Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]1C=C(C=[C:52](C)[CH:53]=1)C(N[C@@H](CC1C=C(F)C=C(F)C=1)[C@@H]([C@H]1C[C@@H](OCCC)CN1C(OC(C)(C)C)=O)O[Si](C(C)(C)C)(C)C)=O)(=O)[C:2]1C=CC=C[CH:3]=1.C(OC([N:62]1[CH2:66][C@H:65]([O:67][CH2:68][CH2:69][CH3:70])[CH2:64][C@@H:63]1[C@@H:71]([O:95][Si](C(C)(C)C)(C)C)[C@@H:72]([NH:82][C:83]([C:85]1[CH:86]=[C:87]([CH:91]=[C:92]([CH3:94])[CH:93]=1)[C:88]([OH:90])=O)=[O:84])[CH2:73][C:74]1[CH:79]=[C:78]([F:80])[CH:77]=[C:76]([F:81])[CH:75]=1)=O)(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NCCC)CC>ClCCl>[F:81][C:76]1[CH:75]=[C:74]([CH2:73][C@H:72]([NH:82][C:83](=[O:84])[C:85]2[CH:93]=[C:92]([CH3:94])[CH:91]=[C:87]([C:88]([N:9]([CH2:10][CH2:53][CH3:52])[CH2:1][CH2:2][CH3:3])=[O:90])[CH:86]=2)[C@H:71]([OH:95])[C@H:63]2[CH2:64][C@@H:65]([O:67][CH2:68][CH2:69][CH3:70])[CH2:66][NH:62]2)[CH:79]=[C:78]([F:80])[CH:77]=1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(NC(=O)c3ccccc3)c2)N(C(=O)OC(C)(C)C)C1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(C(=O)O)c2)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCNCCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCO[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cc(C)cc(C(=O)N(CCC)CCC)c2)C1
Reaction time: 0.33 h
Yield: 90 %

Procedure:
Step 10 (A): Preparation of (2R,4R)-tert-butyl 2-((1S,2S)-2-(3-(benzamido)-5-methylbenzamido)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of 3-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)-5-methylbenzoic acid (Preparation G, 26 mg, 0.037 mmol) in dichloromethane (1 mL) was added Hunig's base (15 mg, 0.114 mmol) to make a clear solution and HATU (18 mg, 0.05 mmol) was then added. After stirring for 20 min, the reaction mixture was added dipropylamine (6 mg, 0.057 mmol) and the reaction mixture was stirred at rt for 6 h. The crude mixture was purified by silica gel Flash Chromatography (0% to 10% to 30% EtOAc/Hexane step gradient) to give 27 mg of the title compound (90% yield): 1H NMR (CDCl3, 500 MHz) δ ppm 0.02 (3H, s), 0.06 (3H, s), 0.71 (3H, m), 0.85 (9H, s), 0.88 (3H, m), 0.96 (3H, m), 1.48-1.54 (12H, m), 1.67 (2H, m), 1.74 (2H, m), 2.03-2.09 (1H, m), 2.19 (1H, m), 2.38 (3H, s), 2.62 (1H, m), 2.94 (1H, m), 3.13 (2H, brd s), 3.26-3.36 (3H, m), 3.43 (2H, brd s), 3.76 (1H, m), 3.97 (1H, m), 4.04-4.07 (1H, m), 4.10-4.12 (1H, m), 4.58 (1H, m), 6.59 (1H, m), 6.76 (2H, d, J=5 Hz), 7.25 (1H, s), 7.60 (1H, s), 7.70 (1H, s), 7.98 (1H, brd s). MS (ESI) (M+H)+ 774.63.
