Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[C:6]([O:9][CH3:10])(=[O:8])[CH3:7].[Li+].CC([N-]C(C)C)C.[Br:19][C:20]1[CH:21]=[CH:22][C:23]([F:36])=[C:24]([C:26](=[N:29][S@@:30]([C:32]([CH3:35])([CH3:34])[CH3:33])=[O:31])[CH2:27][F:28])[CH:25]=1>C1COCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].Cl[Ti+3]>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([F:36])=[C:24]([C@:26]([NH:29][S@@:30]([C:32]([CH3:34])([CH3:33])[CH3:35])=[O:31])([CH2:27][F:28])[CH2:7][C:6]([O:9][CH3:10])=[O:8])[CH:25]=1
Reactant: CC(C)(C)[S@@](=O)N=C(CF)c1cc(Br)ccc1F
Reactant: COC(C)=O
Agent: Cl[Ti+3]
Agent: CC(C)[N-]C(C)C
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: COC(=O)C[C@](CF)(N[S@](=O)C(C)(C)C)c1cc(Br)ccc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 107.4 %

Procedure:
A flame dried RBF equipped with an addition funnel was charged with DIPA (9.32 ml, 66.5 mmol, Aldrich) and THF (70 ml). The solution was cooled to 0° C. before adding a solution of n-butyllithium (2.5M in hexanes; 26.8 ml, 67 mmol, Aldrich) drop wise. The reaction was stirred at 0° C. for 15 minutes then cooled to −78° C. A solution of methyl acetate (4.9 g, 66.5 mmol, Aldrich) in THF (25 ml) was added dropwise via cannula to the LDA solution at −78° C. After 30 minutes, a solution of chlorotitanium triisopropoxide, (18.5 g, 71.0 mmol, Aldrich) in THF (70 ml) was added drop wise via cannula and the reaction was stirred at −78° C. After 1 h, a solution of (R)—N-(1-(5-bromo-2-fluorophenyl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide (15.0 g, 27.1 mmol, step 3) in THF (100 ml), was added drop wise via cannula at −78° C. and the reaction was stirred at −78° C. for 45 minutes. The reaction was quenched with aqueous, saturated ammonium chloride solution, diluted with water and EtOAc and stirred vigorously for 20 minutes. The reaction was filtered through celite and the filter cake was washed with additional EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure. The crude material was purified via silica gel flash chromatography using a solvent gradient of 10-60% acetone in hexanes to afford the title compound as a light yellow oil (12.0 g, 29.1 mmol, 65.6% yield, dr: 97:3 by LC/MS). MS m/z=411.9 M+. Calculated for C15H20BrF2NO3S: 412.290
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]1[CH2:19][CH:18]([C:20]([F:23])([F:22])[F:21])[O:17][CH:16]([CH3:24])[C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([N:14]1[CH2:19][C@H:18]([C:20]([F:23])([F:21])[F:22])[O:17][C@H:16]([CH3:24])[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC1OC(C(F)(F)F)CN(Cc2ccccc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C[C@@H]1CN(Cc2ccccc2)C[C@H](C(F)(F)F)O1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Dry LiAlH4 (797 mg, 21 mmol, Aldrich) is suspended in dry, inhibitor free THF (15 ml) and treated with a solution of 4-benzyl-2-methyl-6-(trifluoromethyl)morpholin-3-one (2.73 g, 10 mmol) in dry, inhibitor free THF (15 ml). The mixture is heated to 60° C. with stirring for 30 minutes. The mixture is diluted with MTBE (25 mL) and quenched sequentially with H2O (0.8 mL), 6.0M NaOH (0.8 mL) and H2O (2.4 mL). The white slurry is filtered and the inorganic salts were washed with MTBE (200 mL). The solvent is removed by rotary evaporation and the product is purified in 3 portions on Biotage Flash 40M+ cartridges using a 10 minute linear gradient of 3%-10% MTBE in heptane. The products are combined and dried under high vacuum yielding a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([S:11][CH2:12][C:13]([OH:15])=O)[N:3]1[CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1.N1C=CC=CC=1.Cl>ClCCl.CN(C=O)C.C1COCC1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([S:11][CH2:12][C:13]([NH:28][C:29]2[N:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[O:15])[N:3]1[CH2:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)CSC1c2ccccc2C(=O)N1Cc1cccs1
Reactant: Nc1ncccn1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(CSC1c2ccccc2C(=O)N1Cc1cccs1)Nc1ncccn1
Reaction time: 0.17 h
Yield: 28 %

