Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([S:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=2)[C:9]#[N:10])=[CH:3][CH:2]=1.[CH3:25][O-].[Na+].CI.[Cl-].[NH4+]>CO>[C:1]1([CH3:24])[CH:2]=[CH:3][C:4]([S:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=2)([CH3:25])[C:9]#[N:10])=[CH:5][CH:6]=1
Reactant: C[O-]
Reactant: Cc1ccc(SC(C#N)c2cccc(Oc3ccccc3)c2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: Cc1ccc(SC(C)(C#N)c2cccc(Oc3ccccc3)c2)cc1
Yield: 86 %

Procedure:
1.245 g of alpha-(p-tolylthio)(m-phenoxyphenyl)-acetonitrile was dissolved in 5 ml of anhydrous methanol, and a 2.2 M methanol solution of sodium methoxide was added at room temperature in an atmosphere of argon. The mixture was stirred, and 0.35 ml of methyl iodide was added dropwise. The mixture was further stirred for 30 minutes at room temperature. Then, an aqueous solution of ammonium chloride (3 g/20 ml) was added, and the mixture was extracted with 20 ml of ether three times. The extract was washed with 30 ml of water three times, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily residue was purified by column chromatography (silica gel; hexane and methylene chloride) to afford 1.125 g (yield 86%) of alpha-(p-tolylthio)-alpha-(m-phenoxyphenyl)propionitrile as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH2:2]1.[CH:25](=O)[CH2:26][CH3:27].[BH4-].[Na+]>CO>[CH2:25]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:14][C:15]4[C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH2:2]1)[CH2:26][CH3:27]
Reactant: CCC=O
Reactant: NC(=O)c1cccc2nc(-c3ccc(C4CCCNC4)cc3)oc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCN1CCCC(c2ccc(-c3nc4cccc(C(N)=O)c4o3)cc2)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 19.8 %

Procedure:
A mixture of 2-(4-(piperidin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide (80 mg, 0.25 mmol) and propionaldehyde (72 mg, 1.25 mmol) in methanol (10 mL) was stirred at room temperature for 40 min. Then the mixture was cooled to 0° C. Sodium borohydride (45 mg, 0.75 mmol) was added. After the addition, the mixture was stirred at this temperature for 2 hr. Methanol was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by pre-HPLC to give 2-(4-(1-propylpiperidin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide as a light yellow solid (18 mg, yield 23%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 0.94 (t, 3H), 1.58-1.64 (m, 3H), 1.81-2.01 (m, 3H), 2.11-2.20 (m, 2H), 2.43 (m, 2H), 2.97 (m, 1H), 3.08 (t, 2H), 7.50-7.54 (m, 3H), 7.91-7.94 (m, 2H), 8.29 (d, 1H); LC-MS (ESI) m/z: 364 (M+1)+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[CH:24][CH:23]=3)[CH2:11][CH:12]=[C:13]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:8]2=[N:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[CH2:1]([C:5]1[N:9]2[CH:10]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][N:37]=[N:36][N:35]=4)=[CH:24][CH:23]=3)[CH2:11][CH:12]=[C:13]([CH2:14][C:15]([OH:17])=[O:16])[C:8]2=[N:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CC=C2CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCCCc1cnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CC=C2CC(=O)O
Temperature: 25 °C

Procedure:
To a solution of biphenyl imidazolyl tert-butyl ester (0,039 mmol, the title compound of Example 1445) in 0.5 mL of chloroform is added 0.25 mL of TFA, and the progress of the reaction is monitored by 1H NMR. The resulting solution is stirred at room temperature until the reaction is complete. The mixture is quenched with methanol and concentrated in vacuo. The residue is purified to give the title compound of Example 1446.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]1[NH:16][C:15]([CH3:17])=[N:14][CH:13]=1.C1C(=O)N([Cl:25])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Cl:25][C:13]1[NH:14][C:15]([CH3:17])=[N:16][C:12]=1[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[CH3:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(C)c(-c2cnc(C)[nH]2)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C)c(-c2nc(C)[nH]c2Cl)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 82.1 %

