Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](OC)=[O:16])[CH2:11][CH2:10]1)=[CH2:8].O.Cl>C1COCC1>[CH:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][OH:16])[CH2:11][CH2:10]1)=[CH2:8]
Reactant: C=C[C@H]1CC[C@H](C(=O)OC)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: C=C[C@H]1CC[C@H](CO)CC1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 105.7 %

Procedure:
5.7 g of lithium aluminium hydride was dispersed in 50 mL of THF. 29.5 g of methyl trans-4-vinylcyclohexane carboxylate was dissolved in 75 mL of THF, which was added dropwise to the above solution at 15 to 16° C. for 40 minutes. The solution was further stirred at 10 to 20° C. for 30 minutes, and then water was slowly added thereto. About 70 mL of 10% hydrochloric acid was added. While washing and rinsing with hexane, a sludge-like insoluble matter was removed by a decanter. Then, the obtained organic phase was washed with 10% hydrochloric acid, saturated sodium bicarbonate water, and saturated saline, in this order. The resultant product was dried over anhydrous sodium sulfate, and concentrated, to obtain 26 g of (trans-4-vinylcyclohexyl)methanol.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:9](=O)[CH3:10].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH3:10][C:9]1[C:3]2[CH:4]=[CH:5][O:1][C:2]=2[CH2:6][CH2:7][N:8]=1
Reactant: CC(=O)NCCc1ccco1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1=NCCc2occc21
Yield: 94 %

Procedure:
In close analogy to the procedure described above, N-(2-Furan-2-yl-ethyl)-acetamide is reacted with phosphorus pentoxide to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]([NH:14][C:15]([NH:17]C(=O)C3C=CC=CC=3)=[S:16])[CH:11]=[CH:12][CH:13]=2)[CH:3]=1.[OH-].[Na+].Cl>CO.O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[C:10]([NH:14][C:15]([NH2:17])=[S:16])[CH:11]=[CH:12][CH:13]=2)[CH:3]=1
Reactant: Cc1ccnc(-c2cccc(NC(=S)NC(=O)c3ccccc3)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccnc(-c2cccc(NC(N)=S)c2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a suspension of N-(3-(4-methylpyridin-2-yl)phenyl)-N′-benzoylthiourea (540 mg) in methanol (5 ml) was added an aqueous sodium hydroxide solution (1N, 1.55 ml) dropwise. The mixture was stirred at 60° C. for 1 hour, cooled to ambient temperature, and the pH was adjusted to 8.0 with 1N hydrochloric acid. The mixture was diluted with water (50 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was triturated with diisopropyl ether, collected by filtration, washed with diisopropyl ether and dried under reduced pressure to give N-(3-(4-methylpyridin-2-yl)phenyl)thiourea (356 mg).
Reaction SMILES: C(O)CCC.Cl[C:7]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][N:8]=1.O.[NH2:16][NH2:17].C(=O)([O-])[O-].[K+].[K+]>O>[NH:16]([C:7]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][N:8]=1)[NH2:17]
Reactant: NN
Reactant: COc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: COc1cccnc1NN

