Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1.Cl.[CH:20](=[NH:24])OCC>C1COCC1>[NH:24]=[CH:20][NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CCOC=N
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)cs1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(NC=N)cc2)cs1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
N-{4-[2-(4-Aminophenyl)ethyl]-1,3-thiazol-2-yl}acetamide (150 mg) was dissolved in THF (2 ml) and pH=7 buffer (2 ml). Then, ethyl imidoformate hydrochloride (1.26 g) was added to the solution at 0° C. The reaction mixture was stirred at 0° C. for 2 hours, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with CH3CN/water (7:3) as an eluent. The oil was purified again by preparative silica gel chromatography with CHCl3/MeOH (5:1) as an eluent to give N-[4-(2-{4-[(iminomethyl)amino]phenyl}ethyl)-1,3-thiazol-2-yl]acetamide (110 mg) as pale brown oil.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.[F:12][C:13]([F:47])([F:46])[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:17]=[C:16]([C:30]2[CH:31]=[C:32]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:37]=3)[CH:33]=[CH:34][CH:35]=2)[N:15]=1>C1COCC1>[OH:2][CH2:1][CH2:3][NH:4][S:42]([C:38]1[CH:37]=[C:36]([C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([C:16]3[N:15]=[C:14]([C:13]([F:12])([F:46])[F:47])[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=4)[N:17]=3)[CH:31]=2)[CH:41]=[CH:40][CH:39]=1)(=[O:43])=[O:44]
Reactant: O=S(=O)(Cl)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Reactant: NCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCO)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Temperature: 0 °C
Yield: 67.8 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of ethanolamine (0.071 g, 1.16 mmol), triethylamine (0.06 ml, 0.42 mmol) and THF (2 ml) was added drop wise a solution of 3′-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-sulfonyl chloride (example 1.3) (0.21 g, 0.39 mmol) in THF (3 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.15 g, 69%). MS (ISP) 567.7 [(M+H)+]; mp 153° C.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:24]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:29]=[CH:30][C:31]([O:34][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:32][CH:33]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)C(Br)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Product: COC(=O)C(Oc1ccc(C(C)(C)C)cc1)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Yield: 73.5 %

Procedure:
In a manner similar to Example 16, 7.62 g of methyl α-bromo-α-[p-(α,α,α-trifluoro-m-tolyloxy)phenyl]acetate was reacted with 3.75 g of p-tert-butylphenol to give 6.6 g of product as an amber oil.
Reaction SMILES: [C:1]([C:4]1[NH:8][N:7]=[C:6]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]=1[C:20]([CH3:23])([CH3:22])[CH3:21])(=O)[CH3:2].[F:24][C:25]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:26]=1[C:27]([NH:29][NH2:30])=O>C1(C)C(C)=CC=CC=1>[C:20]([C:5]1[C:6]([O:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[N:7][N:8]2[C:4]=1[C:1]([CH3:2])=[N:30][N:29]=[C:27]2[C:26]1[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:25]=1[F:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(=O)c1[nH]nc(OS(=O)(=O)c2ccc(C)cc2)c1C(C)(C)C
Reactant: NNC(=O)c1cc(F)ccc1F
Solvent: Cc1ccccc1C
Product: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4cc(F)ccc4F)nnc(C)c3c2C(C)(C)C)cc1
Temperature: 180 °C
Yield: 53.4 %

Procedure:
5-Acetyl-4-tert-butyl-3-(4-methylphenyl)sulfonyloxypyrazole (0.4 g, 1.19 mmol) was dissolved in xylene (20 ml) with 2,5-difluorobenzoic hydrazide (0.225 g, 1.31 mmol) and heated under reflux for 14 h. The xylene was removed by evaporation and replaced with Dowtherm A (15 ml) and heated at 180° C. for 4 h. The reaction mixture was allowed to cool to room temperature and poured directly onto a silica column and eluted with dichloromethane then 1-5% ethyl acetate/dichloromethane to give the required product (0.3 g) as a white solid. 1H NMR (360 MHz, CDCl3) δ 1.64 (9H, s), 2.42 (3H, s), 3.11 (3H, s), 7.11-7.83 (8H, m); MS (ES+) m/e 473 [MH]+.
Reaction SMILES: I.CSC1NCCCN=1.I.CS[C:13]1[NH:14][CH2:15][CH2:16][N:17]=1.NC1[N:20]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[C:21]2[N:22]([C:27](=[O:31])C=1N=O)[CH2:23][CH2:24][CH2:25][N:26]=2>>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][N:20]2[C:15]3[NH:14][CH:13]=[N:17][C:16]=3[C:27](=[O:31])[N:22]3[CH2:23][CH2:24][CH2:25][N:26]=[C:21]23)=[CH:34][CH:35]=1
Reactant: CSC1=NCCN1
Reactant: NC1=C(N=O)C(=O)N2CCCN=C2N1Cc1ccc(Cl)cc1
Agent: CSC1=NCCCN1
Agent: I
Product: O=C1c2nc[nH]c2N(Cc2ccc(Cl)cc2)C2=NCCCN12