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][C:4]1[O:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]=1.[NH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[NH2:17]>C(O)C>[CH3:15][C:2]1[CH:3]=[C:4]([NH:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:9])=[O:10])[N:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:17]=1
Reactant: NNc1ccccn1
Reactant: CC(=O)Cc1nc2ccccc2c(=O)o1
Solvent: CCO
Product: Cc1cc(Nc2ccccc2C(=O)O)n(-c2ccccn2)n1
Temperature: 25 °C
Yield: 50.2 %

Procedure:
A solution of 2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one (68.2 g, 0.34 mol) and 2-hydrazinopyridine (37.1 g, 0.34 mol) in ethanol (500 mL) was heated under reflux for 1 hour. After the solution was cooled to room temperature, the resulting crystals were collected by filtration. The crystals were washed with ethanol and air dried to give the title compound (50.2 g, 51% yield).
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[C:9]([OH:10])=[C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]([CH2:19][OH:20])=[N:6][CH:5]=1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>CN(C)C=O>[CH2:12]([O:11][C:8]1[C:7]([CH2:19][OH:20])=[N:6][CH:5]=[C:4]([C:9]=1[OH:10])[C:3]([NH:28][CH2:27][C:26]1[CH:29]=[CH:30][C:23]([F:22])=[CH:24][CH:25]=1)=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1cnc(CO)c(OCc2ccccc2)c1O
Reactant: NCc1ccc(F)cc1
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(F)cc1)c1cnc(CO)c(OCc2ccccc2)c1O
Temperature: 120 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
The compound 18 (3.76 g, 13.0 mmol) was dissolved in dimethylformamide (38 ml), and 4-fluorobenzylamine (2.44 ml, 21.3 mmol) was added, followed by stirring at 120° C. for 2 hours. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure, followed by dilution with ethyl acetate. Thereafter, this was washed with 2N hydrochloric acid and water, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with diethyl ether to obtain 5-benzyloxy-N-(4-fluoro-benzyl)-4-hydroxy-6-hydroxymethyl-nicotinic acid amide 10 (3.59 g, 72%) as a beige crystal.
Reaction SMILES: Cl.[F:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][C:8]2[CH:9]=[C:10]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=O)[CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:4]=1>C1COCC1>[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[C:10]([NH:14][CH2:15][CH:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)[CH:11]=[CH:12][CH:13]=2)=[CH:23][CH:24]=1
Reactant: O=C(Nc1cccc(Oc2ccc(F)cc2)c1)C1CCNCC1
Agent: Cl
Solvent: C1CCOC1
Product: Fc1ccc(Oc2cccc(NCC3CCNCC3)c2)cc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A heavy-walled glass tube was charged with piperidine-4-carboxylic acid [3-(4-fluoro-phenoxy)-phenyl]-amide hydrochloride (Example 1D, 5.1 g, 0.016 mol) in dry THF (20 mL) followed by addition of BH3 (1 M in THF, 48 mL) at room temperature. The tube was sealed and then heated at 65° C. for 20 hours. The resulting reaction mixture was cooled to room temperature, evaporated to dryness, and quenched by the addition of 1 N HCl (5 mL) with stirring for 2 hours. The pH was then adjusted to pH 8 with 1 N ammonium hydroxide and the product was extracted with ethyl acetate (100 mL×2), dried over MgSO4, and concentrated to give an off-white solid (4.5 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1.[BH3-]C#N.[Na+].C(=O)C1C=CC=CC=1>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH2:18][NH:22][CH:23]4[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]4)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CN1CCC(N)CC1
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O=Cc1ccccc1
Product: CN1CCC(NCc2cncc(-c3c(C#N)c4ccc(Cl)cc4n3C)c2)CC1
Reaction time: 16 h

Procedure:
To a solution of 6-chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126, 0.150 g, 0.482 mmol) in THF (3 mL) and DMF (1 mL) is added 4-amino-1-methylpiperidine (0.067 g, 0.578 mmol), followed with MP-NaBH3CN (2.42 mmol/g, 0.498 g, 1.205 mmol). After 16 h, MP-NaBH3CN (2.42 mmol/g, 0.200 g, 0.484 mmol) is added. After another 46 h and PL-benzaldehyde (1.8 mmol/g, 0.268 g, 0.482 mmol) is added and after another 8 h, the mixture is filtered and the solids are washed with THF. After evaporation of the solvents, the residue is purified by reverse phase HPLC on a Sunfire C18, eluting with a gradient of 0.1% aqueous TFA-acetonitrile to give 6-chloro-1-methyl-2-{5-[(1-methyl-piperidin-4-ylamino)-methyl]-pyridin-3-yl}-1H-indole-3-carbonitrile as a gum which is triturated with 1M HCl in ether to give the HCl salt. 1H NMR (400 MHz, DMSO-d6) δ ppm (HCl salt) 1.46-1.66 (m, 2H), 1.93-2.04 (m, 2H), 2.50-2.57 (m, 4H), 2.66-2.76 (m, 2H), 3.10-3.20 (m, 2H), 3.80 (s, 3H), 3.95 (br. s., 2H), 7.37 (dd, J=8.6, 1.8 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.98 (d, J=1.8 Hz, 1H), 8.16 (s, 1H), 8.79 (d, J=2.0 Hz, 1H), 8.80 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 394.1804 [(M+H)+ Calcd for C22H25ClN5: 394.1798].
