Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:10]([CH:11]([CH3:14])[CH:12]=[O:13])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[Si]([C:26]([F:29])([F:28])[F:27])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-]>C1COCC1>[CH3:1][C:2]1[N:10]([CH:11]([CH:12]([OH:13])[C:26]([F:29])([F:28])[F:27])[CH3:14])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1c(C(=O)OC(C)(C)C)c2cccnc2n1C(C)C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(C(=O)OC(C)(C)C)c2cccnc2n1C(C)C(O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a solution of tert-butyl 2-methyl-1-(1-oxopropan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (100 mg, 0.35 mmol) in dry THF (2 ml) was added a solution of TMS-CF3 (0.02 ml, 1M in THF) and the reaction mixture was cooled to 0° C. under Ar, Added TBAF (73.97 mg, 0.52 mmol), via drop-wise addition and stirred for 30 min at 0° C. A solution of saturated NH4Cl was added and most of the solvent was stripped on the ratary evaporator. The reminder was taken up EtOAc and H2O and transferred to a separatory funnel. The mixture was shaken and the organic layer was separated, dried over Na2SO4, and evaporated under reduced pressure to give tert-butyl 2-methyl-1-(4,4,4-trifluoro-3-hydroxybutan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate as a white crystal (40 mg, yield 32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[N:14]=[C:15]([C:24]([CH3:28])([CH3:27])[CH2:25][NH2:26])[NH:16][C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH:7]=[CH:6]2.[CH3:29][C:30]([N:32]=[C:33]=[O:34])=[O:31]>>[CH3:29][C:30]([NH:32][C:33]([NH:26][CH2:25][C:24]([C:15]1[NH:16][C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:13]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)[N:14]=1)([CH3:28])[CH3:27])=[O:34])=[O:31]
Reactant: CC(=O)N=C=O
Reactant: COc1ccc2cc(-c3nc(C(C)(C)CN)[nH]c3-c3ccncc3)ccc2c1
Product: COc1ccc2cc(-c3nc(C(C)(C)CNC(=O)NC(C)=O)[nH]c3-c3ccncc3)ccc2c1
Yield: 51 %

Procedure:
The title compound (13 mg, 51%) was prepared starting from the product of Example 2 and methylformyl isocyanate using the method described in Example 4; MS(ES) m/e 474 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([CH3:13])=[CH:5][C:4]=1[OH:14].O[CH2:16][CH:17]=[C:18]([CH3:37])[CH2:19][CH2:20][CH:21]=[C:22]([CH3:36])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:35])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:34])[C:31]([OH:33])=[O:32]>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[C:31]([C:30]([CH3:34])=[CH:29][CH2:28][CH2:27][C:26]([CH3:35])=[CH:25][CH2:24][CH2:23][C:22]([CH3:36])=[CH:21][CH2:20][CH2:19][C:18]([CH3:37])=[CH:17][CH2:16][C:5]1[C:4]([OH:14])=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]=1[CH3:13])([OH:33])=[O:32]
Reactant: CC(=CCO)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: COc1c(C)cc(O)c(OC)c1OC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: COc1c(C)c(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O)c(O)c(OC)c1OC
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
5 g of 2,3,4-trimethoxy-5-methylphenol was dissolved in 10 ml of benzene and 6 g of silica gel (Wako gel C-200) and 3 g of zinc chloride were added thereto. 3 g of 16-hydroxy-2,6,10,14-tetramethyl-2,6,10,14-hexadecatetraenoic acid dissolved in 5 ml of benzene was added to the above solution. After reacting at room temperature for 30 min, the reaction mixture was filtered and the precipitate was washed with ethyl ether while the filtrate was washed with water, dried over magnesium sulfate anhydride and concentrated. The concentrate was purified by means of silica gel chromatography with the use of ether/n-hexane as the eluent to give 2.1 g of the title compound as a colorless oil.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[CH3:32][C:33]1[O:37][N:36]=[C:35]([CH2:38][NH2:39])[CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:39][CH2:38][C:35]1[CH:34]=[C:33]([CH3:32])[O:37][N:36]=1)=[O:5]
Reactant: Cc1cc(CN)no1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(CNC(=O)C(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)no1
Reaction time: 1 h
Yield: 48.3 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 25 mg, 0.058 mmol), (5-methylisoxazol-3-yl)methanamine (9.75 mg, 0.087 mmol), HATU (28.7 mg, 0.075 mmol), and 4-methylmorpholine (23.45 mg, 0.232 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention=14.0 min) to provide 2-hydroxy-N-((5-methylisoxazol-3-yl)methyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (15 mg, 0.028 mmol, 48.2% yield) as a single enantiomers. LCMS=526.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.11-8.23 (2 H, m), 7.50-7.82 (7 H, m), 5.98 (1 H, s), 5.18 (1 H, s), 4.43 (2 H, s), 2.36 (3 H, s); HPLC peak RT=10.0 min (Method A).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1B(O)O>>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[CH3:12]
Reactant: Cc1ccncc1B(O)O
Reactant: O=[N+]([O-])c1ccc(Cl)c(Br)c1
Product: Cc1ccncc1-c1cc([N+](=O)[O-])ccc1Cl