Procedure:
Procedure 1 is repeated with substitution of 2-(methylthio)-3,4,5,6-tetrahydropyrimidine hydroiodide for the 2-(methylthio)-2-imidazoline hydroiodide specified. The resulting 8-amino-3,4-dihydro-9-[(4-chlorophenyl)methyl]-7-nitroso-2H,5H-pyrimido(1,2-a)pyrimidin-6(9H)-one is converted to the corresponding 7-formylamino compound according to the method of Procedure 2, and the latter is then cyclized to the desired product by the method of Procedure 4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@@H:4]1[CH2:8][C:7](=[O:9])[CH2:6][N:5]1[C:10]([O:12][CH3:13])=[O:11].CCCCCCCCCCCCCCCC>C([O-])(=O)C.[Na+].ClCCl>[CH3:1][O:2][C:3](=[O:14])[C@H:4]1[CH2:8][C:7](=[O:9])[CH2:6][N:5]1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCCCCCCCCCCCC
Product: COC(=O)[C@H]1CC(=O)CN1C(=O)OC
Reaction time: 31 h

Procedure:
An aqueous solution (5.0 mL) containing 25 mM N-(methoxycarbonyl)-4-keto-Dproline methyl ester and 25 mM N-(methoxycarbonyl)-4-keto-L-proline methyl ester in 0.200M sodium acetate (pH 5.0) was mixed with 2.5 g of immobilized Candida antartica lipase fraction B (Boehringer Mannheim, CHIRAZYME® L-2, c.-f., C2, lyo.) at 25° C. The reaction mixture was analyzed after 31 h by mixing the entire reaction mixture with 5.0 mL of 20 mM hexadecane in dichloromethane for 10 minutes, which resulted in the complete extraction of the unreacted D- and L-isomers. The dichloromethane extract was then analyzed by chiral gas chromatography on a Chiraldex G-TA column (Advanced Separation Technologies, Inc., 50 m×0.32 mm ID) to determine the amounts of the unreacted D- and L-isomers. After 31 h, an 85% enantiomeric excess of N-(methoxycarbonyl)-4-keto-D-proline methyl ester was obtained at 41% conversion of the racemic mixture.
Reaction SMILES: ClC1C=C([N:8]2[CH2:13][C@H:12]([CH3:14])[NH:11][C@H:10]([CH3:15])[CH2:9]2)C=CN=1.Br[C:17]1[CH:18]=[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[N:21][CH:22]=1>>[CH3:15][C@H:10]1[NH:11][C@@H:12]([CH3:14])[CH2:13][N:8]([C:17]2[CH:18]=[C:19]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:20]=[N:21][CH:22]=2)[CH2:9]1
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: C[C@@H]1CN(c2ccnc(Cl)c2)C[C@H](C)N1
Product: CCOC(=O)c1cncc(N2C[C@@H](C)N[C@@H](C)C2)c1

Procedure:
The title compound was prepared in a similar manner to cis-1-(2-chloro-4-pyridinyl)-3,5-dimethylpiperazine using ethyl 5-bromo-3-pyridinecarboxylate and cis-2,2-dimethylpiperazine as the starting materials (D19). MS (ES+) m/e 264 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20])=[O:8].[OH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.O>C1C=CC=CC=1>[OH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]2[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[C:15]3[CH3:20])=[O:8])[CH2:28][CH2:27]1
Reactant: OCCN1CCNCC1
Reactant: COc1cc(NC(=O)CCCCCBr)c2nccc(C)c2c1
Solvent: c1ccccc1
Solvent: O
Product: COc1cc(NC(=O)CCCCCN2CCN(CCO)CC2)c2nccc(C)c2c1
Yield: 72.4 %