Procedure:
To a solution of methyl 4-methyl-3-(2-methyl-1H-imidazol-5-yl)benzoate (compound 7.1, 317 mg, 1.38 mmol) in carbon tetrachloride (30 mL) was added NCS (184 mg, 1.38 mmol). The mixture was stirred at 50° C. for 16 hours, then cooled to room temperature and washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-50% EtOAc in hexanes) to yield the title compound as a solid (300 mg, 82%). m/z (ES+) 265 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.55 (br s, 1H), 8.01-7.87 (m, 2H), 7.37 (d, J=7.8 Hz, 1H), 3.91 (s, 3H), 2.42 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:24][C:25]#[N:26])[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.Cl.C(N(CC)CC)C.[CH:35]1([S:38](Cl)(=[O:40])=[O:39])[CH2:37][CH2:36]1>O1CCOCC1.C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([C:13]3([CH2:24][C:25]#[N:26])[CH2:14][N:15]([S:38]([CH:35]4[CH2:37][CH2:36]4)(=[O:40])=[O:39])[CH2:16]3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3ccnc(Cl)n3)cn2)C1
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCC1(n2cc(-c3ccnc(Cl)n3)cn2)CN(S(=O)(=O)C2CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of tert-butyl 3-(4-(2-chloropyrimidin-4-yl)-1H-pyrazol-1-yl)-3-(cyanomethyl)azetidine-1-carboxylate (0.241 g, 0.643 mmol) in 2 mL of dioxane was added 4 M HCl in dioxane (4.0 mL). The reaction was stirred at room temperature for 30 min, then evaporated to dryness. To the resulting crude HCl salt in methylene chloride (5.0 mL) was added triethylamine (0.269 mL, 1.93 mmol) followed by cyclopropanesulfonyl chloride (0.0786 mL, 0.771 mmol). The mixture was stirred at room temperature for 30 min, washed with saturated sodium bicarbonate, dried, and evaporated to dryness. The residue was used directly in next step (229 mg, 94%). LCMS (M+H) 379.0.
Reaction SMILES: [Cl:1][C:2]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:5]2[O:6][C:7]([CH3:12])([CH3:11])[C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[H-].[Na+].I[CH3:21].O>CN(C=O)C>[Cl:1][C:2]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:5]2[O:6][C:7]([CH3:12])([CH3:11])[C:8](=[O:10])[N:9]([CH3:21])[C:4]=2[CH:3]=1
Reactant: CI
Reactant: CC1(C)Oc2cc([N+](=O)[O-])c(Cl)cc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)C(C)(C)Oc2cc([N+](=O)[O-])c(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Chloro-2,2-dimethyl-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (2.29 g, 8.9 mmol) was stirred in DMF at 0° C. under an atmosphere of nitrogen then sodium hydride (60% dispersion in oil) (392 mg, 9.79 mmol) was added. The reaction was allowed to stir at room temperature for 30 min then iodomethane (1.89 g, 13.4 mmol) was added and the reaction was stirred at room temperature for 18 h. Analysis by LCMS indicated that the reaction was complete. Water (10 mL) was added carefully then the DMF was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous phase was extracted with ethyl acetate. The organic portions were combined then passed through a phase separation cartridge. The solvents were evaporated to afford an orange solid (2.4 g, quant.) which was taken through to the next step with no further purification.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:31])[CH2:14][NH:15][C:16](=O)[C@@H:17]([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])[CH3:18])=[CH:9][CH:8]=1>C1(C)C=CC=CC=1.ClCCl>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:31][C:16]([C@@H:17]([N:19]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:29])[CH3:18])=[N:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: C[C@@H](C(=O)NCC(=O)c1ccc(Cl)cc1)N1C(=O)c2ccccc2C1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@@H](c1ncc(-c2ccc(Cl)cc2)o1)N1C(=O)c2ccccc2C1=O
Temperature: 110 °C
Yield: 20.9 %

