Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH2:8]2)[C:3]1=[O:23].F[C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][C:26]=1[F:35].C([O-])([O-])=O.[Na+].[Na+].O>CS(C)=O>[F:35][C:26]1[CH:27]=[C:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:29]=[CH:30][C:25]=1[NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH2:8]2)[C:3]1=[O:23]
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Reactant: N[C@H]1CCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(C(=O)OCc4ccccc4)CC3)C2=O)c(F)c1
Yield: 42.9 %

Procedure:
A solution of (S)-benzyl 4-(3-amino-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (2.0 g, 6.3 mmol), 1,2-difluoro-4-(methylsulfonyl)benzene (1.2 g, 6.3 mmol), and Na2CO3 (3.3 g, 32 mmol) in DMSO (20 mL) was stirred at 120° C. for 48 hours. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine and dried over MgSO4, filtered then concentrated in vacuo. The material was purified over silica gel (100% EtOAc) to yield (S)-benzyl 4-(3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (1.3 g, 2.7 mmol, 42%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[F:18][C:19]([F:29])([F:28])[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[NH2:21].CO>CCCCCCC>[F:29][C:19]([F:18])([F:28])[CH:20]([NH:21][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: NC(c1ccccn1)C(F)(F)F
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Solvent: CO
Solvent: CCCCCCC
Product: O=C(NC(c1ccccn1)C(F)(F)F)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α-(trifluoromethyl)-2-pyridinemethanamine (CAN 503173-14-6) as starting materials. The product was isolated by chiral chromatography on Reprosil Chiral NR using heptane/20% ethanol as eluent. The (S)-(−)-enantiomer was isolated. LC-MS (UV peak area/ESI) 100%, 392.1950 (M+H)+; αD20 (MeOH)=−91.1°.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:26]#[N:27])[C:12](=[O:25])[NH:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH:6]=[CH:5][N:4]=1.[C:28](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:28][N:13]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=2)[CH:10]=[C:11]([C:26]#[N:27])[C:12]1=[O:25]
Reactant: CSc1nccc(-c2cc(C#N)c(=O)[nH]c2-c2cccc(C(F)(F)F)c2)n1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1nccc(-c2cc(C#N)c(=O)n(C)c2-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a solution of 5-(2-methylsulfanylpyrimidin-4-yl)-2-oxo-6-(3-trifluoromethylphenyl)-1,2-dihydropyridine-3-carbonitrile (150 mg, 0.00040 mol) in 3 mL DMF was added cesium carbonate (200 mg, 0.00060 mol) and methyl iodide (1 mL, 0.0154 mol) and the solution stirred at room temperature for 1 h. The mixture was the partitioned between H2O and EtOAc and the organic phase dried over anhydrous sodium sulfate and concentrated. Chromatography on silica with 3% MeOH in CH2Cl2 yields 100 mg (65%) 1-methyl-5-(2-methylsulfanyl-pyrimidin-4-yl)-2-oxo-6-(3-trifluoromethyl-phenyl)-1,2-dihydropyridine-3-carbonitrile as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:24])[C:5]([NH:7][C@H:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6].[OH-].[Li+].CO.ClCl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:24])[C:5]([NH:7][C@H:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6]
Reactant: CCOC(=O)CCC1CCCN1C(=O)c1ccc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Agent: ClCl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCCC2CCC(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 23 %

Procedure:
Prepared analogously to Example 19b from 3-chloro-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-4-[(2R/S)-2-(ethoxycarbonylethyl)pyrrolidin-1-ylcarbonyl]benzamide and lithium hydroxide in tetrahydrofuran. Yield: 23%; Rf value: 0.34 (Reversed phase RP 8: methanol/5% sodium chloride solution=6:4); C24H24C12N4O4 (503.384); mass spectrum: (M+H)+=503/505/507 (chlorine isotope).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([OH:33])=[C:26]([S:28]([NH:31][CH3:32])(=[O:30])=[O:29])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC.C(OCC)(=O)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:33][CH2:2][C:3]([N:5]2[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:7][C@H:6]2[CH3:20])=[O:4])=[C:26]([S:28]([NH:31][CH3:32])(=[O:29])=[O:30])[CH:27]=1
Reactant: CNS(=O)(=O)c1cc(Cl)ccc1O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)c1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Yield: 52.5 %

