Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([O:32][CH3:33])=[N:15][N:16]2[C:20]([C:21]3[C:26]([O:27][CH3:28])=[CH:25][C:24]([OH:29])=[CH:23][C:22]=3[O:30][CH3:31])=[CH:19][S:18][C:17]=12)([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].I[CH2:42][CH2:43][F:44]>O>[C:6]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([O:32][CH3:33])=[N:15][N:16]2[C:20]([C:21]3[C:22]([O:30][CH3:31])=[CH:23][C:24]([O:29][CH2:42][CH2:43][F:44])=[CH:25][C:26]=3[O:27][CH3:28])=[CH:19][S:18][C:17]=12)([CH3:9])([CH3:8])[CH3:7]
Reactant: COc1cc(O)cc(OC)c1-c1csc2c(NC(=O)OC(C)(C)C)c(OC)nn12
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCCF)cc(OC)c1-c1csc2c(NC(=O)OC(C)(C)C)c(OC)nn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a DMF (2.28 ml) solution of tert-butyl[3-(4-hydroxy-2,6-dimethoxyphenyl)-6-methoxypyrazolo[5,1-b][1,3]thiazol-7-yl]carbamate (115 mg, 0.273 mmol) were added potassium carbonate (49.0 mg, 0.355 mmol) and 1-iodo-2-fluoroethane (61.7 mg, 0.355 mmol), and the mixture was stirred at room temperature for 20 hours and 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product of the title compound (128 mg, 0.273 mmol)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C:9]3[CH:14]=[C:13]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=4)[N:12]=[CH:11][C:10]=3[N:23]=2)=[N:4][O:5][N:6]=1.[CH3:31][CH:32]([CH3:36])[C:33](O)=[O:34].O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH3:31][CH:32]([CH3:36])[C:33]([O:30][C:27]1[CH:28]=[CH:29][C:24]([N:8]2[C:9]3[CH:14]=[C:13]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=4)[N:12]=[CH:11][C:10]=3[N:23]=[C:7]2[C:3]2[C:2]([NH2:1])=[N:6][O:5][N:4]=2)=[CH:25][CH:26]=1)=[O:34]
Reactant: Nc1cccc(Oc2cc3c(cn2)nc(-c2nonc2N)n3-c2ccc(O)cc2)c1
Reactant: CC(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)C(=O)Oc1ccc(-n2c(-c3nonc3N)nc3cnc(Oc4cccc(N)c4)cc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.2 %

Procedure:
A solution of the product of Step 4 (80 mg, 0.20 mmol) and 2-methylpropanoic acid (18.4 mg, 0.21 mmol) in 2 ml DMF was treated with 1-hydroxybenzotriazole hydrate (HOBT)(29.7 mg, 0.22 mmol). The resulting mixture was stirred for 10 minutes at room temperature before being treated with triethylamine (22 mg, 0.22 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) (42 mg, 0.22 mmol). The reaction was kept at room temperature overnight. Purification of the crude mixture by reverse phase (CH3CN 30%-80% in H2O with 0.1% TFA) afforded 20 mg (31%) oil as title compound. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.89 (s, 1H), 7.68 (d, 2H, 8.8 Hz), 7.38 (d, 2H, 8.8 Hz), 7.32 (t, 1H, 8.0 Hz), 6.85 (d, 1H, 7.6 Hz), 6.79-6.91 (m, 3H), 5.5-6.8 (M, 6H), 2.88 (m, 1H), 1.28 (d, 6H, 6.8 Hz). MS (ES+) m/e 372.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:6]=2[CH:19]=1.C[O-].[Na+].CN(C)C=O.Br[CH:29]([CH2:34][CH2:35][CH3:36])[C:30]([O:32][CH3:33])=[O:31]>O.C1(C)C=CC=CC=1>[CH3:33][O:32][C:30](=[O:31])[CH:29]([CH2:34][CH2:35][CH3:36])[N:11]1[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:19][C:6]=2[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:8][CH2:9][C:10]1=[O:12]
Reactant: O=C1CN=C(c2ccccn2)c2cc(Br)ccc2N1
Reactant: CCCC(Br)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)N1C(=O)CN=C(c2ccccn2)c2cc(Br)ccc21
Reaction time: 0.33 h

