Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([C:17]4[CH:22]=[CH:21][C:20]([C:23](=O)[NH2:24])=[CH:19][C:18]=4[CH3:26])[C:15]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O=P(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:16]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][C:18]=4[CH3:26])[C:15]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(-n3ccnc3)cc2)n1-c1ccc(C(N)=O)cc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(-c2ccc(-n3ccnc3)cc2)n1-c1ccc(C#N)cc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.2 %

Procedure:
To a solution of ethyl 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoate (30A) (2.0 g, 4.52 mmol) in DMF (9 mL) was added POCl3 (693 mg, 4.52 mmol) at 0° C., and then stirred at room temperature for 1.5 h. After cooling to room temperature, the reaction mixture was added to ice-water (20 mL). Sat. Na2CO3 was added to adjust pH=8 followed by extraction with ethyl acetate (50 mL×4). The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (PE:EA=1:1) to afford ethyl 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-cyano-2-methylphenyl)-1H-pyrrol-2-yl)propanoate (30B) (1.02 g, 53%), LC-MS: [M+H]+ 425.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].C(N(CC)CC)C.C1COCC1.[C:48]1(=[O:52])[O:51][CH2:50][CH2:49]1>C(OCC)(=O)C>[OH:52][CH2:48][CH2:49][C:50]([N:33]1[CH2:32][CH2:31][CH:30]([NH:29][C:27]([C:4]2[N:5]([CH3:26])[C:6]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]([CH2:16][C:17](=[O:24])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:8](=[O:25])[C:7]=3[C:3]=2[O:2][CH3:1])=[O:28])[CH2:35][CH2:34]1)=[O:51]
Reactant: O=C1CCO1
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1c(C(=O)NC2CCN(C(=O)CCO)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 30.4 %

Procedure:
To a mixture of the compound of Example 77 (200 mg, 0.423 mmol), triethylamine (423 μL, 3.18 mmol) and THF (10 mL) was added β-propiolactone (39.9 μL, 0.635 mmol) at 0° C., and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate). Recrystallization of the obtained solid from ethyl acetate gave the title compound (70.0 mg, 30%) as a white powder.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([C:15]([O:17]C)=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.I[CH2:20][CH:21]([CH3:23])[CH3:22]>O1CCCC1>[CH2:20]([C:9]1([CH2:15][OH:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)[CH:21]([CH3:23])[CH3:22]
Reactant: COC(=O)C1CCCCC1
Reactant: CC(C)CI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CC1(CO)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of lithium diisopropylamide (2.0 M, 7.74 mL) at −78° C. was added methyl cyclohexanecarboxylate (2.0 g) dropwise as a solution in tetrahydrofuran (20 mL). After stirring for 30 minutes. 1-iodo-2-methylpropane (1.956 mL) was added dropwise as a solution in tetrahydrofuran (1 mL). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with 1N HCl (25 mL) and diluted with water (25 mL) and extracted into diethyl ether (50 mL). The ether layer was washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in diethyl ether (25 mL) and lithium aluminum hydride (1.0M in tetrahydrofuran, 16.88 mL) was added dropwise. After stirring overnight, the reaction was quenched with water (0.65 mL), 15% aqueous NaOH (0.65 mL), more water (1.95 mL), then magnesium sulfate was added and the reaction filtered and concentrated. The residue was loaded onto silica gel and eluted using a gradient of 3% to 20% ethyl acetate/hexanes to provide the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([N:12]([CH3:21])[CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([O:4][CH2:5][CH:6]([N:12]([CH3:21])[CH2:13][C:14]([OH:16])=[O:15])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(COC(C)=O)N(C)CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC(COC(C)=O)N(C)CC(=O)O

