Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14]>FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[N+](C)([O-])=O>[CH3:9][C:10]1[CH:11]=[C:12]([C:13]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)=[O:14])[CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccccc1
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(=O)c2cccc(C)c2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To commercially available nitromethane (5 ml) were added commercially available anisole (541 mg), commercially available 3-methylbenzoyl chloride (773 mg) and commercially available scandium(III) trifluoromethanesulfonate (49 mg), and the admixture was stirred at 60° C. overnight. The reaction mixture was partitioned between water and chloroform, and the chloroform layer was dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel eluting with hexane/acetone to obtain 635 mg of the title compound (yield: 56%).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][N:13]([C:15]1[S:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1)[NH2:14].CN(C)C=O>O>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([NH:14][N:13]([CH3:12])[C:15]1[S:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1)=[O:11])([OH:6])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CN(N)c1nc(-c2ccccc2)cs1
Solvent: CN(C)C=O
Solvent: O
Product: CN(NC(=O)c1ccccc1C(=O)O)c1nc(-c2ccccc2)cs1

Procedure:
A solution of 1.5 g. of phthalic anhydride and 2.0 g. of 1-methyl-1-(4-phenylthiazol-2-yl)hydrazine in 50 ml. of dimethylformamide is stirred for 16 hours. Addition of water precipitates a gummy solid which is taken up in ethyl acetate and the ethyl acetate solution is extracted with water, dried over anhydrous sodium sulfate and evaporated, giving a residue which is crystallized from ether/petroleum ether, yielding 0.6 g. of product, m.p. 122°-4°.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:11])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16]>CCOC(C)=O>[Cl:20][C:19]([Cl:22])([Cl:21])[CH2:18][O:17][C:15](=[O:16])[NH:11][C:7]1[N:8]([CH3:10])[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: Cn1nc(C(C)(C)C)cc1N
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
A solution of 5-tert-butyl-2-methyl-2H-pyrazol-3-ylamine (0.5 g, 3.26 mmol) in EtOAc (10 mL) was treated with aqueous NaOH (1M, 5.87 mmol), followed by 2,2,2-trichloroethyl chloroformate (0.54 mL, 3.92 mmol) and the reaction mixture was stirred at RT for 1 h. The mixture was partitioned between EtOAc (10 mL) and water (2×10 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by FCC, using 0-100% EtOAc in cyclohexane to afford the title compound as a pale orange gum (0.915 g, 86%). LCMS (Method 3): Rt 3.88 min, m/z 328/330 [MH+].
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.[CH3:15][N:16]1C(=O)CCC1.C([Cu])#N>CCOC(C)=O>[N+:8]([C:7]1[C:2]([C:15]#[N:16])=[N:3][CH:4]=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: CN1CCCC1=O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Agent: N#C[Cu]
Solvent: CCOC(C)=O
Product: N#Cc1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 33.7 %

Procedure:
A microwave reaction vial was charged with 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (2 g, 8.83 mmol), NMP (4.41 ml) and CuCN (0.830 g, 9.27 mmol). The vial was sealed and the mixture was irradiated in the MW at 175° C. for 15 min. Upon cooling to RT, the reaction mixture was poured onto ice and EtOAc was added. The mixture was filtered through Celite, washing with EtOAc and a small amount of MeOH. The layers of the filtrate were separated, and the aqueous portion was extracted again with EtOAc. The combined organic portions were dried with sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography, using a gradient of 0-30% EtOAc in heptane to provide 3-nitro-5-(trifluoromethyl)picolinonitrile (645 mg, 2.97 mmol, 33.7% yield) as a yellow oil that solidified upon standing. LC/MS (ESI) m/z=218.1 (M+H).
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:6]=2[O:5][CH:4]=1)#[N:2].C(O)=[O:28]>Cl>[C:1]([C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:6]=2[O:5][CH:4]=1)(=[O:28])[NH2:2]
Reactant: O=CO
Reactant: CS(=O)(=O)Nc1cc2occ(C#N)c(=O)c2cc1Oc1ccccc1F
Agent: Cl
Product: CS(=O)(=O)Nc1cc2occ(C(N)=O)c(=O)c2cc1Oc1ccccc1F
Reaction time: 24 h
Yield: 65 %

