Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:14][C@H:15]([CH2:39][NH:40][C:41](=[O:53])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[CH2:16][S:17][CH2:18][C@H:19]([NH:28]C(=O)OCC1C=CC=CC=1)[C:20]([NH:22][C:23]1([CH2:26][OH:27])[CH2:25][CH2:24]1)=[O:21])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>CCO.[OH-].[OH-].[Pd+2]>[NH2:28][C@H:19]([C:20]([NH:22][C:23]1([CH2:26][OH:27])[CH2:25][CH2:24]1)=[O:21])[CH2:18][S:17][CH2:16][C@H:15]([NH:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:39][NH:40][C:41](=[O:53])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: CCCCCCCCCCCC(=O)NC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)NC1(CO)CC1)NC(=O)CCCCCCCCCCC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCC(=O)NC[C@H](CSC[C@H](N)C(=O)NC1(CO)CC1)NC(=O)CCCCCCCCCCC

Procedure:
Benzyl (R)-3-((R)-2,3-didodecanamidopropylthio)-1-(1-(hydroxymethyl)cyclopropyl amino)-1-oxopropan-2-ylcarbamate (1 eq) was stirred in dry EtOH (0.05 M) under N2 at room temperature. Pd(OH)2 (2.1 eq) was then added in one portion. The reaction was then stirred under hydrogen atmosphere (1 atm) until complete reduction was observed. The crude reaction was filtered twice through celite and cotton, then the organics concentrated and purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-10% MeOH/DCM to afford N,N′-((R)-3-((R)-2-amino-3-(1-(hydroxymethyl)cyclopropylamino)-3-oxopropylthio)propane-1,2-diyl)didodecanamide as an oil. 1H NMR (CDCl3): δ 8.02 (s, 1H), 6.83 (t, 1H), 6.70 (t, 1H), 3.50-3.71 (m, 6H), 3.00-3.12 (m, 3H), 2.88-2.94 (m, 2H), 2.21 (t, 4H), 1.64 (t, 4H), 1.21-1.35 (m, 32H), 0.93 (m, 4H), 0.82 (t, 6H). LRMS [M+H]=628.0.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](OC(F)(F)F)[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:3]=1.[CH:30]1(B(O)O)[CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:30]3[CH2:32][CH2:31]3)[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:3]=1
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(OC(F)(F)F)ccc3n2)Cc2ccccc21
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=S1(=O)CCN(c2cc(Cl)c3cc(C4CC4)ccc3n2)Cc2ccccc21
Temperature: 90 °C
Yield: 32.7 %