Procedure:
Tert-butyl 2-{[1,3-bis(acetyloxy)propan-2-yl](methyl)amino}acetate (1.32 g, 4.3 mmol) was stirred in a solution of 20% TFA:dichloromethane (20 ml) for 5 hours. Upon completion of reaction (assessed by LC-MS) the reaction was concentrated in vacuo and re-dissolved in dichloromethane (10 ml). The HCl salt was treated with polymer supported-diisopropylamine (3.5 g) for 18 hours and the resin removed by filtration. The resin was washed with MeCN (3×10 ml) and the title compound isolated by concentration in vacuo. (1.0 g, 93%) 1H NMR (500 MHz, CHLOROFORM-d) δ 4.18 (4H, d, 6.4 Hz), 3.41 (2H, s), 3.17-3.29 (1H, m), 2.50 (3H, s), 2.11 (6H, s).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[F:9].[NH:10]1[C:18]2[C:13](=[CH:14][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.C(Cl)Cl>[F:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:10][CH:11]=[CH:12]2
Reactant: Fc1cccc(F)c1Br
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Fc1cccc(F)c1-c1ccc2[nH]ccc2c1
Temperature: 125 °C
Yield: 74.9 %

Procedure:
A glass microwave reaction vessel was charged with 1-bromo-2,6-difluorobenzene (1.145 mL, 7.71 mmol) and 5-indoleboronic acid pinacol ester (1.50 g, 6.17 mmol) in toluene/H2O (4:1, 15 mL) followed by dichloro(1,1-bis(diphenylphosphinoferrocene)) palladium(ii) complex with DCM (0.252 g, 0.309 mmol) and Na2CO3 (0.645 mL, 15.43 mmol). The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 125° C. for 4 h, and then the mixture was diluted with DCM. The organic layer was separated, washed with water, dried over Na2SO4, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 10-15% EtOAc in Hexanes) to give 5-(2,6-difluorophenyl)-1H-indole (1.06 g, 4.62 mmol, 74.9% yield) as a light yellow oil. MS (ESI, pos. ion) m/z: 230 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=1[CH3:8].[OH-].[Na+].Cl[CH2:16][CH:17]=[CH2:18]>CS(C)=O>[CH3:16][CH:17]1[CH2:18][C:3]2[C:2]([Cl:1])=[C:7]([CH3:8])[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=2[O:12]1
Reactant: Cc1cc([N+](=O)[O-])c(O)cc1Cl
Reactant: C=CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])c2c(c1Cl)CC(C)O2
Temperature: 190 °C
Reaction time: 8 h

Procedure:
A mixture of 93.4 g of 2B, 750 ml of DMSO, 48 g of 50% aqueous sodium hydroxide and 45.9 g of 3-chloropropene was stirred for 8 hours at 75°-80° C., then for 16 hours at room temperature, The resulting mixture was added to 3 liters of ice water and the resulting mixture was extracted with methylene chloride. The extract was washed with water, dried (MgSO4) and evaporated to dryness. The residue, in a nitrogen atmosphere, was heated slowly to 190° C. (one hour) and held at 185°-195° C. for two hours, cooled to room temperature, and dissolved in 250 ml of acetic acid. 150 ml of 48% aqueous hydrogen bromide solution was added. The mixture was stirred at reflux for three hours, then mixed with 2 liters of ice water, and the resulting mixture was extracted with a 1:1 v:v mixture of hexane and ether. The extract was washed with water, 5 % aqueous sodium bicarbonate solution, dried (MgSO4), charcoaled and concentrated to dryness. The residue was crystallized from 500 ml of 9:1 v:v hexane/ether mixture, giving 2,3-dihydro-2,5-dimethyl-4-chloro-7-nitrobenzofuran (2C), m.p.: 114°-116° C.
Reaction SMILES: CO.C([O:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:17][N:16]=2)=[CH:11][CH:10]=1)[CH3:8])(=O)C.[OH-].[Na+].Cl>C1(C)C=CC=CC=1.O1CCCC1>[OH:6][CH:7]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:17][N:16]=2)=[CH:13][CH:14]=1)[CH3:8]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C(C)OC(C)=O)cc2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCCCCCCCOc1cnc(-c2ccc(C(C)O)cc2)nc1
Yield: 98.4 %