Procedure:
The title compound was prepared by a Suzuki coupling of 3-bromo-4-chloronitrobenzene and 4-methyl-3-pyridylboronic acid. This gave (D61) (0.2 g, 33%).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.Cl>O.O1CCOCC1.CN(C)C1C=CN=CC=1>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([N:1]2[CH2:8][CH2:7][CH2:6][C@@H:2]2[C:3]([OH:5])=[O:4])(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: O=C(O)[C@H]1CCCN1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)N2CCC[C@@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
D-proline (15 g, 130.3 mmol) is dissolved in a 1:1 mixture of water (150 mL) and p-dioxane (150 mL) and then triethyl amine (40 mL, 287 mmol), 4-methoxyphenylsulfonyl chloride (29.0 g, 140.3 mmol), and the 4-dimethylaminopyridine (1.5 g, 13.0 mmol) are added. The solution is stirred at room temperature overnight. The reaction mixture is then treated with 1N HCl until the solution is acidic (pH=2). The resulting solution is extracted three times with ethyl acetate. The ethyl acetate layers are washed with ammonium chloride, dried (MgSO4), filtered and evaporated to give the crude compound. Cl+ MS: m/z (rel intensity) (M+ +H 286, 100 ).
Reaction SMILES: [N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3].O.[C:11]([O-:15])(=[O:14])[CH:12]=[O:13].[Na+].[CH3:17][O:18][CH:19]([O:22][CH3:23])[CH:20]=[O:21].[OH-].[Na+]>>[N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3].[CH3:17][O:18][CH:19]([O:22][CH3:23])[CH:20]=[O:21].[C:11]([OH:15])(=[O:14])[CH:12]=[O:13]
Reactant: O=CC(=O)[O-]
Agent: COC(C=O)OC
Agent: Nc1nc(N)nc(N)n1
Agent: [Na+]
Solvent: O
Product: O=CC(=O)O
Temperature: 52.5 °C
Reaction time: 2 h

Procedure:
170 g of melamine (1.35 mol) were added to an aqueous solution made up of 311.6 g of 15% sodium glyoxylate monohydrate (Sigma Aldrich, 0.41 mol) and 495 g of 60% dimethoxyethanal (2.86 mol). This mixture was heated under stirring for 2 h at 50-55° C. while maintaining the pH close to 9-9.5 with adjustment, if necessary, with as much 20% sodium hydroxide as was required (about 7 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[N:3]1.CN(CCN(C)C)C.[Li]CCCC.CN(OC)[C:22]([C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:23].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:30][C:29]1[C:24]([C:22]([C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)=[O:23])=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cn1cnnn1
Reactant: CON(C)C(=O)c1ncccc1C
Agent: CN(C)CCN(C)C
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccnc1C(=O)c1nnnn1C
Yield: 39.7 %

