Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:10](=[O:23])[CH:11]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:12][C:13]=2[O:14][CH3:15])=[C:4]([CH3:24])[CH:3]=1.[F-].[Cs+].[C:27]([Sn](CCCC)(CCCC)CCCC)#[CH:28]>CN(C)C=O.[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:27]([C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:10](=[O:23])[CH:11]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:12][C:13]=2[O:14][CH3:15])=[C:4]([CH3:24])[CH:3]=1)#[CH:28]
Reactant: COC1=C(c2c(C)cc(Br)cc2C)C(=O)C(Cc2ccccn2)C1
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CN(C)C=O
Product: C#Cc1cc(C)c(C2=C(OC)CC(Cc3ccccn3)C2=O)c(C)c1
Temperature: 110 °C

Procedure:
To a mixture of rac-2-(4-bromo-2,6-dimethylphenyl)-3-methoxy-5-pyridin-2-ylmethylcyclopent-2-enone (0.50 g, 1.29 mmol), cesium fluoride (0.39 g, 2.59 mmol) and copper(I) iodide (0.025 g, 0.129 mmol) in N,N-dimethylformamide (5.0 ml) is added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.053 g, 0.065 mmol) and ethynyltributylstannane (1.22 g, 3.88 mmol). The reaction mixture is heated at 110°C. under microwave irradiation for 60 mins, then allowed to cool to room temperature and is quenched with distilled water (20 ml) and extracted with ethyl acetate. The combined organic fractions are dried over magnesium sulfate, filtered and the filtrate evaporated in vacuo. The crude product is purified by flash column chromatography (0-8% methanol in dichloromethane as eluant) to afford rac-2-(4-ethynyl-2,6-dimethylphenyl)-3-methoxy-5-pyridin-2-ylmethylcyclopent-2-enone.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:26][CH2:27][CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[OH:29].C(N(CC)CC)C>O1CCCC1>[OH:29][CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:27][NH:26][CH2:24][CH2:23][NH:22][C:19]1[CH:20]=[CH:21][C:2]([Cl:1])=[C:3]([CH:18]=1)[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:13][CH:12]([CH2:11][CH:10]([CH2:16]3)[CH2:9]1)[CH2:17]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCCl)ccc1Cl
Reactant: NCC(O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCNCC(O)c2ccccc2)ccc1Cl
Temperature: 80 °C
Yield: 34.8 %

Procedure:
2-Chloro-5-(2-chloroethyl)amino-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)benzamide from Example 63 (0.1 g), 2-amino-1-phenylethanol (0.539 g) and triethylamine (0.5 ml) were dissolved in tetrahydrofuran (3 ml) and heated at 80° C. for 60 hours in a sealed tube. The reaction mixture was concentrated under reduced pressure, the residue was suspended in aqueous sodium hydrogen carbonate (30 ml), the product was extracted into ethyl acetate (3×30 ml), dried over magnesium sulphate filtered and concentrated under reduced pressure. Purification by NPHPLC eluting with 0 to 25% ethanol in dichloromethane gave title compound as a white solid (0.044 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][CH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][N:23]2[CH2:27][CH2:26][C@@H:25]([F:28])[CH2:24]2)[CH2:18][CH2:17]1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([Cl:45])[C:31]=1[OH:46]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][CH:16]2[CH2:17][CH2:18][CH:19]([CH2:22][N:23]3[CH2:27][CH2:26][C@@H:25]([F:28])[CH2:24]3)[CH2:20][CH2:21]2)[CH:33]=[C:32]([Cl:45])[C:31]=1[OH:46]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCC(CN2CC[C@@H](F)C2)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1NC1CCC(CN2CC[C@@H](F)C2)CC1
Yield: 68.4 %