Procedure:
Into 100 ml of methanol and 50 ml of tetrahydrofuran were dissolved 15 g of the (-)-2-{4-(1-acetoxyethyl)phenyl}-5-decyloxypyrimidine obtained in Preparation Example [starting material compound (VI)] 70, and then 50 ml of 20% aqueous sodium hydroxide solution were added thereto, to subject to reaction at 40° to 45° C. for 4 hours. After completion of the reaction, 4N hydrochloric acid was added to the reaction mixture to adjust it to pH 7 to 8, and then 200 ml of toluene were added to effect extraction and separation. After the organic phase was washed with water, the solvent was distilled off under reduced pressure to obtain 13.2 g (yield: 98.5%) of (-)-2-{4-(1-hydroxyethyl)phenyl}-5-decyloxypyrimidine.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3]>C(CC(C)(C)C)(C)C>[CH3:4][C:2]([CH2:3][C:2]([CH3:4])([CH3:3])[CH3:1])=[CH2:1].[CH3:4][C:2]([CH3:3])=[CH:1][C:2]([CH2:3][C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:1])[CH3:4]
Reactant: C=C(C)C
Solvent: CC(C)CC(C)(C)C
Product: C=C(C)CC(C)(C)C
Product: CC(C)=CC(C)(C)CC(C)(C)C

Procedure:
Isobutylene is dimerized according to U.S. Pat. No. 5,877,372 at a temperature of 190° F. to produce a stream of 49.2 wt. % diisobutylene (DIB) and 1.5 wt. % triisobutylene (TIB) in isooctane. The product diisobutylene stream contains 700 ppb of sulfur.
Reaction SMILES: [NH:1]([C:15]([O:17][CH2:18][CH:19]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(C)C=CC(S(O)(=O)=[O:39])=CC=1.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH:1]([C:15]([O:17][CH2:18][CH:19]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[O:17]1[CH2:18][C:19](=[O:39])[NH:1][CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(N[C@@H](COCc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1COCN1

Procedure:
A suspension of FMOC-Ser(O-Bzl) (4.16 g), paraformaldahyde (2.0 g), and p-toluenesulfonic acid (0.2 g) in toluene (400 ml) was heated under reflux with azeotropic water removal for 45 min. The solution was cooled, diluted with ethyl acetate (250 ml) and washed three times with 5% aqueous NaHCO3, dried (Na2SO4), and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with (8:2) hexane:ethyl acetate to give FMOC-Ser(O-Bzl)-oxazolidin-4-one as a crystalline product, m.p. 108°-109° C. Fab Mass spec. m/e 430(M+H)+. FMOC-Ser-(O-Bzl)-oxazolidin-4-one (3.14 g) was dissolved in chloroform (40 ml) and trifluoroacetic acid (40 ml) and triethylsilane (2.55 g) was added. The solution was stirred at room temperature for 22 hours, then concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with (95:5) methylene chloride:methanol to give FMOC-N-Me-Ser(O-Bzl)-OH as a colorless oil. Fab Mass spec., m/e 432 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][CH:6](N)[CH:7]=[CH2:8])[CH3:2].[C:11]([O:15][CH2:16]C)(=O)[CH:12]=C.[CH2:18]([N:20](CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][O:15][C:11]1[N:20]=[CH:18][C:7]([CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:10])=[CH:8][CH:12]=1
Reactant: CCN(CC)CC
Reactant: C=CC(N)CC(=O)OCC
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Product: CCOC(=O)C=Cc1ccc(OC)nc1
Temperature: 90 °C

Procedure:
A solution of the 5-bromo-2-methoxypyridine 18-2 (74.3 g, 0.4 mol), ethyl acrylate (150 mL, 1.4 mol), triethylamine (150 mL, 1.08 mol), palladium acetate (10 g, 0.045 mol) and tri-o-tolylphosphine (20 g, 0.066 mol) in 100 mL acetonitrile was degassed with argon for 10 minutes. The mixture was heated at 90° C. for 12 hr then the volatiles were removed in vacuo. Toluene (300 mL) was added and the mixture concentrated again. Diethyl ether (300 mL) was added and the mixture filtered through a pad of silica gel eluting with 800 mL of diethyl ether. After removal of the diethyl ether, the residue was chromatographed on silica gel eluting with EtOAc/hexane, 1:19 then 1:14 then 1:9, to give 19-3 as a yellow solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:38])[C:19]([C:32]3[N:33]=[C:34]([NH2:37])[S:35][CH:36]=3)=[N:20][O:21][CH2:22][CH2:23][S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH2:31])[C:15](=[O:39])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+:44]>CO.C(O)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:38])[C:19]([C:32]3[N:33]=[C:34]([NH2:37])[S:35][CH:36]=3)=[N:20][O:21][CH2:22][CH2:23][S:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH2:31])[C:15](=[O:39])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[CH3:2].[Na+:44]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCSc3ccccc3N)c3csc(N)n3)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NOCCSc3ccccc3N)c3csc(N)n3)[C@H]2SC1