Procedure:
To 50 ml of a butanol solution of 9.376 g of 2-chloro-3-methoxypyridine were added 16 ml of hydrazine monohydrate and 9.03 g of anhydrous potassium carbonate, and the mixture was heated under reflux for 20 hours. After cooling, the reaction mixture was poured into 200 ml of water and extracted with a mixed solvent of methanol-chloroform (1:9 by volume). The organic layer was washed with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was removed by evaporation. The residue was subjected to silica gel column chromatography using a mixture of chloroform-methanol (20:1 by volume) as an eluate. The fraction containing the desired compound was concentrated to afford 5.952 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=[C:4]([CH2:10][O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[N:25]1[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]1)[NH2:21].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:13]1([CH2:12][O:11][CH2:10][C:4]2[N:3]=[C:2]([NH:21][C:20]3[CH:22]=[CH:23][C:24]([N:25]4[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]4)=[C:18]([O:17][CH3:16])[CH:19]=3)[N:7]=[C:6]([NH:8][CH3:9])[CH:5]=2)[CH2:15][CH2:14]1
Reactant: CNc1cc(COCC2CC2)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: CNc1cc(COCC2CC2)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 120 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2-chloro-6-((cyclopropylmethoxy)methyl)-N-methylpyrimidin-4-amine (41 mg, 0.18 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (73 mg, 0.36 mmol), cesium carbonate (117 mg, 0.36 mmol), palladium acetate (6 mg, 0.03 mmol) and 2-(dicyclohexyl-phosphino)biphenyl (9 mg, 0.03 mmol) was stirred under argon at 120° C. for 90 minutes in microwave oven. The mixture was filtered through a short silica gel plug which was washed with 10% solution of methanol in ethyl acetate (75 mL). The eluate was concentrated and the residue was purified by preparative HPLC to give the title compound as a dry film (30 mg, 42%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:13]([NH:15][C:16]1[S:17][C:18]([CH2:31][C:32]([O:34]CC)=[O:33])=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])[N:20]=1)=[O:14])(=O)C>C(O)C>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:13]([NH:15][C:16]1[S:17][C:18]([CH2:31][C:32]([OH:34])=[O:33])=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[O:29][CH3:30])[N:20]=1)=[O:14]
Reactant: CCOC(=O)Cc1sc(NC(=O)c2cc3ccccc3n2C(C)=O)nc1-c1ccc(OC)cc1OC
Solvent: CCO
Product: COc1ccc(-c2nc(NC(=O)c3cc4ccccc4[nH]3)sc2CC(=O)O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.5 g of 2-[(1-acetyl-2-indolyl)carbonylamino]-4-(2,4-dimethoxyphenyl)-5-ethoxycarbonylmethylthiazole, prepared above according to Example 10, is dissolved in 10 ml of 950 ethanol and then 1.5 ml of 2N NAOH are added. The reaction mixture is stirred overnight at room temperature and then concentrated under vacuum. The residue is taken up in a buffer solution, pH=2, a precipitate is separated by filtration, washed with water, filtered and then rinsed with ether.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:12]2[CH2:11][CH2:10][N:9]([C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:14][CH2:13]2)[CH:16]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Cc1ccc(C)c(N2CCN(Cc3cccc(-c4ccccc4)c3)CC2)c1

Procedure:
62.1 mg of the target compound (0.17 mmol, 21.2%) was obtained using 1-(2,5-dimethylphenyl)piperazine (312 mg, 1.64 mmol), biphenyl-3-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: COC1C=CC(B2[O:13][C:12](C)(C)[C:11]([CH3:17])([CH3:16])O2)=CC=1CS(N)(=O)=O.[F:23][C:24]1[CH:25]=[C:26]([CH:64]=[CH:65][CH:66]=1)[CH2:27][N:28]1[CH:32]=[C:31]([C:33]2[C:41]3[C:36](=[N:37][CH:38]=[C:39]([C:42]4[CH:43]=[N:44][C:45]([N:48]5[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]5)=[CH:46][CH:47]=4)[CH:40]=3)[N:35]([S:54]([C:57]3[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=3)(=[O:56])=[O:55])[CH:34]=2)[CH:30]=[N:29]1.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=NC(N5CCN(C)CC5)=CC=4)C=3)NC=2)C=N1.C1(C(Cl)=O)CC1.C(N(CC)CC)C>C(Cl)Cl>[CH:11]1([C:12]([N:51]2[CH2:52][CH2:53][N:48]([C:45]3[CH:46]=[CH:47][C:42]([C:39]4[CH:40]=[C:41]5[C:33]([C:31]6[CH:30]=[N:29][N:28]([CH2:27][C:26]7[CH:64]=[CH:65][CH:66]=[C:24]([F:23])[CH:25]=7)[CH:32]=6)=[CH:34][N:35]([S:54]([C:57]6[CH:63]=[CH:62][C:60]([CH3:61])=[CH:59][CH:58]=6)(=[O:56])=[O:55])[C:36]5=[N:37][CH:38]=4)=[CH:43][N:44]=3)[CH2:49][CH2:50]2)=[O:13])[CH2:17][CH2:16]1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1CS(N)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Agent: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Agent: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)C6CC6)CC5)nc4)cnc32)cc1
Yield: 100 %

