Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[CH2:22]>C(O)CCC.O.C(OCC)(=O)C>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([CH2:22][CH2:21][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCCNC1
Reactant: C=Cc1ccccn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCO
Product: OC(c1ccccc1)(c1ccccc1)C1CCCN(CCc2ccccn2)C1
Yield: 21.5 %

Procedure:
A mixture of 3-(diphenylhydroxymethyl)piperidine (267 mg, 1.0 mmol), 2-vinylpyridine (0.32 g, 3.0 mol) and Triton B (3 drops) in 1-butanol (10 ml) was heated under reflux for 18 hours, diluted with water and ethyl acetate and the layers separated. The organic layer was washed with water, dried over magnesium sulphate and evaporated. The residue was twice taken up in toluene and evaporated and it was then purified by chromatography on SiO2 using dichloromethane plus 0-5% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (80 mg) as a pale brown oil which was characterised containing 0.25 equivalents of water.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Cl)[CH:33]=1.CCN(C(C)C)C(C)C.O>C(#N)C>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH:21][CH2:38][C:34]3[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=3)[C@@H:17]2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CC[C@@H](N)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: ClCc1cccnc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: C[C@@H](O[C@H]1CC[C@@H](NCc2cccnc2)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C

Procedure:
To a solution of 75 mg of non-racemic 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-2-(S)-(4-fluorophenyl)-3-(R)-aminocyclopentane from Example 39 in 2 mL of acetonitrile was added 34 mg of 3-picolyl chloride hydrochloride and 0.090 mL of DIPEA. The reaction was heated at 50° C. for 3 days and then poured into water and extract twice with ethyl acetate. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated. The residue was purified on a 3×1 mm preparative silica gel plates eluted with 5% methanol in methylene chloride to give 40 mg of title compound as an oil. Mass spec (NH3 /CI): 527 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C:13]([C:15]([OH:17])=[O:16])=[CH:12][CH2:11][C@H:10]1[C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO.C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C:13]([C:15]([O:17][CH3:27])=[O:16])=[CH:12][CH2:11][C@@H:10]1[C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[F:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC(C(=O)O)=CC[C@H]1c1cc(F)c(F)cc1F
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1=CC[C@H](c2cc(F)c(F)cc2F)[C@@H](NC(=O)OC(C)(C)C)C1

Procedure:
A solution of Example 39A (510 mg) was dissolved in methanol (1 mL) and CH2Cl2 (1 mL), and then (trimethylsilyl)diazomethane solution (0.4 mL, 2M in ether) was added. After ten minutes, acetic acid (0.2 mL) was added. The mixture was concentrated, filtered through a silica gel plug, and purified by chromatography (Column: Chiralcel AD, Mobile Phase: hexane/ethanol/methanol=95/2.5/2.5) to give the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.31 (s, 9H), 2.18-2.28 (m, 1H), 2.41-2.50 (m, 1H), 2.57-2.67 (m, 1H), 2.86 (d, J=16.48 Hz, 1H), 3.10-3.18 (m, 1H), 3.76 (s, 3H), 4.02 (s, 1H), 4.37 (d, J=7.63 Hz, 1H), 6.86-6.94 (m, 1H), 6.99 (s, 1H), 7.11 (s, 1H). MS (DCI) m/z 403 (M+NH4)+.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([O-])([O-])=[O:24].[NH4+].[Ce].C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O>[C:1]1([N:7]2[C:11]3[CH:12]=[C:13]([CH:16]=[O:24])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Ce]
Product: O=Cc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
1 g of 1,2-diphenyl-6-methyl-1H-benzimidazole was suspended in 31 ml of 40% sulfuric acid and mixed with 13.5 g of cerium ammonium nitrate. It was allowed to stir for 2.5 hours at 80° C., cooled to 20° C., and carefully stirred into saturated aqueous sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate, the combined extracts were washed with saturated aqueous sodium chloride solution, dried on sodium sulfate solution and evaporated to the dry state in a vacuum. The residue was chromatographed on silica gel.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH:18]1([N:13]2[C:12]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccccc1
Product: c1ccc(-c2c3c(nn2C2CC2)CCNCC3)cc1
Yield: 103.3 %