Procedure:
1 ml of methanol was added to a mixture of the product of Example 23 and 1.5 ml of molar sodium acetate in methanol and the mixture was diluted with 6 ml of ethanol and was vacuum filtered. The recovered product was washed with ethanol and empasted with ether to obtain 235 mg of the syn isomer of sodium 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-{2-(2-aminophenylthio)-ethoxyimino}-acetamido]-ceph-3-eme-4-carboxylate.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][N:25]3C(=O)C4=CC=CC=C4C3=O)[CH:16]=2)=[C:7]([NH:36][C:37]([NH:39][C:40]2[C:45]([CH:46]([CH3:48])[CH3:47])=[CH:44][CH:43]=[CH:42][C:41]=2[CH:49]([CH3:51])[CH3:50])=[O:38])[C:6]1=[O:52])[CH2:2][CH2:3][CH3:4].O.NN>C(O)C>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH:16]=2)=[C:7]([NH:36][C:37]([NH:39][C:40]2[C:41]([CH:49]([CH3:50])[CH3:51])=[CH:42][CH:43]=[CH:44][C:45]=2[CH:46]([CH3:48])[CH3:47])=[O:38])[C:6]1=[O:52])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCCN3C(=O)c4ccccc4C3=O)c2)c2cccnc21
Agent: NN
Solvent: O
Solvent: CCO
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCCN)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.5 %

Procedure:
To a solution of N-[1-butyl-4-{3-(3-phthalimidopropoxy)phenyl}-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (157 mg, 0.22 mmol) in ethanol (10 ml) was added hydrazine monohydrate (100 mg, 2 mmol), and the mixture was stirred at room temperature for 3 hours. The precipitates were removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue was added methylene chloride, and the insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% methanol in chloroform) to give the title compound (58 mg, 0.10 mmol).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Cl.[H][H].[CH2:13]1[C@@H:21]2[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:15][NH:14]1>[C].[Ru]>[CH2:1]1[C@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][NH:2]1.[CH3:15][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[CH2:13][NH2:14]
Reactant: c1ccc2c(c1)CNC2
Reactant: C1CC[C@H]2CNC[C@H]2C1
Reactant: [H][H]
Agent: [Ru]
Agent: Cl
Product: C1CC[C@H]2CNC[C@@H]2C1
Product: CC1CCCCC1CN
Yield: 0.4 %
Yield: 0.3 %