Procedure:
A mixture of 0.1 mole of 7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one and 0.11 mole of sodium methoxide in about 200 ml. of dimethylformamide is heated at about 95° c. for about 20 minutes. To the mixture is added a solution of 0.11 mole of methyl 2-bromovalerate in about 200 ml. of toluene over a period of about 1 hour at about 95° C., and heating is continued for an additional period of about 6 hours. The reaction mixture is then evaporated in vacuo and the residue thus obtained is stirred with about 500 ml. of water. The resulting suspension is filtered and the solids thus obtained are crystallized from a suitable organic solvent such as ether, methanol, methylene chloride, methylene chloride-methanol and the like to obtain 7-bromo-2,3-dihydro-2-oxo-α-propyl-5-(2-pyridyl)-1H-1,4-benzodiazepine-1-acetic acid methyl ester.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21][C:22]([C:24]2[C:33]([NH:34]C(=O)OCC3C=CC=CC=3)=[CH:32][C:31]3[C:26](=[CH:27][C:28]([CH:45]([OH:47])[CH3:46])=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:10]1)=O)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>CO.[Pd]>[NH2:34][C:33]1[C:24]([C:22]([NH:21][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10]2)=[O:23])=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([CH:45]([OH:47])[CH3:46])[CH:27]=2
Reactant: CC(O)c1ccc2cc(NC(=O)OCc3ccccc3)c(C(=O)Nc3cnccc3N3CCC[C@H](NC(=O)OC(C)(C)C)C3)nc2c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(O)c1ccc2cc(N)c(C(=O)Nc3cnccc3N3CCC[C@H](N)C3)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of benzyl [2-{[(4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-(1-hydroxyethyl)quinolin-3-yl]carbamate (0.020 g, 0.031 mmol) and 10% Pd on carbon (0.100 g, 0.0940 mmol) in MeOH (20 mL) was hydrogenated under 20 psi of H2 for 2 h. The catalyst was removed by vacuum filtration, and the clear filtrate was concentrated under reduced pressure. To the residue, a mixture of DCM (1.0 mL) and TFA (1.0 mL, 13 mmol) was added. The resulting mixture was stirred at room temperature for 1 h. The mixture was then concentrated under reduced pressure and the residue was diluted with MeOH and neutralized with small amount of NH4OH. The mixture was filtered and purified by prep LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with NH4OH) to give the title compound as white powder. LCMS calc. for C22H27N6O2 (M+H)+: m/z=407.3. Found: 407.2. 1H NMR (500 MHz, DMSO) δ 9.40 (s, 1H), 8.26 (d, J=5.3 Hz, 1H), 7.79 (s, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.54 (s, 1H), 7.51 (dd, J=8.7, 1.5 Hz, 1H), 7.16 (d, J=5.3 Hz, 1H), 6.84 (s, 2H), 5.29 (d, J=3.8 Hz, 1H), 4.89-4.79 (m, 1H), 3.20 (d, J=10.9 Hz, 1H), 3.16 (d, J=4.2 Hz, 1H), 3.15-3.06 (m, 1H), 2.71-2.63 (m, 1H), 2.47-2.41 (m, 1H), 1.95 (d, J=12.9 Hz, 1H), 1.92-1.82 (m, 2H), 1.41 (d, 3H), 1.27-1.16 (m, 1H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[CH3:23][Si](C=[N+]=[N-])(C)C>C(Cl)Cl>[CH3:23][O:14][C:13](=[O:15])[C:12]1[CH:16]=[C:17]([Cl:20])[C:18]([F:19])=[C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:11]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NCc1cc(C(=O)O)cc(Cl)c1F
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Reaction time: 4.5 h