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][C@@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1[OH:20])#[N:2].[CH3:23][NH:24][CH3:25]>>[C:1]([N:3]=[C:4]([N:24]([CH3:25])[CH3:23])[NH:5][C@@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1[OH:20])#[N:2]
Reactant: CSC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Reactant: CNC
Product: CN(C)C(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O

Procedure:
A mixture of (3S,4R)-4-(3-cyano-2-methyl-1-isothioureido)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (16.3 g) and 50% aqueous dimethylamine solution (81.5 ml) was stirred under reflux for 1.5 hours to form white precipitates. These precipitates were collected by filtration, washed with cold water, and recrystallized from ethanol to give (3S,4R)-4-(2-cyano-3,3-dimethylguanidino)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (12.05 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][CH2:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.B(F)(F)F.[CH3:17]COCC.[Li]C.Cl>CCOC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:17])[CH2:9][CH2:10][CH2:11][NH:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(C2=NCCC2)c1
Reactant: CCOCC
Agent: Cl
Agent: FB(F)F
Agent: [Li]C
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(c2cccc(F)c2)CCCN1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
A solution of 5-(3-fluorophenyl)-3,4-dihydro-2H-pyrrole (6.1 g, 37.4 mmol) in 100 mL THE was cooled to −78° C., and boron trifluoride diethyl etherate (9.47 mL, 74.8 mmol) was added drop-wise over 5 minutes. The resulting cloudy reaction mixture was stirred at −78° C. for 40 minutes. MeLi (1.6 M in diethyl ether, 46.7 mL, 74.8 mmol) was added drop-wise over 10 minutes. The mixture was stirred at −78° C. for another 2 hours, then warmed up to ambient temperature overnight. For workup, water and EtOAc were added to the reaction mixture, and the aqueous layer was acidified with HCl solution. After separating and discarding the organic layer, the aqueous layer was basified with NaOH (6 N, aq.) to pH=12 and extracted twice with EtOAc. The combined organic extracts was dried over Na2SO4 and concentrated to get a mixture of the desired product (2-(3-fluorophenyl)-2-methylpyrrolidine) and starting material (4.3 g, 1.3:1 of the desired product:starting material, 37% yield). The crude product was used in the next step without any further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][C:5]=1[OH:17].CS(O[CH:23]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]1)(=O)=O.O>CN(C=O)C>[CH3:3][C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][C:5]=1[O:17][CH:23]1[CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: Cc1cc(CN2CCOCC2)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(CN2CCOCC2)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of NaH (55-65% disp. in oil, 0.55 g, 12.5 mmol) in dry DMF (10 mL) under nitrogen was cooled by an ice-bath. A solution of 2-methyl-4-(morpholin-4-ylmethyl)phenol—see WO 2006133567—(2.0 g, 9.6 mmol) in DMF (25 mL) was added drop-wise over 10 minutes. The mixture was stirred for one hour and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (3.2 g, 12.5 mmol) in DMF (15 mL) was added. The mixture was heated to 80° C. over night and then cooled to RT. Water (150 mL) was added and the mixture was extracted three times with EtOAc (100 mL). The residue was purified by column chromatography on SiO2 using 10-75% EtOAc/heptane as eluent. The product was further purified using 0.5% NH3 in MeOH/DCM as eluent. There was obtained 2.6 g (75%) of 12A as an oil. 1H NMR (400 MHz, CDCl3): δ 1.45 (s, 9H), 2.22 (s, 3H), 2.34-2.49 (m, 4H), 3.40 (s, 2H), 3.62-3.76 (m, 4H), 3.94-4.07 (m, 2H), 4.23-4.35 (m, 2H), 4.79-4.92 (m, 1H), 6.38 (d, 1H), 7.03 (d, 1H), 7.11 (s, 1H).