Procedure:
To a solution of 1-methyltetrazole (2.9 g, 34.7 mmol) and TMEDA (10 ml, 66.2 mmol) in THF (100 ml) cooled at −78° C. is added dropwise 2.5 M nBuLi in hexanes (13.9 ml, 34.7 mmol) with vigorous stirring and maintaining the reaction temperature below −65° C. On complete addition, the mixture is is stirred 20 minutes before adding dropwise a solution of N-methyl-N-methoxy-(3-methylpyridin-2-yl)carboxamide (6.3 g, 34.7 mmol) in THF. On complete addition, the mixture is stirred for six hours at −78° C. before adding slowly a half-diluted saturated aqueous NaHCO3 solution (300 ml). The mixture is extracted with ethyl acetate (500 ml). After separation, the organic layer is dried (MgSO4), filtered and concentrated. Silica-gel chromatography of the residue affords 2.8 g of (3-methylpyridin-2-yl)-(1-methyltetrazol-5-yl)methanone [yield 39.7%; 1H-NMR (DMSO-d6) δppm: 2.6 (s, 3H), 4.17 (s, 3H), 7.65 (dd, 1H), 7.95 (d, 1H), 8.56 (d, 1H)].
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>COCCO.[Pd]>[CH2:1]([N:8]1[C:16](=[O:17])[CH:15]2[CH:10]([NH:11][CH2:12][CH2:13][CH2:14]2)[C:9]1=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2cccnc2C(=O)N1Cc1ccccc1
Agent: [Pd]
Solvent: COCCO
Solvent: O
Product: O=C1C2CCCNC2C(=O)N1Cc1ccccc1
Temperature: 90 °C
Reaction time: 6 h
Yield: 58.5 %

Procedure:
To a solution of 6-benzyl-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione (5.00 g) in glycol monomethyl ether was added a catalytic amount of 10% Pd/C. The reaction mixture was heated to 90° C. and stirred for 6 h under H2, then cooled to rt. The resulted mixture was poured into 100 mL of water and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 1:2 (v/v) PE/EA) to give the title compound as colorless oil (3.00 g, 60.00%), HPLC: 95.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 245.1 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.47-1.53 (m, 4H), 2.12 (s, 1H), 2.63-2.69 (m, 1H), 2.76-2.88 (m, 2H), 3.83 (d, J=8.2, 2H), 4.64 (s, 1H), 7.25-7.36 (m, 5H) ppm.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=1)C(=O)C>[OH-].[Na+]>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][NH:5][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=1
Reactant: CC(=O)N(CCN(C)C)c1ccc(C)cn1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(NCCN(C)C)nc1

Procedure:
To N-(2-dimethylaminoethyl)-N-(5-methyl-2-pyridyl) acetamide (50.0 g, 0.226 mole) is added 200 ml of 5 N sodium hydroxide. The mixture is stirred rapidly at reflux for 16 hours. The mixture is cooled and the oil is extracted into ether. The ether extract is dried and evaporated under reduced pressure. Distillation of the residue gives a pale yellow liquid, b.p. 105°-112°, n25D 1.5355. Weight obtained is 35 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O.C(#N)C>[CH3:8][C:6]1[CH:7]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[CH:4][N:5]=1
Reactant: Cc1cc(Cl)ncn1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Cc1cc(-c2ccccc2)ncn1
Yield: 46 %