Procedure:
Phosphoryl trichloride (1.m7 ml, 10.8 mmol) was added to a solution of (S)—N-(2-(4-chlorophenyl)-2-oxoethyl)-2-(1,3-dioxoisoindolin-2-yl)propanamide (2.162 g, 5.83 mmol) in toluene and heated at 110° C. for 15 hours. Dilute with dichloromethane (50 ml), wash with saturated sodium bicarbonate solution, water, brine, dried and concentrated in vacuo. Flash column chromatography (silica, 80 g) eluting with 0-50% EtOAc/DCM afforded the pure product 430 mg (yellow foam). HRMS(B) tR=1.42 min; MS m/z 353.1
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:30]([C:33]1[CH:38]=[CH:37][C:36](OC(ON=C(C#N)C(N)=O)=O)=[CH:35][CH:34]=1)([O-:32])=[O:31].O>O1CCCC1>[N+:30]([C:33]1[CH:38]=[CH:37][C:36]([O:21][C:20](=[O:22])[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])=[CH:35][CH:34]=1)([O-:32])=[O:31]
Reactant: N#CC(=NOC(=O)Oc1ccc([N+](=O)[O-])cc1)C(N)=O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.3 %

Procedure:
To a solution of N-benzyloxycarbonyl-L-phenyl alanine (0.6 g) and triethylamine (0.28 ml) in dry tetrahydrofuran (12 ml), 2-p-nitrophenyloxycarbonyloxyimino-2-cyanoacetic acid amide (0.6 g) is added, and the resulting mixture is stirred at room temperature for 1.5 hours. The reaction mixture is admixed with water and extracted with ethyl acetate. The organic layer is washed with an aqueous solution of sodium chloride, dried and concentrated. The residue is recrystallized from an ethanol-petroleum ether mixture to give N-benzyloxycarbonyl-L-phenylalanine p-nitrophenyl ester (0.5 g) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:42]#[N:43])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C:34]3([C:37]([F:40])([F:39])[F:38])[CH2:36][CH2:35]3)[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:41])[CH:9]=2)[CH:7]=1.FC(F)(F)C(O)=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:42]#[N:43])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C:34]3([C:37]([F:39])([F:40])[F:38])[CH2:36][CH2:35]3)[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:41])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2(C(F)(F)F)CC2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CC2(C(F)(F)F)CC2)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
157 mg (255 μmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclopropyl]propanoyl}amino)benzoate (racemate) were hydrolysed with 393 μl (5.10 mmol) of trifluoroacetic acid according to General Method 2, and after preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase: acetonitrile/0.1% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)], the title compound was obtained. Yield: 94 mg (65% of theory)
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][C:10](=O)[CH2:9]1)=[O:7].[CH3:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:32]=1[NH:38][C:39](=[O:47])[CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>CO.[Pd]>[F:28][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([C:24]([F:25])([F:27])[F:26])[CH:23]=1)[C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:11][C@H:10]([N:44]2[CH2:45][CH2:46][N:41]([CH2:40][C:39]([NH:38][C:32]3[C:33]([CH3:37])=[CH:34][CH:35]=[CH:36][C:31]=3[CH3:30])=[O:47])[CH2:42][CH2:43]2)[CH2:9]1)=[O:7]
Reactant: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Reactant: O=C1CC(Cc2ccccc2)N(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(C)c1NC(=O)CN1CCN([C@H]2C[C@@H](Cc3ccccc3)N(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C2)CC1
Yield: 14.6 %

Procedure:
A mixture of (±)-1-[3,5-bis(trifluoromethyl)benzoyl]-5-(phenylmethyl)-3-pyrrolidinone (0.0037 mol) and N-(2,6-dimethylphenyl)-1-piperazineacetamide (0.0037 mol) in methanol (150 ml) was hydrogenated at 50° C. with palladium on activated carbon (10%, 1 g) as a catalyst in the presence of tiophene solution (1 ml). After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The desired fractions were collected and the solvent was evaporated. The residue was dried and then crystallized from DIPE. The precipitate was filtered off and dried, yielding 0.35 g (15%) of (±)-cis-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-5-(phenylmethyl)-3-pyrrolidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (compound 131).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([O:12][CH3:15])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C(C)(C)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid (10.03 g, 49.4 mmol) in MeOH/DCM (60 mL/140 mL) at room temperature was added drop wise (trimethylsilyl)diazomethane (37.0 mL, 74.0 mmol). The reaction mixture was stirred for 30 minutes. Acetic acid was added drop wise to quench (trimethylsilyl)diazomethane. The reaction mixture was concentrated under reduced pressure to afford the desired product as a white solid (10.56 g). LCMS m/z 240.2 (M+Na)+, Rt 0.71 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.S(Cl)([Cl:20])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:20])=[O:7])=[C:4]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1Sc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc(Cl)cc1Sc1ccccc1