Procedure:
To a solution of 3-(tert-butoxycarbonylamino-methyl)-5-chloro-4-fluoro-benzoic acid (4.00 g, 13.2 mmol) in CH2Cl2 (100 mL) were added MeOH (6.94 mL, 171 mmol) and subsequently trimethylsilyldiazomethane (8.56 mL, 17.1 mmol) in a dropwise manner over 15 min. Stirring was continued at RT for 4.5 h. Volatiles were then evaporated under reduced pressure to afford the title compound as a colorless oil, which was used directly in the next step without further purification. TLC Rf (c-hexane/EtOAc 6:1)=0.40; tR (HPLC conditions c): 5.56 min.
Reaction SMILES: [C:1](#[N:6])[CH2:2][CH:3]=[CH:4][CH3:5].[CH:7]1([OH:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:14][OH:15]>>[CH:7]1([O:13][C:14](=[O:15])[CH2:5][CH2:4][CH2:3][CH2:2][C:1]#[N:6])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CO
Reactant: OC1CCCCC1
Reactant: CC=CCC#N
Product: N#CCCCCC(=O)OC1CCCCC1
Temperature: 160 °C
Reaction time: 4 h
Yield: 47.3 %

Procedure:
Example 3 is carried out with an equal amount of 3-pentenonitrile in place of 4-pentenonitrile, and with the methanol replaced by 25 parts of cyclohexanol, the mixture is heated to 160° C, and the autoclave is shaken for 4 hours, under a final pressure of 260 bars. 9.9 parts of 5-cyanovaleric acid cyclohexyl ester (47.3% of theory) of boiling point 124.5°-125.5° C/0.5 mm Hg, nD20 = 1.4598, are obtained.
Reaction SMILES: O.O.Cl.[NH2:4][C:5]1[N:14]=[C:13]([NH2:15])[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:16][N:17]([CH3:27])[C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)[N:11]=2)[N:6]=1.NC1N=C(N)C2C(=NC=C(C[N:41]([C:43]3[CH:51]=CC(C(O)=O)=C[CH:44]=3)C)N=2)N=1.O.O.C([P:56](=[O:63])([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59])#N.CCN(C(C)C)C(C)C.C(O)(=O)C(O)=O.C(OP(CCCN)(=O)OCC)C>CN(C=O)C>[CH2:58]([O:57][P:56]([CH2:51][CH:43]([NH:41][C:22](=[O:24])[C:21]1[CH:20]=[CH:19][C:18]([N:17]([CH2:16][C:10]2[N:11]=[C:12]3[C:7](=[N:8][CH:9]=2)[N:6]=[C:5]([NH2:4])[N:14]=[C:13]3[NH2:15])[CH3:27])=[CH:26][CH:25]=1)[CH3:44])(=[O:63])[O:60][CH2:61][CH3:62])[CH3:59]
Reactant: CN(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)O)cc1
Reactant: CCOP(=O)(C#N)OCC
Agent: CCOP(=O)(CCCN)OCC
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(CC(C)NC(=O)c1ccc(N(C)Cc2cnc3nc(N)nc(N)c3n2)cc1)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.7 %