Procedure:
To a solution of 4-(6-bromo-4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (1.0 g, 2.3 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1) in toluene (150 mL) was added cyclopropylboronic acid (200 mg, 2.3 mmol), palladium acetate (52 mg, 0.23 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (143 mg, 0.23 mmol) and potassium carbonate (320 mg, 2.3 mmol) under argon protection. After being heated at 90° C. for 16 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL), and the solution was washed with water (50 mL×3), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (eluting with 16% ethyl acetate in petroleum ether) to afford 300 mg of the desired product (yield was 33%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[C:12]2[N:13]=[C:14]([Cl:18])[CH:15]=[C:16](Cl)[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:19]=[C:12]2[N:13]=[C:14]([Cl:18])[CH:15]=[C:16]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cc(Cl)n2nc(OCc3ccccc3)cc2n1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: Clc1cc(N2CCOCC2)n2nc(OCc3ccccc3)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
There was dissolved, in 1,4-dioxane (3 mL), 2-benzyloxy-5,7-dichloro-pyrazolo-[1,5-a]-pyrimidine (167 mg, 0.568 mM), then morpholine (99.1 μL, 1.14 mM) was added to the solution and the mixture was stirred at room temperature for one hour. The solvent was distilled off from this reaction mixture, followed by the dilution of the residue with water and the subsequent extraction of the mixture with methylene chloride. The resulting extracts were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and the resulting solid was washed with methanol to thus give the title compound (188 mg, yield: 96%).
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[F:8][C:9]([F:20])([F:19])[C:10]1[CH:11]=[C:12]([N:16]=[C:17]=[O:18])[CH:13]=[CH:14][CH:15]=1>>[CH3:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[N:1][C:17]([NH:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:9]([F:8])([F:19])[F:20])[CH:11]=1)=[O:18]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CN1CCCC1=N
Product: CN1CCCC1=NC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Conversion of the hydrochloride salt of 2-imino-1-methylpyrrolidine (6.73 g.; 0.05 mole) to the free base (4.9 g. assuming 100% conversion) is carried out in the usual manner. After drying over K2CO3, the benzene layer is stirred at room temperature and 9.36 g. (0.05 mole) of m-trifluoromethylphenylisocyanate is added (some solid precipitates). The reaction mixture is stirred overnight. The resulting solid is collected, m.p. = 155°-156° C. The benzene filtrate, upon removal of the solvent, affords an additional crop of solid material, m.p. 131°-137° C. Recrystallizations of the combined solids from acetone-pet. ether gives the pure product, 1-(1-methyl-2-pyrrolidylidene)-3-(m-trifluoromethylphenyl)urea, m.p. = 155°-156.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH3:30])[C:5]1[C:10]([C:11]#[N:12])=[CH:9][C:8]([NH:13][C:14]2[N:19]=[C:18]([NH:20][CH:21]3[CH2:23][CH2:22]3)[C:17]3=[N:24][CH:25]=[C:26]([C:27]#[N:28])[N:16]3[N:15]=2)=[C:7]([Cl:29])[CH:6]=1.[O:31]1[CH2:34][C:33](=O)[CH2:32]1.COC(OC)OC.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(Cl)Cl>[Cl:29][C:7]1[CH:6]=[C:5]([N:4]([CH3:30])[CH2:3][CH2:2][NH:1][CH:33]2[CH2:34][O:31][CH2:32]2)[C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:13][C:14]1[N:19]=[C:18]([NH:20][CH:21]2[CH2:22][CH2:23]2)[C:17]2=[N:24][CH:25]=[C:26]([C:27]#[N:28])[N:16]2[N:15]=1
Reactant: CN(CCN)c1cc(Cl)c(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)cc1C#N
Reactant: O=C1COC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Solvent: ClCCl
Product: CN(CCNC1COC1)c1cc(Cl)c(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)cc1C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14 %

Procedure:
A solution of 2-((4-((2-aminoethyl)(methyl)amino)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 412)(63 mg, 0.149 mmol), oxetan-3-one (215 mg, 2.98 mmol), trimethylorthoformate (0.823 mL, 7.45 mmol), and acetic acid (0.085 mL, 1.490 mmol) in a mixture of MeOH (0.5 mL) and DCM (0.5 mL) was stirred at room temperature for 15 min. Added sodium cyanoborohydride (1M in THF, 1.49 mL, 1.49 mmol) and left the reaction stirring for 3 hrs. The reaction was partitioned between EtOAc and sat. aq. NaHCO3 solution. After stirring for 15 min, the aqueous phase was separated and washed with EtOAc. The combined organic phases were washed with brine, dried with sodium sulfate, and the solvent removed. Preparative HPLC (Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium acetate; Gradient: 20-60% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min) afforded the title compound (10 mg).
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[C:5]([OH:7])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:20][C:21]1[N:22]=[C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([CH3:46])=[C:34]([NH:36][C:37]([C:39]4[N:43]([CH3:44])[N:42]=[C:41]([CH3:45])[CH:40]=4)=[O:38])[CH:35]=3)=[N:25][N:24]2[CH:47]=1>CN(C)C=O.CN(C)C(=O)C>[CH3:44][N:43]1[C:39]([C:37]([NH:36][C:34]2[CH:35]=[C:30]([O:29][C:26]3[CH:27]=[CH:28][C:23]4[N:24]([CH:47]=[C:21]([NH:20][C:5]([CH:3]5[CH2:4][CH:2]5[CH3:1])=[O:7])[N:22]=4)[N:25]=3)[CH:31]=[CH:32][C:33]=2[CH3:46])=[O:38])=[CH:40][C:41]([CH3:45])=[N:42]1
Reactant: CC1CC1C(=O)O
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5C)cn4n3)ccc2C)n(C)n1
Yield: 70.3 %