Procedure:
To a stirred suspension of 59.2 g. (0.224 mole) of 4-chloro-2-(phenylthio)benzoic acid in 200 ml. of benzene is added dropwise 41.6 g. (0.35 mole) of thionyl chloride during a 1 hour period, and the reaction mixture is heated under reflux for an additional hour. The reaction mixture is then concentrated to dryness under reduced pressure, and the residue is recrystallized from 300 ml. of boiling hexane to yield 41.9 g. of pale yellow product, melting point 94°-96°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([S:16][CH3:17])[C:4]=1[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[O:51]1[C:55]2([CH2:60][CH2:59][O:58][CH2:57][CH:56]2[NH2:61])[O:54][CH2:53][CH2:52]1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([S:16][CH3:17])[C:4]=1[C:5]([NH:61][CH:56]1[CH2:57][O:58][CH2:59][CH2:60][C:55]21[O:54][CH2:53][CH2:52][O:51]2)=[O:7]
Reactant: NC1COCCC12OCCO2
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1COCCC12OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (intermediate A, 400 mg, 1.5 mmol) was dissolved in 10 mL dimethylformamide. N,N-Diisopropyl ethyl amine (505 mg, 3.9 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (571 mg, 1.5 mmol) were added. After 10 minutes of stirring at room temperature 1,4,8-trioxaspiro[4,5]decan-6-amine (CAS 1068523-26-1) (359 mg, 2.2 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated off. The residue was taken up in 2N sodium carbonate solution and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (heptane/ethyl acetate/triethylamine 1:0:0→10:10:1) yielded 2-methoxy-6-methylsulfanyl-4-trifluoromethyl-N-(1,4,8-trioxa-spiro[4.5]dec-6-yl)-benzamide as a white solid (462 mg, 75%), MS: m/e=408.2 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:31])([F:30])[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:28](=[O:29])[NH:27][N:26]=[N:25]2)=[CH:20][CH:19]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:27]1[C:28](=[O:29])[N:24]([C:21]2[CH:20]=[CH:19][C:18]([O:17][C:16]([F:15])([F:31])[F:30])=[CH:23][CH:22]=2)[N:25]=[N:26]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]nnn1-c1ccc(OC(F)(F)F)cc1
Product: C[C@@H](n1nnn(-c2ccc(OC(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 66.5 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.54 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.52 g of 1-(4-trifluoromethoxyphenyl)-5(1H,4H)-tetrazolone, 1.76 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-(4-trifluoromethoxyphenyl)-5(1H,4H)-tetrazolone was obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]1[C:11]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]2[CH3:29])=[N:12][C:13]([Cl:18])=[N:14][C:15]=1[CH2:16][CH3:17]>CN(C)C=O>[ClH:18].[CH3:9][C:10]1[C:11]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]2[CH3:29])=[N:12][C:13]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[N:14][C:15]=1[CH2:16][CH3:17]
Reactant: CCc1nc(Cl)nc(N2CCc3ccccc3C2C)c1C
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: CCc1nc(Nc2ccc(F)cc2)nc(N2CCc3ccccc3C2C)c1C
Product: Cl
Yield: 50.3 %

Procedure:
After 4-fluoroaniline(0.50 ml, 5.28 mmol) was added to a mixture solution of 5-methyl-6-ethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloropyrimidine (0.80 g, 2.65 mmol) and dimethylformamide(5 ml), 0.55 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C@@H:13]([CH3:23])[CH2:12][N:11]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[N+:30]([O-])=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C.[Pd]>[Si:1]([O:8][C@H:9]1[C@H:14]([O:15][Si:16]([C:19]([CH3:21])([CH3:22])[CH3:20])([CH3:18])[CH3:17])[C@@H:13]([CH3:23])[CH2:12][N:11]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[NH2:30])[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@H]1CN(c2ccncc2[N+](=O)[O-])C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1CN(c2ccncc2N)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 14 h