Procedure:
First, in a recovery flask equipped with a reflux pipe were put 4.90 g of 4-chloro-6-methylpyrimidine, 4.80 g of phenylboronic acid, 4.03 g of sodium carbonate, 0.16 g of bis(triphenylphosphine)palladium(II)dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 10 mL of acetonitrile, and the air in the flask was replaced with argon. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes so that heating was performed. Here, in the flask were further put 2.28 g of phenylboronic acid, 2.02 g of sodium carbonate, 0.082 g of Pd(PPh3)2Cl2, 5 mL of water, and 10 mL of acetonitrile, and the mixture was subjected to irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes so that heating was performed. After that, water was added to this solution and an organic layer was subjected to extraction with dichloromethane. The solution of the obtained extract was washed with a saturated sodium carbonate aqueous solution, water, and saturated brine in this order and dried over magnesium sulfate. After the drying, the solution was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by silica gel column chromatography using dichloromethane and ethyl acetate as a developing solvent in a volume ratio of 9:1. As a result, a pyrimidine derivative Hmppm, which was the object of the synthesis, was obtained (orange oily substance, 46% yield). Note that for the microwave irradiation, a microwave synthesis system (Discover, produced by CEM Corporation) was used. A synthesis scheme (y-1) of Step 1 is illustrated below.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].F[C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[N:22][C:23]([NH2:27])=[N:24]2)=[CH:19][CH:18]=1>CN(C)C=O>[NH2:27][C:23]1[N:22]=[CH:21][C:20]2[C:25](=[CH:26][C:17]([N:4]3[C:5]4[CH2:6][C:7]([CH3:13])([CH3:12])[CH2:8][C:9](=[O:11])[C:10]=4[C:2]([CH3:1])=[CH:3]3)=[CH:18][CH:19]=2)[N:24]=1
Reactant: Cc1c[nH]c2c1C(=O)CC(C)(C)C2
Reactant: Nc1ncc2ccc(F)cc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(-c2ccc3cnc(N)nc3c2)c2c1C(=O)CC(C)(C)C2
Yield: 81.4 %

Procedure:
3,6,6-Trimethyl-1,5,6,7-tetrahydro-indol-4-one (0.65 g, 3.68 mmol), sodium hydride (60% in oil, 0.177 g, 4.4 mmol), 7-fluoroquinazolin-2-amine (0.60 g, 3.68 mmol), and N,N-dimethylformamide are sealed in a microwave vessel and irradiated at 150 degrees Celsius for 1500 seconds. The mixture is purified by column chromatography and recrystallized from dichloromethane/hexane, affording 0.96 g of 1-(2-Amino-quinazolin-7-yl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-indol-4-one (81%). LC/MS m/z=321 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[N:5]2[C:4](=[O:15])[NH:3]1.Br[CH2:17][CH2:18][Cl:19]>>[Cl:19][CH2:18][CH2:17][N:3]1[C:2](=[O:1])[N:6]2[CH2:7][CH2:8][CH2:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[N:5]2[C:4]1=[O:15]
Reactant: ClCCBr
Reactant: COC(=O)C1CCCn2c(=O)[nH]c(=O)n21
Product: COC(=O)C1CCCn2c(=O)n(CCCl)c(=O)n21

Procedure:
Alkylation of methyl hexahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate with 1-bromo-2-chloroethane in a manner analogous to that described in the preceding paragraph gave methyl 2-(2-chloroethyl)-2,3,5,6,7,8-hexahydro-1,3-dioxo-1H-1,2,4-triazolo[1,2-a]pyridazine-5-carboxylate of melting point 94°-95° C.
Reaction SMILES: [CH3:1][CH:2]1[O:6][CH2:5][S:4][C:3]1=[N:7][OH:8].[CH3:9][N:10]([S:14][C:15]([CH3:22])([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH3:16])[C:11](Cl)=[O:12].C(N(CC)CC)C>O1CCOCC1>[CH3:9][N:10]([S:14][C:15]([CH3:16])([C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH3:22])[C:11]([O:8][N:7]=[C:3]1[CH:2]([CH3:1])[O:6][CH2:5][S:4]1)=[O:12]
Reactant: CC1OCSC1=NO
Reactant: CC(C)C(=O)C(C)(C)SN(C)C(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)C(=O)C(C)(C)SN(C)C(=O)ON=C1SCOC1C