Procedure:
In the same manner as in Example 279 and using 2-methylcyclopropanecarboxylic acid (97 mg, 0.97 mmol), tetrahydrofuran (1.5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (83 μL, 0.97 mmol), N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (200 mg, 0.48 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (155 mg, 70%) was obtained as a white solid.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.CN1CCOCC1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[C:28]([F:31])([F:30])[F:29]>C(Cl)(Cl)Cl>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([N:25]=[C:2]=[O:4])=[CH:23][C:22]=1[C:28]([F:29])([F:30])[F:31]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 40 °C
Reaction time: 15 h
Yield: 161.2 %

Procedure:
With a waste gas absorption device, triphosgen (167 g, 0.56 mol, 0.5 eq) was dissolved in chloroform (500 mL). A solution of N-methyl morpholine (11.4 g, 0.11 mol, 0.1 eq) in chlorofrom (100 mL) was added dropwise into the above mixture at 5° C. After addition, a solution of 4-chloro-3-(trifluoromethyl)aniline (220 g, 1.13 mol, 1.0 eq) in chloroform (700 mL) was added dropwise at 10° C. The mixture was warmed to 40° C. and stirred for 15 hours, and then warmed to 50° C. and stirred for 5 hours, and then heated to 60-65° C. and refluxed for 5 hours. The solvent was removed under atmospheric pressure. The residue was distilled under vacumm (oil temperature 110-120° C., vacuum 200 Pa) and the fractions at 95-100° C. were collected to give the title compound (200 g, purity 98.7%, yield 84%) as a colorless liquid.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:9]2[C:10]([C:16](=[O:26])[CH2:17][C:18]3[C:23]([Cl:24])=[CH:22][N:21]=[CH:20][C:19]=3[Cl:25])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH:6]=1)([OH:3])=[O:2].[CH2:27](O)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[Cl:24][C:23]1[CH:22]=[N:21][CH:20]=[C:19]([Cl:25])[C:18]=1[CH2:17][C:16]([C:10]1[C:9]2[C:5]([CH2:4][C:1]([O:3][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:2])=[CH:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:26]
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c(CC(=O)O)coc12
Reactant: OCCc1ccccc1
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c(CC(=O)OCCc3ccccc3)coc12
Yield: 36 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 151 (0.30 g) obtained in Example 151 and phenethyl alcohol (0.7 ml) to give Compound 153 (0.14 g, 36%) as white crystals.
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7][Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:17][C:18]1[CH:19]=[C:20]([C:28]2[O:32][N:31]=[C:30]([C:33]3[CH:34]=[CH:35][CH:36]=[C:37]4[C:41]=3[N:40]([CH3:42])[CH:39]=[C:38]4/[CH:43]=[CH:44]/[C:45]([O:47][CH2:48][CH3:49])=[O:46])[N:29]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH:25]([CH3:27])[CH3:26]>CS(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([C:28]2[O:32][N:31]=[C:30]([C:33]3[CH:34]=[CH:35][CH:36]=[C:37]4[C:41]=3[N:40]([CH3:42])[CH:39]=[C:38]4[C@@H:43]3[CH2:7][C@H:44]3[C:45]([O:47][CH2:48][CH3:49])=[O:46])[N:29]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH:25]([CH3:26])[CH3:27]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)/C=C/c1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 20 °C

