Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: II.[CH3:3][C:4]([CH3:6])=O.[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:11]=1Cl)([O-:9])=[O:8]>C(OCC)(=O)C.[Cu]>[N+:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:11]=1[C:4]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:15][CH:10]=[CH:11][C:3]=1[N+:16]([O-:18])=[O:17])([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: CC(C)=O
Agent: [Cu]
Agent: II
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1-c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 180 °C
Reaction time: 0.17 h
Yield: 63.9 %

Procedure:
Pre-treatment of copper powder: The copper powder (5.0 g, 78 mmol) was weighted and added into to a 20 mL of 2% iodine/acetone solution. The mixture was stirred for 10 minutes, and filtered in vacuum. The resultant was added into 20 mL of mixed solution of acetone:hydrochloric acid=1:1. The resultant mixture was stirred for 10 minutes, filtered, and dried in vacuum. The 2,6-dinitrochlorobenzene (3.04 g, 15 mmol) and copper powder (2.88 g, 45 mmol) were added into a 250 mL round flask, and were mixed homogeneously. Under the protection of nitrogen gas, the mixture was heated at 180° C. under stirring in an oil bath for two hours. Upon completion of the reaction, the solid in the flask was grounded, and dissolved in 20 mL of ethyl acetate. The solid was filtered off, and the filtration was collected and rotary evaporated. The residue was recrystallized from a mixed solution of ethyl acetate: petroleum ether=10:1, to precipitate a pale yellow needle-like crystal. The crystal was filtered in vacuum, to afford the product in a yield of 63.9%.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:14]2[CH:15]=[CH:16][C:17]([O:24]C)=[C:18]([NH:20][C:21](=[O:23])[CH3:22])[CH:19]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.COC.O>C(Cl)Cl>[NH2:1][C:2]1[N:3]=[N:4][C:5]([C:14]2[CH:15]=[CH:16][C:17]([OH:24])=[C:18]([NH:20][C:21](=[O:23])[CH3:22])[CH:19]=2)=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: COc1ccc(-c2nnc(N)nc2-c2ccccc2)cc1NC(C)=O
Agent: COC
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1cc(-c2nnc(N)nc2-c2ccccc2)ccc1O
Temperature: -78 °C
Reaction time: 16 h

Procedure:
N-[5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-hydroxyphenyl]acetamide was prepared by O-demethylation of N-[5-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-methoxyphenyl]acetamide (0.05 g, 0.15 mmol; vide supra). The methyl ether was dissolved in DCM (5 mL), cooled to −78° C. and treated with borontribromide (5.25 mmol, 1.32 g). The resulting mixture was gradually warmed to RT then stirred at this temperature for a further 16 hours. The mixture was poured into water (15 mL) and extracted with DCM (3×15 mL). The combined organic extracts were dried over Na2SO4, concentrated in vacuum and purified by gradient flash chromatography, eluting with 30% ethyl acetate in hexane to afford the target compound (0.30 g, 85%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:24])=[C:7]([C:16]([CH3:23])=[C:17]([O:19][C:20](=[O:22])[CH3:21])[CH:18]=1)[C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])(=[O:3])[CH3:2].[Br:25]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:20]([O:19][C:17]1[C:16]([CH2:23][Br:25])=[C:7]([C:6]([CH3:24])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:18]=1)[C:8]([O:10][CH2:11][C:12]([Cl:14])([Cl:13])[Cl:15])=[O:9])(=[O:22])[CH3:21]
Reactant: CC(=O)Oc1cc(OC(C)=O)c(C)c(C(=O)OCC(Cl)(Cl)Cl)c1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1cc(OC(C)=O)c(CBr)c(C(=O)OCC(Cl)(Cl)Cl)c1C