Procedure:
To a suspension of compound 15 (200 mg, 0.63 mmol) in dichloromethane (8 mL) at 0° C. was added oxalyl chloride (0.35 mL of a 2M solution in dichloromethane, 0.69 mmol) and catalytic DMF (5 drops) and the resulting reaction mixture was allowed to stir at 0 C for 10 minutes and then at room temperature for 20 minutes. Thereafter a mixture of 2-aminopyrimidine (132 mg, 1.39 mmol) and pyridine (0.11 mL, 1.39 mmol) in THF (2 mL) was added to the reaction mixture and was allowed to stir at room temperature for 4 hours. The reaction mixture was poured onto 1N HCl and extracted with ethyl acetate (3×20 mL). The combined ethyl extracts were dried over anhydrous sodium sulfate and dried in vacuo. Chromatography (SiO2, 20 to 70% EtOAc-Hexanes eluant) provided 70 mg of 16 as a white solid. (170 mg theoretical, 41% yield). 1H NMR (300 MHz, DMSO): δ 10.55 (br s, 1H), 8.5(d, J=3 Hz, 2H), 7.75-7.6(m, 3H), 7.5(m, 1H), 7.4(m, 1H), 7.2-7.05(m, 2H), 7.0-6.9(m, 1H), 5.75(s, 1H0, 5.15(d, J=15 Hz, 1H0, 4.65(d, J=15 Hz, 1H), 3.3(d, J=15 Hz, 1H), 3.1(d, J=15 Hz, 1H). MS: m/z (MH+) 397.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].Cl[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11].Cl>CCC(C)C>[CH2:13]([O:12][C:10]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:11])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCOC(=O)Cl
Reactant: NCCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)C
Product: CCCCOC(=O)NCCC(=O)O
Temperature: 23 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
A solution containing β-alanine (8.9 g; 0.1 mol) and 100 ml of a 1N solution of sodium hydroxide is cooled down to 10° C. n-butyl chloroformate (13.66 g; 0.1 mol) and 50 ml of a 2N solution of sodium hydroxide are added simultaneously. After stirring for 16 hours at 23° C., approximately 10 ml of a solution of concentrated hydrochloric acid (approximately 11 N) is added in order to adjust the pH to 4-5. The oil obtained is extracted with ethyl acetate (2×50 ml), washed with water then dried over magnesium sulphate. The product crystallizes from isopentane in the form of a white powder (yield of 68%). Melting point: 50.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]([CH3:45])[CH3:44])=O>>[CH3:44][N:43]([CH3:45])[CH2:41][CH2:40][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=3[CH2:21]2)=[CH:37][CH:38]=1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Reactant: CN(C)C(=O)CCl
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCCc2ccc(OCCN(C)C)cc2)c1
Yield: 56.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 2-chloro-N,N-dimethylacetamide (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (16 mg) was obtained.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH:12]([C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([O:47][CH3:48])[CH:45]=2)[N:40]=[CH:39][C:38]=1[F:49])[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[CH2:17][CH:16]1[CH2:32][C:33]([O:35][CH3:36])=[O:34].C(N(CC)CC)C>ClCCl.O>[O:11]=[C:12]([C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([O:47][CH3:48])[CH:45]=2)[N:40]=[CH:39][C:38]=1[F:49])[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[CH2:17][CH:16]1[CH2:32][C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)CC1CN(CCSc2cc(F)ccc2F)CCC1CCC(O)c1c(F)cnc2ccc(OC)cc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)CC1CN(CCSc2cc(F)ccc2F)CCC1CCC(=O)c1c(F)cnc2ccc(OC)cc12
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 80.9 %