Procedure:
To a suspension of trimethylsulfoxonium iodide (132 mg) in DMSO (3 mL) stirred under nitrogen at 20° C. was added NaHMDS (1.0 mol/L in THF, 0.6 mL) dropwise during 5 mins. The reaction mixture was stirred at this temperature for 15 mins. A solution of ethyl (2E)-3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]-2-propenoate (D62) (140 mg) in DMSO was added dropwise. After addition was complete, the reaction was stirred at room temperature for 1.5 h, and then warmed to 50° C. for 2 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (25 mL) and water (25 mL). The organic phase was washed with water, aqueous HCl (2 M) and brine, dried over sodium sulphate and evaporated to afford ethyl (1R,2R)-2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]cyclopropanecarboxylate (D64) (80 mg). MS (ES): C26H26ClN3O4 requires 479. found 480.2 (M+H+).
Reaction SMILES: CNC1C=CC(C(N[C@H](C(OCC)=O)CCC(OCC)=O)=O)=NC=1.[C:25]([O:29][C:30]([N:32]([C:34]1[CH:35]=[CH:36][C:37]([C:40]([O:42]C)=[O:41])=[N:38][CH:39]=1)[CH3:33])=[O:31])([CH3:28])([CH3:27])[CH3:26].CI.O>C(O)C>[C:25]([O:29][C:30]([N:32]([C:34]1[CH:35]=[CH:36][C:37]([C:40]([OH:42])=[O:41])=[N:38][CH:39]=1)[CH3:33])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)c1ccc(N(C)C(=O)OC(C)(C)C)cn1
Agent: CCOC(=O)CC[C@H](NC(=O)c1ccc(NC)cn1)C(=O)OCC
Solvent: CCO
Solvent: CI
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)O)nc1

Procedure:
Note (6): Diethyl N-[5-(methylamino)picolinoyl]-L-glutamate used as starting material was prepared as follows:-A mixture of methyl 5-(N-tert-butoxycarbonyl-N-methylamino)picolinate (prepared using the method described in the Journal of Medicinal Chemistry, 1980, 23, 1405 except that methyl iodide was used in place of 3-trifluoromethylbenzyl chloride; 1.13 g), aqueous N-sodium hydroxide solution (8.5 ml), water (21 ml) and ethanol (15 ml) was stirred at laboratory temperature for 16 hours. The mixture was concentrated to a volume of 5 ml, acidified to pH 4 with 2N-hydrochloric acid solution and extracted with ethyl acetate (2×40 ml). The combined extracts were dried over magnesium sulphate, filtered and evaporated to give 5-(N-tert-butoxycarbonyl-N-methylamino)picolinic acid (0.8 g).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]([CH2:14][CH3:15])[NH:12][C:11](=[O:16])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:25]([CH3:26])=[C:24](I)[CH:23]=[CH:22][C:19]=1[C:20]#[N:21].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][C@@H:9]1[CH2:10][C:11](=[O:16])[N:12]([C:24]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([Cl:17])[C:25]=2[CH3:26])[C@H:13]1[CH2:14][CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC[C@@H]1NC(=O)C[C@H]1O[Si](C)(C)C(C)(C)C
Reactant: Cc1c(I)ccc(C#N)c1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(Cl)c1C

Procedure:
Using (4R,5S)-4-(tert-butyldimethylsilyloxy)-5-ethylpyrrolidin-2-one (1.00 g), 2-chloro-4-iodo-3-methylbenzonitrile (1.31 g), cesium carbonate (2.08 g), tris(dibenzylideneacetone)dipalladium(0) (193 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (490 mg), and in the same manner as in Reference Example 3, the title compound was obtained as a colorless solid (yield: 650 mg, 39%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:18]([O:20]CC=C)=[O:19])=[C:8]([C:10]3[CH:14]=[C:13]([CH3:15])[N:12]([CH2:16][CH3:17])[N:11]=3)[CH2:9][C@H:5]12)[CH3:3].C(C(CCCC)C([O-])=O)C.[Na+:36].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)C>ClCCl.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:18]([O-:20])=[O:19])=[C:8]([C:10]3[CH:14]=[C:13]([CH3:15])[N:12]([CH2:16][CH3:17])[N:11]=3)[CH2:9][C@H:5]12)[CH3:3].[Na+:36]
Reactant: C=CCOC(=O)C1=C(c2cc(C)n(CC)n2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCn1nc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1C
Reaction time: 0.75 h
Yield: 66.4 %