Procedure:
Prepared as in Example I by reacting 2.64 g (0.02 m) of 5-methyl-4-oximino-1,3-oxathiolane, 4.47 g (0.02 m) of N-methyl-N-(2,4-dimethyl-3-oxo-2-pentanesulfenyl)carbamoyl chloride and 2.02 g (0.02 m) of triethylamine in 25 ml of dioxane. Crystallized from isopropyl etherto yield 1.2 g of a white solid, m.p. 90°-92° C.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:9]([C:10](O)=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[F:27][C:28]([F:42])([F:41])[C:29](=[N:31][NH:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[NH2:30]>ClCCl.O1CCOCC1.CN(C)C=O>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([N:32]2[C:10]([C:9]3[CH:13]=[CH:14][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[CH:2]4)=[CH:7][CH:8]=3)=[N:30][C:29]([C:28]([F:27])([F:41])[F:42])=[N:31]2)=[CH:38][CH:37]=1
Reactant: O=C(O)c1ccc(-n2cccc2)cc1
Reactant: COc1ccc(NN=C(N)C(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(F)(F)F)nc2-c2ccc(-n3cccc3)cc2)cc1
Reaction time: 8 h
Yield: 12.8 %

Procedure:
To a suspension of 4-(1H-pyrrol-1yl)benzoic acid (337 mg, 1.8 mmol) in dichloromethane (3.5 mL), oxalyl chloride (0.157 mL, 1.8 mmol) and then dimethylformamide (10 microL) were added. The mixture was stirred overnight. The solvent was removed under reduced pressure. Pyridine (0.146 mL, 1.8 mmol) and a solution of 2,2,2-trifluoro-N′-(4-methoxyphenyl)ethanehydrazonamide (350 mg, 1.5 mmol) in 3.5 mL of dioxane were added to a suspension of the acyl chloride in 3.5 mL of dioxane. The mixture was refluxed with stirring for 3 hours. After cooling, the solvent was removed under reduced pressure and 0.1 N hydrochloric acid and dichloromethane were added to the residue. The organic layer was separated and the aqueous layer was extracted with dichloromethane. A combined layer was washed with 0.1 N hydrochloric acid and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The desired product was purified by silica gel column chromatography (hexane-ethyl acetate 8:1-5:1) to give 1-(4-methoxyphenyl)-5-[4-(1H-pyrrol-1yl)phenyl]-3-(trifluoromethyl)-1H-1,2,4-triazole (74 mg, 12.8% yield)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][C:7](=O)[CH2:6][CH2:5]2.Cl.[CH3:15][C:16]([C:21]1[S:25][C:24]([NH:26][C:27](=[O:33])[CH:28]([NH2:32])[CH2:29][CH2:30][CH3:31])=[N:23][N:22]=1)([CH3:20])[CH2:17][CH2:18][CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BH3-]C#N.[Na+]>ClCCl.CN(C=O)C>[CH3:20][C:16]([C:21]1[S:25][C:24]([NH:26][C:27](=[O:33])[C@@H:28]([NH:32][CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)[CH2:29][CH2:30][CH3:31])=[N:23][N:22]=1)([CH3:15])[CH2:17][CH:18]=[CH2:19]
Reactant: CCCC(N)C(=O)Nc1nnc(C(C)(C)CCC)s1
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=CCC(C)(C)c1nnc(NC(=O)[C@H](CCC)NC2CCc3cc(F)cc(F)c3C2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6,8-difluoro-3,4-dihydro-1H-naphthalen-2-one (182 mg, 1 mmol), 2-amino-pentanoic acid [5-(1,1-dimethyl-butyl)-[1,3,4]thiadiazol-2-yl]-amide HCl (318 mg, 1.2 mmol), 95% pure sodium triacetoxy borohydride (335 mg, 1.5 mmol) in 7.0 mL of anhydrous dichloromethane and 2 ml of DMF was stirred at rt overnight. The reaction was not complete. The mixture was treated with NaBH3CN (140 mg) and stirred at room temperature for 15 hrs. All starting material and imine intermediate were consumed. The crude solution was diluted with dilute NaOH and extracted with methylene chloride. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude products were purified by silica gel column chromatography to give the title compound. LC-MS, RT=2.2 min, M+1=449.0. The corresponding HCl salt was prepared as a beige solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:26][C@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:26][C@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)nc1C(F)(F)F
Reactant: C[C@H]1CCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C[C@H]1CCCN1c1ccc([N+](=O)[O-])c(C(F)(F)F)n1
Temperature: 140 °C
Yield: 86.2 %