Procedure:
In a 3-liter GL (Glass Lining) autoclave fitted with a electromagnetic stirrer are added 129 g of isoindoline, 545 g of 7.2% hydrochloric acid aqueous solution (pH 4.0) and 26 g of 5% ruthenium-carbon catalyst (50% water-containing). The reaction mixture is subjected to a hydrogen-pressure of 20 kg/cm2 and a temperature of 130° C. After a 2 hour hydrogen introduction, the drop in the rate of the hydrogen-absorption is observed, at this point the introduction of hydrogen is ceased to terminate the reaction. After the termination of reaction, the catalyst is filtered out from the reacted solution. By the result of the capillary chromatographic analysis, the yield of cis-hexahydroisoindoline is 98.3%. In addition, 0.3% of trans-hexahydroisoindoline and 0.4% of 2-methylcyclohexylmethylamine is formed. After cooling the reacted solution, 240 g of 20% sodium hydroxide aqueous solution is added to neutralize, and it is extracted with toluene. After concentrating the organic phase, the residue is purified by distillation to give 128.0 g of cis-hexahydroisoindoline (yield 94.5%).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:12]3[N:21]=[CH:22][CH:23]=[C:11]3[N:10]=2)=[O:7])=[CH:4][CH:3]=1.N1C=CC=C[CH:27]=1.[F:32][C:33]([F:45])([F:44])[O:34]C1C=CC(C(Cl)=O)=CC=1>>[CH3:27][C:22]1[CH:23]=[C:11]2[N:10]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:24]=[CH:25][C:2]([O:34][C:33]([F:45])([F:44])[F:32])=[CH:3][CH:4]=3)[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:12]2[N:21]=1
Reactant: O=C(Nc1cc(N2CCOCC2)n2nccc2n1)c1ccc(Br)cc1
Reactant: c1ccncc1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Product: Cc1cc2nc(NC(=O)c3ccc(OC(F)(F)F)cc3)cc(N3CCOCC3)n2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
A suspension of 2-methyl-7-morpholinopyrazolo[1,5-a]pyrimidin-5-amine (9B, 52 mg, 0.151 mmol) and pyridine (60 mg, 0.467 mmol) was cooled to 0° C. and treated with 4-trifluoromethoxybenzoyl chloride (78 mg, 0.395 mmol). After stirring for 30 min, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate (5 mL). The aqueous mixture was extracted with ethyl acetate and the combined organics dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was dissolved in DMF/DMSO, filtered, and purified via preparative HPLC (60-80% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (44.0 mg, 41%). Melting point (226.2-226.3° C.). 1H NMR (DMSO-d6) δ: 11.10 (s, 1H), 8.01-8.27 (m, 2H), 7.51 (dd, J=9.0, 0.9 Hz, 2H), 7.30 (s, 1H), 6.18 (s, 1H), 3.79-3.91 (m, 4H), 3.69-3.75 (m, 4H), 2.38 (s, 3H); ESI-MS: m/z 422.1 (M+H)+. Melting point (226.2-226.3° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:16][N:15]2[C:27](=[O:44])[CH:28]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]C=C)=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]12[CH2:8][CH:7]1[CH:9]=[CH:10][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH:28]([NH:36][C:37]([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38])[C:27](=[O:44])[N:15]1[CH:14]([CH2:18][CH:17]([O:19][Si:20]([C:23]([CH3:24])([CH3:26])[CH3:25])([CH3:21])[CH3:22])[CH2:16]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCCC(NC(=O)OC(C)(C)C)C(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: CCOC(=O)C12CC1C=CCCCCCC(NC(=O)OC(C)(C)C)C(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1C(=O)N2
Yield: 96.3 %

Procedure:
To a solution of 1-{[1-(2-tert-butoxycarbonylamino-non-8-enoyl)-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-2-carbonyl]-amino}-2-vinyl-cyclopropanecarboxylic acid ethyl ester (1.63 g, 2.56 mmoL) in 640 mL of methylene chloride was added 215 mg (0.26 mmoL) of tricyclohexylphosphine[1,3-bis(2,4,6-tri[benzylidene]ruthenium(IV) dichloride. The mixture was heated at reflux for 15 min. The residue was concentrated in vacuo, and then purified by flash chromatography eluting with 30% ethyl acetate/hexane. To further decolorize the sample, the crude product was chromatographed a second time eluting with 50% ether in hexane to give 1.5 g (96%) of 14-tert-butoxycarbonylamino-18-(tert-butyl-dimethyl-silanyloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid ethyl ester as a white solid. 1H NMR (500 MHz, CD3Cl) δ 0.06 (s, 3H), 0.07 (s, 3 H), 0.86 (s, 9 H), 1.18-1.24 (m, 6 H), 1.34-1.64 (m, 14 H), 1.86-1.96 (m, 3 H), 2.02-2.09 (m, 1 H), 2.11-2.17 (m, 1 H), 2.19-2.28 (m, 1 H), 2.57-2.63 (m, 1H), 3.50-3.54 (m, 1 H), 3.71 (dd, J=10.22, 6.26 Hz, 1 H), 4.06-4.17 (m, 2 H), 4.52-4.58 (m, 2 H), 4.75 (d, J=8.55 Hz, 1 H), 5.21 (t, J=9.92 Hz, 1 H), 5.35 (d, J=7.63 Hz, 1 H), 5.45-5.50 (m, 1 H), 6.94 (s, 1 H); MS m/z 608 (M++1).