Procedure:
3.73 g of 3-cyano-6-(2-fluorophenoxy)-7-methylsulfonylamino-4H-1-benzopyran-4-one was dissolved in 100 ml of formic acid saturated with hydrogen chloride. The mixture was stirred for 24 hours at 25°-30° C. The solvent was removed by distillation under reduced pressure. The residue was mixed with 100 ml of water. The resulting crystal was collected by filtration and recrystallized from acetic acid to obtain 2.54 g (yield: 65%) of 3-carbamoyl-6-(2-fluorophenoxy)-7-methylsulfonylamino-4H-1-benzopyran-4-one. The properties (melting point and IR) of this compound agreed with those of the compound obtained in Example 4.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]1=[O:20])[CH3:4].CC(C)=O>C(O)C>[CH2:3]([C:5]1[CH:6]([OH:20])[C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:10]=[CH:9][CH:8]=2)[CH3:4]
Reactant: CCC1Cc2c(cccc2-c2ccccc2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: CCC1=Cc2c(-c3ccccc3)cccc2C1O
Reaction time: 3.5 h
Yield: 100.1 %

Procedure:
A 200-ml three-necked round flask equipped with a stirring bar, a Dimroth condenser, a dropping funnel and a thermometer was charged with 0.85 g (22.6 mmol) of sodium borohydride and 28 ml of ethanol. To the mixture was dropwise added a solution containing 10.6 g (45.1 mmol) of the above-obtained 2-ethyl-4-phenyl-1-indanone dissolved in 20 ml of ethanol at room temperature under a nitrogen atmosphere. After the addition was completed, the temperature of was elevated to 50° C., and the reaction mixture was stirred for 3.5 hours. After the reaction was completed, the unreacted sodium borohydride was decomposed by acetone. Then, the reaction mixture was concentrated under reduced pressure, and then dissolved in 50 ml of water and extracted with 50 ml of ether. After the organic phase was separated, the aqueous phase was extracted with 50 ml of ether two times. The combined organic phase was washed with 100 ml of a saturated aqueous solution of sodium chloride, followed by drying over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain 10.67 g of the desired product as a pasty pale yellow liquid (mixture of two kinds of isomers) (yield; 99%).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][OH:7])[C:3]([OH:5])=[O:4].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1>COCCOC>[CH3:1][C:2]([CH3:8])([CH2:6][OH:7])[C:3]([O:5][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=1)=[O:4]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(CO)C(=O)O
Solvent: COCCOC
Product: COc1ccc(COC(=O)C(C)(C)CO)cc1

Procedure:
A solution of 1.03 g (8.7 mmol) of 2,2-dimethyl-3-hydroxypropionic acid, 1.8 mL (12.9 mmol), of TEA and 1.3 mL (9.5 mmol) of para-methoxybenzyl chloride in 8 mL of DME was stirred at rt for 24 h. The mixture was partitioned between 200 mL Et2O and 100 mL of H2O. After separating layers, the organic phase was washed with 100 mL of 1 N NaHCO3, 100 mL of 2 N HCl, 2×100 mL of H2O, 100 mL of brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography using a gradient of 3:1 v/v to 3:2 v/v of hexanes/EtOAc as the eluant to afford the title compound: RF: 0.17 (4:1 v/v hexanes/EtOAc); 1H-NMR (500 MHz) δ 1.21 (s, 6H), 3.57 (s, 2H), 3.82 (s, 3H), 5.09 (s, 2H), 6.90 (d, J=8.8, 2H), 7.28 (d, J=8.8, 2H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([Cl:13])[C:6]([Cl:12])=[C:7]([OH:11])[CH:8]=2)[C:3]1=[O:14].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[C:5]([Cl:13])[C:6]([Cl:12])=[C:7]([O:11][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:8]=2)[C:3]1=[O:14]
Reactant: CC1Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1Cc2cc(OCc3ccccc3)c(Cl)c(Cl)c2C1=O