Procedure:
The title compound (128 mg) was prepared according to Example 263 using 208 mg of 2-cyclopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester and 84 mg of phenylboronic acid. MS (ESI): exact mass calculated for C16H19N3, 253.16; found, m/z 254.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.57-7.44 (m, 5H), 3.57-3.54 (m, 1H), 3.42-3.40 (m, 2H), 3.17-3.14 (m, 2H), 2.93-2.84 (m, 2H), 0.91-0.85 (m, 4H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH3:30][C:31]1[N:36]=[CH:35][N:34]=[C:33](Cl)[CH:32]=1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:33]4[CH:32]=[C:31]([CH3:30])[N:36]=[CH:35][N:34]=4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Reactant: Cc1cc(Cl)ncn1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2cc(C)ncn2)C3)cc1

Procedure:
Compound du was prepared according to the procedure described in Example 2 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 6-methyl-4-chloropyrimidin. LC-MS: m/z=+489 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH2:12][O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[N:9]=[C:8]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[C:29]([O:31][CH3:32])[N:28]=[CH:27]3)=[C:22]([O:33][CH3:34])[CH:21]=2)[N:7]=1)=[CH2:5])C.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.[Cl-].[Na+].O>[CH3:34][O:33][C:22]1[CH:21]=[C:20]([NH:19][C:8]2[N:7]=[C:6]([C:4](=[O:3])[CH3:5])[CH:11]=[C:10]([CH2:12][O:13][CH2:14][C:15]([F:16])([F:17])[F:18])[N:9]=2)[CH:25]=[CH:24][C:23]=1[N:26]1[CH:30]=[C:29]([O:31][CH3:32])[N:28]=[CH:27]1
Reactant: C=C(OCC)c1cc(COCC(F)(F)F)nc(Nc2ccc(-n3cnc(OC)c3)c(OC)c2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Product: COc1cn(-c2ccc(Nc3nc(COCC(F)(F)F)cc(C(C)=O)n3)cc2OC)cn1
Temperature: 40 °C

Procedure:
4-(1-Ethoxyvinyl)-N-(3-methoxy-4-(4-methoxy-1H-imidazol-1-yl)phenyl)-6-((2,2,2-trifluoro-ethoxy)methyl)pyrimidin-2-amine (0.31 g, 0.65 mmol) was dissolved in dioxane (30 mL) and water (3 mL). Hydrochloric acid (conc., 0.164 mL, 1.94 mmol) was added. The mixture was heated at 40° C. for 35 min. Sodium bicarbonate (1 g) was added. Brine (5 mL) was added and the mixture was extracted with EtOAc (×2). The combined organic phases were dried over sodium sulfate and evaporated to give the title compound as a solid, 0.28 g (98%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][OH:34]>O1CCOCC1.CN(C=O)C>[CH3:30][N:31]([CH3:35])[CH2:32][CH2:33][O:34][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6]
Reactant: CN(C)CCO
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(OCCN(C)C)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and 2-dimethylaminoethanol in dioxane and DMF. ES-MS m/e (%): 458 (M+H+, 100).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:11]([O:13][C:14](=[O:19])[C:15](Br)([F:17])[F:16])[CH3:12]>C(OCC)C>[CH2:11]([O:13][C:14](=[O:19])[C:15]([F:17])([F:16])[O:10][C:7]1[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=1)[CH3:12]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(F)(F)Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.7 %

Procedure:
A suspension of 60% of NaH in oil (3.84 g, 96 mmol) was washed three times with hexanes and the solid was suspended in dry DMF (80 ml). 4-Fluorophenol (8.96 g, 80 mmol) was slowly added over a period of 5 min and the reaction mixture was stirred at rt for about 10 min. The reaction mixture was cooled at 0° C. and 2-bromo-2,2-difluoroacetic acid ethyl ester (16.24 g, 80 mmol) was slowly added. The reaction mixture was heated at 90° C. for 20 h. After allowing the reaction to reach room temperature, ethyl ether (300 ml) was added and the suspension was washed with water and brine. After drying the organic layer over sodium sulfate for 15 min, the solvent was evaporated and the crude was purified by flash chromatography, using a mixture of ethyl acetate/hexanes (1/10) to give 2,2-difluoro-2-(4-fluorophenoxy)acetic acid ethyl ester as an oil (11.0 g, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[N:10]([C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[C:16]([CH3:23])[N:17]=[CH:18]2)=[C:11]=[O:12]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:11]([NH:10][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[C:16]([CH3:23])[N:17]=[CH:18]2)=[O:12]
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Reactant: NCc1cccc(Cl)c1
Solvent: CCOCC
Product: Cc1cc2c(NC(=O)NCc3cccc(Cl)c3)cccc2cn1