Procedure:
To a solution of (2R, 5S)-2-Chloro-1-[4-(4-fluoro-benzyl)-2,5-dimethyl-piperazin-1-yl]-ethanone (375 mg, 1.26 mmol) in butanone (12 ml) was added 5-Chloro-2-hydroxy-N-methyl-benzenesulfonamide (280 mg, 1.26 mmol), potassium carbonate (348 mg, 2.52 mmol) and potassium iodide (209 mg, 1.26 mmol). The resulting reaction mixture was refluxed for 4 hours. It was allowed to cool, diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the above titled compound (320 mg, 53% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([O:23][C@@H:24]([C@H:26]3[CH2:30][NH:29][C:28](=[O:31])[CH2:27]3)[CH3:25])=[N:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)=[CH:10][C:5]=2[N:4]=[CH:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[C:63](O)(=[O:67])[CH:64]([CH3:66])[CH3:65]>CN(C=O)C>[C:63]([N:20]1[CH2:19][CH2:18][N:17]([C:14]2[CH:13]=[CH:12][C:11]([C:9]3[N:8]=[C:7]([O:23][C@@H:24]([C@H:26]4[CH2:30][NH:29][C:28](=[O:31])[CH2:27]4)[CH3:25])[C:6]4[N:2]([CH3:1])[CH:3]=[N:4][C:5]=4[CH:10]=3)=[CH:16][CH:15]=2)[CH2:22][CH2:21]1)(=[O:67])[CH:64]([CH3:66])[CH3:65]
Reactant: C[C@@H](Oc1nc(-c2ccc(N3CCNCC3)cc2)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Reactant: CC(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C(=O)N1CCN(c2ccc(-c3cc4ncn(C)c4c(O[C@H](C)[C@H]4CNC(=O)C4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.3 %

Procedure:
A vial was charged with (R)-4-((R)-1-(3-methyl-6-(4-(piperazin-1-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 3A.13 (32 mg, 0.076 mmol), HATU (58 mg, 0.15 mmol) and N-methylmorpholine (33 μL, 0.30 mmol) in DMF (2.0 mL). Isobutyric acid (8.5 μL, 0.091 mmol) was added and the reaction was stirred at room temperature for 18 h. The reaction was concentrated under reduced pressure and the residue was purified via prep HPLC (2-95% acetonitrile in water, 0.1% trifluoroacetic acid buffer) to isolate (R)-4-((R)-1-((6-(4-(4-isobutyrylpiperazin-1-yl)phenyl)-3-methyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one 3.36 (21 mg) as the trifluoroacetic acid salt.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:47]1[NH:52][CH2:51][CH2:50][N:49]2[CH2:53][CH2:54][CH2:55][C@H:48]12.CN(C)C(=O)C>CC1CCCO1>[Cl:11][C:9]1[CH:10]=[C:2]([Cl:1])[C:3]([C:4]([N:52]2[CH2:51][CH2:50][N:49]3[CH2:53][CH2:54][CH2:55][C@@H:48]3[CH2:47]2)=[O:6])=[CH:7][C:8]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])(=[O:14])=[O:13]
Reactant: C1C[C@@H]2CNCCN2C1
Reactant: O=C(O)c1cc(S(=O)(=O)Nc2ccccc2F)c(Cl)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CC1CCCO1
Product: O=C(c1cc(S(=O)(=O)Nc2ccccc2F)c(Cl)cc1Cl)N1CCN2CCC[C@@H]2C1
Reaction time: 0.75 h

