc; 1.1 g, 1.5 eq.) and DIPEA (0.40 g, 2.5 eq.) were added under nitrogen atmosphere at −60° C. and the progress of the reaction was monitored by TLC (using 10% MeOH:CH2Cl2 as mobile phase and visualization with UV light). The reaction mixture was concentrated under reduced pressure (25° C., 20 mmHg) to afford 0.65 g of crude solid. Purification was performed on Combi-Flash Column chromatography in CH2Cl2 and MeOH (desired compound started eluting at 3.3% MeOH in CH2Cl2). The fractions containing the desired compound were combined and concentrated under reduced pressure (35° C., 20 mm Hg) to afford 90.0 mg (yield: 18%) (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-methyl-N′-(pyridin-2-yl)acrylohydrazide. 1H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 9.79 (brs, 1H), 8.57-8.62 (d, 2H), 7.92-7.94 (d, J=11.2 Hz, 1H), 7.59-7.64 (m, 1H), 7.19-7.25 (q, 1H), 6.75-6.89 (m, 2H), 5.85-5.88 (d, J=10.8 Hz, 1H), 3.46 (d, 3H); LCMS for C19H15F6N6O [M+H]+ 457.35. found 456.26 (RT 2.52 min, purity: 100.0%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][CH3:3].[I-].[NH2:9][N+:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[N:9]1[N:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=[C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH:3]=1
Reactant: CCOC(=O)CC
Reactant: N[n+]1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
Ethyl propionate (50.2 mL, 49.54 mmol) and 1-aminopyridinium iodide (10.0 g, 45 mmol) were added to a suspension of potassium carbonate (8.71 g, 63.02 mmol) in N,N′-dimethylformamide (100 mL) and the resulting mixture was stirred at room temperature for 2 h before being poured into 100 mL of water. Ethyl acetate was then added and the aqueous layer was separated and washed with ethyl acetate (×2). The combined organic layers were dried over magnesium sulphate, filtered and evaporated. The crude product was purified by flash chromatography (hexanes to 4:1 hexanes/ethyl acetate) to give the title compound (4.30 g, 50%) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH2:11][S:10][CH:9]2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:4][CH:3]=1.O1CCC[CH2:22]1.C([Li])CCC.CI>C(Cl)Cl.C(OCC)(=O)C.C(OCC)C.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[CH:12]([CH3:22])[CH2:11][S:10][CH:9]2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=C1CCSC(c2cccnc2)N1c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: CCOCC
Solvent: CI
Product: CC1CSC(c2cccnc2)N(c2ccc(Cl)cc2)C1=O
Temperature: -75 °C

Procedure:
3-(4-Chlorophenyl)tetrahydro-2-(3-pyridyl)-4H-1,3-thiazin-4-one, 3.05 g. (0.01 mole), prepared as described in Example 70, supra, was added with mechanical stirring to 40 ml. of anhydrous tetrahydrofuran maintained under a nitrogen atmosphere and then cooled to about -75° C. To the cold solution there was added, over a period of about 15-20 minutes, 4.28 ml. of a hexane solution of n-butyllithium (2.4 molar in hexane), while maintaining the reaction temperature below -70° C. After the addition was complete, the reaction mixture was stirred for about 30 minutes at a temperature of about -75° C., followed by the dropwise addition of 5 ml. of methyl iodide over a period of about 10-15 minutes. The reaction product mixture was stirred overnight while being cooled in a dry iceacetone bath, warming gradually to about 0° C., by morning. A peach-colored solid precipitated during the night. The reaction product mixture was warmed to room temperature and methylene chloride added, forming a red solution. The solution was concentrated in vacuo. The residue thus obtained was redissolved in methylene chloride and the solution was washed twice with cold salt water and dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate concentrated in vacuo to leave a residue. The residue was taken up in ethyl acetate and passed through a layer of silica gel (400 ml.). The ethyl acetate solution so treated was concentrated in vacuo, and the oil which remained was dissolved in methylene chloride, treated with decolorizing carbon, filtered, and the filtrate concentrated to dryness in vacuo. The residue thus obtained was dissolved in ethyl ether, and upon cooling a solid crystallized, and was filtered off. The solid had a melting point of about 128°-130° C., and weighed 1.1 g. The solid was identified by NMR spectrum and elemental analyses as 3-(4-chlorophenyl)tetrahydro-5-methyl-2-(3-pyridyl)-4H-1,3-thiazin-4-one. Analyses calculated for C16H15ClN2OS: