Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>>[CH2:25]([N:27]([CH2:28][CH3:29])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)[CH3:26]
Reactant: CCNCC
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Product: CCN(CC)CCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1

Procedure:
The product from Example 1C and diethylamine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.75 (m, 1H), 7.80 (m, 4H), 7.60 (m, 2H), 6.85 (s, 1H), 3.6 (t, J=7.5 Hz, 2H), 3.25-3.5 (m, 6H), (t, 6H, J=6.6 Hz); MS (DCI) m/z 319 (M+H)+;
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[OH:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20]([N:38]4[CH2:39][CH2:40][CH:35]([OH:34])[CH2:36][CH2:37]4)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Reactant: OC1CCNCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N4CCC(O)CC4)c3)n2)n1
Yield: 57.4 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available 4-hydroxypiperidine [CAS-no. 5382-16-1] (0.207 g, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.130 g, 57%) as a white solid. MS (ISP) 554.3 [(M+H)+]; mp 195° C.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[NH:12]1[CH2:15][CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>O1CCCC1>[N:12]1([CH2:2][C:3]2[N:7]([CH3:8])[N:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: Cn1nc([N+](=O)[O-])cc1CBr
Reactant: C1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1nc([N+](=O)[O-])cc1CN1CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.8 %

Procedure:
To a solution of 5-(bromomethyl)-1-methyl-3-nitro-1H-pyrazole (436 mg, 1.98 mmol) in tetrahydrofuran (10 mL) was added azetidine (141 mg, 0.17 mL, 2.48 mmol) and diisopropylethyl amine (307 mg, 0.42 mL, 2.38 mmol) drop wise and the resulting mixture was stirred at room temperature for 24 h. The solution was concentrated and the residue dissolved in dichloromethane (50 mL), washed with water (50 mL). The aqueous layer was extracted with methylene chloride (2×50 mL) and the organic phases combined and dried over magnesium sulfate. The resulting mixture was filtered and evaporated and the residue purified by flash chromatography (40 g, 1% to 5% methanol in dichloromethane) to give 5-(azetidin-1-ylmethyl)-1-methyl-3-nitro-1H-pyrazole (349 mg, 90%) as a colorless oil.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH:4]=[CH2:5].[CH2:17]([Zn]CC)C.ICI>C1(C)C=CC=CC=1>[CH:4]1([CH2:3][CH:2]([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=2[CH3:16])[C:9]([O:11][CH3:12])=[O:10])[OH:1])[CH2:17][CH2:5]1
Reactant: C=CCC(O)c1cc(C(=O)OC)ccc1C
Reactant: CC[Zn]CC
Solvent: ICI
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C)c(C(O)CC2CC2)c1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
Into a 100-mL 3-necked round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 3-(1-hydroxybut-3-en-1-yl)-4-methylbenzoate (compound 4.3, 50 mg, 0.23 mmol). Diethylzinc (1 M in toluene) (3.45 mL, 3.45 mmol) in toluene (10 mL) was added and the mixture was cooled to 0-5° C., then diiodomethane (924 mg, 3.45 mmol) was added drop-wise. The resulting mixture was stirred for 2 h at room temperature, then carefully quenched with 1 M aqueous HCl (50 mL) and diluted with MTBE (50 mL). The aqueous phase was extracted with MTBE (3×20 mL) and the combined organics was washed with saturated sodium bicarbonate (2×20 mL), brine (2×20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:3) as the eluent to yield the title compound as a yellow oil (40 mg, 74%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:20][O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>O1CCCC1>[CH3:20][O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([O:18][CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:19])[S:12][CH:13]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (7.0 g) synthesized in Example 4 and 4-hydroxybenzoic acid methyl ester (3.5 g) were dissolved in tetrahydrofuran (100 mL), triphenylphosphine (6.06 g) and diethyl diazodicarboxylate (4.0 g) were added under ice-cooling, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1) to give the title compound (7.0 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=O.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:20][CH3:21]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH2:7][C:17]2[CH:16]=[CH:15][C:14]([O:19][CH2:20][CH3:21])=[C:13]([F:12])[CH:18]=2)[CH:10]=1
Reactant: CCOc1ccccc1F
Reactant: O=C(O)c1cc(Br)ccc1Cl
Product: CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1F