Procedure:
1.88 cm3 of dimethyl sulfoxide in 6 cm3 of dichloromethane are poured, over 10 minutes, over a solution of 1.32 cm3 of oxalyl dichloride in 30 cm3 of dichloromethane cooled to −70° C., with stirring and under an inert atmosphere. After 10 minutes, a solution of 1.7 g of methyl (3RS,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylsulfanyl)ethyl]piperidine-3-acetate in 15 cm3 of dichloromethane is poured in 10 minutes. After 15 minutes, 8.4 cm3 of triethylamine in 10 cm3 of dichloromethane are added dropwise over 15 minutes and the reaction medium is stirred for 45 minutes in the region of −70° C. and then for 20 hours in the region of 20° C. 50 cm3 of distilled water are poured over the reaction mass, and the organic phase is separated after settling out, and washed with 50 cm3 of a saturated aqueous sodium hydrogen carbonate solution, with 2 times 30 cm3 of distilled water and with 30 cm3 of saturated aqueous sodium chloride solution. The organic extract is dried over magnesium sulfate, filtered, and evaporated under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40–60 μm; diameter 3 cm), eluting with a mixture of cyclohexane-ethyl acetate (60/40 by volume) and collecting fractions of 10 cm3. The fractions containing the expected product are pooled and then evaporated according to the conditions described above. 1.37 g of methyl (3RS,4RS)-4-[3-oxo-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylsulfanyl)ethyl]piperidine-3-acetate are obtained.
Reaction SMILES: N1C=CN=C1CN1C(=O)COC2N=C(C3C=CC(C4(N)CCC4)=CC=3)C(C3C=CC=CC=3)=CC1=2.C(OC(=O)[NH:41][C:42]1([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[C:53]([C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)=[CH:54][C:55]4[N:60]([CH2:61][CH2:62][O:63][CH3:64])[C:59](=[O:65])[CH2:58][O:57][C:56]=4[N:66]=3)=[CH:48][CH:47]=2)[CH2:45][CH2:44][CH2:43]1)(C)(C)C>>[NH2:41][C:42]1([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[C:53]([C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)=[CH:54][C:55]4[N:60]([CH2:61][CH2:62][O:63][CH3:64])[C:59](=[O:65])[CH2:58][O:57][C:56]=4[N:66]=3)=[CH:48][CH:47]=2)[CH2:43][CH2:44][CH2:45]1
Reactant: COCCN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ncc[nH]3)C(=O)CO4)cc2)CCC1
Product: COCCN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Yield: 81.5 %

Procedure:
Following the procedure for 1-((1H-imidazol-2-yl)methyl)-6-(4-(1-aminocyclobutyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one, tert-butyl(1-(4-(1-(2-methoxyethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (10 mg, 0.02 mmol) was reacted to afford the title compound (7 mg, 68%). LCMS (Method D): RT=4.11 min, M-16=423. 1H NMR (500 MHz, MeOD): 7.77 (1H,S), 7.43-7.38 (4H,m), 7.33-7.28 (3H, m), 7.23-7.21 (2H, m), 4.96 (2H, s), 4.24-4.22 (2H, t), 3.72-3.70 (2H, t), 3.36 (3H, s), 2.77-2.72 (2H, m), 2.59-2.53 (2H, m), 2.25-2.21 (1H, m), 1.98-1.94 (1H, m).
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[CH2:15][C@H:14](OS(C(F)(F)F)(=O)=O)[CH:13]([O:24][CH3:25])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.O>CN(C=O)C>[C:1]([O:9][CH2:10][C@@H:11]1[CH2:15][C@@H:14]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:13]([O:24][CH3:25])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1O[C@H](COC(=O)c2ccccc2)C[C@@H]1OS(=O)(=O)C(F)(F)F
Reactant: C1CCNC1
Solvent: CN(C)C=O
Solvent: O
Product: COC1O[C@H](COC(=O)c2ccccc2)C[C@H]1N1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.4 %