Procedure:
A mixture of 4.76 g 2,2,2-trichloroethyl 3,5-diacetoxy-dimethylbenzoate and 2.24 g N-bromosuccinimide in 36 ml of carbontetrachloride was heated at reflux temperature and with light irradiation for 30 minutes. The mixture was cooled in an ice bath and insoluble material was removed by filtration. The filtrate was diluted with methylene chloride, washed with water, dried over sodium sulphate and evaporated in vacuo to provide crude 2,2,2-trichloroethyl 3,5-diacetoxy-2-bromomethyl-6-methylbenzoate, which was used directly without further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][O:25][CH2:26][CH2:27][N:28]1[C:36]2[C:31](=[N:32][CH:33]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:35]=2)[N:30]([CH3:46])[C:29]1=[O:47]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:34]5[CH:35]=[C:36]6[N:28]([CH2:27][CH2:26][O:25][CH3:24])[C:29](=[O:47])[N:30]([CH3:46])[C:31]6=[N:32][CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: COCCn1c(=O)n(C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: COCCn1c(=O)n(C)c2ncc(-c3ccc4ncc5c(c4c3)n(-c3cn(C)nc3C)c(=O)n5C)cc21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 1-(2-methoxy-ethyl)-3-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one (Stage 69.1.1) to give the title compound as a white solid. (HPLC: tR 2.46 min (Method A); M+H=499 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.15-8.05 (m, 3H), 7.97-7.91 (m, 1H), 7.64-7.60 (m, 1H), 7.57-7.53 (m, 1H), 4.11-4.03 (m, 2H), 3.90 (s, 31-1), 3.67-3.62 (m, 2H), 3.57 (s, 3H), 3.36 (s, 3H), 3.23 (s, 3H), 1.98 (s, 3H))
Reaction SMILES: [C:1]([NH:11][C@@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.[NH2:26][CH2:27][CH:28]([O:31][CH3:32])[O:29][CH3:30]>C1COCC1>[CH3:30][O:29][CH:28]([O:31][CH3:32])[CH2:27][NH:26][C:16](=[O:18])[C@H:12]([NH:11][C:1](=[O:2])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH:13]([CH3:14])[CH3:15]
Reactant: COC(CN)OC
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(CNC(=O)[C@H](NC(=O)OCc1ccccc1)C(C)C)OC
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
A solution of Cbz-D-Valine (500 g, 1.99 mol) and N-methylmorpholine (201.8 g, 1.99 mol) in anhydrous THF (8 L) was cooled to −15° C. and i-butyl chlorofomate (299 g, 2.19 mol) was added dropwise under stirring. After 30 min, a solution of 1-amino-2,2-dimethyoxyethane (209.5 g, 1.99 mol) in THF (1 L) was added slowly and the temperature was maintained at −15° C. for 2 h. The reaction mixture was washed with brine (2 L) and the organic phase was concentrated to remove the THF. The residue was diluted with EtOAc (4 L), washed with 1N aq HCl (2×2 L), sat. aq. NaHCO3 (2 L) and sat. aq. Na2CO3 (2 L) and brine (1.5 L). After drying over Na2SO4, the organic solvent was removed under reduce pressure to afford (R)-benzyl (1-((2,2-dimethoxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate as a white solid (670 g, yield 99.5%), which was used for next step without further purification. LC-MS m/z 360.9 [M+Na]+.
Reaction SMILES: [F:1][CH:2]([F:14])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[C:5]([F:13])[CH:4]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[F:14][CH:2]([F:1])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[C:5]([F:13])[CH:4]=1
Reactant: COC(=O)c1ccc(C(F)F)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C(F)F)cc1F
Reaction time: 3.5 h

Procedure:
To a solution of methyl 4-(difluoromethyl)-2-fluorobenzoate (61 mg, 0.27 mmol) in THF (2.7 mL), was added a solution of lithium hydroxide, monohydrate (170 mg, 4.0 mmol) in water (0.90 mL). The mixture was stirred for 3.5 hours. Hydrochloric acid (1 N) was added to adjust the pH to 2, and the product was extracted with ethyl acetate. The extracts were washed twice with water, once with brine, dried over sodium sulfate and concentrated to afford crude acid, used directly in the next step (51 mg, 99%). 1H NMR (300 MHz, d6-dmso): δ 13.56 (br s, 1H), 8.00 (t, 1H), 7.53 (t, 2H), 7.11 (t, 1H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8].[N+](C1C=C(C=CC=1)C=O)([O-])=O.C(N(CC)CC)C.[C:32](Cl)(=[O:40])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>ClCCl>[CH3:1][O:2][CH:3]([O:12][CH3:13])[CH2:4][C:5]1[CH:6]=[C:7]([NH:8][C:32](=[O:40])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:9]=[CH:10][CH:11]=1
Reactant: CCCCCCCC(=O)Cl
Reactant: COC(Cc1cccc(N)c1)OC
Agent: O=Cc1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)Nc1cccc(CC(OC)OC)c1
Reaction time: 0.17 h