Procedure:
Synthesis was performed by a similar method as in Preparation Example 14 using 5-bromo-2-chlorobenzoic acid and 2-fluorophenetole.
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][CH3:8])=[CH:5][N:4]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[O:25]=[C:26]1[C@H:31]2[CH2:32][C@H:28]([CH:29]=[CH:30]2)[N:27]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>C1COCC1>[C:36]([O:35][C:33](=[O:34])[NH:27][C@@H:28]1[CH2:32][C@H:31]([C:26](=[O:25])[N:7]([C:6]2[C:2]([Cl:1])=[N:3][N:4]([C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)[CH:5]=2)[CH3:8])[CH:30]=[CH:29]1)([CH3:37])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C=C[C@H]1C2
Reactant: CNc1cn(-c2cccnc2)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C(=O)[C@@H]1C=C[C@H](NC(=O)OC(C)(C)C)C1)c1cn(-c2cccnc2)nc1Cl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-chloro-N-methyl-1-(pyridin-3-yl)-1H-pyrazol-4-amine (0.20 g, 0.96 mmol) in THF (10 mL) was cooled to a temperature of about −78° C. LHMDS (1 M solution in hexanes, 1.0 mL, 1.00 mmol) was added, and the solution was stirred at a temperature of about −78° C. for 15 minutes. A solution of (1R,4S)-tert-butyl 3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2- carboxylate (0.20 g, 0.96 mmol) dissolved in THF (3 mL) was added to the solution at a temperature of about −78° C. in one portion. After stirring for one hour at a temperature of about −78° C., the cooling bath was removed and the reaction warmed to a temperature of about 20° C. After stirring for an additional five minutes, acetic acid (AcOH, 0.1 mL) was added to the solution. The reaction mixture was concentrated and purified via silica gel chromatography eluting with EtOAc/hexanes to give the title compound F109 as a white solid (0.25 g, 59%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[C@H:10]([C:15]([F:18])([F:17])[F:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-]S([O-])(=O)=O.[Na+].[Na+].[O:26]=[C:27]1[NH:32][C:31]2[CH:33]=[C:34]([CH:37]=O)[CH:35]=[CH:36][C:30]=2[S:29][CH2:28]1.[BH4-].[Na+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][CH2:37][C:34]2[CH:35]=[CH:36][C:30]3[S:29][CH2:28][C:27](=[O:26])[NH:32][C:31]=3[CH:33]=2)[C@H:10]([C:15]([F:18])([F:16])[F:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](C(F)(F)F)C1
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccc3c(c2)NC(=O)CS3)[C@H](C(F)(F)F)C1
Reaction time: 12 h

Procedure:
To a solution of (3R,4S)-4-amino-3-(trifluoromethyl)piperidine-1-carboxylic acid tert-butyl ester (2d) (1 equiv.) in acetonitrile is added Na2SO4 and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxaldehyde (in) (1 equiv.). After 12 hr at RT, the reaction is filtered through a sintered-glass funnel and the filtrate is concentrated under vacuum. The remaining residue is dissolved in EtOH and NaBH4 (1 equiv.) is added. After 12 h, the reaction is concentrated and the residue is dissolved in 1 N HCl. The solution is neutralized with 6 N NaOH and extracted with EtOAc. The organic fraction is dried over Na2SO4 and concentrated under vacuum. The crude product is purified by flash chromatography on silica gel to afford the title compound.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:10][CH2:11][CH2:12][CH:3]([C:4]=23)[C:2]1=[O:13].[Cl:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>>[Cl:14][CH2:15][CH2:16][C:17]([C:6]1[CH:7]=[CH:8][C:9]2[NH:1][C:2](=[O:13])[CH:3]3[CH2:12][CH2:11][CH2:10][C:5]=1[C:4]=23)=[O:18]
Reactant: O=C1Nc2cccc3c2C1CCC3
Reactant: O=C(Cl)CCCl
Product: O=C(CCCl)c1ccc2c3c1CCCC3C(=O)N2