Procedure:
Using similar reaction conditions as described in step i of intermediate 17, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 1 compound of example 137) (80 mg, 0.13 mmol) was acylated with cyclopropane carbonyl chloride (22 mg, 0.196 mmol) using triethylamine (40 mg, 0.39 mmol) in DCM (3 mL) to afford 100 mg (100% yield) of the titled compound. MS: m/z=676.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:13])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.C([Li])CCC.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.Cl>O1CCCC1>[F:13][C:4]1[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=[C:2]([B:19]([OH:24])[OH:20])[CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC1(C)Cc2cc(Br)cc(F)c2O1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(B(O)O)cc(F)c2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of 5-bromo-7-fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran (18.9 g) in tetrahydrofuran (250 mL) was added butyllithium (53 mL, 1.60 M hexane solution) under an argon atmosphere at −78° C., and the mixture was stirred for 1 hr. Triisopropyl borate (21 mL) was added, and the mixture was stirred for 12 hr while allowing to warm to room temperature. 1 M hydrochloric acid (150 mL) was added, and the mixture was stirred for 1 hr, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (6.54 g, 40%).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[OH:33])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:53][C@H:54]1[CH2:59][CH2:58][C@H:57](O)[CH2:56][CH2:55]1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][C@H:57]2[CH2:58][CH2:59][C@@H:54]([Cl:53])[CH2:55][CH2:56]2)/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O[C@H]1CC[C@H](Cl)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)/C(=N\O[C@H]1CC[C@@H](Cl)CC1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
Ethyl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-(hydroxyimino)acetate (0.91 g), triphenylphosphine (0.58 g) and trans-4-chlorocyclohexanol (0.54 g) were dissolved together in anhydrous benzene (20 ml). Diethyl azodicarboxylate (0 35 ml) was added and the solution heated at reflux for 16 h with exclusion of moisture. Evaporation of solvent followed by chromatography afforded the title compound as a near colourless gum (225 mg, 20%); νmax (KBr) 1737, 1595 (w), 1529, 1491 and 1446 cm-1 ; δHH (CDCl3) 1.39 (3H, t, J 7 Hz), 1.69, 1.96 and 2.06 (8H, 3m), 4.04 (1H, qt, J 6 Hz), 4.39(2H, q, J 7Hz), 4.44 (1H, qt, J 3 Hz), 6.49 (1H, s), 6.97 (1H, brs, D2O exch), and 7.32 (15H, s). [Mass spectrum: +ve ion (thioglycerol) MH+ (574), MNa+ (596)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:15]3[C:11](=[N:12][N:13]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])[C:14]=3[CH:24]([CH3:26])[CH3:25])[C:10]2=[O:35])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:36][O:37][C:38](=[O:42])[CH2:39][CH2:40]I>>[CH3:36][O:37][C:38](=[O:42])[CH2:39][CH2:40][C:16]1([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[C:15]2[C:11](=[N:12][N:13]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[C:14]=2[CH:24]([CH3:26])[CH3:25])[C:10](=[O:35])[N:9]1[C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: COc1ccccc1-n1nc2c(c1C(C)C)C(c1ccc(Cl)cc1)N(c1ccc(F)c(Cl)c1)C2=O
Reactant: COC(=O)CCI
Product: COC(=O)CCC1(c2ccc(Cl)cc2)c2c(nn(-c3ccccc3OC)c2C(C)C)C(=O)N1c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared in analogy to the procedure described for example 74 but using the compound prepared in example 88 and 2 equivalents of 3-iodo-propionic acid methyl ester (Scapens, D.; Adams, H.; Johnson, T. R.; Mann, B. E.; Sawle, P.; Aqil, R.; Perrior, T.; Motterlini, R. Dalton Transactions 2007, 43, 4962-4973). The reaction mixture was stirred for 2 h at rt. The crude material was purified by silica gel column chromatography (heptane/ethyl acetate, 1:0→7:3→2:3) followed by preparative HPLC (Column: XBridge, 30×100 mm. Flow: 30 mL/min. Gradient: 30% to 60% B in 15 min, 60% B for 5 min, 60% to 90% B in 5 min; A=0.1% TFA in water, B=0.1% TFA in acetonitrile). tR: 1.42 min (LC-MS 3); ESI-MS: 596.3 [M+H]+ (LC-MS 3).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([NH2:10])[CH2:4][C:3]1([CH3:12])[CH3:11].C(N(CC)CC)C.[C:20](Cl)(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(Cl)Cl>[OH:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([NH:10][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: CCCCCCCC(=O)Cl
Reactant: CC1(C)CC(N)CC(C)(C)N1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)NC1CC(C)(C)N(O)C(C)(C)C1
Temperature: 25 °C

Procedure:
To a stirred 0° C. solution of 1.0 g of 1-oxyl-4-amino-2,2,6,6-tetramethylpiperidine and 0.65 g of triethylamine in 10 mL of methylene chloride is added dropwise a solution of 0.95 g of octanoyl chloride in 5 mL of methylene chloride. After the addition is complete, the reaction mixture is allowed to warm to ambient temperature. After two more hours, the reaction mixture is washed with 1% aqueous sodium hydroxide and finally water. The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated. The title compound is isolated as a red oil after column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][NH:22][CH2:23][CH3:24])[CH:6]=1.Cl[C:27]([O:29][CH3:30])=[O:28]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:22]([CH2:23][CH3:24])[C:27]([O:29][CH3:30])=[O:28])[CH:6]=1
Reactant: COC(=O)Cl
Reactant: CCNCc1cc(Br)ccc1Oc1cc(CC(=O)OC)ccc1OC
Product: CCN(Cc1cc(Br)ccc1Oc1cc(CC(=O)OC)ccc1OC)C(=O)OC