Procedure:
By the method outlined in example 9 above, 3-(2,2-dimethoxyethyl)aniline is prepared from 3-nitrobenzaldehyde. To a solution of this material (2.13 g) in dichloromethane (25 ml) is added triethylamine (1.7 ml). The solution is cooled in an ice bath, and octanoyl chloride (2.0 ml) is added dropwise with stirring. After 10 min, the solvent is removed in vacuo and the residue is taken up in ether, filtered, and washed with aqueous sodium bicarbonate. The solution is dried, filtered, and concentrated to leave N-(3-(2,2-dimethoxyethyl)phenyl)octanamide (3.4 g) as a light brown oil. By the method of example 2 above, this is converted into the title compound, mp 128°-130° after recrystallization from dichloromethane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18]CC2C=CC=CC=2)=[CH:14][CH:13]=1)([OH:9])[CH:6]([CH3:8])[CH3:7].C>[Pd].C1COCC1.CO>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@@:5]([OH:9])([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1)[CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)CC(O)(CCc1ccc(OCc2ccccc2)cc1)C(C)C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C[C@@](O)(CCc1ccc(O)cc1)C(C)C

Procedure:
The title compound was prepared as described in General Method 4 using 3-[2-(4-benzyloxy-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid methyl ester (8.6 g, 24.2 mmol) from Example SSSS. Three grams of 20% Pd over charcoal and THF:MeOH 1:1 (100 mL). The crude compound was recrystallized from hexanes-ethyl acetate to give racemic title compound (m.p. 89°-91° C.). The title compound was obtained by resolution on a semi-preparative Chiralcel OD column eluting with 90% hexanes, 10% isopropanol and 0.1% trifluoroacetic acid. 1H-NMR (CDCl3) δ 0.93 (d, 3H), 0.95 (d, 3H), 1.68-1.85 (m, 2H), 1.93 (m, 1H), 2.53 (dd, 2H), 2.62 (m, 2H), 3.63 (br s, 1H), 3.71 (s, 3H), 4.97 (br s, 1H), 6.73 (d, 2H), 7.03 (d, 2H).
Reaction SMILES: [CH2:1]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]3[CH:18]=[CH:19][C:20]([NH:22][C:14]=3[CH:13]=2)=[O:21])[CH2:5][CH2:4][N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[Cl:30])[CH2:2]1.CC(C)([O-])C.[K+].CC1CCCO1.Cl[C:44]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:45]>O>[C:44](=[O:45])([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[O:21][C:20]1[CH:19]=[CH:18][C:15]2[C:14](=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]3[CH2:5][CH2:4][N:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=4[Cl:30])[CH2:2][CH2:1]3)=[CH:17][CH:16]=2)[N:22]=1
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Reactant: CCCCCCOC(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC1CCCO1
Product: CCCCCCOC(=O)Oc1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of dehydro-aripiprazole (1.5 g, 3.4 mmol), potassium tert-butoxide (0.75 g, 6.7 mmol) and 2-methyltetrahydrofuran (30 mL) at 0° C. was added hexyl chloroformate (1.32 mL, 8.1 mmol). The reaction mixture was stirred for 2 h, allowed to self warm to room temperature and stirred for a further 4 h. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and evaporated. The residue was further purified on silica eluting with ethyl acetate/tetrahydrofuran and the major product containing fractions evaporated to give a yellow solid. This was triturated in heptane (30 mL) for 2.5 h, filtered and dried to give Compound-328 (1.55 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13]O)=[C:11]([CH3:15])[O:10][N:9]=2)=[N:6][CH:7]=1.S(Cl)([Cl:18])=O>C(Cl)Cl>[Cl:18][CH2:13][C:12]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=2)=[N:9][O:10][C:11]=1[CH3:15]
Reactant: Cc1onc(-c2ccc(F)cn2)c1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1onc(-c2ccc(F)cn2)c1CCl
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
To a solution of [3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-methanol (1.0 g, 4.8 mmol) in DCM (9.6 mL) at 0° C. was added thionyl chloride (697 μL, 9.6 mmol) and the resulting mixture stirred for 30 min and then evaporated. After 1 h the reaction mixture was concentrated to give the title compound (1.07 g, 98%) as an off white solid. MS: m/e=227.2 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([C:5]([O:18][CH3:19])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]#[N:4].C([O-])([O-])=O.[K+].[K+].CS([C:30]1[N:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[N:31]=1)(=O)=O.O>CN(C=O)C>[CH3:39][O:38][C:32]1[CH:33]=[C:34]([O:36][CH3:37])[N:35]=[C:30]([O:1][CH:2]([C:5]([O:18][CH3:19])([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]#[N:4])[N:31]=1
Reactant: COC(c1ccccc1)(c1ccccc1)C(O)C#N
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(OC(C#N)C(OC)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
7.3 g (28.8 mmol) of 2-hydroxy-3-methoxy-3,3-diphenylpropionitrile were dissolved in 90 ml of DMF, and 4 g (28.8 mmol) of K2CO3 and 6.3 g (28 mmol) of 2-methanesulfonyl-4,6-dimethoxypyrimidine were added. The mixture was stirred at room temperature for about 12 h, then poured into water and extracted with ethyl acetate. The combined organic phases were washed again with H2O, dried and concentrated. The residue obtained in this way was then purified by chromatography on silica gel (n-hepane/ethyl acetate).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]3[CH:12]=[C:11]([C:13]([OH:15])=O)[O:10][C:8]3=[CH:9][C:4]=2[NH:3][C:2]1=[O:16].C(N(CC)CC)C.[CH2:24]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH2:24]([CH:31]1[CH2:36][CH2:35][N:34]([C:13]([C:11]2[O:10][C:8]3[C:7](=[CH:6][C:5]4[O:1][C:2](=[O:16])[NH:3][C:4]=4[CH:9]=3)[CH:12]=2)=[O:15])[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)c1cc2cc3oc(=O)[nH]c3cc2o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cc2cc3oc(=O)[nH]c3cc2o1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.5 %