Procedure:
Using 2a,3,4,5-tetrahydrobenz[cd]indol-2(1H)-one and 3-chloropropionyl chloride, the same procedure as in Reference Example 2 was followed, to yield the title compound as a colorless needle crystal having a melting point of 175° to 178° C.
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:15]=2[N:14]=[C:13]([C:16]([N:18]2[CH2:23][CH2:22][C:21]4([CH2:32][C:31](=[O:33])[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([C:34]6[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=6)[CH:29]=5)[O:24]4)[CH2:20][CH2:19]2)=[O:17])[CH:12]=[C:11]3[C:40]2[CH:49]=[CH:48][C:43]([C:44]([O:46]C)=[O:45])=[CH:42][CH:41]=2)[CH2:5][CH2:4]1.CO.Cl>C1COCC1>[CH:3]1([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:15]=2[N:14]=[C:13]([C:16]([N:18]2[CH2:19][CH2:20][C:21]4([CH2:32][C:31](=[O:33])[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([C:34]6[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=6)[CH:29]=5)[O:24]4)[CH2:22][CH2:23]2)=[O:17])[CH:12]=[C:11]3[C:40]2[CH:49]=[CH:48][C:43]([C:44]([OH:46])=[O:45])=[CH:42][CH:41]=2)[CH2:5][CH2:4]1
Reactant: COC(=O)c1ccc(-c2cc(C(=O)N3CCC4(CC3)CC(=O)c3cc(-c5cnn(C)c5)ccc3O4)nc3c(C4CC4)cccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCN(C(=O)c4cc(-c5ccc(C(=O)O)cc5)c5cccc(C6CC6)c5n4)CC2)O3)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
Aqueous 1N NaOH (0.500 ml, 0.500 mmol) was added to a stirred solution of methyl 4-(8-cyclopropyl-2-{[6-(1-methyl-1H-pyrazol-4-yl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl]carbonyl}quinolin-4-yl)benzoate (160 mg, 0.255 mmol) in THF (1 ml)-MeOH (1 ml) and the mixture was stirred at room temperature overnight. Aqueous 1N HCl (0.5 ml) was added to the mixture and the solvent was evaporated under reduced pressure. The residue was suspended in CHCl3-MeOH (8:2) and the mixture stirred for 1 h. at room temperature. The insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (CHCl3/MeOH=92/8) and the product was precipitated with CHCl3/hexane to give intended compound (106 mg, 0.173 mmol, 67.8% yield) as a pale yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C(=O)([O-])[O-].[Na+].[Na+].[Cl:11][C:12]([Cl:19])([Cl:18])[CH2:13][O:14][C:15](Cl)=[O:16]>CC(C)=O.O>[Cl:11][C:12]([Cl:19])([Cl:18])[CH2:13][O:14][C:15]([NH:1][CH2:2][CH2:3][OH:4])=[O:16]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NCCO)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2-Aminoethanol (20 g.) and sodium carbonate (27.8 g.) is dissolved in acetone-water (4:1) (500 ml.) and 2,2,2-trichloroethylchloroformate (104.2 g.) is added dropwise to the stirred solution at 0° C. over a period of 0.5 hours. The mixture is stirred at 0° C. for a further 3 hours. The solids are filtered off and washed with acetone and the filtrate is evaporated to dryness. The resulting gum is taken up in chloroform (500 ml.) and washed with water (3×100 ml.). The chloroform solution is evaporated to dryness to give 2-(2,2,2-trichloroethoxycarbonylamino)ethanol; ν max (film), 3300, 2910, 1700, 1520, 1240, 1140, 1055, cm-1 ; δ (CDCl3) 3.43 (2H, t, J 7.5 Hz, HOCH2CH2NH--), 3.77 (2H, t, J 7.5 Hz, HOCH2CH2NH--) and 4.77 ppm (2H, s, --COOCH2CCl3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11](C(O)=O)=[N:12][CH:13]=1)([O-:3])=[O:2].C1(P([N:34]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C(O)(C)(C)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:34])=[N:12][CH:13]=1)([O-:3])=[O:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc(Oc2cccc([N+](=O)[O-])c2)cn1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: Nc1ccc(Oc2cccc([N+](=O)[O-])c2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.7 %

Procedure:
A mixture of 5-(3-nitrophenoxy)pyridine-2-carboxylic acid (10.4 g, 40.0 mmol), diphenylphosphoryl azide (10.8 mL, 50.0 mmol), triethylamine (6.92 mL, 50.0 mmol) and tert-butanol (200 mL) was stirred at room temperature for 3 hr, and then stirred with heating under reflux for 15 hr. The reaction mixture was concentrated under reduced pressure, trifluoroacetic acid (20 mL) was added to the residue, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, 8N aqueous sodium hydroxide solution (70 mL) was added to the residue, and the mixture was stirred with heating under refluxing conditions for 3 hr. After extraction with ethyl acetate (×3), the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was dried to give the title compound (5.80 g, 63%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].O.[OH-].[Na+].[C:14](#[N:17])[CH:15]=[CH2:16]>C(O)(=O)C>[C:14]([CH2:15][CH2:16][NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])#[N:17]
Reactant: C=CC#N
Reactant: Nc1cccc(C(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: N#CCCNc1cccc(C(=O)O)c1
Temperature: 5 °C

