Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6]([C:8]1[S:9][C:10]([C:23](=O)[CH2:24][C:25]#[N:26])=[CH:11][C:12]=1[O:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])[CH3:15])=[O:7]>CCO>[CH3:4][O:5][C:6]([C:8]1[S:9][C:10]([C:23]2[NH:2][N:3]=[C:25]([NH2:26])[CH:24]=2)=[CH:11][C:12]=1[O:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])[CH3:15])=[O:7]
Reactant: NN
Reactant: COC(=O)c1sc(C(=O)CC#N)cc1OC(C)c1ccccc1Cl
Solvent: O
Solvent: CCO
Product: COC(=O)c1sc(-c2cc(N)n[nH]2)cc1OC(C)c1ccccc1Cl
Temperature: 80 °C
Yield: 28.1 %

Procedure:
Hydrazine hydrate (17.4 mg, 0.35 mmol, 1.1 Eq.) was added to a stirred solution of 3-[1-(2-Chlorophenyl)-ethoxy]-5-cyanoacetyl-thiophene-2-carboxylic acid methyl ester (115 mg, 0.32 mmol, 1.0 Eq.) in EtOH (4 mL) and the reaction heated at 80° C. overnight. The reaction mixture was concentrated in vacuo and purified by column chromatography (70/9/1 DCM/MeOH/Aq. NH3) to give the sub-title compound as a white solid (35 mg, 0.09 mmol, 29%);
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH2:8][CH2:9][CH2:10][S:11][C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)[C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1csc(CNCCCSc2ccncc2)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)N(CCCSc1ccncc1)Cc1cccs1
Yield: 35.9 %

Procedure:
To a solution of 2.5 g (9.45 mmol) of 4-[3-(N-(2-thienylmethyl)amino)propylthio]pyridine and 1.32 ml (9.45 mmol) of triethylamine in 50 ml of methylene chloride, 1.1 ml (9.45 mmol) of benzoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 1.25 g of the desired compound (yield: 35.9%, yellow oil).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:19])([CH2:12][O:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[CH2:10][OH:11].[CH3:20][S:21](Cl)(=[O:23])=[O:22].N1C=CC=CC=1.Cl>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:19])([CH2:10][O:11][S:21]([CH3:20])(=[O:23])=[O:22])[CH2:12][O:13][C:14](=[O:18])[CH:15]([CH3:16])[CH3:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)C(=O)OC[C@](O)(CO)c1ccc(F)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)C(=O)OC[C@](O)(COS(C)(=O)=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
Into a solution wherein 12 g of (R)-2-(2,4-difluorophenyl)-3-isobutyryloxy-1,2-propanediol obtained in Example 40 was dissolved in 120 ml of ethyl acetate was added dropwise 10 g of methanesulfonyl chloride at a temperature of 0° to 5° C., and thereto was added dropwise 6.92 g of pyridine at a temperature of 0° to 5° C. After dropping, the resulting liquid was stirred at room temperature for 16 hours. To the reaction mixture was added 400 ml of 1N hydrochloric acid and an organic layer separated. The organic layer was washed with saturated aqueous solution with sodium hydrogencarbonate and with saturated aqueous solution with sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give 15.2 g of oily (S)-2-(2,4-difluorophenyl)-1-isobutyryloxy-3-methanesulfonyloxy-2-propanol. An optical purity thereof was determined in the same manner as in Example 35. (Elution time: 22.5 minutes ((R)-form) and 24.7 minutes ((S)-form)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:20]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])=[CH:4][CH:3]=1.[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[CH3:28])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:20]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])=[CH:4][CH:3]=1
Reactant: CN(C)CCCO
Reactant: O=C(Nc1nccs1)c1nc(-c2ccc(O)cc2)[nH]c1-c1ccc(Cl)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN(C)CCCOc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(Cl)cc3)[nH]2)cc1

Procedure:
5-(4-Chlorophenyl)-2-(4-hydroxyphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide, 3-dimethylaminopropanol, triphenyl-phosphine and diethyl azodicarboxylate are reacted and treated in the same manner as in Example 24 to give 5-(4-chlorophenyl)-2-(4-(3-dimethylaminopropyloxy)phenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: Cl[CH2:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.[C:14]([OH:17])(=[O:16])[CH3:15].C(N(CC)CC)C>CC(C)=O>[C:14]([O:17][CH2:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)O
Reactant: O=C(CCl)Cc1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)OCC(=O)Cc1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 33.3 %