Procedure:
To a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acid hemihydrochloride dihydrate (61.2 mg, 161 μmol) in DMF (2.8 mL) were added diethyl cyanophosphonate (31.8 μL, 210 μmol) and DIEA (27.8 μL, 161 μmol). The solution was stirred at ambient temperature for 3 hours, when diethyl(aminopropyl)phosphonate oxalate (34.9 mg, 122.6 μmol) was added. The solution was stirred for 2 additional hours, whereupon complete consumption of the starting materials was observed. The reaction was worked up by removal of the solvent in vacuo and purifying the residue by silica gel chromatography using MeOH—CH2Cl2 (10-30%). The product (65.5 mg) collected from this chromatography step was sufficiently pure to be carried on to the next reaction. A small amount (32.8 mg) was re-purified by RP HPLC on C18 column using H2O/acetonitrile (2-95%) to provide 23.2 mg (75%) of the pure product. 1H NMR (300 MHz, DMSO-d6) δ 1.20 (t, 6H, J=7.2 Hz), 1.64-1.75 (m, 4H), 3.22 (s, 3H), 3.41 (m, 2H), 3.98 (appt septet, 4H, J=7.2 Hz), 4.85 (s, 2H), 6.79 (d, 2H, J=9 Hz), 7.68 (d, 2H, J=9 Hz), 8.17 (br s, 1H), 8.70 (s, 1H); 31P (121.4 MHz, DMSO-d6) δ 31.9; MS (m/z) 503.2 [M+H]+.
Reaction SMILES: P(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.[NH2:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:19]=1[C:20]([OH:22])=O.[C:28]([O:32][C:33]([NH:35][C@@H:36]([CH3:40])[C:37](O)=O)=[O:34])([CH3:31])([CH3:30])[CH3:29].[NH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>N1C=CC=CC=1.CCOC(C)=O>[Cl:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:18]2[C:19]=1[C:20](=[O:22])[N:41]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:37]([C@@H:36]([NH:35][C:33](=[O:34])[O:32][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:40])=[N:17]2
Reactant: Nc1ccccc1
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=[PH](Oc1ccccc1)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Diphenyl phosphonate (1.9 mL, 10 mmol) was added to a solution of 2-amino-6-chlorobenzoic acid (495 mg, 2.9 mmol) and (S)-2-(tert-butoxycarbonylamino)propanoic acid (710 mg, 3.77 mmol) in pyridine (3 mL). The reaction mixture was stirred at 40° C. for 2 hours. Aniline (274 mg, 3.48 mmol) was then added to the reaction mixture, which was then stirred at 55° C. for 12 hours. The reaction mixture was cooled to room temperature. This mixture was then diluted with EtOAc (50 mL), washed with 1N aqueous HCl (2×50 mL), brine (50 mL), and dried over sodium sulfate. The organics layer was filtered and concentrated in vacuuo to afford material which was purified by column chromatography on SiO2 eluting with EtOAc in hexanes (0-50%) to afford (S)-tert-butyl 1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate as a solid. ES/MS m/z=400.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[NH:14][C:13](=O)[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH2:11][C:12]([CH3:17])([CH3:16])[CH2:13][NH:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC1(C)CCC(c2ccc(F)c(F)c2)NC1=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)CCC(c2ccc(F)c(F)c2)NC1

Procedure:
To a stirred solution of 6-(3,4-difluorophenyl)-3,3-dimethylpiperidin-2-one (50.0 mg, 0.209 mmol, prepared according to Intermediate 14, Step A) in THF (1 mL) at 0° C. was added diisobutylaluminum hydride (1.05 mL of a 1 M solution in toluene, 1.05 mmol). The reaction mixture was stirred for 4 days, with additional diisobutylaluminum hydride (1.05 mL of a 1 M solution in toluene, 1.05 mmol) added on the 2nd and 3rd days. The reaction was quenched with saturated potassium sodium tartrate (5 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of MeOH:CH2Cl2—0:100 to 5:95, to give the title compound. MS: m/z=226 (M+1).
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[CH3:7][CH2:8][CH2:9][CH2:10][SnH:11]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15]>C1C=CC=CC=1.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:2]1([Sn:11]([CH2:12][CH2:13][CH2:14][CH3:15])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:9][CH2:8][CH3:7])[CH2:1][CH2:6][CH2:5][CH2:4][CH:3]=1
Reactant: C1=CCCC=C1
Reactant: CCCC[SnH](CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCCC[Sn](CCCC)(CCCC)C1=CCCCC1
Reaction time: 0.25 h
Yield: 235 %