Procedure:
A suspension of 6-bromo-3-nitro-2-(trifluoromethyl)pyridine (400 mg, 1.5 mmoL), (S)-2-methylpyrrolidine tosylate salt (381 mg, 1.5 mmoL) and K2CO3 (620 mg, 4.5 mmoL) in H2O (4 mL) was heated at 140° C. under microwave irradiation for 30 minutes. The solution was extracted with EtOAc (50 mL×3) and the combined organic layer was washed with brine, dried over anhydrous Na2SO4 and purified by silica gel column chromatography to afford (S)-6-(2-methylpyrrolidin-1-yl)-3-nitro-2-(trifluoromethyl)pyridine (350 mg, 88% yield). 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=9.2 Hz, 1H), 6.44 (d, J=8.4 Hz, 1H), 4.55-4.42 (m, 1H), 4.02-3.30 (m, 2H), 2.30-2.00 (m, 3H), 1.81 (brs, 1H), 1.27 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.FC(F)(F)C(O)=O.[C:30]([C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([CH2:43][N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[CH:42]=1)[C:37](O)=[O:38])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([C:34]1[CH:35]=[C:36]([CH:40]=[C:41]([CH2:43][N:44]2[CH2:45][CH2:46][CH2:47][CH2:48]2)[CH:42]=1)[C:37]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:38])([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Reactant: CC(C)(C)c1cc(CN2CCCC2)cc(C(=O)O)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)c2cc(CN3CCCC3)cc(C(C)(C)C)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
35 mg (0.12 mmol) of the compound of Example 6A and 47 mg (0.12 mmol) of the compound of Example 22A were reacted and worked up analogously to the procedure of Example 16. This gave 55 mg (95% pure, 81% of theory) of the title compound.
Reaction SMILES: [ClH:1].FC1C=CC(CN)=C(N2C=NC=N2)C=1.[F:16][C:17]1[CH:24]=[C:23]([N:25]2[CH:29]=[N:28][CH:27]=[N:26]2)[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]>>[ClH:1].[F:16][C:17]1[CH:24]=[C:23]([N:25]2[CH:29]=[N:28][CH:27]=[N:26]2)[CH:22]=[CH:21][C:18]=1[CH2:19][NH2:20]
Reactant: N#Cc1ccc(-n2cncn2)cc1F
Agent: Cl
Agent: NCc1ccc(F)cc1-n1cncn1
Product: NCc1ccc(-n2cncn2)cc1F
Yield: 79 %

Procedure:
This compound was prepared (79% yield) following the procedure for (4-fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride using (2-fluoro-4-(1H-1,2,4-triazol-1-yl)benzonitrile. 1H NMR (500 MHz, CD3OD) δ: 9.25 (1H, s), 8.46 (1H, s), 7.80 (1H, dd, J=8.6, 5.8 Hz), 7.64 (1H, dd, J=8.8, 2.4 Hz), 7.44 (1H, td, J=8.3, 2.6 Hz), 4.17 (2H, s). LCMS (M+H) calcd for C9H10N4F: 193.08; found: 193.16.