Procedure:
Prepared according to the procedure described in Example 3 Step 3, using the following starting materials: [3-(4-bromo-2-ethylaminomethyl-phenoxy)-4-methoxy-phenyl]-acetic acid methyl ester and methyl chloroformate.
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:9](=[O:10])[CH:8]=[CH:7][N:6]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]1=[O:16].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][C:21]=1[S:31]([NH2:34])(=[O:33])=[O:32]>O1CCOCC1>[OH:10][C:9]1[CH:8]=[CH:7][N:6]([CH2:11][CH2:12][CH:13]([CH3:14])[CH3:15])[C:5](=[O:16])[C:4]=1[C:3]1[NH:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:22][C:21]=2[S:31](=[O:33])(=[O:32])[N:34]=1
Reactant: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Reactant: CSC(SC)=C1C(=O)C=CN(CCC(C)C)C1=O
Solvent: C1COCCO1
Product: CC(C)CCn1ccc(O)c(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)c1=O
Temperature: 25 °C
Yield: 88.7 %

Procedure:
A solution of the product of Example 457C (0.195 g, 0.68 mmol) in dioxane (10 mL) was reacted with the product of Example 425D (0.17 g, 0.64 mmol) at 115° C. for 1 hour. After cooling to about 25° C., the solid precipitate was collected by filtration and dried to provide the title compound (0.258 g, 89%). 1H NMR (300 MHz, DMSO-d6) δ 0.93 (d, J=6.25 Hz, 6 H) 1.58 (m, 3 H) 3.08 (s, 3 H) 3.99 (m, 2 H) 6.33 (d, J=6.62 Hz, 1 H) 7.57 (m, 2 H) 7.67 (d, J=8.82 Hz, 1 H) 8.07 (d, J=6.62 Hz, 1 H) 10.25 (s, 1 H) 13.84 (s, 1 H) 14.28 (s, 1 H). MS (ESI−) m/z 453 (M−H)−.
Reaction SMILES: C(OC([N:8]([CH:19]1[C:44](=[O:45])[N:21]2[C:22]([C:28]([O:30]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:29])=[C:23]([CH:26]=[CH2:27])[CH2:24][S:25][C@H:20]12)[C:9](=[O:18])[CH:10]([C:12]1[N:13]=[C:14]([NH2:17])[S:15][CH:16]=1)[NH2:11])=O)(C)(C)C.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>C(Cl)Cl>[NH2:17][C:14]1[S:15][CH:16]=[C:12]([CH:10]([C:9]([NH:8][CH:19]2[C:44](=[O:45])[N:21]3[C:22]([C:28]([OH:30])=[O:29])=[C:23]([CH:26]=[CH2:27])[CH2:24][S:25][C@H:20]23)=[O:18])[NH2:11])[N:13]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N(C(=O)OC(C)(C)C)C(=O)C(N)c3csc(N)n3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 34.8 %

Procedure:
To a suspension of benzhydryl 7-[N-tert-butoxycarbonyl-2-(2-aminothiazol-4-yl)glycinamido]-3-vinyl-3-cephem-4-carboxylate (3.9 g) in methylene chloride (20 ml) were added trifluoroacetic acid (13.7 g) and anisole (3.8 g) under ice-cooling, and the mixture was stirred at ambient temperature for an hour. After evaporation of the reaction mixture, to the residue were added water (100 ml) and ethyl acetate, followed by adjusting to pH 7 with 2 N aqueous solution of sodium hydroxide. The precipitated solid was removed by filtration and the aqueous layer was separated out. Thereto was added ethyl acetate, followed by adjusting to pH 5 with 10% hydrochloric acid. After separating out the aqueous layer, the organic solvent was completely removed therefrom by evaporation, and then the resultant aqueous solution was adjusted to pH 4 with 10% hydrochloric acid under cooling, followed by subjecting to column chromatography on a nonionic adsorption resin "Diaion HP-20" (120 ml). After washing with water (270 ml), elution was carried out with 10% isopropyl alcohol and then 30% isopropyl alcohol, and the fractions containing the desired compound were collected and evaporated under reduced pressure to give a residue, which was lyophilized to obtained 7-[2-(2-aminothiazol-4-yl)glycinamido]-3-vinyl-3-cephem-4-carboxylic acid (0.8 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:35][C:36]1[CH:47]=[CH:46][C:39]2[S:40][C:41](B(O)O)=[CH:42][C:38]=2[CH:37]=1>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(O)=O.[Na+].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>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:41]3[S:40][C:39]4[CH:46]=[CH:47][C:36]([F:35])=[CH:37][C:38]=4[CH:42]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1cc2cc(F)ccc2s1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cc3cc(F)ccc3s2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O