Procedure:
3-chlorobenzylamine (141 mg, 1.0 mmol) in ether (20 mL) was treated with an ethereal solution of 5-isocyanato-3-methylisoquinoline. The precipitate that formed was collected by filtration, washed with diethyl ether, and air-dried to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.69 (s, 1H), 8.20 (d, 1H, J=7.8 Hz), 7.75 (s, 1H), 7.70 (d, 1H, J=8.2 Hz), 7.51 (t, 1H, J=7.8 Hz), 7.31-7.43 (m, 4H), 7.10 (m, 1H), 4.38 (d, 2H, J=5.7 Hz), 2.65 (s, 3H); MS (ESI+) m/z 326/328 (M+H, 35Cl/37Cl).
Reaction SMILES: C(C1C2CCCCC=2C(C)=NC=1OC)#N.[C:16]([C:18]1[C:27]2[CH2:26][CH2:25][CH2:24][C:23](=[O:28])[C:22]=2[C:21]([CH3:29])=[N:20][C:19]=1[O:30][CH2:31]C)#[N:17]>>[C:16]([C:18]1[C:27]2[CH2:26][CH2:25][CH2:24][C:23](=[O:28])[C:22]=2[C:21]([CH3:29])=[N:20][C:19]=1[O:30][CH3:31])#[N:17]
Reactant: CCOc1nc(C)c2c(c1C#N)CCCC2=O
Agent: COc1nc(C)c2c(c1C#N)CCCC2
Product: COc1nc(C)c2c(c1C#N)CCCC2=O

Procedure:
4-Cyano-3-methoxy-1-methyl-5,6,7,8-tetrahydroisoquinolin-8-one was prepared from 4-cyano-3-methoxy-1-methyl-5,6,7,8-tetrahydroisoquinoline following essentially the same procedure as that described in Tetrahedron, 1975, 31, 527 for the synthesis of 4-cyano-3-ethoxy-1-methyl-5,6,7,8-tetrahydroisoquinolin-8-one and was obtained as white crystals, mp 128° C. Pmr spectrum (CDCl3 ; δ in ppm): 2.04-3.19 (6H,m); 2.86 (3H,s); 4.12 (3H,s).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:21][CH2:20][CH2:19][C:9]2=[N:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]([CH3:18])=[C:8]2[CH2:7]1)=[O:5])[CH3:2].[OH:22]O>>[CH2:1]([O:3][C:4]([N:6]1[CH2:21][CH2:20][CH2:19][C:9]2=[N+:10]([O-:22])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]([CH3:18])=[C:8]2[CH2:7]1)=[O:5])[CH3:2]
Reactant: OO
Reactant: CCOC(=O)N1CCCc2nc3ccccc3c(C)c2C1
Product: CCOC(=O)N1CCCc2c(c(C)c3ccccc3[n+]2[O-])C1
Yield: 60 %

Procedure:
2,3,4,5-Tetrahydro-11-methyl-1H-2-azepino[4,3-b]quinoline-carboxylic acid ethyl ester 6-oxide was prepared analogous to Example 111 from 2,3,4,5-tetrahydro-11-methyl-1H-2-azepino[4,3-b]quinoline-carboxylic acid ethyl ester and hydrogen peroxide.
Reaction SMILES: [C:1]([Si:5]([CH3:63])([CH3:62])[O:6][C@H:7]1[C@@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@H:10]([N:20]2[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:21]2=[O:36])[O:9][C@@H:8]1[C@H:37]([OH:61])[C@H:38]([N:46](CC1C=CC=CC=1)CC1C=CC=CC=1)[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[NH2:46][C@@H:38]([C@H:37]([C@@H:8]1[C@@H:7]([O:6][Si:5]([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:63])[CH3:62])[C@@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15])[C@H:10]([N:20]2[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:21]2=[O:36])[O:9]1)[OH:61])[C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H]([C@H](O)[C@@H](C(=O)OC(C)(C)C)N(Cc4ccccc4)Cc4ccccc4)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H]([C@H](O)[C@H](N)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 25 %