Procedure:
To 2,4-dichloro-5-{[(2-fluorophenyl)amino]sulfonyl}benzoic acid (800 mg, 2.197 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (919 mg, 2.416 mmol) in 2-methyltetrahydrofuran (15 mL) was added (R)-octahydropyrrolo[1,2-α]pyrazine (388 mg, 3.08 mmol). The reaction was stirred at room temperature for 45 minutes at which time N,N-dimethylacetamide (1 mL) was added. The reaction was stirred for an additional 45 minutes and N,N-dimethylacetamide (3 mL) was added. The reaction was stirred for an addition 2.5 hours, diluted with 2-methyltetrahydrofuran (15 mL), and washed with a solution of 6% sodium bicarbonate and 6% brine (2×15 mL). The aqueous layers were combined and re-extracted with 2-methyltetrahydrofuran (15 mL). The organic layer was washed with saturated brine (4×25 mL), dried over MgSO4, and concentrated. The residue was taken up in ethanol (20 mL) and reconcentrated to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9]([NH:12][C@H:13]2[CH2:18][CH2:17][C@@H:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=3[OH:26])[CH2:15][CH2:14]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH4+].[Cl-].[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C>[OH:26][C:20]1[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:19]=1[C@@H:16]1[CH2:15][CH2:14][C@H:13]([NH:12][S:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]3[NH:31][N:30]=[N:29][N:2]=3)[CH:4]=2)(=[O:11])=[O:10])[CH2:18][CH2:17]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(S(=O)(=O)N[C@H]2CC[C@@H](c3ccc(O)cc3O)CC2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(N[C@H]1CC[C@@H](c2ccc(O)cc2O)CC1)c1cccc(-c2nnn[nH]2)c1
Temperature: 20 °C
Reaction time: 18 h
Yield: 71.3 %

Procedure:
A solution of Example 9 (20 mg, 54 μmol) in DMF (2 ml) was treated with NH4Cl (17 mg, 323 μmol) and NaN3 (21 mg, 323 μmol). The mixture was heated under reflux for 6 hr, then stirred for 18 hr at 20° C., before being partitioned between EtOAc (30 ml) and H2O (5 ml). The aqueous phase was extracted with EtOAc (3×15 ml) and the combined organic extracts were washed with brine (30 ml) and dried (MgSO4). Filtration, solvent evaporation under reduced pressure, and FCC (EtOH-EtOAc, 1:3) afforded the title compound (16 mg, 72%) as a pale yellow solid. δH ((CD3)2CO) 1.30–1.88 (m, 8H), 2.60–2.71 (m, 1H), 3.62–3.69 (m, 1H), 4.23–4.30 (m, 1H), 6.20 (dd, 1H), 6.44 (d, 1H), 6.50 (d, 1H), 6.87 (d, 1H), 7.55 (t, 1H), 7.63–7.68 (m, 1H), 7.72–7.76 (m, 1H), 7.80 (d, 1H), 8.30 (d, 1H), 8.73 (s, 1H); m/z (ES−) 414 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][C:7]([N+:15]([O-])=O)=[C:6]2[CH3:18].[H][H]>O1CCCC1.[Pd]>[NH2:15][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[CH3:18])=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2
Reactant: [H][H]
Reactant: COc1cc2ncc([N+](=O)[O-])c(C)c2cc1OC
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc2ncc(N)c(C)c2cc1OC
Yield: 79.5 %

Procedure:
6,7-Dimethoxy-4-methyl-3-nitroquinoline (5.80 g, 23.36 mmol) is dissolved in tetrahydrofuran (60 ml). Palladium on carbon (5%, 2.90 g, water-moist) is subsequently added, and the suspension is stirred turbulently in a hydrogen atmosphere at room temperature for 16 h. When the reaction is complete, the solid material is filtered off with suction through kieselguhr and rinsed with tetrahydrofuran. The filtrate is evaporated to dryness in vacuo, giving 3-amino-6,7-dimethoxy-4-methylquinoline (4.05 g, 18.56 mmol) as a solid. MS: 219.0 (M+H+), TLC (HPTLC): Rf=0.35 (ethyl acetate/ethanol 8:1, parts by volume).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[OH-].[K+].[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15]Br>CS(C)=O.O>[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(O)ccc1F
Reactant: COC(CBr)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COC(COc1ccc(F)c(C)c1)OC