Procedure:
Following general procedure II, 1-(6-chloro-4-((4-(((R)-3-fluoropyrrolidin-1-yl)methyl)cyclohexyl)amino)-1,5-naphthyridin-3-yl)ethanone (58 mg, 0.143 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (62 mg, 0.21 mmol) to afford the desired product (52 mg, 60%) as an orange solid: 1H NMR (500 MHz, CD3OD) δ 9.15 (s, 1H), 8.46 (d, J=9.0 Hz, 1H), 8.33 (d, J=9.0 Hz, 1H), 8.12 (s, 2H), 5.74-5.69 (m, 1H), 5.53-5.43 (m, 1H), 4.12-3.84 (m, 2H), 3.31-3.17 (m, 2H), 2.76 (s, 3H), 2.50-2.43 (m, 2H), 2.18-1.96 (m, 3H), 1.74-1.62 (m, 2H), 1.50-1.38 (m, 2H); ESI MS m/z 531 [M+H]+; HPLC 96.7% (AUC), tR=10.05 min.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[I:14][C:15]1[CH:16]=[C:17]([O:24][CH3:25])[C:18]([OH:23])=[C:19]([CH:22]=1)[CH:20]=O>>[OH:23][C:18]1[C:17]([O:24][CH3:25])=[CH:16][C:15]([I:14])=[CH:22][C:19]=1[CH2:20][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: COc1cc(I)cc(C=O)c1O
Product: COc1cc(I)cc(CN2CCN(c3cc(=O)[nH]cn3)CC2)c1O

Procedure:
6-[4-(2-Hydroxy-5-iodo-3-methoxy-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 5-iodo-o-vanillin (available from Alfa Aesar, Ward Hill, Mass., USA). 1H NMR (400 MHz, CDCl3) δ 2.60-2.64 (m, 4H), 3.48-3.52 (m, 4H), 3.69 (s, 2H), 3.85 (s, 3H), 5.39 (s, 1H), 6.94-6.96 (m, 1H), 7.07 (s, 1H), 7.84 (s, 1H), 12.13 (br s, 1H). Mass spectrum (ES) MH+=443.
Reaction SMILES: C([O-])(O)=O.[Na+].[CH:6]1([C:11]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[NH:20][C:21]([NH:23][C:24]2[S:25][C:26]([CH:29]=O)=[CH:27][N:28]=2)=[O:22])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1.Cl.[NH2:32][OH:33]>C1COCC1>[CH:6]1([C:11]([C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[NH:20][C:21]([NH:23][C:24]2[S:25][C:26]([CH:29]=[N:32][OH:33])=[CH:27][N:28]=2)=[O:22])=[O:12])[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: Cc1ccc(NC(=O)Nc2ncc(C=O)s2)c(C(=O)C2CCCC2)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)Nc2ncc(C=NO)s2)c(C(=O)C2CCCC2)c1
Temperature: 60 °C
Yield: 75.2 %

Procedure:
To a mixture of 2M aq NaHCO3 (5 mL) and 1-(2-cyclopentanecarbonyl-4-methyl-phenyl)-3-(5-formyl-thiazol-2-yl)-urea (72 mg, 0.2 mmol) in THF (5 mL) was added hydroxylamine hydrochloride (200 mg) at room temperature with stirring. The resulting mixture was heated at 60° C. for 12 h. The reaction mixture was cooled and extracted with ethyl acetate. The organic layer was washed (brine), dried (Na2SO4) and concentrated to obtain 1-(2-cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(hydroxyimino-methyl)-thiazol-2-yl]-urea (56 mg, 76%) as a mixture of syn and anti-isomers.
Reaction SMILES: [CH:1]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[C:12]([F:15])([F:14])[F:13].[OH-].[K+].CN(C)C=O.Br[CH2:24][C:25]([O:27][CH3:28])=[O:26]>C(OCC)C.O>[F:15][C:12]([F:13])([F:14])[C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:7]([F:9])([F:8])[F:10])[CH:1]=1)[O:11][CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: COC(=O)COc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a stirred solution containing 11.5 g (0.05 mole) of 3,5-ditrifluoromethylphenol, 3.3 g (0.05 mole) of 85% potassium hydroxide, 200 ml of N,N-dimethylformamide and 10 ml of water, 0.055 mole of methyl bromoacetate was added in one portion. The stirred reaction mixture was heated at 80°-90° C. for 22 hours. After cooling to 25° C., 500 ml of water and 500 ml of ethyl ether were added; and stirring was continued for 15 minutes. The separated ether layer was washed with water until neutral to litmus and dried over sodium sulfate. The ether was removed in vacuo at a maximum temperature of 80°-90° C. at 1-2 mm of Hg. A product with a melting point of 65°-67° C. (after recrystallization from heptane) was obtained with a yield of 99%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[CH:11][C:10]=2[N+:28]([O-])=O)=[CH:4][CH:3]=1.[Cl-].[NH4+].O1CCCC1.O>CO.[Fe]>[NH2:28][C:10]1[CH:11]=[C:12]([NH:15][C:16](=[O:27])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=2)[CH:13]=[CH:14][C:9]=1[S:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: O=C(Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1)c1cccc(C(F)(F)F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Nc1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1Sc1ccc(O)cc1
Yield: 97.6 %