Procedure:
200.0 g of 3-aminobenzoic acid in 2 1 of water were admixed with 53.2 g of sodium hydroxide. At 30° C., 126.6 g of acrylonitrile were added dropwise, and the mixture was then heated under reflux for 22 hours. The mixture was then cooled to 5° C. and acetic acid was added (pH=5) and the precipitate which had formed was filtered off with suction and washed with water.
Reaction SMILES: [F:1][C:2]([F:30])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:29]=[CH:28][C:22](C(N=[N+]=[N-])=O)=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].C1(C)C=CC=CC=1.[N-:38]=[C:39]=[O:40]>ClCCl>[N:38]([C:22]1[CH:28]=[CH:29][C:19]([C:16]2[N:17]=[CH:18][N:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][C:2]([F:30])([F:1])[C:3]([F:4])([F:5])[F:6])=[CH:9][CH:10]=3)[N:15]=2)=[CH:20][CH:21]=1)=[C:39]=[O:40]
Reactant: [N-]=[N+]=NC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Reactant: [N-]=C=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A 250 mL, three-neck flask, fitted with magnetic stirring, air condenser, temperature probe and nitrogen inlet, was charged with 4-(1-(4-(perfluoroethoxy)-phenyl)-1H-1,2,4-triazol-3-yl)benzoyl azide (5.00 g, 11.2 mmol) and toluene (100 mL). The brown solution was heated to 100° C. slowly and allowed to stir for 1 hour. Analysis of crude reaction mixture by LCMS shows the desired isocyanate. The reaction was cooled to 25° C. and the solvent removed by rotary evaporation to give a solid. The solid was dissolved in dichloromethane and the solution filtered to remove a small amount of a black insoluble material. The light-brown filtrate was rotary evaporated to yield 4.6 g of a tan solid. The solid was taken up in 30 mL of methyl tert-butyl ether, heated to effect a slightly turbid solution and filtered hot. The filtrate was re-heated to effect solution again and heptane (about 10-15 mL) was slowly added. The solution was placed on a rotary evaporator and the solvent was slowly removed under reduced pressure. When the first sign of solid was noted, the vacuum was broken and the mixture was allowed to slowly rotate at 40° C. to effect precipitation of solid. The solid was collected by vacuum filtration to give 3.4 g (77% yield) of a light tan solid, mp=119-121° C. 1H NMR (600 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.10-8.05 (m, 4H), 7.60 (d, J=8.7 Hz, 2H), 7.38 (dd, J=8.3, 1.6 Hz, 2H). 13C NMR (151 MHz, DMSO) δ 161.77, 146.66, 144.37, 136.23, 134.45, 128.26, 127.78, 125.91, 124.93, 123.57, 121.59.
Reaction SMILES: [F:1][C:2]([F:18])([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)[C:3](OCC)=[O:4].[NH2:19][NH2:20].Cl>C(O)C>[F:1][C:2]([F:18])([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)[C:3]([NH:19][NH2:20])=[O:4]
Reactant: CCOC(=O)C(F)(F)c1ccc2ncccc2c1
Reactant: NN
Agent: Cl
Solvent: CCO
Product: NNC(=O)C(F)(F)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
As shown in step 3-ii in Scheme 3, Compound 1009 (10.0 g, 39.80 mmol) was dissolved in ethanol (100 mL), hydrazine (7.65 g, 7.50 mL, 239 mmol) was added, and the reaction mixture was stirred at room temperature for 10 minutes. After pouring the mixture into 2N HCl solution, the aqueous mixture was washed twice with DCM and the pH was adjusted to 8 while bubbling nitrogen gas through the solution. The resulting aqueous solution was exhaustively extracted with DCM (10×) and the combined organics dried over MgSO4, filtered, and the volatiles removed under reduced pressure to provide 2,2-difluoro-2-(quinolin-6-yl)acetohydrazide as a yellow solid (Compound 1010, 91% yield). This compound that was used directly without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([SH:8])=[N:5][N:4]=1.[H-].[Na+].Cl[C:12]1[C:17]([Cl:18])=[N:16][CH:15]=[CH:14][N:13]=1>CN(C=O)C.C1C=CC=CC=1>[Cl:18][C:17]1[C:12]([S:8][C:6]2[S:7][C:3]([S:2][CH3:1])=[N:4][N:5]=2)=[N:13][CH:14]=[CH:15][N:16]=1
Reactant: Clc1nccnc1Cl
Reactant: CSc1nnc(S)s1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CSc1nnc(Sc2nccnc2Cl)s1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
The title compound was prepared according the procedure described in Example 1 by using 5-(methylthio)-1,3,4-thiadiazole-2-thiol (1.64 g, 10.00 mmol), NaH (60% dispersion in mineral oil, 445 mg, 11.00 mmol), and 2,3-dichloropyrazine (1.04 ml, 10.00 mmol) in DMF and benzene (12 ml, 1/1) by stirring at 50° C. for 20 hr and then at 110° C. for 4 hr under nitrogen atmosphere.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7](/[CH:11]=C/C(Cl)=O)[CH:8]=[CH:9][CH:10]=1)[CH2:2][CH3:3].[OH:16]C1C=C(C=CC=1)C=O.ICCC>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH:11]=[O:16])[CH2:2][CH3:3]
Reactant: O=Cc1cccc(O)c1
Reactant: CCCOc1cccc(/C=C/C(=O)Cl)c1
Solvent: CCCI
Product: CCCOc1cccc(C=O)c1