Procedure:
A mixture of 7 g (0.019 mol) of 6-bromo-N-(6-methoxy-4-methyl-8-quinolinyl)hexanamide and 4.4 g (0.038 mol) of hydroxyethylpiperazine in 100 ml of benzene was heated under reflux for 48 hours, allowed to cool, mixed well with 50 ml of water and filtered to collect the crude product. Recrystallization from toluene with hexane afforded 5.7 g (72%) of crystalline material, mp 88°-90°.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([N:9]2[CH2:14][C:13]3([CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:22]=[C:23]([CH:36]=[CH:37][CH:38]=4)[CH2:24][CH2:25][O:26][CH2:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[CH2:16][CH2:15]3)[O:12][CH2:11][CH2:10]2)=[O:8])[N:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([N:9]2[CH2:14][C:13]3([CH2:15][CH2:16][N:17]([CH2:20][C:21]4[CH:22]=[C:23]([CH:36]=[CH:37][CH:38]=4)[CH2:24][CH2:25][O:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:18][CH2:19]3)[O:12][CH2:11][CH2:10]2)=[O:8])[N:6]=1
Reactant: Cc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)OC(C)(C)C)c4)CC3)C2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)O)c4)CC3)C2)cs1
Reaction time: 2 h

Procedure:
tert-Butyl 3-(3-((4-(2-methylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanoate (Example 277, step a) was dissolved in DCM (10 mL) and TFA (2 mL) was added. The resulting mixture was stirred for 2 h then evaporated. The residue was azeotroped with toluene and redissolved in MeCN (10 mL). This was applied to a SCX cartridge (50 g, Varian) which had been pre-wetted with MeCN. The cartridge was washed with MeCN (100 mL) and eluted with 880 aqueous ammonia in MeCN (1:4, 100 mL). The eluent was evaporated to afford the subtitled compound. Material used directly in the next step.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([C:14]([OH:16])=O)[O:7][N:6]=1)[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1.[F:23]C1N=C(F)N=C(F)N=1>ClCCl>[CH2:1]([C:5]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([C:14]([F:23])=[O:16])[O:7][N:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)Cc1noc(C(=O)O)c1C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)Cc1noc(C(=O)F)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a mixture of 3-isobutyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (0.200 g, 0.843 mmol) and pyridine (0.082 mL, 1.01 mmol) in dichloromethane (8 mL) at room temperature was added 2,4,6-trifluoro-1,3,5-triazine (cyanuric fluoride) (0.085 mL, 1.01 mmol). The reaction mixture was stirred at room temperature overnight. The heterogeneous reaction was diluted with dichloromethane, washed with an ice-cold solution of 0.5N aqueous hydrochloric acid (2×), and the organic layer was collected. The aqueous layer was back-extracted with dichloromethane, and the combined organic layers were dried anhydrous sodium sulfate and concentrated to afford 3-isobutyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride (0.130 g, 0.544 mmol, 65% yield) as a yellow solid. The product had an HPLC ret. time=2.51 min. (corresponding to the methyl ester)−Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA.
Reaction SMILES: [CH2:1]([O:3][C:4](=[NH:10])[NH:5][C:6]([O:8][CH3:9])=[O:7])[CH3:2].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[N:19]=[C:20]=[O:21]>C1C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[NH:19][C:20]([NH:10][C:4](=[N:5][C:6]([O:8][CH3:9])=[O:7])[O:3][CH2:1][CH3:2])=[O:21]
Reactant: CCOC(=N)NC(=O)OC
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Solvent: c1ccccc1
Product: CCOC(=NC(=O)OC)NC(=O)Nc1ccc(Cl)cc1Cl
Yield: 80.8 %

Procedure:
2 g of 2-ethyl-1-methoxycarbonylisourea [prepared as described in Japanese Patent Provisional Publication No. 49-25133 (1974)] and 1.88 g of 2,4-dichlorophenyl isocyanate were dissolved in 100 ml of benzene and the mixture was refluxed for 1 hour. The benzene was then removed by evaporation under reduced pressure and the residue was recrystallized from hexane, giving 2.7 g (yield 81%) of the desired compound as white needles melting at 92°-93° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:11]([NH:15][OH:16])([CH3:14])([CH3:13])[CH3:12]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[N+:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[O-:16]
Reactant: CC(C)(C)NO
Reactant: COc1ccccc1C=O
Product: COc1ccccc1C=[N+]([O-])C(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Example 7 using 2-methoxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 82.9% overall yield as white crystals, m.p. 109.1° C. (Rf=0.53 on a silica gel plate using ethyl acetate as the eluant).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:6]=[CH:7][CH:8]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=2)[CH:26]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=3)[CH:26]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: COc1ccccc1N(Cc1ccnc(-c2cc(OC)c(OC)c(OC)c2)c1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
4-(o-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)=[CH:6][C:5]=1[NH:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30].[CH3:34]I.Cl>CN(C)C=O>[CH3:34][N:27]([C:5]1[CH:6]=[C:7]([C:10]2[CH2:14][C:13]([C:19]3[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=3)([C:15]([F:18])([F:16])[F:17])[O:12][N:11]=2)[CH:8]=[CH:9][C:4]=1[Cl:3])[C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]
Reactant: CI
Reactant: O=C(Nc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Cl)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)C(F)(F)F)c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Cl
Reaction time: 0.33 h
Yield: 100.8 %