Procedure:
To a solution of 1,3-cyclohexadiene (0.96 g, 12 mmol, d=0.84, 1143 uL) and Pd(PPh3)4 (462.2 mg, 0.4 mmol) in benzene (10 mL) under nitrogen atmosphere, was added Bu3SnH (1.16 g, 4 mmol, d=1.098, 1.06 mL) dropwise at room temperature and stirred for 15 minutes. After the solvent was removed on rotavap, the product was purified on silica flash chromatography (column 1.5 cm ID×20 cm) using a solvent gradient of 10:0 (100 mL) to 19:1(100 mL) to 9:1 (100 mL) of hexanes/EtOAc to afford cyclohexenyltributyltin (3.5 g, 9.4 mmol, 78.6% yield) as a clear liquid. Cyclohexenyltributyltin was characterized by 1H-NMR (CDCl3, 500 MHz). See FIG. 51.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]=1[C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=Cc1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Product: COc1ccc(-c2ccc(C=O)cc2Cl)cc1

Procedure:
The title compound was prepared by reacting trifluoro-methanesulfonic acid 2-chloro-4-formyl-phenyl ester (5 g, 17.4 mmol) with 4-methoxyphenylboronic acid (3.44 g, 22.6 mmol) according to Method B to yield 3.83 g (89%) of white solid: mp 85-87° C.; 1H NMR (DMSO-d6): δ 3.82 (3H, s), 7.07 (2H, d, J=8.83 Hz), 7.46 (2H, d, J=8.45 Hz), 7.63 (1H, d, J=7.87 Hz), 7.92 (1H, dd, J=7.87 Hz, J=1.56 Hz), 8.07 (1H, d, J=1.49 Hz); 13C NMR (DMSO-d6): δ 55.14, 113.72, 127.80, 129.72, 130.42, 130.82, 132.15, 132.21, 136.11, 144.90, 159.33, 191.73; IR 1692 cm−1; MS (EI) m/z 246/248 M+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[CH:3]=[N:2]1.Cl.[CH3:10][NH:11][O:12][CH3:13].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(OCC)(=O)C.CN(C)C=O>[CH3:13][O:12][N:11]([CH3:10])[C:6]([C:4]1[CH:3]=[N:2][NH:1][CH:5]=1)=[O:8]
Reactant: CNOC
Reactant: O=C(O)c1cn[nH]c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cn[nH]c1

Procedure:
A N,N-dimethylformamide solution (3 mL) of 4-pyrazolecarboxylic acid (150 mg, 1.34 mmol), N,O-dimethylhydroxylamine hydrochloride (261.4 mg, 2.68 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, hydrochloride (513.8 mg, 2.68 mmol), 1-hydroxybenzotriazoleimidazole anhydride (54.2 mg, 0.40 mmol), and triethylamine (0.38 mL, 2.68 mmol) was stirred for 1 day. After completion of the reaction, the reaction solution was mixed with ethyl acetate and washed with saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude reaction product containing the desired product was used for the next step (142.7 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10](O)[CH2:11][CH2:12][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[Cl:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=1>C(Cl)Cl.CN(C=O)C>[Cl:37][C:38]1[CH:44]=[CH:43][C:41]([N:42]2[CH:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:11][CH2:12][CH:13]2[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:40][CH:39]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(C(O)CCC(O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C2CCC(c3ccc([N+](=O)[O-])cc3)N2c2ccc(Cl)cc2)cc1
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
The product of Example 1B (0.50 g, 1.51 mmol) was suspended in CH2Cl2 (15 mL). Triethylamine (0.626 mL, 4.51 mmol) was added at 0° C., the resulting mixture was stirred for 30 min, and methanesulfonyl chloride (0.293 mL, 3.76 mmol) was added. The mixture was stirred at rt for 1 hr and then concentrated in vacuo to give a light yellow solid. The solid was dissolved in DMF (6 mL), 4-chloroaniline (1.92 g, 15.05 mmol) was added, and the resulting mixture was stirred at 50° C. overnight. The mixture was partitioned between EtOAc and 1N aq HCl, and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-12% EtOAc in hexane to give the title compound (0.226 g, 35%).
Reaction SMILES: [S:1]([C:4]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8]=2[C:7]([OH:13])=[CH:6][CH:5]=1)C#N.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>C(#N)C>[CH3:25][O:24][C:22](=[O:23])[CH2:21][O:13][C:7]1[CH:6]=[CH:5][C:4]([SH:1])=[C:12]2[C:8]=1[CH2:9][CH2:10][CH2:11]2
Reactant: COC(=O)CBr
Reactant: N#CSc1ccc(O)c2c1CCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)COc1ccc(S)c2c1CCC2