Procedure:
To a solution of [(2S,4S)-5-methoxy-4-(trifluoromethylsulfonyloxy)tetrahydrofuran-2-yl]methyl benzoate (compound 32c, 400 mg, 1.04 mmol) in DMF (3 mL) was added pyrrolidine (142 mg, 2.0 mmol) at room temperature and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted by water and extracted with EtOAc, the organic layers were combined and concentrated in vacuo to afford 230 mg crude product of [(2S,4R)-5-methoxy-4-pyrrolidin-1-yl-tetrahydrofuran-2-yl]methyl benzoate (compound 32d) as an oil, which was used in next step without further purification. MS obsd. (ESP) [(M+H)+]: 306.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:9]1[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[C:11]([C:18](O)=[O:19])[CH:10]=1)=[O:8].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[NH2:44][C@@H:45]([C:48]1[CH:55]=[CH:54][C:51]([C:52]#[N:53])=[C:50]([Cl:56])[CH:49]=1)[CH2:46][CH3:47].C(N(CC)CC)C>CN(C)C=O>[Cl:56][C:50]1[CH:49]=[C:48]([C@H:45]([NH:44][C:18]([C:11]2[CH:10]=[C:9]([C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])=[O:8])[N:17]3[CH2:16][CH2:15][O:14][CH2:13][C:12]=23)=[O:19])[CH2:46][CH3:47])[CH:55]=[CH:54][C:51]=1[C:52]#[N:53]
Reactant: C[C@H]1CCCN1C(=O)c1cc(C(=O)O)c2n1CCOC2
Reactant: CC[C@@H](N)c1ccc(C#N)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccc(C#N)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid (Comp. No. 7c) (75 mg, 0.270 mmol) in dimethylformamide (2 ml) was added 1-hydroxybenzotriazole (41 mg, 0.30 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58 mg, 0.30 mmol). The mixture was stirred for 2 h at 50° C., then 4-((R)-1-amino-propyl)-2-chloro-benzonitrile hydrochloride (68 mg, 0.3 mmol) and triethylamine (60 mg, 0.6 mmol) were added and the mixture was stirred at 25° C. overnight. The mixture was filtered through a small filter cartridge and the solution was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 82 mg (67%) of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(3-chloro-4-cyano-phenyl)-propyl]-amide as white solid. LC/MS (method 2): Rt=1.24 min; m/z=455.08 (M+H+). 1H-NMR: δ (ppm)=8.20 (1H, d), 7.94 (1H, d), 7.70 (1H, s), 7.50 (1H, d), 7.24 (1H, s), 4.95 (1H, d), 4.82-4.92 (2H, m), 4.20-4.29 (2H, m), 3.70-4.00 (5H, m), 2.07 (1H, m), 1.97 (1H, m), 1.74-1.85 (3H, m), 1.57 (1H, m), 1.19 (3H, d), 0.89 (3H, t).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17]>N1C=CC=CC=1>[N:18]1([C:16]([C:8]2[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:7]=2[NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[O:17])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)N1CCOCC1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1C(=O)N1CCOCC1
Reaction time: 0.5 h
Yield: 14.2 %

Procedure:
Methanesulfonyl chloride (0.179 mL, 2.302 mmol) was added to a solution of (2-amino-4-nitrophenyl)(morpholino)methanone (0.5783 g, 2.302 mmol) in pyridine (3 mL) at 0° C. After 30 min at 0° C., the pyridine solvent was evaporated under reduced pressure. The resulting brown oil was triturated with hot CH2Cl2 and filtered. The filtrate was concentrated and purified by silica gel chromatography, eluting with 30-100% EtOAc in hexanes, to give the expected product as yellow solid (108 mg, 14% yield). LCMS: (M+H)+=330.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.83 (1H, s), 8.24 (1H, d, J=2.26 Hz), 8.07 (1H, dd, J=8.41, 1.88 Hz), 7.61 (1 H, d, J=8.53 Hz), 3.69 (2H, d, J=4.02 Hz), 3.61 (2H, br. s.), 3.57 (2H, d, J=4.27 Hz), 3.16-3.22 (2H, m), 3.10 (3H, s).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)[NH2:21]>C(O)(C)C.C(=O)([O-])O.[Na+]>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][N:10]1[C:3]2[C:2]([NH:21][C:20]3[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=4)=[C:18]([Cl:17])[CH:19]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)[CH3:16]
Reactant: CCOC(=O)Cn1ccc2ncnc(Cl)c21
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CCOC(=O)Cn1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 73.9 %