Procedure:
Allyl(5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1-ethyl-5-methylpyrazol-3-yl)carbapen-2-em-3-carboxylate (267 mg) in dichloromethane (3 ml) and ethyl acetate (3 ml) under argon was treated with sodium 2-ethylhexanoate (183 mg), followed by triphenylphosphine (24 mg), followed by tetrakis(triphenylphosphine)palladium(0) (35 mg) and the mixture was stirred for 45 min. Diethyl ether (100 ml) was then added, and after stirring for 90 minutes, the mixture was centrifuged. The residual solid was dried under a stream of argon, and then in a desiccator. The solid was then taken up in water containing sodium chloride and chromatographed on DIAION HP20SS resin, eluting with water, followed by water/THF mixtures; 1%, 2%, and 3%, THF. Fractions were monitored by HPLC, and those containing the product were combined, reduced in volume and freeze-dried to give sodium (5R,6S)-6-[(R)-1-hydroxyethyl]-2-(1-ethyl-5-methylpyrazol-3-yl)carbapen-2-em-3-carboxylate as a solid (168 mg); νmax (KBr) 1761, 1608, 1577, 1381, 1225 cm-1 ; λmax (H2O)/nm 298 (ε/dm3 mol-1 cm-1 8,531); δ (D2O) 1.26 (d, J ca. 6 Hz), 1.27 (d, J ca. 7 Hz) (together 5H), 2.23 (3H, s), 3.17 (2H, approx d, J ca. 9 Hz), 3.44 (1H, dd, J 2.9 & 6.0 Hz), 4.04 (2H, q, J 7.3 Hz), 4.15-4.25 (2H, m), 6.41 (1H, s) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[C:4](Cl)[N:3]=1.Cl.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH:14]1[CH2:19][OH:20].C(N(CC)CC)C>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH:14]2[CH2:19][OH:20])[C:5]([O:9][CH3:10])=[C:6]([Cl:8])[N:7]=1
Reactant: OCC1COCCN1
Reactant: COc1c(Cl)nc(Cl)nc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1c(Cl)nc(Cl)nc1N1CCOCC1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.6 %

Procedure:
A mixture of 2,4,6-trichloro-5-methoxy-pyrimidine (1 g, 4.68 mmol), morpholin-3-yl-methanol hydrochloride (0.86 g, 5.6 mmol) and triethylamine (0.9 mL, 6.5 mmol) in IMS (30 mL) was stirred at RT for 3 h, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 0 to 50% ethyl acetate in cyclohexane) affording [4-(2,6-Dichloro-5-methoxy-pyrimidin-4-yl)-morpholin-3-yl]-methanol (614 mg, 45%). LCMS (method A): RT=2.63 min, [M+H]+=294/296.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C@@H:10]1[C@@H:15]([NH:16]C(=O)OC(C)(C)C)[CH2:14][C@@H:13]([N:24]2[CH2:31][C:30]3[C:26](=[N:27][N:28]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:29]=3)[CH2:25]2)[CH2:12][O:11]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C@@H:10]1[C@@H:15]([NH2:16])[CH2:14][C@@H:13]([N:24]2[CH2:31][C:30]3[C:26](=[N:27][N:28]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:29]=3)[CH2:25]2)[CH2:12][O:11]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3cn(S(C)(=O)=O)nc3C2)CO[C@@H]1c1cc(F)c(F)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)n1cc2c(n1)CN([C@H]1CO[C@H](c3cc(F)c(F)cc3F)[C@@H](N)C1)C2
Reaction time: 2 h