Procedure:
A mixture of 4-fluoro-3-methylphenol (36.7 g), potassium hydroxide pellets (19.5 g) and bromoacetaldehyde dimethyl acetal (34.6 ml) in dimethyl sulphoxide (240 ml) was heated at 110° for 24 h. The mixture was cooled, diluted with water (350 ml) and extracted with hexane. Evaporation of the extracts gave the title compound as an oil (52.3 g).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[O:4][N:3]=1.[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23]O)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[O:4][N:3]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Cc1ccccc1-c1cc(O)no1
Product: Cc1ccccc1-c1cc(OCCNC(=O)OC(C)(C)C)no1
Yield: 85.3 %

Procedure:
3-Hydroxy-5-(2-methylphenyl)isoxazole (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.2 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.31 g, 86%) as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[C:12]([CH:14]=[CH2:15])[N:11]=[C:10]([CH3:16])[N:9]=2)[N:3]=1.[N+](=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N-]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:9]=[C:10]([CH3:16])[N:11]=[C:12]([C@@H:14]3[CH2:15][C@H:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:13]=2)[N:3]=1
Reactant: C=Cc1cc(-n2nc(C)nc2C)nc(C)n1
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@H]1c1cc(-n2nc(C)nc2C)nc(C)n1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methyl-6-vinylpyrimidine (1-3) (1.00 g, 4.65 mmol, 1.0 eq.) in degassed toluene (20 mL) was added ethyl diazoacetate (0.98 mL, 9.30 mmol, 2.0 eq.) and the reaction was heated to 120° C. The reaction was monitored by LC-MS and after 2 hours the mixture was cooled to room temperature and the toluene was removed by roto-evaporation. The resulting residue was purified by silica gel column chromatography (10-40% ethyl acetate in hexanes) to afford ethyl trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2-methylpyrimidin-4-yl)cyclopropanecarboxylate (2-1) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.58 (s, 1H), 4.17 (q, 2H, J=7.1 Hz), 2.88 (s, 3H), 2.64-2.55 (m, 1H), 2.62 (s, 3H), 2.41 (s, 3H), 2.36 (ddd, 1H, J=8.6, 5.7, 3.8 Hz), 1.74-1.61 (m, 2H), 1.28 (t, 3H, J=7.1 Hz). LRMS m/z (M+H+) 302 found, 302 required.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1>CCN(C(C)C)C(C)C>[OH:17][CH:14]1[CH2:15][CH2:16][N:11]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)[CH2:12][CH2:13]1
Reactant: OC1CCNCC1
Reactant: NC(=O)c1ccc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc(N2CCC(O)CC2)nc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To the solution of 6-chloronicotinamide (5.0 g, 32 mmol) in DIPEA (50 mL), piperidin-4-ol (3.2 mg, 32 mmol) was added and the mixture was stirred at 110° C. for 8 h. The reaction mixture was concentrated under reduced pressure to afford the crude product. The residue was further purified by silica gel chromatography (DCM: MeOH=20:1) to afford the title compound (5.3 g, 75%) as a yellowish solid. [LCMS RtB=1.39 min, [M+H]+=222.1].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:18]([CH3:38])=[C:19]([CH3:37])[C:20]4[O:24][C:23]([CH3:26])([CH3:25])[C:22]([C:28]5[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=5)(O)[C:21]=4[C:35]=3[CH3:36])[CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>CCCCCC.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]3[C:18]([CH3:38])=[C:19]([CH3:37])[C:20]4[O:24][C:23]([CH3:26])([CH3:25])[CH:22]([C:28]5[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=5)[C:21]=4[C:35]=3[CH3:36])[CH2:15][CH2:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(C)cc3)C(C)(C)O4)CC2)cc1OC
Solvent: CCCCCC
Solvent: CO
Product: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)C(c3ccc(C)cc3)C(C)(C)O4)CC2)cc1OC
Yield: 51 %