Procedure:
To a solution of ethyl (4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)acetate (530 mg) in isopropyl alcohol (4.0 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (695 mg), and the mixture was stirred in an oil bath at a temperature of 100° C. for 2.5 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with ethyl acetate (30 mL×3). The organic layer washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel chromatography (eluent:hexane/ethyl acetate=95/5→20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (743 mg) as a white solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][Cl:8])=[O:3].[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]2[CH2:21][NH:20][CH2:19][CH:18]2[N:22]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[C:27]([F:35])[CH:26]=2)[CH3:23])[CH:13]=[CH:14][C:15]=1[Cl:16].C(N(CC)CC)C>C1COCC1>[Cl:8][CH2:7][CH2:6][CH2:5][O:4][C:2]([N:20]1[CH2:19][CH:18]([N:22]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[C:27]([F:35])[CH:26]=2)[CH3:23])[CH:17]([C:12]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=2)[CH2:21]1)=[O:3]
Reactant: O=C(Cl)OCCCCl
Reactant: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CNCC1c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(C(=O)OCCCCl)CC1c1ccc(Cl)c(Cl)c1
Yield: 104.9 %

Procedure:
To a stirred solution of 3-chloropropyl chloroformate (0.058 ml, 0.47 mmol) in THF (5 ml) at RT was added over 1 hour a solution of [(3RS,4SR)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-(3-fluoro-4-trifluoromethyl-benzyl)-methyl-amine (Intermediate VIII-1, 0.187 g, 0.44 mmol) and triethyl amine (0.068 ml, 0.48 mmol) in THF (2 mL). The reaction was stirred over night, quenched by addition of an aqueous solution of NaHCO3, and the product extracted with EtOAC. The organic phases were concentrated under vacuo to yielded 0.25 g (99%) of the title compound as a light yellow oil. The product was used in the next steps without further purification. ES-MS m/e: 542.7 (M+H+).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:15]=[C:16]([NH:25][C:26]2[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=2)[CH:17]=[C:18]([C:20]2[S:24][CH:23]=[N:22][CH:21]=2)[CH:19]=1.[CH3:36][C:37]([CH3:39])=[O:38]>C1COCC1>[Br:13][C:14]1[CH:19]=[C:18]([C:20]2[S:24][C:23]([C:37]([OH:38])([CH3:39])[CH3:36])=[N:22][CH:21]=2)[CH:17]=[C:16]([NH:25][C:26]2[N:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][N:27]=2)[CH:15]=1
Reactant: FC(F)(F)c1ccnc(Nc2cc(Br)cc(-c3cncs3)c2)n1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(O)c1ncc(-c2cc(Br)cc(Nc3nccc(C(F)(F)F)n3)c2)s1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 61.6 %

Procedure:
A solution of diisopropylamine (0.220 mL, 1.545 mmol) in 4 mL THF was cooled to 0° C., then n-BuLi (2.5 M in hexanes, 0.598 mL, 1.495 mmol) was added dropwise. The mixture was stirred at this temperature for 15 minutes, then cooled to −78° C. Intermediate 11 (200 mg, 0.498 mmol) was then added dropwise as a solution in 1.0 mL THF, and the mixture stirred for 30 minutes. Acetone (0.110 mL, 1.495 mmol) was then added, and the mixture was stirred at −78° C. for 30 minutes, then allowed to warm to room temperature. The reaction was quenched by the addition of ˜1 mL brine, then the mixture was diluted with ethyl acetate (100 mL) and washed with brine (100 mL). The organic extracts were dried (sodium sulfate) filtered, and concentrated in vacuo. Purification by chromatography on silica gel (80:20 to 40:60, hexanes:ethyl acetate) provided 141 mg (0.307 mmol, 61.6%) of 2-[5-(3-bromo-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propan-2-ol as an off-white solid.
Reaction SMILES: C[Si](C)(C)Cl.[CH3:6][C:7](=[O:11])[CH2:8][CH2:9][CH3:10].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>C(OC(C)C)(=O)C.[Zn]>[OH:11][C:7]([CH3:6])([CH2:8][CH2:9][CH3:10])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CBr
Reactant: CCCC(C)=O
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)OC(C)C
Product: CCCC(C)(O)CC(=O)OCC
Temperature: 65 °C
Reaction time: 0.42 h