Procedure:
A solution of the product of Example 114B (0.660 g, 1.52 mmol), iron powder (0.339 g, 6.07 mmol) and ammonium chloride (0.099 g, 1.82 mmol), tetrahydrofuran (18 mL), and water (6 mL) solution was heated to reflux for 3 hours. The resultant mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was diluted with water (50 mL) and extracted with dichloromethane (2×100 mL). The combined extracts were dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (0.60 g, 97%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1([C:13]([OH:15])=[O:14])[C:10]([OH:12])=[O:11].F[C:17](F)(F)[C:18](O)=O>C(Cl)Cl>[CH2:17]([O:11][C:10]([C:2]1([C:13]([OH:15])=[O:14])[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)=[O:12])[CH3:18]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(O)C1(C(=O)O)Cc2ccccc2C1
Solvent: ClCCl
Product: CCOC(=O)C1(C(=O)O)Cc2ccccc2C1
Reaction time: 20 h

Procedure:
A 200 mL round bottom flask is charged with indan-2,2-dicarboxylic acid tent-butyl ester ethyl ester (8.69 g, 29.93 mmol). DCM (40 mL) and a stirring bar are added. Stirring is initiated. Trifluoroacetic acid (20.0 mL, 269 mmol) is added. After 20 h, tlc analysis (silica, 1:1 ethyl actetate:heptanes), indicates complete consumption of starting material. The reaction mixture is diluted with DCM (50 mL) and evaporated under reduced pressure. The resultant oil is diluted with DCM (55 mL) and evaporated under reduced pressure. The resultant oil is diluted with toluene (50 mL) and evaporated under reduced pressure by pumping to constant weight to give 6.78 g of white solid material.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH:29][CH:30]([CH2:35][CH:36]3[O:38][CH2:37]3)[C:31]([O:33]C)=[O:32])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([NH:29][CH:30]([CH2:35][CH:36]([OH:38])[CH2:37][S:9][C:7]3[O:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=4[N:6]=3)[C:31]([OH:33])=[O:32])(=[O:27])=[O:28])=[CH:24][CH:25]=2)=[CH:18][CH:19]=1
Reactant: Sc1nc2ccc(Cl)cc2o1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nc4ccc(Cl)cc4o3)C(=O)O)cc2)cc1

Procedure:
Example 37 is prepared from 6-chloro-2-benzoxazolethiol and 1d using the procedure described for compound 20.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([C:11](=[O:26])[NH:12][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:25])([F:24])[F:23])[CH:16]=2)[CH3:14])[CH:3]=1.[CH3:27][NH2:28]>>[CH3:27][NH:28][C:8]([C:6]1[CH:5]=[C:4]([C:11]([NH:12][CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]([F:23])([F:25])[F:24])[CH:16]=2)[CH3:14])=[O:26])[CH:3]=[C:2]([CH3:1])[N:7]=1)=[O:10]
Reactant: Cc1cc(C(=O)NC(C)c2cccc(OC(F)(F)F)c2)cc(C(=O)O)n1
Reactant: CN
Product: CNC(=O)c1cc(C(=O)NC(C)c2cccc(OC(F)(F)F)c2)cc(C)n1