Procedure:
Using 5-(4-(3,4-dimethoxyphenyl)piperidino)-3-(4-methylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Example 78, the title compound was synthesized in the same manner as in Example 46. Yield 51%. mp. 103–105° C. (hexane-methanol).
Reaction SMILES: [Li]N([Si](C)(C)C)[Si](C)(C)C.C1COCC1.[CH3:16][O:17][C:18]1([O:26][CH3:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=[O:25].[CH2:28]([O:30][C:31](=[O:37])[C:32](OCC)=[O:33])[CH3:29].OP([O-])(O)=O.[K+]>CCOCC>[CH3:27][O:26][C:18]1([O:17][CH3:16])[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]([C:32](=[O:33])[C:31]([O:30][CH2:28][CH3:29])=[O:37])[C:19]1=[O:25]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COC1(OC)CCCCCC1=O
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(=O)C1CCCCC(OC)(OC)C1=O
Reaction time: 8 h
Yield: 65 %

Procedure:
1M LiN(TMS)2 in THF (28.5 mL, 28.5 mmol) were added dropwise at −50° C. to a solution of 2,2-dimethoxycycloheptanone (4.10 g, 23.8 mmol) in 25 mL of Et2O under argon. After 30 minutes at the same temperature, 3.55 mL of diethyloxalate were also added under stirring. The solution was kept at room temperature overnight. 10% solution of KH2PO4 (20 mL) were then added and the resulting solution extracted with Et2O (3×50 mL). The organic layer was dried over Na2SO4 and evaporated to dryness. The crude was purified by chromatography on a silica gel column (eluant: AcOEt/cyclohexane 1/9) to afford 3.98 g (65% yield) as a colorless oil.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:13][CH2:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)[C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:19]([O:22][CH2:23]C)(=[O:21])C.C(N(CC)CC)C>CO>[CH3:23][O:22][C:19]([C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:4]([O:13][CH2:14][CH:15]2[CH2:18][CH2:17][CH2:16]2)[N:3]=1)=[O:21]
Reactant: CCOC(C)=O
Reactant: Brc1cnc(N2CCCC2)c(OCC2CCC2)n1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cnc(N2CCCC2)c(OCC2CCC2)n1
Temperature: 100 °C
Yield: 75 %

Procedure:
A 50 mL bomb with a glass liner was charged with the 5-bromo-3-cyclobutylmethoxy-2-pyrrolidin-1-yl-pyrazine (2.27 g, 7.3 mmol), ethyl acetate (6 mL, degassed), methanol (7 mL, degassed) and triethylamine (2.0 mL, 14.5 mmol). PdCl2dppfCH2Cl2 (0.29 g, 0.36 mmol) was charged to the bomb; the bomb was sealed and degassed under vacuum. The reaction was purged with carbon monoxide (×5) then pressurized to 5 bar and heated to 100° C. for 1 hour. The reaction mixture was filtered through celite and washed with methanol then ethyl acetate and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL) and washed with water (100 mL) the organic layer was dried over MgSO4 and concentrated in vacuo to afford 6-cyclobutylmethoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid methyl ester as an orange solid, 2.2 g (75% yield). LC@215 nm; Rt 2.39: 75%, m/z (ES+): 292 (M+H).
Reaction SMILES: N#N.[NH2:3][CH2:4][C:5]([OH:7])=O.[Cl:8][C:9]1[CH:21]=[CH:20][C:12]2[N:13](C)[C:14](=O)[O:15][C:16](=O)[C:11]=2[CH:10]=1>CC(O)=O>[Cl:8][C:9]1[CH:21]=[CH:20][C:12]2[N:13]([CH3:14])[C:5](=[O:7])[CH2:4][NH:3][C:16](=[O:15])[C:11]=2[CH:10]=1
Reactant: NCC(=O)O
Reactant: Cn1c(=O)oc(=O)c2cc(Cl)ccc21
Agent: N#N
Solvent: CC(=O)O
Product: CN1C(=O)CNC(=O)c2cc(Cl)ccc21
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 44 %