Procedure:
A solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (33 mg, 0.066 mmol), 5-fluorobenzo[b]thiophen-2-ylboronic acid (12.91 mg, 0.066 mmol) and tetrakis(triphenylphosphine)palladium(0) (76 mg, 0.066 mmol) in toluene (3 mL) was heated to 120° C. via microwave irradiation for 30 minutes. The reaction mixture was diluted with EtOAc (50 mL) and saturated aqueous NaHCO3 (100 mL). The organic layer was separated and the aqueous layer was washed with EtOAc (50 mL). The organic layers were combined and dried over Na2SO4, and the solvent was removed in vacuo to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(5-fluorobenzo[b]thiophen-2-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dispersed in TFA and DCM (1:1, 10 mL). The mixture was stirred at room temperature for 60 minutes and then concentrated. The resulting crude material was reconstituted in MeOH and DCM (6.0 mL) and purified via preparative HPLC, eluting with a gradient of 25-30% ACN (0.035% TFA) and H2O (0.05% TFA). The collected fractions were combined and the solvent was stripped to dryness via rotary evaporation to yield a TFA salt of the title compound (12 mg, 44%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.82 (d, J=9.76 Hz, 1H), 2.15 (d, J=8.30 Hz, 1H), 3.59-3.70 (m, 1H), 3.82 (s, 1H), 3.91 (br s, 1H), 3.98-4.11 (m, 2H), 4.38 (br s, 1H), 4.43-4.55 (m, 2H), 7.23-7.33 (m, 1H), 7.42 (d, J=4.88 Hz, 1H), 7.76 (dd, J=9.76, 2.44 Hz, 1H), 7.93-8.03 (m, 3H), 8.62-8.74 (m, 1H), 9.41 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H18F2N4O2S, 417. found, 417.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[OH:20][CH:21]([CH2:28][OH:29])[CH2:22][C:23]1[NH:24][CH:25]=[CH:26][N:27]=1.[H-].[Na+]>>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[CH2:22][CH:21]([OH:20])[CH2:28][OH:29])=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCC(O)Cc1ncc[nH]1
Reactant: ICCCCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: OCC(O)Cc1nccn1CCCCc1ccc(OCc2ccccc2)cc1
Yield: 57.8 %

Procedure:
Using benzyl 4-(4-iodobutyl)phenyl ether (2.05 g), 2-(2,3-dihydroxypropyl)imidazole (1.0 g) and 65% oily sodium hydride (0.259 g), the same reaction as Reference Example 11-(iv) was carried out to yield the titled compound (1.23 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:15][C@H:14]([CH2:16][O:17][P:18]([NH:27][C@@H:28]([CH3:35])[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])[C@@H:13]([O:36]C(OCC3C=CC=CC=3)=O)[C@:12]2([F:48])[CH3:47])=[C:4]([O:49][CH3:50])[N:3]=1.[H][H]>CO.[Pd]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:15][C@H:14]([CH2:16][O:17][P:18]([NH:27][C@@H:28]([CH3:35])[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])([O:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:19])[C@@H:13]([OH:36])[C@:12]2([F:48])[CH3:47])=[C:4]([O:49][CH3:50])[N:3]=1
Reactant: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](COP(=O)(N[C@@H](C)C(=O)OC(C)C)Oc2ccccc2)[C@@H](OC(=O)OCc2ccccc2)[C@@]1(C)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](COP(=O)(N[C@@H](C)C(=O)OC(C)C)Oc2ccccc2)[C@@H](O)[C@@]1(C)F

Procedure:
To a solution of crude phosphoramidate 116 in MeOH (2.5 mL) was added 5% Pd on charcoal (40 mg). The atmosphere in the flask was exchanged with hydrogen twice. The mixture was stirred at ambient temperature under one atmosphere of hydrogen for 1 h. The mixture was filtered through a short pad of Celite and the filtrate was concentrated. The crude residue was checked by 1H-NMR and 31P-NMR and ratio of two isomers was ca. 17:1 favored the desired SP isomer (117) and also matched the Sp isomer by thin layer chromatography. 31P-NMR (DMSO-d6): δ 4.91.