Procedure:
The title compound is prepared from 6-methyl-4-((1-(3-(trifluoromethoxy)phenyl)ethyl)carbamoyl)picolinic acid (20 mg, 0.05 mmol, Step-2, single enantiomer) and methanamine (11 mg, 0.16 mmol) by the similar manner in Example-2.
Reaction SMILES: [Se](=O)=[O:2].[Cl:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:15])=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1>O1CCOCC1.O>[Cl:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH:15]=[O:2])=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1
Reactant: Cc1ccnc2cc(Cl)ccc12
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccnc2cc(Cl)ccc12
Temperature: 85 °C
Reaction time: 6 h
Yield: 74.7 %

Procedure:
Selenium dioxide (4.52 g; 40.3 mmol) in a mixture of 25 ml of dioxane and 6 ml of water was added in a dropwise fashion to 7-chlorolepidine (6; 6.50 g; 36.6 mmol) in 25 ml of dioxane to 65°-75° C. The temperature was raised to 85° C. and maintained there with stirring for 6 hours. After cooling, the-mixture was filtered through Celite™ and concentrated. The crude material was purified on a flash column, eluting with 10% ethyl acetate/hexane to obtain 5.24 g (74%) of aldehyde 7 as a yellow solid. 1H NMR (CDCl3): δ 7.68 (d, 1H); 7.79 (d, 1H); 8.19 (d, 1H); 9.01 (dd, 1H); 9.21 (m, 1H); 10.45 (s, 1H). IR (KBr): 1702, 1499, 1216, 1041, 900, 653 cm-1.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([NH:14][CH3:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=2)[CH3:17])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:41])[CH2:37][CH:38]([CH3:40])[CH3:39]>CC#N.CN(C1C=CN=CC=1)C>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([N:14]([CH3:15])[C:36](=[O:41])[CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:13][C:8]=3[N:7]=[C:6]2[CH:16]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH3:26])=[CH:22][CH:23]=2)[CH3:17])[CH2:3][CH2:2]1
Reactant: CCOc1ccc(C(C)c2nc3cc(NC)ccc3n2CC2CC2)cc1
Reactant: CC(C)CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(C(C)c2nc3cc(N(C)C(=O)CC(C)C)ccc3n2CC2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of 1-(cyclopropylmethyl)-2-[1-(4-ethoxyphenyl)ethyl]-N-methyl-1H-benzimidazol-5-amine (349.5 mg, 1.0 mmol) in MeCN (25 mL) was added DIPEA (258.5 mg, 2.0 mmol), DMAP (10 mg) and isovaleryl chloride (180.9 mg, 1.5 mmol) at 0° C. The reaction mixture was stirred overnight at room temperature which was quenched with H2O (150 mL) and extracted with EtOAc (4×50 mL). The combined organic phases were washed with brine and dried with Na2SO4. Upon filtration and evaporation of the solvent, the residue was purified by MPLC using EtOAc on silica gel to give 431.9 mg (99%) of the desired product as a colorless syrup, which was converted to a TFA salt as a white solid. 1HNMR (400 MHz, CD3OD): δ 0.22 (m, 1H), 0.45 (m, 2H), 0.57 (m, 1H), 0.86 (d, J=5.9 Hz, 6H), 1.02 (m, 1H), 1.38 (t, J=7.0 Hz, 3H), 1.83 (d, J=7.0 Hz, 3H), 2.06 (m, 2H), 2.10 (m, 1H), 3.34 (s, 3H), 4.02 (m, 3H), 4.21 (dd, J=15.0, 6.6 Hz, 1H), 4.65 (q, J=7.0 Hz, 1H), 6.90 (d, J=8.6 Hz, 2H), 7.21 (d, J=8.6 Hz, 2H), 7.28 (d, J=8.4 Hz, 1H), 7.62 (s, 1H), 7.72 (d, J=8.6 Hz, 1H). MS (ESI) (M+H)+=434.42 (M+1)+. Anal: Calcd for C27H35N3O2+0.80TFA+0.90MeOH: C, 64.00; H, 7.17; N, 7.54. Found: C, 63.98; H, 7.02; N, 7.34.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH:6][CH2:7][C@@H:8]2[O:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH2:23][C@H:22]([NH:25]C(=O)C)[CH2:21]4)=[C:16]([F:29])[CH:15]=3)[CH2:9]2)=[N:2]1.Cl.N[C@H]1CCN(C2C=CC(N3C[C@H](CN(C4C=CON=4)C(OCC(Cl)(Cl)Cl)=O)OC3=O)=CC=2F)C1.[CH3:65][S:66](Cl)(=[O:68])=[O:67]>>[O:1]1[CH:5]=[CH:4][C:3]([NH:6][CH2:7][C@@H:8]2[O:12][C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH2:23][C@H:22]([NH:25][S:66]([CH3:65])(=[O:68])=[O:67])[CH2:21]4)=[C:16]([F:29])[CH:15]=3)[CH2:9]2)=[N:2]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1
Agent: Cl
Agent: N[C@H]1CCN(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)C1
Product: CS(=O)(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)C1