Reaction SMILES: [N:1]([C:4]1[CH:13]=[C:12]([CH3:14])[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]=1[CH3:15])=[C:2]=[S:3].[CH2:16]([NH2:19])[CH2:17][NH2:18]>C1(C)C=CC=CC=1>[NH2:18][CH2:17][CH2:16][NH:19][C:2](=[S:3])[NH:1][C:4]1[CH:13]=[C:12]([CH3:14])[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]=1[CH3:15]
Reactant: NCCN
Reactant: Cc1cc(N=C=S)c(C)c2c1OCCO2
Solvent: Cc1ccccc1
Product: Cc1cc(NC(=S)NCCN)c(C)c2c1OCCO2
Reaction time: 0.08 h

Procedure:
A solution of 2.0 g of 6-isothiocyanato-5,8-dimethyl-1,4-benzodioxane in 40 mL of toluene at 25° C. is added to a solution of 2.42 mL of ethylenediamine in 75 mL of toluene. After five minutes, the mixture is concentrated under reduced pressure to 20 mL at which point a solid precipitates from solution. This solid is collected and dried under vacuum to give 2.6 g of 6-[N'-(2-aminoethyl)thioureido]-5,8-dimethyl-1,4-benzodioxane as a white solid.
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH3:16])=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])=O.Cl.[C:19](=[NH:22])([NH2:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:20][C:19]1[NH:21][C:3]([C:5]2[C:6]([CH3:16])=[CH:7][C:8]([CH3:15])=[C:9]([CH:14]=2)[C:10]([O:12][CH3:13])=[O:11])=[C:2]([CH3:17])[N:22]=1
Reactant: CC(=N)N
Reactant: COC(=O)c1cc(C(=O)C(C)Br)c(C)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(-c2[nH]c(C)nc2C)c(C)cc1C
Temperature: 80 °C
Reaction time: 15 h
Yield: 57.8 %

Procedure:
Into a round-bottom flask, was placed a solution of methyl 5-(2-bromopropanoyl)-2,4-dimethylbenzoate (compound 1.6, 400 mg, 1.34 mmol) in acetonitrile (30 mL). Acetimidamide hydrochloride (260 mg, 2.75 mmol) and potassium carbonate (550 mg, 3.99 mmol) were added and the resulting mixture was stirred at 80° C. for 15 h. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (50 mL) and washed with brine (2×25 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:1) to ethyl acetate as the eluent to yield the title compound as a yellow oil (0.20 g, 58%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].[C:14](#[N:16])[CH3:15]>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]([OH:10])[CH2:15][C:14]#[N:16])[CH:11]=[CH:12][CH:13]=1
Reactant: CC#N
Reactant: COCCOc1cccc(C=O)c1
Product: COCCOc1cccc(C(O)CC#N)c1

Procedure:
Addition of acetonitrile to 3-(2-methoxy-ethoxy)benzaldehyde gave 3-(3-(2-methoxy-ethoxy)-phenyl)-3-hydroxypropionitrile as yellow oil. Yield (1.4 g, 63%): 1H NMR (400 MHz, CDCl3) δ 7.27-7.32 (m, 1H), 6.95-7.0 (m, 2H), 6.91 (dd, J=8.0, 1.8 Hz, 1H), 5.0 (t, J=6.2 Hz, 1H), 4.12 (t, J=4.8 Hz, 2H), 3.76 (t, J=4.8 Hz, 2H), 3.48 (s, 3H), 2.75 (d, J=6.2 Hz, 2H).