Procedure:
A stirred mixture of 2-methyl-5-hydroxy-6,7-dichloro-1-indanone (27.6 g., 0.12 mole), potassium carbonate (24.9 g., 0.18 mole) and benzyl bromide (21.4 ml., 0.18 mole) in dimethylformamide (100 ml.) is warmed at 55°-60° C. for 2 hrs., then poured into water (1 l.) to precipitate 35.5 g. of 2-methyl-5-benzyloxy-6,7-dichloro-1-indanone which melts at 153°-155° C. after crystallization from benzene:hexane, 3:2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[C:4]([CH3:17])[N:3]=1.[NH2:18][CH2:19][C:20]1[C:21]([Cl:36])=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25](C(OC(C)(C)C)=O)[CH:24]=[CH:23]2.ClC1N=C(NC2NN=C(C3CC3)C=2)C=CN=1.C(O)(=O)CCCCC(O)=O.N1C2C(=CC(C(N)C)=CC=2)C=C1>>[Cl:36][C:21]1[C:20]([CH2:19][NH:18][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([CH:14]4[CH2:16][CH2:15]4)[NH:11][N:10]=3)[CH:5]=[C:4]([CH3:17])[N:3]=2)=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[CH:24][NH:25]2
Reactant: CC(C)(C)OC(=O)n1ccc2c(Cl)c(CN)ccc21
Reactant: Cc1cc(Nc2cc(C3CC3)[nH]n2)nc(Cl)n1
Agent: CC(N)c1ccc2[nH]ccc2c1
Agent: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Agent: O=C(O)CCCCC(=O)O
Product: Cc1cc(Nc2cc(C3CC3)[nH]n2)nc(NCc2ccc3[nH]ccc3c2Cl)n1

Procedure:
N2-((4-chloro-1H-indol-5-yl)methyl)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methylpyrimidine-2,4-diamine (I-19) was prepared using procedure analogous to the preparation of I-8, step 1, except 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-6-methyl-pyrimidin-4-amine 185 and tert-butyl 5-(aminomethyl)-4-chloro-1H-indole-1-carboxylate were used in place of 53 and 1-(1H-indol-5-yl)ethanamine adipic acid salt, respectively, to afford I-19; MS (ESI) m/z=394.1 [M+1]+.
Reaction SMILES: [C:1]([O:7][C:8]1[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=1)[NH:11][C:12](=[O:17])[CH2:13][C:14](=[O:16])[CH3:15])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1.N1C2C(=CC=CC=2)C=CC=1.C1(C)C=CC=CC=1>C([O-])([O-])OC>[C:1]([O:7][C:8]1[CH:9]=[C:10]([CH:18]=[CH:19][CH:20]=1)[NH:11][C:12](=[O:17])/[CH:13]=[C:14](\[O:16][CH3:21])/[CH3:15])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Oc1cccc(NC(=O)CC(C)=O)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COC([O-])[O-]
Solvent: Cc1ccccc1
Solvent: c1ccc2ncccc2c1
Product: CCCCC(=O)Oc1cccc(NC(=O)/C=C(/C)OC)c1
Temperature: 140 °C
Yield: 2955.3 %