Procedure:
7-Thiocyanato-indan-4-ol (Example 7B) (1.47 g, 7.7 mmol), cesium carbonate (3.77 g, 11.6 mmol) and methyl bromoacetate (1.24 g, 8.08 mmol) were stirred in 20 ml acetonitrile at ambient temperature for 4 h. The reaction was filtered and concentrated. The crude product was treated under the conditions of Example 2D to afford the title product. MS m/z 239 (M+1).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[C@H:14]([C:15](O)=[O:16])[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:40]1[C:44]2[CH:45]=[CH:46][C:47]([NH2:49])=[CH:48][C:43]=2[N:42]=[N:41]1.CN1CCOCC1>C(#N)C>[NH:40]1[C:44]2[CH:45]=[CH:46][C:47]([NH:49][C:15]([C@@H:14]3[CH2:13][CH2:12][N:11]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:19])[N:10]3[C:8](=[O:9])[C@@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[O:16])=[CH:48][C:43]=2[N:42]=[N:41]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: Nc1ccc2[nH]nnc2c1
Solvent: CN1CCOCC1
Solvent: CC#N
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2ccc3[nH]nnc3c2)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 72 h
Yield: 69.3 %

Procedure:
To a solution of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidine carboxylic acid (103.1 mg, 0.192 mmol), 1H-1,2,3-benzotriazol-5-amine (56.6 mg, 0.422 mmol), and N-methylmorpholine (46.4 μl, 0.422 mmol) in acetonitrile (1.87 ml) was added DMTMM tetrafluoroborate (69.2 mg, 0.211 mmol). The solution was stirred for 3 days, and then concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), and washed with 1 N aq. HCl (50 mL), followed by 5% aq. NaHCO3. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Gilson RPLC (20% to 90% MeCN in water, 8 min gradient), and the desired fractions were combined, and concentrated in vacuo. The residue was azeotroped with MeOH (2×30 mL) to give phenylmethyl (3S)-3-[(1H-1,2,3-benzotriazol-5-ylamino)carbonyl]-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-pyrazolidinecarboxylate (87.2 mg, 0.133 mmol, 69.6% yield) as a light yellow oil. LC/MS: (M+H)+: 654.5. Reference for DMTMM tetrafluoroborate: Raw, S. A. Tetrahedron Lett. 2009, 50, 946.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)[C:6](=[O:21])[C:5]2([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31])[N:22]([CH3:24])[CH3:23].C([CH:34]([NH2:37])[CH2:35][CH3:36])C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:49]2C=CC=C[C:48]=2N=N1.CCN(C(C)C)C(C)C>CCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](=[O:18])[N:37]([CH2:34][CH2:35][CH3:36])[CH2:48][CH3:49])=[CH:14][CH:13]=1)[C:6](=[O:21])[C:5]2([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31])[N:22]([CH3:24])[CH3:23]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CN(C)C1(c2ccccc2Cl)C(=O)N(Cc2ccc(C(=O)O)cc2)c2ccc(Cl)cc21
Reactant: CCC(N)CC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCN(CC)C(=O)c1ccc(CN2C(=O)C(c3ccccc3Cl)(N(C)C)c3cc(Cl)ccc32)cc1

Procedure:
This compound is prepared according to the procedure described in step B of EXAMPLE 94 from 0.623 g of the compound obtained in step A of EXAMPLE 94 and 0.24 ml of 1-ethylpropylamine, in the presence of 0.605 g of BOP and in the presence of DIPEA in order to maintain a pH of 7. Chromatography on silica using a gradient of a hexane/AcOEt mixture (from 90/10; v/v to 70/30; v/v) as the eluent gives the expected product after crystallization from a DCM/hexane mixture. m=0.490 g. M.p.=208° C.