Procedure:
In a round-bottomed flask, 1-chloro-3-(3,4-dichlorophenyl)propan-2-one (0.545 g, 2.30 mmol) was taken up in 2 mL acetone, and acetic acid (0.26 mL, 0.28 g, 4.6 mmol) was added. The solution was cooled in an ice water bath, and triethylamine (0.64 mL, 0.47 g, 4.6 mmol) added dropwise via syringe over 30 minutes. The reaction mixture was then stirred overnight. Precipitated triethylammonium chloride was removed by filtration, and the filtrate was evaporated, taken up in 10 mL ethyl acetate, washed twice with brine, dried over anhydrous MgSO4, filtered, and evaporated. The crude product was purified by flash chromatography over silica gel (10-30% ethyl acetate in hexanes) to give a pure product (0.200 g, 33% yield): 1H NMR (400 MHz, CDCl3) δ 2.17 (s, 3H) 3.71 (s, 2H) 4.71 (s, 2H) 7.05 (dd, J=8.2, 2.2 Hz, 1H) 7.32 (d, J=2.0 Hz, 1H) 7.41 (d, J=8.1 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[F:20][C:21]([F:32])([F:31])[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>CCO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])/[CH:12]=[CH:27]/[C:26]2[CH:29]=[CH:30][C:23]([O:22][C:21]([F:20])([F:31])[F:32])=[CH:24][CH:25]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(/C=C/C(C)=O)cc1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(/C=C/C(=O)/C=C/c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 11.9 %

Procedure:
A suspension of (E)-4-(4-methoxyphenyl)-but-3-en-2-one (615 mg, 3.5 mmol) in EtOH (10 mL) was stirred for 5 min at 0° C. A solution of K2CO3 (965 mg, 7.0 mmol) in H2O (5 mL) was added and the reaction mixture was stirred for further 10 min at 0° C. After the dropwise addition of 4-(trifluoromethoxy)-benzaldehyde (528 μl, 3.7 mmol), the pale yellow suspension was stirred for further 4 h at 0° C. The resulting yellow precipitate was filtered and dried in vacuo to obtain NW350 as a pale yellow solid (145 mg, 12%). mp: 105-107° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[O:11][C:10]([C:12](O)=[O:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>CN(C=O)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[O:11][C:10]([C:12]([Cl:19])=[O:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cc2ccc(F)cc2)o1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cc2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.6 %

Procedure:
To 5-(4-fluorobenzyl)-2-furan carboxylic acid (450 mg, 2 mmol) were added thionylchloride (1 ml, 13.7 mmol) and DMF (0.025 ml). The mixture was stirred for 30 minutes at room temperature. The excess amount of thionylchloride was evaporated. The precipitated residue was washed with n-hexane to give crude 5-(4-fluorobenzyl)-2-furan carboxylic acid chloride (480 mg).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].F[C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[C:14]([NH:19][C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=3)[CH:15]=[C:16]([CH3:18])[CH:17]=2)[CH:9]=[N:10][CH:11]=1.[H-].[Na+]>C1COCC1>[CH3:18][C:16]1[CH:17]=[C:12]([C:8]2[CH:7]=[C:6]([NH:4][CH2:3][CH2:1][OH:2])[CH:11]=[N:10][CH:9]=2)[CH:13]=[C:14]([NH:19][C:20]2[N:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][N:21]=2)[CH:15]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncc(F)c2)c1
Reactant: NCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncc(NCCO)c2)c1
Temperature: 80 °C

Procedure:
Ethanolamine (26.3 mg, 0.431 mmol) was added to a mixture of N-[3-(5-fluoropyridin-3-yl)-5-methylphenyl]-4-(trifluoromethyl)pyrimidin-2-amine (50.0 mg, 0.144 mmol) and sodium hydride (17.2 mg, 0.431 mmol) in THF (0.718 mL, 0.2 M). The reaction mixture was heated overnight at 80° C. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with chloroform. The organic layer was concentrated in vacuo and purified by reverse phase liquid chromatography (10:90 to 60:40, acetonitrile:water) afforded 2-{[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-3-yl]amino}ethanol as the formic acid salt. MS APCI calc'd for C19H19F3N5O [M+H]+ 390. found 390. 1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.83 (d, J=4.9 Hz, 1H), 8.48 (s, 1H), 8.34 (d, J=2.6 Hz, 1H), 7.99 (d, J=11.4 Hz, 3H), 7.59 (d, J=26.7 Hz, 2H), 7.34-7.12 (m, 2H), 4.33 (t, J=4.9 Hz, 2H), 3.77 (br s, 3H), 3.27 (t, J=5.3 Hz, 2H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)=[O:8])[CH2:3]1.[NH:19]1[CH:23]=[C:22]([CH2:24][CH2:25][CH2:26][C:27](O)=[O:28])[N:21]=[N:20]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[NH:19]1[CH:23]=[C:22]([CH2:24][CH2:25][CH2:26][C:27]([NH:1][CH:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=3)=[O:8])[CH2:3]2)=[O:28])[N:21]=[N:20]1
Reactant: NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)C1
Reactant: O=C(O)CCCc1c[nH]nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCCc1c[nH]nn1)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)C1
Reaction time: 2 h