Procedure:
A solution of 47 g of m-valeryloxy-acetylacetanilide in 50 ml of methyl orthoformate and 0.5 g of p-toluene sulfonic acid stood at room temperature for 16 hours and then 1 g of quinoline and 200 ml of toluene were added thereto. The mixture was heated at 140°C. for 4 hours while removing the methanol formed and the solvent was then evaporated. The residue was chromatographed over silica gel and was eluted with an 8-2 methylene chloride-acetone mixture to obtain 25 g of m-valeryloxy-3-methoxy-crotonanilide (isomer E) melting at 84°C.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:19]([OH:21])=[O:20])[CH2:18][CH2:17][CH:16]=[CH:15][CH2:14]1.IC>C1COCC1>[CH3:1][C:13]1([C:19]([OH:21])=[O:20])[CH2:18][CH2:17][CH:16]=[CH:15][CH2:14]1
Reactant: O=C(O)C1CC=CCC1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C(=O)O)CC=CCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
N-isopropylpropan-2-amine (50.1 g, 69.5 mL, 495.5 mmol) was dissolved in 50 mL of THF. To the solution was added n-butyllithium (174.4 mL of 2.5 M solution in hexanes, 436.0 mmol) at −78° C. The resulting solution was stirred for 30 minutes at −78° C. To the reaction was then added cyclohex-3-ene-1-carboxylic acid (25.0 g, 198.2 mmol) and the reaction was allowed to warm to 60° C. for 2 hrs. The reaction was cooled to room temp and iodomethane (29.5 g, 13.0 mL, 208.1 mmol) was added and the reaction was allowed to stir overnight and then quenched with 1 N HCl until the pH<4. The crude product was extracted into CH2Cl2 and water. The organic phase was concentrated in vacuo to a yellow oil (27 g) and used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][NH2:13])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([C:24](OCC)=[O:25])[N:23]=2)[CH:20]=1>>[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([CH:21]=[C:22]([C:24]([NH:13][CH2:12][C:4]3[CH:5]=[CH:6][C:7]([C:8]([F:10])([F:11])[F:9])=[C:2]([F:1])[CH:3]=3)=[O:25])[N:23]=2)[CH:20]=1
Reactant: NCc1ccc(C(F)(F)F)c(F)c1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(NCc1ccc(C(F)(F)F)c(F)c1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using (3-fluoro-4-(trifluoromethyl)phenyl)methanamine and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [C:1]([Mg]Br)([CH3:3])=[CH2:2].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O.[NH4+].[Cl-]>C1COCC1>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:8]=1[NH:13][C:1]([CH3:3])=[CH:2]2
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: C=C(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc2cccc(F)c2[nH]1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
1600 ml of a 0.5M solution of isopropenylmagnesium bromide in THF are cooled to −25° C. under an argon atmosphere, a solution of 37.65 g of 2-fluoronitrobenzene in 250 ml of THF is then added dropwise and the mixture is left stirring at −20° C. for 1 hour. The reaction mixture is poured into a saturated NH4Cl solution, the aqueous phase is extracted with ether and the combined organic phases are concentrated under vacuum. The residue is taken up in water and extracted with DCM, the organic phase is washed with water and with a saturated NaCl solution and dried over MgSO4, and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, elution being carried out with a cyclohexane/EtOAc mixture (95/5; v/v). 12.35 g of the expected compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8].[OH-].[Na+].[CH2:27]([NH:30][C:31](=[O:36])C(Cl)(Cl)Cl)[CH2:28][CH3:29]>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([S:18]([NH:21][C:31]([NH:30][CH2:27][CH2:28][CH3:29])=[O:36])(=[O:20])=[O:19])[CH2:14][CH2:13]1)=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)NCCC1CCN(S(N)(=O)=O)CC1
Reactant: CCCNC(=O)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CCCNC(=O)NS(=O)(=O)N1CCC(CCNC(=O)c2cc(Cl)ccc2OC)CC1
Yield: 14.1 %

Procedure:
376 mg (1 mmol) of 4-(2-(5-chloro-2-methoxybenzamido)ethyl)piperidine-1-sulfonamide and 160 mg (4 mmol) of sodium hydroxide were heated in 5 ml of N-methyl-2-pyrrolidone with 410 mg (2 mmol) of N-(n-propyl)trichloroacetamide at 80° C. for 10 minutes. The reaction mixture was poured onto ice/2 M hydrochloric acid, and the precipitated solid was filtered off with suction and washed with water until neutral. Purification by chromatography (silica gel; toluene/ethanol/ethyl acetate 8/1/1) resulted in 65 mg (14%) of the title compound as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([S:13][C:14](=O)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].FC1C=[C:26]2[C:31](=[CH:32][C:33]=1[Cl:34])[CH:30]=[N:29][CH:28]=[CH:27]2.C1CCN2C(=NCCC2)CC1>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([S:13][C:14]2[CH:15]=[C:26]3[C:31](=[CH:32][C:33]=2[Cl:34])[CH:30]=[N:29][CH:28]=[CH:27]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1cc2ccncc2cc1Cl
Reactant: CC(=O)S[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Sc2cc3ccncc3cc2Cl)C1
Yield: 86.8 %