Procedure:
A mixture of 0.42 g (1.9 mmol) of 3H-furo[2,3-f]benzoxazole-2-one-6-carboxylic acid, 0.3 ml (2.1 mmol) of triethylamine, 0.35 ml (2.0 mmol) of 4-benzylpiperidine, 0.76 g (2.0 mmol) of HBTU (Advanced Chem. Tech.) and 10 ml of dimethylformamide is stirred at room temperature for 6 h. The reaction mixture is concentrated and the residue is purified by column chromatography using Kieselgel 60 as adsorbent (Merck) and toluene:aceton=2:1 as eluent, then the product is crystallized with diethylether to yield 0.39 g (54%) of the title compound. Mp.: 205-210° C. (diethyl ether).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH2:24][CH2:25][CH:26]1[CH2:28][CH2:27]1>>[CH:26]1([CH2:25][NH:24][C:20]([C:17]2[S:16][C:15]([CH2:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][C:11]=3[CH3:23])=[N:19][CH:18]=2)=[O:22])[CH2:28][CH2:27]1
Reactant: NCC1CC1
Reactant: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)O)s1
Product: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)NCC2CC2)s1
Yield: 50 %

Procedure:
As described for example 40c, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-thiazole-5-carboxylic acid (67 mg, 0.20 mmol) was converted, using aminomethylcyclopropane instead of 4-aminotetrahydropyran, to the title compound (39 mg, 50%) which was obtained as a white solid. MS: m/e=387.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[CH2:12][CH2:11][CH2:10][C@H:9]([NH:13]C(=O)OC(C)(C)C)[CH2:8]2)=[C:5]([NH2:21])[CH:4]=[N:3]1.C(OC([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43](O)=[O:44])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43]([NH:21][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[N:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([NH2:13])[CH2:8]1)=[O:44]
Reactant: Cn1ncc(N)c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCC[C@H](N)C1
Yield: 11 %

Procedure:
Following the procedures as described in Example 113, (S)-tert-butyl 1-(1-methyl-4-amino-1H-pyrazol-5-yl)piperidin-3-ylcarbamate, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, and HATU were reacted to give 106 as a white solid (32 mg, 11%) over two steps. 1H NMR (400 MHz, DMSO) δ 8.80 (s, 1H), 7.60-7.42 (m, 4H), 7.27 (t, J=8.7, 2H), 3.62 (d, J=10.3, 3H), 3.09 (dd, J=11.1, 3.3, 1H), 3.03-2.88 (m, 2H), 2.83 (t, J=8.7, 1H), 2.69 (dd, J=11.0, 8.5, 1H), 1.87-1.64 (m, 2H), 1.55 (d, J=8.9, 1H), 1.17 (dd, J=19.9, 9.3, 1H). ESIMS m/z=434.1 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27]([OH:29])=O)[CH:5]=[CH:6][CH:7]=1.[CH3:30][NH:31][CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:30][N:31]([CH3:32])[C:27]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:24])([CH3:26])[CH3:25])[NH:10]1)=[O:29]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C1NC(CC(C)(C)C)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1
Yield: 90 %