Procedure:
For example, (E)-3-(3′-propyloxyphenyl)-2-propenoyl chloride, used in Example 3 (i), can be prepared from commercially available 3-hydroxybenzaldehyde by reacting 3-hydroxybenzaldehyde with 1-iodopropane to give 3-propyloxy benzaldehyde. 3-Propyloxy benzaldehyde is then reacted with malonic acid to give the corresponding propenonic acid which is subsequently converted into (E)-3-(3′-propyloxyphenyl)-2-propenoyl chloride by reaction with oxalyl chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[C:6](=[O:16])[NH:5]2.[CH3:17][O:18][C:19]([C:21]1(OC)[CH2:25][CH2:24][CH:23](OC)O1)=[O:20].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:17][O:18][C:19]([C:21]1[N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[C:6](=[O:16])[NH:5]3)[CH:23]=[CH:24][CH:25]=1)=[O:20]
Reactant: Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Reactant: COC(=O)C1(OC)CCC(OC)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1cccn1-c1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-]

Procedure:
7 g (27.1 mmol) of 6-amino-7-nitro-2,3(1H,4H)-quinoxalinedione, 5.1 g (27.1 mmol) of 2-methoxycarbonyl-2,5-dimethoxytetrahydrofuran and 4.5 g (54.2 mmol) of sodium acetate in 500 ml of glacial acetic acid were refluxed for one hour. The reaction mixture was concentrated and then the crude product was purified by column chromatography on silica gel (mobile phase: toluene/acetone/glacial acetic acid=10/10/1).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:10]=2)[CH:5]=[CH:4][N:3]=1.Cl.[OH2:23]>>[F:8][C:7]1[C:2](=[O:23])[NH:3][CH:4]=[CH:5][C:6]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:10]=1
Reactant: Fc1c(-c2ccnc(NC3CCOCC3)n2)ccnc1Cl
Reactant: O
Agent: Cl
Product: O=c1[nH]ccc(-c2ccnc(NC3CCOCC3)n2)c1F
Temperature: 140 °C
Yield: 75.1 %

Procedure:
4-(2-Chloro-3-fluoropyridin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine (0.08 g, 0.259 mmol) and 1M HCl (3.89 mL, 3.89 mmol) were added to a microwave vial. The vial was heated in a microwave at 140° C. for a total of 10 hours in 2 hour segments. The reaction mixture was diluted with water, and the desired 3-fluoro-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.0565 g, 0.195 mmol, 75.1% yield) was collected by vacuum filtration.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:10][CH3:11])[NH:9][CH2:8][CH2:7][S:6]1)=[O:4].[Cl:12][C:13]1[CH:14]=[C:15]([N:20]=[C:21]=[O:22])[CH:16]=[C:17]([Cl:19])[CH:18]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1([CH2:10][CH3:11])[N:9]([C:21](=[O:22])[NH:20][C:15]2[CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]([Cl:12])[CH:14]=2)[CH2:8][CH2:7][S:6]1)=[O:4]
Reactant: CCC1(C(=O)OC)NCCS1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Solvent: Cc1ccccc1
Product: CCC1(C(=O)OC)SCCN1C(=O)Nc1cc(Cl)cc(Cl)c1
Yield: 78.4 %

Procedure:
A mixture of 0.62 g of the 2-ethyl thiazolidine-2-carboxylic acid methyl ester thus obtained, 0.66 g of 3,5-dichlorophenyl isocyanate and 10 ml of toluene was stirred at room temperature for 1 hour. Then, the precipitate was filtered to give 1.00 g (yield 77.8%) of 2-ethyl-3-(3,5-dichlorophenylcarbamoyl) thiazolidine-2-carboxylic acid methyl ester with a melting point of 187°-188° C. The results of the elementary analysis were as follows: Found (calculated in parentheses): C 46.48% (46.29%), H b 4.35% (4.44%), N 7.50% (7.71%), Cl 19.86% (19.52%).