Procedure:
3.5 g (14.2 mmol) (S)-3-Acetylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester (266) were dissolved in 95 ml MeOH and treated with 2.34 g (16.9 mmol) potassium carbonate and stirred over night. After evaporation of all volatiles the residue was taken up in 60 ml of degassed DMF, 1.27 g (15 mmol) 6-Fluoro-7-chloroisoquinoline and 2.25 ml (15 mmol) DBU were added. After 3 h at RRT the mixture was concentrated, taken up in ethyl acetate and washed with brine. The organic phases were dried over Sodium sulfate and evaporated. Purification over silica gel (10% to 40% ethyl acetate in heptane) gave 4.5 g of the expected compound.
Reaction SMILES: [O-:1][N+:2]1[C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:6]=2[N:5]=[C:4]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH:21]([C:24]#[N:25])[CH2:20]2)[N:3]=1)[CH2:12][CH2:11][CH2:10]3.[O-:26][N+]1C2C3CCCC=3C=CC=2N=C(NCCN(CCC)CCC)N=1>>[O-:1][N+:2]1[C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:6]=2[N+:5]([O-:26])=[C:4]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH:21]([C:24]#[N:25])[CH2:20]2)[N:3]=1)[CH2:12][CH2:11][CH2:10]3
Reactant: N#CC1CCN(CCCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)C1
Reactant: CCCN(CCC)CCNc1nc2ccc3c(c2[n+]([O-])n1)CCC3
Product: N#CC1CCN(CCCNc2n[n+]([O-])c3cc4c(cc3[n+]2[O-])CCC4)C1

Procedure:
H2O2 (70%, 0.67 mL, ca. 13.3 mmol) was added dropwise to a stirred solution of TFAA (1.9 mL, 13.3 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 56 (449 mg, 1.3 mmol) and TFA (0.51 mL, 6.6 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 8 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with DCM (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 56 (198 mg, 44%) and (ii) 1,4-dioxide 57 (70 mg, 15%) as a red gum: 1H NMR δ 8.15 (br t, J=5.3 Hz, 1H, NH), 8.12 (s, 1H, H-9), 8.08 (s, 1H, H-5), 3.62-3.68 (m, 2H, CH2N), 3.15-3.23 (m, 2H, CH2N), 3.11 (br t, J=7.5 Hz, 2H, H-6), 3.07 (br t, J=7.5 Hz, 2H, H-8), 2.90-2.95 (m, 1H, CHCN), 2.73 (t, J=6.3 Hz, 2H, CH2N), 2.50-2.61 (m, 2H, CH2N), 2.33-2.43 (m, 1H, CH2), 2.11-2.24 (m, 3H, CH2, H-7), 1.91 (p, J=6.3 Hz, 2H, CH2); 13C NMR δ 155.7, 149.4, 145.7, 138.0, 129.6, 122.0, 115.8, 111.5, 57.3, 53.5, 52.8, 41.0, 33.4, 32.3, 29.1, 26.9, 26.1, 25.3; MS (FAB+) m/z 355 (MH+, 30%), 339 (10); HRMS (FAB+) calcd for C18H23N6O2 (MH+) m/z 355.1883, found 355.1893.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:20])[C:4](=[O:19])[CH2:5][CH:6]1[NH:11][CH2:10][CH2:9][N:8]2[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=[C:7]12.[C:21]([O:25][C:26]([NH:28][C@H:29]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:30][C:31](O)=[O:32])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([NH:28][C@H:29]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:30][C:31]([N:11]1[CH2:10][CH2:9][N:8]2[N:12]=[C:13]([C:15]([F:17])([F:16])[F:18])[N:14]=[C:7]2[CH:6]1[CH2:5][C:4]([N:3]([CH3:2])[CH3:20])=[O:19])=[O:32])=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Reactant: CN(C)C(=O)CC1NCCn2nc(C(F)(F)F)nc21
Agent: Cl
Product: CN(C)C(=O)CC1c2nc(C(F)(F)F)nn2CCN1C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C