Reaction SMILES: [C:1]([N:6]=[N:7][C:8]([C:15]#[N:16])([CH3:14])[CH2:9][CH2:10][C:11](O)=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>CCCCC>[C:1]([N:6]=[N:7][C:8]([C:15]#[N:16])([CH3:14])[CH2:9][CH2:10][C:11]([Cl:18])=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)N=NC(C)(C#N)CCC(=O)O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCCCC
Product: CCC(C)(C)N=NC(C)(C#N)CCC(=O)Cl
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 83.4 %

Procedure:
To a stirred slurry of 10 grams (.0443 moles) of 4-t-amylazo-4-cyanovaleric acid in 50 mls. of pentane in a 100 ml. flask was added 9.37 grams(.045 moles) of PCl5 over a 10 minute period. After the addition was complete, the reaction was stirred at room temperature for another 50 minutes and poured into 100 mls. of ice water. The pentane layer was separated, washed with 10% NaHCO3 solution, dried over anhydrous Na2SO4, filtered and the pentane evaporated to leave 9.0 grams (84% yield) of 4-t-amylazo-4-cyanovaleryl chloride.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[CH2:30]([S:37]CC1C=CC=CC=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[Na]>CN(C)C=O>[CH2:30]([S:37][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Reactant: c1ccc(CSCc2ccccc2)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CSCc4ccccc4)cc2)CCO3)cc1
Yield: 149.2 %

Procedure:
A solution of N-(4-chloromethylphenyl)-7-(4-methyl-phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.15 g) and sodium benzyl sulfide (0.055 g) in dimethylformamide (10 ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals. which were recrystallized from ethyl acetate-hexane to give N-(4-(benzylthiomethyl)phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 86) (0.17 g) as colorless crystals.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:64][S:65][C:66]2[S:70][N:69]=[N:68][CH:67]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:14])=[S:16])=[C:18]([CH2:64][S:65][C:66]4[S:70][N:69]=[N:68][CH:67]=4)[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=S)OC(c4ccccc4)c4ccccc4)=C(CSc4cnns4)CS[C@H]23)cs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: COc1ccccc1
Solvent: O
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(O)=S)=C(CSc4cnns4)CS[C@H]23)cs1
Reaction time: 0.83 h
Yield: 73.6 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetyl]amino-3-(1,2,3-thiadiazol-5-yl) thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (1.21 g: 1.16 mMol.) in a mixture of anisole (4 ml) and nitromethane (16 ml) cooling at -30° to -40° C. is added a solution of aluminum chloride (1.23 g: 9.25 mMol.) in anisole (4 ml), and the mixture is stirred at -30° to -40° C. for 50 minutes. To the reaction mixture is added 1N-hydrochloric acid (10 ml), diluted with water, and washed with ethyl acetate. The aqueous layer is concentrated to remove the organic solvents, purified by styrene-divinylbenzene copolymer chromatography (methanol: water=4:1) and the resulting powder is washed with ethyl acetate to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetyl]amino-3-(1,2,3-thiadiazol-5-yl)thiomethylthio-3-cephem-4-carboxylic acid as yellow powder (440 mg). Yield 71%.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[N:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([OH:35])=[O:34]>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[N:12][N:13]=2)[NH:8][C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[C:33]([OH:35])=[O:34])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nncs2)=NC1c1ccc(F)cc1Cl