Procedure:
Sodium hydride (60% oily) was suspended in N,N-dimethylformamide (15 mL), and thereto was added dropwise a solution of {N-{2-chloro-5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}-2,2,2-trifluoroacetamide (3.6 g) obtained by Reference Production Example 24 in N,N-dimethylformamide (15 mL) at room temperature, and then the mixture was stirred at the same temperature for 20 minutes. To the mixture was added methyl iodide (1.52 g), and the mixture was further stirred for 1 hour. To the reaction mixture was added 2N hydrochloric acid, and the mixture was extracted with tert-butyl methyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain N-methyl-N-{2-chloro-5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]phenyl}-2,2,2-trifluoroacetamide (3.73 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].C([O-])([O-])=O.[K+].[K+].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[F:22]>CN(C=O)C.O>[F:22][C:14]1[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=1[O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: COCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc([N+](=O)[O-])cc1F
Temperature: 70 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
To a stirred suspension of methyl glycol (2.2 mL, 28.28 mmol, 1.5 eq.) and K2CO3 (7.8 g, 56.60 mmol, 3.0 eq.) in DMF (20 mL) was added 1,2-difluoro-4-nitrobenzene (3.0 g, 18.85 mmol, 1.0 eq.) and the mixture was stirred for 16 h at 70° C. The reaction mixture was cooled and diluted with water (30 mL) and extracted with ethyl acetate (40 mL). The organic layer was separated and washed with water (50 mL), brine (50 mL), and dried over sodium sulfate and the solvent evaporated under vacuum. The crude product was washed with n-pentane (30 mL) to obtain 2-fluoro-1-(2-methoxyethoxy)-4-nitrobenzene (3 g, 74%, as solid; TLC system: EtOAc/PE (1:9), Rf: 0.2).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH:9]1([O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH:18]=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.CC(O)=O>ClCCCl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:18][C:17]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:15]([O:14][CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[CH:16]=2)[CH:3]=1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Nc1cc(Cl)ncn1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(CNc2cc(Cl)ncn2)cc1OC1CCCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 12.4 %

Procedure:
Sodium tiracetoxyl-borohydride (985 mg, 4.65 mmol) was added to a solution of 6-chloro-pyrimidin-4-ylamine (200 mg, 1.55 mmol) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (682 mg, 3.1 mmol) in 25 ml of DCE. 1 ml of HOAc was added, and the mixture was stirred overnight at 50° C., followed by addition of 25 ml of DCE. The organic phase was washed with water, and the product was purified with column (silica gel, hexane:EtOAc 5:1) to give 64 mg of (6-chloro-pyrimidin-4-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine, yield 12%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](Br)[C:5]([F:8])=[N:6][CH:7]=1.[CH2:10]([Sn](CCCC)(CCCC)C=C)[CH2:11]CC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH2:11])[C:5]([F:8])=[N:6][CH:7]=1
Reactant: Nc1cnc(F)c(Br)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(N)cnc1F
Temperature: 100 °C
Yield: 97.9 %

Procedure:
To a stirred solution of 5-amino-3-bromo-2-fluoropyridine (3.25 g, 17.0 mmol) in toluene (20 mL) was added tributyl(vinyl)tin (7.64 g, 20.4 mmol) followed by tetrakis(triphenylphosphine) palladium (Aldrich, 0.63 g, 1.7 mmol). The reaction mixture was heated at 100° C. for 24 h. The solvent was removed in vacuo and the residue was purified by column chromatography (silica gel; EtOAc/hexane, 4:6) to afford the title compound as a beige solid (2.30 g, 98%): 1H NMR (CDCl3, 300 MHz) δ 3.61 (br s, 2H), 5.44 (d, J=11.5 Hz, 1H), 5.83 (d, J=17.5 Hz, 1H), 6.66 (m, 1H), 7.18 (dd, J=3.0, 5.0 Hz, 1H), 7.52 (m, 1H); MS (CI/NH3) m/z 139 (M+H)+, 156 (M+NH4)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[O:9])[CH:3]=1.[CH:20]1([NH:26][CH2:27][CH2:28][O:29][CH3:30])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([N:26]([CH2:27][CH2:28][O:29][CH3:30])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][N:15]=[CH:14]4)=[O:9])[CH:3]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COCCNC1CCCCC1
Reactant: O=C(Nc1ccc2[nH]ncc2c1)c1cc(Cl)ncn1
Product: COCCN(c1cc(C(=O)Nc2ccc3[nH]ncc3c2)ncn1)C1CCCCC1