Procedure:
A 200 mg portion of 8-[2-(dimethylamino)-2-oxoethyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazine, hydrochloride was coupled to (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid essentially following the procedure outlined in Example 2, Step D. Purification by preparative TLC (silica gel, 10% methanol/dichloromethane) followed by HPLC (AD chiral pak column, 15% isopropanol/heptane) separated the first and last eluting diastereomers. LC/MS 593 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)[C:5]([Cl:27])=[CH:4][N:3]=1.Cl.[CH3:29][N:30]1[CH:34]=[C:33]([NH2:35])[CH:32]=[N:31]1.CCN(C(C)C)C(C)C>CCCCO>[Cl:27][C:5]1[C:6]([NH:8][CH:9]2[CH2:26][CH2:25][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:14][CH2:13]3)[CH2:11][CH2:10]2)=[N:7][C:2]([NH:35][C:33]2[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=2)=[N:3][CH:4]=1
Reactant: Cn1cc(N)cn1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Cl)ncc3Cl)CC2)CC1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Nc2ncc(Cl)c(NC3CCC4(CC3)CCN(C(=O)OC(C)(C)C)CC4)n2)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 33.2 %

Procedure:
To a solution of tert-butyl 9-((2,5-dichloropyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (230.0 mg, 0.55 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (185.4 mg, 1.39 mmol) in n-BuOH (3 mL) was added DIPEA (215.7 mg, 1.67 mmol). The mixture was stirred at 150° C. overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/100 to 1/70) to give the product as a light yellow solid (87.0 mg, 33.0%).
Reaction SMILES: [C:1]([C:4]1[C:18]([OH:19])=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])=[C:6]([CH2:20]Cl)[CH:5]=1)(=[O:3])[CH3:2].[CH3:22][OH:23]>Cl([O-])(=O)(=O)=O.[Ag+]>[C:1]([C:4]1[C:18]([OH:19])=[CH:17][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])=[C:6]([CH2:20][O:23][CH3:22])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CO
Reactant: CC(=O)c1cc(CCl)c(OCCCCCCC#N)cc1O
Agent: [Ag+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: COCc1cc(C(C)=O)c(O)cc1OCCCCCCC#N
Temperature: 25 °C

Procedure:
Approximately 3 millimoles of the chloro compound of Example 127 were treated with 0.624 g of silver perchlorate in 50 ml of methanol at 0° C. The reaction mixture was allowed to warm to room temperature over a 2 hour period. The mixture was then partitioned between ethyl acetate and an acidic sodium chloride solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography over silica gel eluting with 1:1 ethyl acetate/hexane providing 50 mg of the title compound. NMR, MS.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16]C(=O)C)[C:13]2[C:8](=[CH:9][C:10]([CH3:20])=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[OH:16][C:14]1[C:13]2[C:8](=[CH:9][C:10]([CH3:20])=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:15]=1
Reactant: CCOC(=O)c1cc(OC(C)=O)c2ccc(C)cc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(O)cc(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 860 mg of 4-Acetoxy-7-methyl-naphthalene-2-carboxylic acid ethyl ester in 3 ml ethanol/water (9:1), 12.6 ml of a 1M NaOH was added and stirred for 5 h at RT. Then, the reaction mixture was acidified to pH 2 with diluted hydrochloric acid to precipitate the product. The product was then collected by filtration and dried under reduced pressure. Yield: 550 mg.