Procedure:
In a 2 L RBF equipped with mechanical stir, condenser and N2 inlet, glycine (38 g, 0.506 mol) was added to crude B1 (107 g, 0.506 mol) followed by the addition of AcOH (500 mL). Reaction flask was heated in a 130° C. oil bath for 7 h. Solvent was evaporated under suction with heating (50-60° C.). To the thick syrupy crude product was added 1 L of EtOAc followed by the slow addition of aqueous NaHCO3 (saturated) to adjust the pH to ˜7. Then 10 mL of 2 M NaOH was added to adjust the pH to ˜9-10. The mixture gave a solid along with organic and aqueous layers. The solid was filtered to give product containing some impurity. The solid was partitioned between 400 mL dichloromethane (DCM) and 200 mL NaHCO3, and the resultant slurry was stirred for 20 min, then filtered to remove an insoluble impurity. The DCM layer was separated and washed with 3% NaHCO3 and then brine (200 mL). The DCM layer was dried (MgSO4), filtered and concentrated to give 50 g of pure product. EtOAc layer was concentrated to give 67 g of solid product with some impurity. The aqueous layer was extracted with EtOAc (2×400 mL). Combined organics were dried over Na2SO4, filtered and concentrated to give an additional 6.7 g of crude product. Total of 123.4 g of product was obtained, 50 g of which was very clean (yield quantitative). 1H NMR (300 MHz, CDCl3) δ 3.2 (s, 3H), 3.5 (m, 1H), 3.8 (m, 1H), 7.35 (d, 1H), 7.6 (m, 2H), 8.8 (t, 1H).
Reaction SMILES: C([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:6]1(=[O:29])=[O:28])(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[F:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[CH2:40][CH2:41]Br>C(O)(C(F)(F)F)=O.CC#N>[F:36][C:37]1[CH:38]=[C:39]([CH2:40][CH2:41][N:5]2[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[S:6]2(=[O:28])=[O:29])[CH:43]=[CH:44][CH:45]=1
Reactant: Fc1cccc(CCBr)c1
Reactant: CC(C)(C)N1C(=O)C(NCCCCc2ccccc2)=C(c2ccccc2)S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=C1C(NCCCCc2ccccc2)=C(c2ccccc2)S(=O)(=O)N1CCc1cccc(F)c1
Temperature: 120 °C
Yield: 65.6 %

Procedure:
2-tert-Butyl-5-phenyl-4-[(4-phenylbutyl)amino]isothiazol-3(2H)-one 1,1-dioxide (Example 1) (0.150 g, 0.36 mmol) was dissolved in TFA (3 ml) and heated in a microwave reactor at 120° C. for 20 mins. The solvent was evaporated and the crude product was reevaporated from DCM (2×5 ml). The crude product, potassium carbonate (0.251 g, 1.82 mmol) and 3-fluorophenethylbromide (0.221 g, 1.09 mmol) was dissolved in dry MeCN (3 ml) and heated at in a microwave reactor 140° C. for 10 mins. The reaction mixture was purified by silica gel column chromatography using a 85:15 mixture of heptane and EtOAc as eluant, to give the title compound (0.113 g, 65%). 1H NMR (500 MHz, CDCl3): δ 7.55-7.41 (m, 5H), 7.34-7.25 (m, 3H), 7.23-7.17 (m, 1H), 7.14-7.01 (m, 4H), 7.00-6.93 (m, 1H), 5.28-5.19 (m, 1H), 3.98-3.90 (m, 2H), 3.18-3.10 (m, 2H), 2.91-2.83 (m, 2H), 2.50-2.43 (m, 2H), 1.44-1.36 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 164.1, 162.2, 159.1, 141.7, 140.3, 140.2, 135.6, 131.8, 130.4, 130.3, 130.0, 128.9, 128.6, 128.5, 126.2, 125.0, 124.8, 116.2, 116.0, 114.1, 113.9, 107.0, 44.2, 41.1, 35.4, 34.4, 29.2, 28.3; Mass Spectrum: M−H+ 479.