Procedure:
tert-Butyl (2S,3R)-3-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl-(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-2-(dibenzylamino)-3-hydroxy-propanoate (3.0 g, 3.33 mmole, obtained from Reference Example 4) was hydrogenated using 10% palladium on carbon (2 g) in methanol (70 ml) under atmospheric pressure. The catalyst was removed, and the volatile was removed in vacuo. The residue was chromatographed (flash column, silica gel, methylene chloride:methanol:diethyl ether=92:4:4) to give the recovered starting material (1.2 g, 50%) and tert-butyl (2S,3R)-2-amino-3-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl-(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-3-hydroxypropanoate (600 mg, 25%) as a white amorphous solid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]1[C:13]([OH:31])=[CH:14][C:15]2[CH2:16][CH2:17][C@@H:18]3[C@@H:27]([C:28]=2[CH:29]=1)[CH2:26][CH2:25][C@@:23]1([CH3:24])[C@H:19]3[CH2:20][CH2:21][C@@H:22]1[OH:30])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:9]([O:11][C:12]1[C:13]([O:31][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][C:15]2[CH2:16][CH2:17][C@@H:18]3[C@@H:27]([C:28]=2[CH:29]=1)[CH2:26][CH2:25][C@@:23]1([CH3:24])[C@H:19]3[CH2:20][CH2:21][C@@H:22]1[OH:30])[CH3:10]
Reactant: BrCc1ccccc1
Reactant: CCOc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOc1cc2c(cc1OCc1ccccc1)CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Temperature: 100 °C
Reaction time: 7.5 h
Yield: 109.7 %

Procedure:
Benzyl bromide (4.5 g, 38 mmol) was added to a suspension of 2-ethoxy-β-estra-3,17β-diol (2) (4.5 g, 13 mmol) and potassium carbonate (8.6 g, 62 mmol) in anhydrous ethanol (100 mL) under argon atmosphere at 0° C. The resulting mixture was stirred at 100±5° C. for 7-8 h. The solvent was evaporated under reduced pressure and the residue was diluted with water, and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic solution was washed with water (100 mL), sodium bicarbonate (120 mL), brine (100 mL), and dried over sodium sulfate. The ethyl acetate layer on evaporation under reduced pressure gave a viscous oil (5.8 g), which was used as such without any further purification in the next step: 1H NMR, (CDCl3) δ 7.35 (s, 5 H), 6.75 (s, 1 H) 6.65 (s, 1 H), 5.5 (s, 1 H), 4.55 (s, 2 H), 4.04 (q, J=6.4, 2 H), 3.5 (t, J=8.5 Hz, 1 H), 2.75 (m, 3 H), 2.20-1.95 (m, 6 H), 1.90-1.80 (m, 2 H), 1.75-1.5 (m, 2 H), 1.45-1.1 (m, 7 H, 0.85 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:49][O:50][CH2:51][CH2:52][N:53]([CH2:60][CH2:61][O:62][CH3:63])[C:54](=[O:59])[O:55][CH:56](Cl)[CH3:57]>CN(C)C=O.C(OCC)(=O)C>[CH3:63][O:62][CH2:61][CH2:60][N:53]([CH2:52][CH2:51][O:50][CH3:49])[C:54]([O:55][CH:56]([O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)[CH3:57])=[O:59]
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: COCCN(CCOC)C(=O)OC(C)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCN(CCOC)C(=O)OC(C)OC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c(OC)c1
Reaction time: 0.17 h
Yield: 63.3 %