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-pyrimidine-4-carboxylic acid (1H-indazol-5-yl)-amide (Intermediate 16) and cyclohexyl-(2-methoxy-ethyl)-amine (Intermediate 26), the title compound was obtained as a yellow solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:42]I>C(#N)C>[I:42][CH2:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCCOc1ccc(CO)cc1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCOC(=O)CCCOc1ccc(CI)cc1
Reaction time: 0.33 h

Procedure:
To a solution of the intermediate from step B (1 g, 4.24 mmol) in acetonitrile was added triphenyl phosphine (1.45 g, 5.5 mmol), imidazole (0.4 g, 5.93 mmol) and iodine (1.51 g, 5.94 mmol). After 20 minutes, the reaction was quenched with saturated Na2S2O3 solution. The resulting mixture was extracted with ethyl acetate washed with brine and dried over anhydrous Na2SO4. The solution was filtered, concentrated in vacuo and purified by flash chromatography using 15% ethyl acetate-hexanes to give the desired product as an oil. 1H NMR (CDCl3, 500 MHz): 7.32 (d, J=8.7 Hz, 2H), 6.82 (d, J=8.7 Hz, 2H), 4.48 (s, 2H), 4.18 (q, J=6.1 Hz, 2H), 4.01 (t, J=6.1 Hz, 2H), 2.53 (t, J=7.4 Hz, 2H), 2.14 (m, 2H), 1.29 (t, J=7.1 Hz, 3H). LC-MS=2.36 min; (M+23)=371.0.
Reaction SMILES: O=C[C:3]([O:5][CH2:6][CH3:7])=O.COC1C=C(N)C(N)=CC=1.CO[C:20]1[CH:21]=[C:22]2[C:27](=CC=1)[NH:26][C:25](=[O:30])[CH:24]=[N:23]2>C1(C)C=CC=CC=1.C(O)C>[CH3:3][O:5][C:6]1[CH:7]=[C:27]2[C:22]([N:23]=[CH:24][C:25](=[O:30])[NH:26]2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)C=O
Reactant: COc1ccc2[nH]c(=O)cnc2c1
Agent: COc1ccc(N)c(N)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc2ncc(=O)[nH]c2c1
Yield: 42 %

Procedure:
A 50% solution of ethyl 2-oxoacetate (18.47 mL, 93 mmol) in toluene was added to a solution of 4-methoxybenzene-1,2-diamine (10.73 g, 78 mmol) in ethanol (100 mL) at ambient temperature and the reaction was refluxed for 2 h. The reaction was concentrated in vacuo and crystallized from ethanol to afford a mixture of 6-methoxyquinoxalin-2(1H)-one and 7-methoxyquinoxalin-2(1H)-one (5.73 g, 32.50 mmol, 42% yield). MS (LC/MS) R.T.=0.68; [M+H]+=177.10.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:11]([C:12](=[S:14])[NH2:13])[N:10]=[C:9]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[S:8]1)=[N+:2]=[N-:3].Br[CH:30]1[C:35](=O)[CH2:34][CH2:33][N:32]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:31]1.CCN(C(C)C)C(C)C>C(O)C>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:11]([C:12]2[S:14][C:30]3[CH2:31][N:32]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:34][C:35]=3[N:13]=2)[N:10]=[C:9]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[S:8]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(N)=S
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCCN=[N+]=[N-])c3ccccc3)sc2C1
Reaction time: 8 h

Procedure:
To a solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothioamide (0.300 g, 0.717 mmol) in 10 mL of ethanol was added tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (0.239 g, 0.860 mmol) followed by DIEA (0.25 mL, 1.43 mmol). The mixture was allowed to stir overnight at reflux, then treated with tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate (100 mg) and stirred at reflux for a further 3 hours. The cooled mixture was partitioned between a saturated NaHCO3 solution (30 mL) and EtOAc (30 mL), and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (5-10% ethyl acetate/hexanes) to afford the desired product as a bright yellow foam, 0.313 g, 73%.