Reactant: O=C(O)C1COCCN1
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nncs2)=NC1c1ccc(F)cc1Cl
Yield: 61.4 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(1,3,4-thiadiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.69 g, 1.5 mmol) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.5 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.47 g, 61%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C([O:8][C:9](=[O:34])[C@H:10]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:11][C:12](=[O:26])[C@H:13]([CH3:25])[NH:14]C(OCC1C=CC=CC=1)=O)C1C=CC=CC=1>C(O)C>[NH2:14][C@H:13]([C:12]([NH:11][C@H:10]([C:9]([OH:34])=[O:8])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26])[CH3:25]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: CCO
Product: C[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 20 °C
Reaction time: 6.5 h
Yield: 100 %

Procedure:
A mixture of N-benzyloxycarbonyl-L-alanyl-L-phenylalanine benzyl ester (0.50 g, 1.1 mmol) and 10% Pd palladium on carbon (0.1 g) in ethyl alcohol (150 mL) was shaken on a Parr hydrogenation apparatus for 6.5 h at 20° C. The reaction mixture was filtered and the filtrate rinsed with water (100 mL). The solution was concentrated to give 0.26 g (100%) of L-alanyl-L-phenylalanine. HPLC analysis showed >99% purity and no evidence of racemization.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:39])[C:11]([NH:13][C@H:14]([C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C@H:21]1[C:26]([NH:28][C@H:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)=[O:27])=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].CCN(C(C)C)C(C)C.[C:49]([NH:52][C:53]1[CH:61]=[CH:60][C:56]([C:57](O)=[O:58])=[CH:55][CH:54]=1)(=[O:51])[CH3:50].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:49]([NH:52][C:53]1[CH:61]=[CH:60][C:56]([C:57]([N:23]2[CH2:24][CH2:25][N:20]([C:18]([C@@H:14]([NH:13][C:11](=[O:12])[C@@H:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:7])([CH3:8])[CH3:6])[CH3:39])[CH:15]([CH3:17])[CH3:16])=[O:19])[C@H:21]([C:26]([NH:28][C@H:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:32][CH2:31][CH2:30]3)=[O:27])[CH2:22]2)=[O:58])=[CH:55][CH:54]=1)(=[O:51])[CH3:50]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCNC[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(C(=O)N2CCN(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C)[C@H](C(=O)N[C@@H]3CCCc4ccccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
Intermediate 7 (191 mg, 0.351 mmol) is dissolved in DMF (10 mL), to which is added DIEA (0.305 mL, 1.75 mmol). This mixture is stirred at room temperature for 0.5 h. 4-Acetamidobenzoic acid (66 mg, 0.368 mmol) is added, and stirring is continued for continued 1 h. HOBt (52 mg, 0.385 mmol) and HBTU (146 mg, 0.385 mmol) are then added and the entire mixture is stirred at room temperature for 2 h. The reaction mixture is diluted with EtOAc (100 mL) and washed sequentially with 1 M citric acid, brine, sat. NaHCO3, brine, water and brine. The EtOAc layer is then dried with MgSO4, filtered, and the solvent removed at room temperature under reduced pressure to afford a colorless gum. This material is purified by flash chromatography on silica gel (EtOAc) to give the title compound as a white foam (211 mg, 85% yield): 1H NMR δ (CDCl3) 6.40-7.62 (m, 11H), 4.25-5.30 (m, 5H), 3.93 (“br d”, 1H, Jobs=11.9 Hz), 3.47 (“br id”, 1H, Jobs=11.4, 3 Hz), 2.65-3.30 (br m, 7H), 1.70-2.22 (br m, 8H), 1.48 and 1.46 (s, 9H total), 1.28-1.34 (m, 3H), 0.60-1.12 (br m, 7H); LCMS (APCl+) 706.7 (MH+, 100%).