Procedure:
To a solution of chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (US20100152190A1, 200 mg, 0.324 mmol) in dimethylformamide (8 mL) was added cesium carbonate (846 mg, 2.6 mmol). After stirring for 10 min, a solution of the above freshly made 1-chloroethyl bis(2-methoxyethyl)carbamate (510 mg, 2.13 mmol) in dimethylformamide (3 mL) was added. The reaction mixture was allowed to stir at room temperature overnight. This reaction mixture was taken up in ethyl acetate, washed with water, brine and concentrated to dryness. The crude material was purified by flash chromatography (hexane/ethyl acetate, 90/10 to 10/90) to give 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-[bis-(2-methoxy-ethyl)-carbamoyloxy]-ethyl ester as a white solid (168 mg, 63% yield). LCMS (ES+) m/z calcd. for C40H47Cl2F2N4O8 [(M+H)+]: 819, found: 819.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:13][C:14]2[CH:19]=[C:18](Cl)[N:17]=[C:16]([NH2:21])[N:15]=2)[C:9]([F:12])([F:11])[F:10])=[C:4]([N:22]2[CH:26]=[CH:25][C:24]([CH3:27])=[N:23]2)[CH:3]=1.[CH2:28]1[C:32]2([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][C@@H:30]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:29]1[C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[NH2:21][C:16]1[N:17]=[C:18]([N:35]2[CH2:34][CH2:33][C:32]3([CH2:28][N:29]([C:43]([O:45][CH2:46][C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=4)=[O:44])[C@H:30]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:31]3)[CH2:37][CH2:36]2)[CH:19]=[C:14]([O:13][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[N:22]2[CH:26]=[CH:25][C:24]([CH3:27])=[N:23]2)[C:9]([F:12])([F:11])[F:10])[N:15]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCNCC2)CN1C(=O)OCc1ccccc1
Reactant: Cc1ccn(-c2cc(Br)ccc2[C@@H](Oc2cc(Cl)nc(N)n2)C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Br)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 90 °C

Procedure:
To a solution of 4-[(1R)-1-[4-bromo-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]-6-chloro-pyrimidin-2-amine (125 mg, 0.3 mmol, Step 1) in dioxane (3 mL) was added (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (95 mg, 0.3 mmol) and Na2CO3 (182 mg, 0.35 mmol). The reaction was heated to 90° C. for 130 h, then cooled to RT, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:9][N:10]=[C:11]([C:15]1[N:16]=[C:17]([NH:20][CH:21]=[O:22])[S:18][CH:19]=1)[C:12]([OH:14])=O)[C:7]#[CH:8].[CH3:23][CH:24]1[CH:29]=[C:28]([C:30]([OH:32])=[O:31])[N:27]2[C:33](=[O:36])[CH:34]([NH2:35])[C@H:26]2[S:25]1.C[Si](CC(N)=O)(C)C.[Cl-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.O1CCCC1.CN(C)C=O>[CH3:23][CH:24]1[CH:29]=[C:28]([C:30]([OH:32])=[O:31])[N:27]2[C:33](=[O:36])[CH:34]([NH:35][C:12](=[O:14])[C:11](=[N:10][O:9][CH2:6][C:7]#[CH:8])[C:15]3[N:16]=[C:17]([NH:20][CH:21]=[O:22])[S:18][CH:19]=3)[C@H:26]2[S:25]1
Reactant: C#CCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: CC1C=C(C(=O)O)N2C(=O)C(N)[C@H]2S1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C#CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(NC=O)n1
Temperature: -25 °C
Yield: 97.6 %

Procedure:
To dimethylformamide (0.4 g) was added dropwise phosphorus oxychloride (0.84 g) under stirring and ice-cooling, and the mixture was stirred for 30 minutes at 40° C. and then suspended in ethyl acetate (10 ml). To the suspension was added 2-(2-propynyloxyimino)-2-(2-formylaminothiazol-4-yl)acetic acid (syn isomer) (1.27 g) under stirring and ice-cooling and then stirred for 30 minutes under ice-cooling. Thus obtained solution was added to a solution, which was prepared by stirring a mixture of 2-methyl-7-amino-3-cephem-4-carboxylic acid (1.44 g) and trimethylsilylacetamide (5.2 g) in tetrahydrofuran (40 ml), under cooling to -25° C. The mixture was stirred for 1 hour at -20° C. to -10° C., and a saturated aqueous solution of sodium chloride (100 ml) was added thereto. Thus obtained mixture was adjusted to pH 7.5 with 20% aqueous solution of sodium carbonate, and the aqueous layer was separated. To the aqueous layer was added ethyl acetate, and adjusted to pH 2 with 10% hydrochloric acid, and then extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated. The residue was pulverized in diethyl ether, collected by filtration and then dried to give 2-methyl-7-[2-(2-propynyloxyimino)-2-(2-formylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer) (2.2 g).