Procedure:
To a solution of 4-((3R,4R,5S)-3,4-bis(tert-butyldimethylsilyloxy)-5-methylpiperidin-1-yl)-3-nitropyridine (1.0 equiv.) in ethanol, at a concentration of 0.05 M, was added 10% palladium on carbon (0.1 eq.). The resultant heterogeneous solution was put under an atmosphere of hydrogen and was stirred for 14 hours. At this time the mixture was filtered through a pad of celite eluting with ethanol. The volatiles were removed in vacuo yielding 4-((3R,4R,5S)-3,4-bis(tert-butyldimethylsilyloxy)-5-methylpiperidin-1-yl)pyridin-3-amine LC/MS=452.4 (M+H), Rt=1.31 min.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[N:12][CH:11]=[C:10]([C@@H:14]3[CH2:16][C@H:15]3[CH:17]=O)[CH:9]=2)[N:3]=1.[CH3:19][NH:20][C:21]1[C:22]([NH2:27])=[CH:23][CH:24]=[CH:25][CH:26]=1.CC(O)=O.N>C(O)C.[O-]S([O-])(=O)=O.[Cu+2]>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[N:12][CH:11]=[C:10]([C@@H:14]3[CH2:16][C@H:15]3[C:17]3[N:20]([CH3:19])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N:27]=3)[CH:9]=2)[N:3]=1
Reactant: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3C=O)cnn2)n1
Reactant: CNc1ccccc1N
Agent: [Cu+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3c3nc4ccccc4n3C)cnn2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)pyridazin-4-yl)cyclopropanecarbaldehyde (23-6, 70 mg, 0.29 mmol, 1.0 eq.) and N1-methylbenzene-1,2-diamine (42 mg, 0.35 mmol, 1.2 eq.) in ethanol (1.5 mL) was added anhydrous CuSO4 (56 mg, 0.35 mmol, 1.2 eq.) and AcOH (21 mg, 0.35 mmol, 1.2 eq.). The mixture was stirred at room temperature for 4 hours then basified with 2 M NH3 in ethanol (1.0 mL). The resulting mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (70% acetone in hexanes) to afford trans-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)pyridazin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (23-7) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 9.07 (d, 1H, J=2.1 Hz), 7.80 (d, 1H, J=2.1 Hz), 7.75-7.66 (m, 1H), 7.35-7.22 (m, 3H), 3.84 (s, 3H), 2.96 (s, 3H), 2.86 (m, 1H), 2.52 (m, 1H), 2.44 (s, 3H), 2.18 (m, 1H), 1.83 (m, 1H). LRMS m/z (M+H) 346.0 found, 346.4 required.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]([CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)=[O:15].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>>[CH3:12][O:13][C:14]([C:16]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]1)=[O:15]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1ncnc2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(c2ncnc3ccccc23)CCN(C(=O)OC(C)(C)C)CC1
Yield: 109 %

Procedure:
A mixture of 4-chloroquinazoline (2.02 g, 12.3 mmol), prepared as described in the preceding step, and piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (3.13 g, 12.8 mmol), as prepared in Example 1b, was treated with 1.08 M LiHMDS/THF in one portion by syringe at 0° C. with stirring under argon. After stirring for an additional 5 min at 0° C., the ice bath was removed and the homogeneous amber solution was stirred at rt for 4.5 h. The reaction was quenched with 1 M NaH2PO4 (30 mL) and extracted with DCM (2×30 mL). The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure to give the crude title compound as a clear amber syrup (4.98 g). 1H-NMR (300 MHz, CDCl3) δ 9.29 (s, 1H), 8.06 (m, 2H), 7.87 (m, 1H), 7.59 (m, 1H), 3.72-3.52 (m, 4H), 3.60 (s, 3H), 2.50-2.40 (br m, 4H), 1.46 (s, 9H). LC/MS (ESI): calcd mass 371.2, found 372.2 (MH)+.