Procedure:
At room temperature, a three-necked flask fitted with reflux condenser, internal thermometer, dropping funnel and stirrer was charged, under nitrogen protective gas, with 11.2 g of zinc powder (170 mmol) in 65 ml of isopropyl acetate. After 3.2 ml of trimethylchlorosilane (25 mmol) had been added, the mixture was heated at 65° C. for 30 min, then left to cool to 60° C., following which 9.7 g of neat pentan-2-one (113 mmol) were added and then, over the course of 8 min, 22.6 g of neat ethyl bromoacetate (136 mmol) were added dropwise, the temperature being maintained at 60° C. by external cooling. The mixture was then stirred for 25 min at 60° C., and following cooling to 0° C., was acidified with 65 ml of 2 N hydrochloric acid to a pH of 1 and stirred for 30 min. Excess zinc was removed by filtration, and the organic phase separated. The organic phase was stirred at 0° C. with 60 ml of 1 N hydrochloric acid and then washed with 30 ml of saturated sodium hydrogen carbonate solution. Following phase separation and drying over sodium sulfate, the solvent was removed by distillation under reduced pressure. The isopropyl acetate solvent was recovered to an extent of greater than 90%). Distillation gave ethyl 3-hydroxy-3-methylcaproate in a yield of 18.2 g (93% of theory) with a boiling point of 41° C. (0.31 mbar).
Reaction SMILES: [NH2:1][CH:2]1[C:29](=[O:30])[N:4]2[C:5]([C:13]([O:15][CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])=[C:6]([CH2:9][N:10]=[N+:11]=[N-:12])[CH2:7][S:8][C@H:3]12.[ClH:31].F[C:33]1[NH:34][CH:35]=[CH:36][N:37]=1.C(#N)C.CN(C=O)C>C(Cl)Cl>[ClH:31].[N:10]([CH2:9][C:6]1[CH2:7][S:8][C@@H:3]2[CH:2]([NH:1][C:33]3[NH:34][CH:35]=[CH:36][N:37]=3)[C:29](=[O:30])[N:4]2[C:5]=1[C:13]([O:15][CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:14])=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=NCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Reactant: Fc1ncc[nH]1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CC#N
Product: [N-]=[N+]=NCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(Nc3ncc[nH]3)[C@H]2SC1
Yield: 38 %

Procedure:
A mixture of diphenylmethyl 7-amino-3-azidomethylceph-3-em-4-carboxylate (1.2 g.), 2-fluoroimidazole hydrochloride (367 mg.) and acetonitrile (4 ml.) was stirred at 85°. When a complete solution was achieved DMF (1 ml.) was added. After 2 hours the solvent was evaporated and the residue, after drying overnight, was purified by chromatography on fine mesh silica (ratio 40:1 w/w) at 0° using methylene chloride/MeOH/HOAc 100:0:0 to 92:4:4 v/v/v as eluant. The oil obtained was dissolved in the minimum of methylene chloride and precipitated with ether. After drying there was obtained diphenylmethyl 3-azidomethyl-7-(imidazol-2-yl)aminoceph-3-em-4-carboxylate hydrochloride (38%) as a white powder having the following n.m.r. in solent A: 3.65 (d, 1H); 3.8 (d, 1H); 3.95 (d, 1H); 4.3 (d, 1H); 5.3 (d, 1H); 5.85 (d, 1H); 6.9 (s, 2H); 7.0 (s, 1H); 7.5-7.7 (m, 10H).