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 3-aminopyrrolidine-1-carboxylate (1 equiv), 4-(1H-1,2,3-triazol-4-yl)butanoic acid (1 equiv.), HATU (1.5 equiv.) and triethylamine (5 equiv.) in dimethylformamide was stirred at RT for 18 hours. Another 1 equivalent of 4-(1H-1,2,3-triazol-4-yl)butanoic acid was added to the reaction mixture and stirring continued for a further 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with DCM. The organic portion was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was dry loaded using silica onto a 12 g ISCO column, eluting with 0-15% MeOH in DCM. The product fractions were combined and concentrated under reduced pressure. Further purification was carried our using preparative LC-MS. The product fractions were concentrated under reduced pressure to give an aqueous solution and extracted with EtOAc to afford the title compound;
Reaction SMILES: [CH2:1]([S:8][CH2:9][P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:23]>C(Cl)Cl>[CH2:12]([O:11][P:10]([CH2:9][S:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:23])(=[O:17])[O:14][CH2:15][CH3:16])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOP(=O)(CSCc1ccccc1)OCC
Solvent: ClCCl
Product: CCOP(=O)(CS(=O)Cc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of diethyl (benzylthiomethyl)phosphonate (10 g., 0.036 mole) in 75 ml. of methylene chloride was, with ice-bath cooling, treated with 7.29 g. (0.036 mole) of m-chloroperoxybenzoic acid portionwise. After the addition was complete, the mixture was stirred for 1 hour at ambient temperature, filtered to remove precipitate, and the filtrate concentrated in vacuo. The residue was chromatographed on silica gel by eluting the column with ethyl acetate which gave 5.9 g. of the title compound.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][CH2:13][OH:14])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=O)[CH2:16][CH3:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:16]([C:15]1([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:9]2[S:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:11][C:10]=2[CH2:12][CH2:13][O:14]1)[CH3:17]
Reactant: OCCc1csc(-c2ccccc2)n1
Reactant: CCOC(=O)CC(=O)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1(CC)OCCc2nc(-c3ccccc3)sc21
Reaction time: 17 h

Procedure:
A mixture of the starting material of formula II, 2-phenyl-4-(β-hydroxyethyl)thiazole (30.8 g, 0.15 mole, described in Example 1), ethyl propionylacetate (28.8 g, 0.2 mole) and p-toluene-sulfonic acid hydrate (0.25 mole) in toluene (1200 ml) is heated at reflux temperature, with water separation, for 17 hr. Additional ethyl propionylacetate (6 g) and p-toluenesulfonic acid hydrate is added and refluxing is continued for 24 hr. The mixture is evaporated under reduced pressure and the residue is triturated with petroleum ether. The residue is dissolved in a mixture of aqueous sodium bicarbonate solution and ether. The organic solution is separated, dried over sodium sulfate and evaporated under reduced pressure to give ethyl 6,7-dihydro-4-ethyl-2-phenyl-4H-pyrano[4,3-d]thiazole-4- acetate (IV, R1 = H, R2 = CH2CH3, A= COOCH2CH3 and n= 1).
Reaction SMILES: [OH:1][C:2]1([C:10]#[C:11][C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18]4[CH:22]=[C:23]([C:25]([NH2:27])=[O:26])[N:24]=[C:17]4[C:16]=3[CH:28]=2)[CH2:8][C@H:7]2[NH:9][C@H:4]([CH2:5][CH2:6]2)[CH2:3]1.[BH-](OC(C)=O)(OC(C)=O)O[C:31](C)=O.[Na+]>CO>[OH:1][C:2]1([C:10]#[C:11][C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18]4[C:17](=[N:24][C:23]([C:25]([NH2:27])=[O:26])=[CH:22]4)[C:16]=3[CH:28]=2)[CH2:3][CH:4]2[N:9]([CH3:31])[CH:7]([CH2:6][CH2:5]2)[CH2:8]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)c1cn2c(n1)-c1cc(C#CC3(O)C[C@H]4CC[C@@H](C3)N4)ccc1OCC2
Agent: [Na+]
Solvent: CO
Product: CN1C2CCC1CC(O)(C#Cc1ccc3c(c1)-c1nc(C(N)=O)cn1CCO3)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.6 %

Procedure:
In a solution of 10-(((1R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-3-yl)ethynyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (0.15 g, 0.4 mmol) in methanol (20 ml) was added (HCHO)n (144 mg, 4.8 mmol) and NaBH(OAc)3 (260 mg, 1.2 mmol). The solution was stirred for 1 h at room temperature. The reaction mixture was quenched with water and purified by Prep HPLC to afford 9-(3-Hydroxy-8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylethynyl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-2-carboxylic acid amide (13.5 mg, 8.5%). 1H NMR (Methanol-d4, 400 MHz): δ 8.30 (m, 1H), 8.10 (s, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 4.67 (s, 4H), 3.94 (s, 2H), 2.81 (s, 3H), 2.65-2.20 (m, 8H). LCMS [M+H]+=393.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:28][CH3:29])[CH2:22][C:23]([CH3:27])([CH3:26])[C:24]#[N:25])[C:11](=[O:30])[C@:10]([CH2:32][CH:33]3[CH2:37][O:36]C(C)(C)[O:34]3)([CH3:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.O.[Na+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:28][CH3:29])[CH2:22][C:23]([CH3:26])([CH3:27])[C:24]#[N:25])[C:11](=[O:30])[C@:10]([CH2:32][CH:33]([OH:34])[CH2:37][OH:36])([CH3:31])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CC(C)(C)C#N)N1C(=O)[C@@](C)(CC2COC(C)(C)O2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@@H](CC(C)(C)C#N)N1C(=O)[C@@](C)(CC(O)CO)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (4S)-4-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)-2,2-dimethylhexanenitrile prepared above in Step G (77 mg, 0.135 mmol) in THF (2.69 mL) was added 3 N hydrochloric acid in water (1.35 μL, 4.04 mmol) at rt. After being stirred at rt for 4 h, the reaction was diluted (sat. aq. NaCl) and extracted (2×EtOAc). The combined organic layers were washed (sat. aq. NaCl solution), dried (Na2SO4), and concentrated under reduced pressure to provide the title compound as a colorless foam.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH2:11])=[O:5].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][C:14]=1[Cl:21].C(O)(=O)C.[BH4-].[Na+]>CO>[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:11][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([F:12])=[C:14]([Cl:21])[CH:15]=1)=[O:5]
Reactant: COC(=O)[C@@H]1CCC[C@@H]1N
Reactant: O=Cc1ccc(F)c(Cl)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(1R,2S)-2-Amino-cyclopentanecarboxylic acid methyl ester hydrochloride (prepared as described in Example 11a, 0.2 g, 1.27 mmol) was dissolved in methanol (5.5 mL), followed by addition of 4-fluoro-3-chlorobenzaldehyde (0.201 g, 1.27 mmol) and stirred at 25° C. for 10 min. After this time, 5.2 M acetic acid (0.245 mL) was added, stirred at 25° C. for 5 min before placing in an ice-bath. Once at 0° C., sodium borohydride (0.203 mg, 3.2 mmol) was added portionwise after which time the mixture was allowed to warm to 25° C. and continued to stir for 17 h. The reaction mixture was quenched by pouring into saturated aqueous sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (200 mL). The organic layer was concentrated in vacuo and purified by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-80% ethyl acetate in hexanes) to afford the desired product, (1R,2S)-2-(3-chloro-4-fluoro-benzylamino)-cyclopentanecarboxylic acid methyl ester (256 mg, 0.898 mmol, 70% as a yellow oil, containing residual ethyl acetate. 1H NMR (400 MHz, CDCl3) δ: 1.55-1.97 (m, 6H), 2.86 (dd, 1H, J1=14.2 Hz, J2=7.0 Hz), 3.19 (dd, 1H, J1=13.1 Hz, J2=6.9 Hz), 3.62 (s, 3H), 3.64 (d, 2H, J=6.2 Hz), 6.96 (t, 1H, J=8.5 Hz), 7.04-7.08 (m, 1H), 7.26-7.28 (m, 1H). LC-MS (ESI) calcd for C14H17ClFNO2 285.09, found 286.0 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].C[Al](C)C.N#N.[F:21][C:22]1[CH:23]=[C:24]([CH:37]=[CH:38][CH:39]=1)[O:25][CH2:26][C:27]([NH:29]/[C:30](/[CH3:36])=[CH:31]\[C:32](OC)=[O:33])=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:32](=[O:33])[CH:31]=[C:30]([CH3:36])[N:29]=[C:27]2[CH2:26][O:25][C:24]2[CH:37]=[CH:38][CH:39]=[C:22]([F:21])[CH:23]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: COC(=O)/C=C(/C)NC(=O)COc1cccc(F)c1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Agent: C[Al](C)C
Agent: N#N
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)c(F)c2)c(COc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
To a solution of 3-fluoro-4-morpholinoaniline (0.55 g, 2.80 mmol) in anhydrous CH2Cl2 (40 mL) was added trimethylaluminium (2.0 mL, 4 mmol, 2 M in heptane) carefully under N2 at rt. The mixture was stirred at rt for 30 min, followed by the addition of a solution of methyl 3-(2-(3-fluorophenoxy)acetamido)crotonate (0.75 g, 2.80 mmol) in anhydrous CH2Cl2 (10 mL). The reaction mixture was stirred for another 7 h, then quenched with an appropriate amount of water and washed with brine twice. The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a white solid (0.24 g, 62%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[C:6]([F:11])=[CH:5][C:3]=1[NH2:4].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[C:6]([F:11])=[CH:5][C:3]=1[NH:4][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(F)c(N)cc(F)c1F
Product: CC(=O)Nc1cc(F)c(F)c(C)c1F
Temperature: 0 °C