Procedure:
Intermediate obtained in Step A above (379 mg, 0.734 mmol) in dichloromethane (20 mL) was treated with trifluoroacetic acid (10 mL) at room temperature. After 2 h, the reaction was concentrated and the crude material was purified on a silica gel column (40S Biotage™) eluting with in 0-2% methanol, containing 10% NH4OH, in dichloromethane to give the title compound as a white solid. 1H NMR (500 MHz, CD3OD): δ 1.50 (q, 1H, J=12 Hz); 2.43-2.49 (m, 1H); 2.88 (td, 1H, J=12, 6 Hz); 3.11-3.18 (m, 1H); 3.34 (s, 3H); 3.40 (t, 1H, J=12 Hz); 3.48-3.92 (m, 4H); 4.23-4.28 (m, 2H); 7.14-7.20 (m, 1H); 7.36-7.42 (m, 1H); 7.86 (s, 1H). LC-MS: 417.12 (M+1).
Reaction SMILES: C([NH2:8])C1C=CC=CC=1.Cl.O=[CH:11][CH2:12][C@@H:13]([C@@H:15]([CH2:17][OH:18])[OH:16])[OH:14].C([BH3-])#N.[Na+].[OH-].[Na+]>O>[NH2:8][CH2:11][CH2:12][C@H:13]([OH:14])[C@@H:15]([OH:16])[CH2:17][OH:18]
Reactant: O=CC[C@H](O)[C@H](O)CO
Reactant: NCc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: NCC[C@H](O)[C@@H](O)CO
Reaction time: 8 h

Procedure:
A solution of benzylamine (4.8 g., 48 mmole) in water (40 ml.) was acidified to pH 5 with 5N hydrochloric acid. 2-Deoxy-D-ribose (3.0 g., 27.5 mmole) and sodium cyanoborohydride (1.35 g., 21.5 mmole) were added and the solution was stirred and allowed to stand overnight at room temperature. The solution was basified to pH 10 with sodium hydroxide, washed several times with ethyl acetate to remove excess benzylamine, and acidified to pH 4 with hydrochloric acid. Methanol (60 ml.) was added and the crude mixture was hydrogenated at 50° C. and 50 p.s.i. in the presence of 10% palladium-on-charcoal catalyst, fresh catalyst being added after 24 hours. After a further 4 days, the solution was filtered and evaporated, the product being chromatographed on Amberlite CG 50 ion exchange resin (NH4+ form) eluting with 0.1N ammonium hydroxide to give 5-amino-1,2(S),3(S)-trihydroxy-pentane (1.6 g., 53%. m/e 135. C5H10NO3 requires m/e 135.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17]([OH:19])=[O:18])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20](=O)([O-])[O-].[K+].[K+].CI.C(OCC)(=O)C>CN(C)C=O>[CH3:20][O:18][C:17]([C:15]1[S:14][C:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][C:10]=2[CH:16]=1)=[O:19]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCc2sc(C(=O)O)cc2C1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2

Procedure:
5-t-Butoxycarbonyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-2-carboxylic acid (300 mg, 1.1 mmol), potassium carbonate (150 mg, 1.1 mol) and methyl iodide (150 mg, 1.1 mmol) were stirred at room temperature for 4.5 hours in anhydrous N,N-dimethylformamide (3 ml). The reaction solution was mixed with ethyl acetate, washed with water and saturated brine and then dried with anhydrous sodium sulfate to obtain crude 5-t-butoxycarbonyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-2-carboxylic acid methyl ester. This was mixed with hydrochloric acid-saturated methanol (4 ml) and stirred at room temperature for 14 hours. By evaporating the solvent from the reaction solution under a reduced pressure, crude 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-2-carboxylic acid methyl ester hydrochloride was obtained. This compound and triethylamine (0.59 ml, 4.2 mmol) and 2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one (310 mg, 1.0 mmol) were stirred at room temperature for 24 hours in anhydrous N,N-dimethylformamide (10 ml). The reaction solution was mixed with ethyl acetate, washed with water and saturated brine and then dried with anhydrous sodium sulfate. The solvent was removed by evaporation under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 240 mg (0.56 mmol, 56% in yield) of the title compound.