Procedure:
Using essentially the method for the intermediate of Example 12, starting from 3-(4-(3(S)-aminopyrrolidin-1-yl)-3-fluorophenyl)-5(R)-(N-(2,2,2-trichloroethyloxycarbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one hydrochloride salt (400 mg, 0.74 mM) and methanesulfonyl chloride gave the desired product (361 mg).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH3:32])[CH:13]([C:22]1([C:25](OC(C)(C)C)=[O:26])[CH2:24][CH2:23]1)[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=O)C1C=CC=CC=1>CO.[C].[Pd]>[Si:15]([O:14][CH:13]1[C:22]2([CH2:24][CH2:23]2)[C:25](=[O:26])[NH:11][C@H:12]1[CH3:32])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(O[Si](C)(C)C(C)(C)C)C1(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1NC(=O)C2(CC2)C1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.5 %

Procedure:
To a solution of tert-butyl 1-((2S)-2-{[(benzyloxy)carbonyl]amino}-1-(tert-butyldimethylsilyloxy)propyl)cyclopropanecarboxylate (693.9 mg) in methanol (8 mL) was added 10% palladium carbon (containing 50% water, 80 mg), and the mixture was stirred at room temperature for 3 hr under a hydrogen atmosphere and filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved in methanol (10 mL). Sodium methoxide (404 mg) was added and the mixture was refluxed for 4 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=30/1→1/3) to give the title compound as a colorless solid (yield: 200.8 mg, yield: 60%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:20][NH:21][O:22][CH3:23].C([Mg]Cl)(C)C>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([N:21]([O:22][CH3:23])[CH3:20])=[O:16])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)C1CCN(Cc2ccccc2)CC1
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A solution of ethyl 1-benzylpiperidine-4-carboxylate (10.0 g, 40.4 mmol) and N,O-dimethylhydroxylamine hydrochloride (6.12 g, 62.6 mmol) in THF (80 mL) was cooled to 0° C. prior to the addition of i-PrMgCl (121.2 mmol, 60.6 mL, 2 M in THF) dropwise. The reaction was stirred for 1 h, then quenched by addition of saturated aqueous ammonium chloride (90 mL). The aqueous and organic layers were separated. The separated aqueous phase was further extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel (2-18% methanol in dichloromethane) to afford the desired product (8.88 g, 84%). Rf 0.45 (10% MeOH/CH2Cl2). 1H NMR (CDCl3, 300 MHz) δ 7.40-7.20 (m, 5H), 3.69 (s, 3H), 3.51 (s, 2H), 3.17 (s, 3H), 2.94 (d, 2H, J=11.4 Hz), 2.63-2.66 (m, 1H), 2.01 (td, J=11.7, 2.9 Hz, 2H), 1.83 (qd, J=12.8, 3.7 Hz, 2H), 1.72-1.67 (m, 2H). ESI MS found for C15H22N2O2 m/z [263.3 (M+1)].
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[CH:5]1([CH2:10]Br)[CH2:9][CH2:8][CH2:7][CH2:6]1>>[CH:5]1([CH2:10][NH:4][CH2:3][CH2:2][OH:1])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: NCCO
Reactant: BrCC1CCCC1
Product: OCCNCC1CCCC1