Procedure:
In a manner similar to the method described in Example 1e, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (61.0 mg, 0.14 mmol) prepared in Example 1d was reacted with dimethylamine (1.0 M in THF, 2 mL), HATU (106.0 mg, 0.28 mmol) and iPr2NEt (38.8 mg, 0.30 mmol) in CH2Cl2 (2 mL) at rt overnight to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid dimethyl amide (57.8 mg, 90.0%).
Reaction SMILES: [H-].[Na+].CI.[CH2:5]([S:7][C:8]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1)=[O:11])[CH3:6].[CH2:31]1COCC1>O>[CH2:5]([S:7][C:8]1[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[CH:23][C:9]=1[C:10]([N:12]([CH3:31])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][N:14]=1)=[O:11])[CH3:6]
Reactant: C1CCOC1
Reactant: CCSc1cc(C(F)(F)F)ccc1C(=O)Nc1ccc(C(F)(F)F)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCSc1cc(C(F)(F)F)ccc1C(=O)N(C)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.12 g of 60% sodium hydride (oil-based) and 0.56 g of methyl iodide were added to a mixture of 0.78 g of 2-ethylsulfanyl-4-trifluoromethyl-N-(5-trifluoromethyl-pyri din-2-yl)-benzamide and 5 mL of THF, and the mixture was stirred at room temperature for 2 hours. 1 g of methyl iodide was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. 1 g of methyl iodide was further added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 0.59 g of 2-ethylsulfanyl-N-methyl-4-trifluoromethyl-N-(5-trifluoromethyl-pyridin-2-yl)-benzamide (hereinafter, referred to as Compound of Present Invention 2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25](O)(=[O:34])[C:26]1[C:27]([O:32][CH3:33])=[CH:28][CH:29]=[CH:30][CH:31]=1.C(N=C=NC(C)C)(C)C>C(Cl)Cl>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1)=[O:34]
Reactant: CN(CCN1CC=C(c2cccc(N)c2)CC1)C(=O)OC(C)(C)C
Reactant: COc1ccccc1C(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: COc1ccccc1C(=O)Nc1cccc(C2CCN(CCN(C)C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
To a solution of 190 (177 mg, 0.530 mmol) and o-Anisic acid (97 mg, 0.636 mmol) in DCM (5 mL) was added drop-wise a solution of 1,3-Diisopropylcarbodiimide (0.100 mL, 0.636 mmol) in 2 mL of DCM and the resulting mixture was stirred at room temperature for 3 hours. After the usual work-up the residue was purified by flash chromatography using 4 to 6% MeOH in DCM to afford 191 (84.7 mg, 0.181 mmol, 34% yield) as a yellow oil. LRMS (ESI): calc. 467.3, found 468.2 (MH)+.
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[Si](C=[N+]=[N-])(C)(C)C.[F:20][C:21]1[C:22]([CH2:31][CH2:32][CH3:33])=C(C=[CH:27][C:28]=1[O:29][CH3:30])C=O>O1CCCC1>[C:10]([C:9]1[CH:8]=[CH:27][C:28]([O:29][CH3:30])=[C:21]([F:20])[C:22]=1[CH2:31][CH2:32][CH3:33])#[CH:11]
Reactant: [Li]CCCC
Reactant: CCCc1c(C=O)ccc(OC)c1F
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C#Cc1ccc(OC)c(F)c1CCC
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
To a solution of diisopropylamine (0.841 mL, 6.0 mmol) in tetrahydrofuran (15 mL) at −78° C. under nitrogen was added slowly the solution of n-butyllithium (3.75 mL, 6.0 mmol, 1.6M in hexanes). After stifling for 30 minutes, the solution of TMS-diazomethane (3.0 mL, 6.0 mmol, 2M in hexanes) was added slowly into the reaction mixture. The mixture was stirred for 30 minutes then was added the solution of 3-fluoro-4-methoxy-2-propylbenzaldehyde (597) (0.589 g, 3.0 mmol) in tetrahydrofuran (3 mL). The resulting mixture was stirred at room temperature for 12 hours, quenched with saturated ammonium chloride and extracted with ethyl ether. The organic phase was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (10% EtOAc in hexanes) to provide 1-ethynyl-3-fluoro-4-methoxy-2-propylbenzene (626) (0.180 g, 31.2%) as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[CH2:3]1.CCN(CC)CC.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl>[C:24]([N:7]1[CH:2]([CH3:1])[CH2:3][N:4]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[CH2:5][CH:6]1[CH3:8])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CC1CN(c2ccc(C=O)cc2)CC(C)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1C(C)CN(c2ccc(C=O)cc2)CC1C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
A solution of 4-(3,5-dimethylpiperazin-1-yl)benzaldehyde (1.0 g, 4.6 mmol.) in CH2Cl2 (15 mL) was cooled to 0° C. and treated with Et3N (0.64 mL, 4.6 mmol) followed by acetyl chloride (0.33 mL, 4.6 mmol). The reaction stirred for 30 minutes, then concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 0% to 50% EtOAc/CH2Cl2, afforded 4-(4-acetyl-3,5-dimethylpiperazin-1-yl)benzaldehyde (1.0 g, 83%).