Procedure:
To 2,4,5-trifluoro-3-methylaniline (1 g) is added acetic anhydride (3 ml) at room temperature with stirring and the mixture is stirred for 15 minutes. The reaction mixture is poured into ice-water, extracted with dichloromethane, and the extract is washed with water and dried. The solvent is distilled off to give 2,4,5-trifluoro-3-methyl-N-acetylaniline (1.14 g), as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.Cl.[Cl:13][CH2:14][CH2:15][N:16]([CH2:24][CH2:25]Cl)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[ClH:13].[CH2:17]([N:16]1[CH2:24][CH2:25][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)([C:10]#[N:11])[CH2:14][CH2:15]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: COc1cccc(CC#N)c1
Agent: Cl
Product: COc1cccc(C2(C#N)CCN(Cc3ccccc3)CC2)c1

Procedure:
Prepare by the method of example 74.1 using 3-methoxyphenyl-acetonitrile (3.68 g, 25 mmol) and N,N-bis(2-chloroethyl)-N-benzylamine hydrochloride (7.05 g, 26.25 mmol) to the title compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15](Cl)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[I:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:15]([C:10]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:4][CH:5]=3)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])=[CH:22][CH:23]=1
Reactant: Nc1ccc(I)cc1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(I)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
A solution of 4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carbonyl chloride (0.019 mol) in DCM (50 ml) was added slowly at 5° C. to a mixture of 1-amino-4-iodo-benzene (0.017 mol) and triethylamine (0.026 mol) in DCM (40 ml). The mixture was stirred at room temperature for 1 hour, then washed with HCl 1N, then with K2CO3 10%. The organic layer was separated, dried, filtered, and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 6.1 g of N-(4-iodophenyl)-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide (intermediate 1; mp. 147° C.).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)[S:5][C:6]=1[C:7](=[O:16])[C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[F:15].[NH2:27][CH2:28][C:29]1([N:33]([CH3:35])[CH3:34])[CH2:32][CH2:31][CH2:30]1>>[NH2:1][C:2]1[N:3]=[C:4]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([NH:27][CH2:28][C:29]3([N:33]([CH3:35])[CH3:34])[CH2:32][CH2:31][CH2:30]3)=[O:24])=[CH:25][CH:26]=2)[S:5][C:6]=1[C:7](=[O:16])[C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[F:15]
Reactant: CN(C)C1(CN)CCC1
Reactant: Nc1nc(Nc2ccc(C(=O)O)cc2)sc1C(=O)c1c(F)cccc1F
Product: CN(C)C1(CNC(=O)c2ccc(Nc3nc(N)c(C(=O)c4c(F)cccc4F)s3)cc2)CCC1
Yield: 61 %

Procedure:
The title compound was prepared in a manner similar to Step 3 in Method A; from coupling 4-[4-amino-5-(2,6-difluoro-benzoyl)-thiazol-2-ylamino]-benzoic acid (3) and 1-(aminomethyl)-N,N-dimethylcyclobutanamine (Yang et al., Eur. J. Med. Chem. 31, 231-239 (1996)) to afford a yellow amorphous powder in 61% yield.