Procedure:
2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopentylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-(cyclopentylmethyl)-1,3-thiazolidine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH3:23][N:24]1[CH:28]=[C:27]([CH2:29]O)[CH:26]=[N:25]1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:29][C:27]3[CH:26]=[N:25][N:24]([CH3:23])[CH:28]=3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Reactant: Cn1cc(CO)cn1
Product: Cn1cc(Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)cn1

Procedure:
Compound IIg was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and (1-methyl-1H-pyrazol-4-yl)methanol following the general procedure for the Mitsunobu reaction as described above.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][NH:6][CH:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16]CC3C=CC=CC=3)=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)C.C([NH:35][C@H:36]([C:38](O)=[O:39])[CH3:37])(OCC1C=CC=CC=1)=O>>[NH2:35][C@H:36]([C:38]([N:6]([CH:7]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)[CH2:5][C:4]([OH:3])=[O:24])=[O:39])[CH3:37]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)CNC1CCc2cc(OCc3ccccc3)ccc21
Product: C[C@H](N)C(=O)N(CC(=O)O)C1CCc2cc(O)ccc21
Yield: 60.8 %

Procedure:
By reacting 10 g of (5-benzyloxyindan-1-yl)glycine ethyl ester with 8 g of N-carbobenzoxy-L-alanine and treating the reaction mixture as in Reference Example 4, there is obtained 5.2 g of L-alanyl-N-(5-hydroxyindan-1-yl)glycine as colorless amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=1.N1C=CC=CC=1.O>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=1)=[O:5]
Reactant: CCOC(=O)c1csc(N)n1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1csc(NC(=O)c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
1.07 g of o-chlorobenzoyl chloride was added to a solution in which 1.00 g of ethyl 2-amino-1,3-thiazole-4-carboxylate and 0.69 g of pyridine were dissolved in THF, under ice cooling. Then, after the reaction mixture was stirred at room temperature for 1 hr, it was poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous 2N-hydrochloric acid solution and dried on anhydrous magnesium sulfate. After distilling off the solvent, the crude product obtained was washed with a mixed solvent of hexane and t-butyl methyl ether to obtain 1.52 g of the aimed ethyl 2-(2-chlorobenzoyl)amino-1,3-thiazole-4-carboxylate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([N:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][C:14]1=[O:26])[CH2:7][CH2:6]2)#[N:2].C(O)C>CCCCCCC>[O:26]=[C:14]1[CH2:15][NH:16][CH2:17][CH2:18][N:13]1[C@H:8]1[CH2:7][CH2:6][C:5]2[CH:4]=[C:3]([C:1]#[N:2])[CH:12]=[CH:11][C:10]=2[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCc3cc(C#N)ccc3C2)C(=O)C1
Solvent: CCO
Solvent: CCCCCCC
Product: N#Cc1ccc2c(c1)CC[C@H](N1CCNCC1=O)C2

Procedure:
tert-Butyl 4-(6-cyano-1,2,3,4-tetrahydronaphthalen-2-yl)-3-oxopiperazine-1-carboxylate was resolved on the OD column with 20% Ethanol and Heptane. The faster eluting isomer was tentatively assigned as the (S)-isomer, and the slower isomer as the (R)-isomer. Treating the (S)-isomer with 4N HCl gave rise to (6S)-6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile, and the (R)-isomer gave rise to (6R)-6-(2-oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile.