Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C1CCCN(C)C1(C)C.C([Li])CCC.[CH:16]1([CH2:19][CH:20]=[CH:21][CH2:22][CH:23]2[CH2:25][O:24]2)[CH2:18][CH2:17]1>CC(OC)(C)C>[CH:16]1([CH2:19][CH:20]2[CH:22]3[CH:21]2[CH2:1][CH2:25][CH:23]3[OH:24])[CH2:18][CH2:17]1
Reactant: CC1CCCN(C)C1(C)C
Reactant: C(=CCC1CO1)CC1CC1
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Product: OC1CCC2C(CC3CC3)C12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of tetramethylpiperidine (0.624 ml, 3.7 mmol) in MTBE (5 mL) was added n-butyllithium 2.5M hexanes (1.5 ml, 3.7 mmol) at −78° C. The solution was slowly warmed to approx 0° C. and was added via cannula to a solution of 2-(4-cyclopropyl-but-2-enyl)-oxirane (0.288 g, 1.898 mmol) in MTBE (2 mL) over 10 min at 0° C. The mixture was allowed to warm to rt, stirred overnight, washed with 1N HCl (2×), and brine. The organics were dried over MgSO4, filtered, and concentrated to give 6-cyclopropylmethyl-bicyclo[3.1.0]hexan-2-ol as clear oil; 1H NMR(400 MHz, CDCl3): δ 4.19 (d, 1H, J=5.5 Hz), 2.15-2.06 (m, 1H), 1.75 (dd, 1H, J1=11.0 Hz, J2=9.7 Hz), 1.69-1.52(m, 4H), 1.42 (dd, 1H, J1=8.1 Hz, J2=6.2 Hz), 0.98-0.87 (m, 2H), 0.75-0.68 (m, 1H), 0.46-0.41 (m, 2H), 0.03 (dd, 2H, J1=9.1 Hz, J2=4.7 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][CH:17]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:19]=2)[C:3]=1[CH3:24].[CH3:25][C:26]1([CH3:41])[C:30]2=[N:31][CH:32]=[C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:34]=[C:29]2[NH:28][CH2:27]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:25][C:26]1([CH3:41])[C:30]2=[N:31][CH:32]=[C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:34]=[C:29]2[N:28]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:19]=3)[C:3]=2[CH3:24])[CH2:27]1
Reactant: Cc1c(-c2cncc(S(C)(=O)=O)c2)nc2cc(F)cc(F)c2c1Cl
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cncc(S(C)(=O)=O)c2)nc2cc(F)cc(F)c2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y by stirring 4-chloro-5,7-difluoro-3-methyl-2-(5-(methylsulfonyl)pyridin-3-yl)quinoline (40 mg, 0.108 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (25.3 mg, 0.108 mmol), Pd2dba3 (10.1 mg, 10.85 μmol), X-Phos (10.3 mg, 0.022 mmol), sodium tert-butoxide (31.3 mg, 0.325 mmol), and toluene (1.1 mL) at 105° C. for 30 min. Purification by reverse-phase HPLC (0-80% acetonitrile in water) gave 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methyl-2-(5-(methylsulfonyl)-3-pyridinyl)quinoline. 1H NMR (400 MHz, chloroform-d) δ ppm 9.28 (1H, d, J=2.2 Hz), 9.17-9.20 (1H, m), 8.56-8.59 (1H, m), 7.67-7.72 (1H, m), 7.58-7.61 (1H, m), 7.06-7.13 (1H, m), 5.79-5.82 (1H, m), 3.86-3.91 (1H, m), 3.74-3.81 (5H, m), 3.23 (3H, s), 3.02-3.08 (4H, m), 2.37-2.41 (3H, m), 1.65-1.74 (3H, m), 1.57-1.65 (3H, m). Mass Spectrum (ESI) m/e=566.2 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH:9]=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1>>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:11]=[CH:9][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C=O)c1ccccc1
Reactant: Nc1ccccn1
Product: CN(C=Nc1ccccn1)c1ccccc1

Procedure:
Prepared following the procedure of Example 1 from N-methylformanilide and 2-aminopyridine. Vacuum distillation of the crude product gave pure 3 as a pale yellow oil: bp 164°-165° C. @ 0.5 mm Hg. 1H-NMR (CDCl3) 8.94 (S, 1H), 8.30 (d, 1H, J=5 Hz), 7.6-6.9 (m, 8H), 3.52 (S, 3H); IR(neat) 3045, 1620, 1580, 1555, 1500, 1460, 1435, 1235; MS (m/e) 211 (M+), 106 (base).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>CC#N.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:20][C:18]1[CH:19]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[C:7]=3[CH2:8]2)[CH3:13])[CH:15]=[N:16][C:17]=1[O:21][CH2:22][C:23]([F:26])([F:25])[F:24]
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)F
Reactant: O=COc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC#N
Solvent: O
Product: Cc1cc(C(C)N2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)cnc1OCC(F)(F)F
Temperature: 80 °C
Yield: 73.4 %

Procedure:
A mixture of 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (50 mg, 0.13 mmol, Intermediate-2, single enantiomer), phenyl formate (32 mg, 0.26 mmol, single enantiomer), palladium acetate (II) (0.87 mg, 0.039 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9.0 mg, 0.016 mmol) in MeCN (1.0 mL) is heated at 80° C. overnight (T. Ueda et al, Org. Lett., 2012, 14, 3100-3103). The mixture is diluted with water, and extracted with EtOAc. The organic layer is dried over sodium sulfate and filtered. The filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (2:1 to 1:2) to give 45 mg (74% yield) of the title compound as off white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH3:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1.[CH:16]1(O)[CH2:20]C[CH2:18][CH2:17]1>>[CH:1]1([O:2][C:3](=[O:15])[C@H:4]([CH3:14])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=2)[CH2:18][CH2:17][CH2:16][CH2:20]1
Reactant: COC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1
Reactant: OC1CCCC1
Product: C[C@H](Nc1ccc(Cl)c(Cl)c1)C(=O)OC1CCCC1

Procedure:
Following transesterification General Procedure AB above and using N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9 above) and cyclopentanol (Aldrich), the title compound was prepared as an oil. The reaction was monitored by silica gel tlc (Rf=0.66 in 25% EtOAc/hexanes). Purification was by preparative plate chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: [C:1]1([CH3:48])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[B:9]([C:39]1[C:44]([CH3:45])=[CH:43][C:42]([CH3:46])=[CH:41][C:40]=1[CH3:47])[C:10]1[CH:11]=[C:12]([Si](C)(C)C)[CH:13]=[C:14]([B:16]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=2[CH3:34])[C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[CH:15]=1.[C:49]1([CH3:68])[CH:54]=[C:53]([CH3:55])[CH:52]=[C:51]([CH3:56])[C:50]=1[B:57]([C:59]1[C:64]([CH3:65])=[CH:63][C:62]([CH3:66])=[CH:61][C:60]=1[CH3:67])F>>[C:1]1([CH3:48])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[B:9]([C:39]1[C:44]([CH3:45])=[CH:43][C:42]([CH3:46])=[CH:41][C:40]=1[CH3:47])[C:10]1[CH:11]=[C:12]([B:57]([C:59]2[C:60]([CH3:67])=[CH:61][C:62]([CH3:66])=[CH:63][C:64]=2[CH3:65])[C:50]2[C:51]([CH3:56])=[CH:52][C:53]([CH3:55])=[CH:54][C:49]=2[CH3:68])[CH:13]=[C:14]([B:16]([C:26]2[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=2[CH3:34])[C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[CH:15]=1
Reactant: Cc1cc(C)c(B(c2cc(B(c3c(C)cc(C)cc3C)c3c(C)cc(C)cc3C)cc([Si](C)(C)C)c2)c2c(C)cc(C)cc2C)c(C)c1
Reactant: Cc1cc(C)c(B(F)c2c(C)cc(C)cc2C)c(C)c1
Product: Cc1cc(C)c(B(c2cc(B(c3c(C)cc(C)cc3C)c3c(C)cc(C)cc3C)cc(B(c3c(C)cc(C)cc3C)c3c(C)cc(C)cc3C)c2)c2c(C)cc(C)cc2C)c(C)c1
Yield: 73 %

Procedure:
The compound of Example 40 is prepared similarly to the compound from Example 29 by threefold treatment with dimesitylfluoroborane. The yield is 73%. Physical data are given in Table 1.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:5]=1[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([OH:19])[C:15]([O:17][CH3:18])=[O:16].[CH3:25]I.O>CN(C)C=O>[CH3:3][C:4]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:5]=1[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([O:19][CH3:25])[C:15]([O:17][CH3:18])=[O:16].[CH3:3][C:4]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:5]=1[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]([OH:19])[C:15]([O:17][CH3:18])=[O:16]
Reactant: CI
Agent: COC(=O)C(O)c1ccccc1COc1cc(C)ccc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(OC)c1ccccc1COc1cc(C)ccc1C
Reaction time: 0.5 h

Procedure:
60% oily sodium hydride (0.13 g, 3.3 mmol) was added to a solution of methyl 2-[2-(2,5-dimethylphenoxymethyl)-phenyl]-2hydroxyacetate (0.72 g, 2.4 mmol) and methyl iodide (0.68 g, 4.8 mmol) in N,N-dimethylformamide (6 ml) at 0° C. with stirring. After 30 minutes, ice and water were added in this order, and the mixture was extracted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=9/1) to give the desired compound methyl 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-hydroxyacetate (0.69 g, 92%) as an oil.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)[CH3:2].Cl.[CH:23]1([CH2:29][NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:23]1([CH2:29][N:30]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:12](=[O:14])[CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([O:3][CH2:1][CH3:2])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][CH:15]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CCCCCCCNCC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCN(CC1CCCCC1)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy} acetic acid (0.108 g, 0.36 mmol) in methylene chloride (3.6 mL) were added N-(cyclohexylmethyl)-N-heptylamine hydrochloride (0.090 g, 0.36 mmol) and DMAP (0.098 g, 0.80 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.070 g, 0.36 mmol) and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with methylene chloride (25 mL) and the organic phase was washed with 5% HCl (3×25 mL), aqueous NaHCO3 (25 mL) and brine (25 mL), dried over Na2SO4, and concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:24].[NH2:25][C:26]1[N:31]=[CH:30][C:29]([C:32]([NH:34]O)=[NH:33])=[CH:28][N:27]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]4[O:22][N:34]=[C:32]([C:29]5[CH:28]=[N:27][C:26]([NH2:25])=[N:31][CH:30]=5)[N:33]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:24]
Reactant: N=C(NO)c1cnc(N)nc1
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1Cl
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4nc(-c5cnc(N)nc5)no4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.6) (178 mg, 0.5 mmol) and 2-amino-N-hydroxy-pyrimidine-5-carboxamidine (example B.5) (115 mg, 0.75 mmol) according to general procedure II. Obtained after flash chromatography on silica gel (ethyl acetate/heptane) and further purification by crystallization (dichloromethane/hexane) as a yellow solid (54 mg, 23%). MS (EI) 472.1 [(M)+]; mp 272° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][N:3]=1.[CH3:15][O-:16].[Na+]>CO>[CH3:15][O:16][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: CC(C)(C)c1cnc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CO
Product: COc1ncc(C(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 40.7 %

Procedure:
To a solution of 2-chloro-3-nitro-5-tert-butyl pyridine (30 mg, 0.14 mmol) in anhydrous MeOH (1.5 mL) under nitrogen was added a solution of sodium methoxide (1.57 g sodium in 40 mL anhydrous MeOH) (85 uL, 0.14 mmol). The reaction was heated in a sealed tube in an oil bath set at 80-90° C. overnight. The volatiles were removed in vacuo, the residue taken up in EtOAc (15 mL), washed with water (10 mL), brine (10 mL), dried (magnesium sulfate), filtered and evaporated to dryness. Flash chromatography of the residue on silica gel (10% EtOAc in hexanes) gave the desired 2-methoxy-3-nitro-5-tert-butyl pyridine as a glassy yellow solid (12 mg, 0.057 mmol, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CCCCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCCCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
To a solution of ethyl 5-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]pentanoate (D56) (120 mg) in tetrahydrofuran (5 mL) and methanol (5 mL) stirred at 20° C. was added a solution of sodium hydroxide (40 mg) in water (5 mL) in one charge. The reaction mixture was stirred at 20° C. for 8 hours. The reaction mixture was concentrated and then H2SO4 (0.1 M) solution was added dropwise to pH around 3. Extracted with EtOAc (100 mL), the organic layer was separated and the organic solvent was evaporated off. The residue was purified by Mass Directed Auto Prep to afford 5-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]pentanoic acid (E34) (70 mg). δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 1.57-1.71 (4H, m), 2.27 (2H, t), 2.77 (2H, t), 4.88-4.92 (1H, m), 7.21 (1H, t), 7.26 (1H, d), 7.47 (1H, d), 7.80 (1H, d), 7.94 (1H, dd), 8.21 (1H, dd), 8.39 (1H, d), 10.82 (1H, s), 12.00 (1H, br s). MS (ES): C24H24ClN3O4 requires 453. found 454.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.[CH3:52][O:53][C:54](=[O:60])[CH2:55][CH2:56][CH2:57][CH2:58][NH2:59]>[Cl-].[Na+].O.CN(C=O)C>[CH3:52][O:53][C:54](=[O:60])[CH2:55][CH2:56][CH2:57][CH2:58][NH:59][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([CH:12]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[CH:14]=1
Reactant: O=C1Nc2ccc(F)cc2C1=Cc1cccc(C(=O)O)c1
Reactant: COC(=O)CCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
3-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzoic acid (283 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzo-triazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 5-aminovaleric acid methyl ester hydrochloride (202 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (337 mg, 89% yield) as a brown solid. LC-MS (m/z) 397 (M+1).
Reaction SMILES: O.[Na].[Na].[C:4]([C:9]1[N:10]=[N:11][NH:12][C:13]=1[SH:14])([O:6][CH2:7][CH3:8])=[O:5].CC(O[CH2:19][C:20]1[CH2:29][S:28][C@@H:23]2[C@H:24]([NH2:27])[C:25](=[O:26])[N:22]2[C:21]=1[C:30]([OH:32])=[O:31])=O.C(=O)(O)[O-].[Na+].Cl>C(O)(=O)C.CC(C)=O.O>[NH2:27][CH:24]1[C:25](=[O:26])[N:22]2[C:21]([C:30]([OH:32])=[O:31])=[C:20]([CH2:19][S:14][C:13]3[NH:12][N:11]=[N:10][C:9]=3[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:29][S:28][C@H:23]12
Reactant: CCOC(=O)c1nn[nH]c1S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CCOC(=O)c1nn[nH]c1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1

Procedure:
4-Carbethoxy-1,2,3-triazole-5-thiol disodium salt hydrate (3.0 g., 13.8 mmol.) was added to a solution of 2.79 g. (10.2 mmol.) of 7-aminocephalosporanic acid and 1.72 g. (20.5 mmol.) of sodium bicarbonate in 40 ml. of water and 10 ml. of acetone. The reaction mixture was acidified to pH 7.2 with glacial acetic acid then refluxed for 2.5 hours. The cooled mixture was acidified to pH 3.9 with 3N hydrochloric acid and the precipitated solid was collected, washed with water and acetone and dried (P2O5 in vacuo) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[C:11]#[C:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1>C(#N)C.[Pd](Cl)Cl>[CH3:1][O:2][C:3]([C:4]1[C:5]2[CH:11]=[C:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[NH:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)=[O:20]
Reactant: COC(=O)c1cccc(N)c1C#Cc1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Solvent: CC#N
Product: COC(=O)c1cccc2[nH]c(-c3ccc(Cl)cc3)cc12
Reaction time: 17 h

Procedure:
3-amino-2-(4-chloro-phenylethynyl)-benzoic acid methyl ester (0.73 g, 2.54 mmol) and palladium (II) chloride (23 mg, 0.13 mmol) were combined in 10 mL acetonitrile. The yellow solution was stirreed under argon at 75° C. for 17 h. The solvent was removed in vacuo leaving an orange solid which was purified by flash chromatography eluting with 50 to 100% CH—Cl3/hecanes. 2-(4-chloro-henyl)-1H-indole-4-carboxylic acid methyl ester; 0.53 g (72%) was isolated as an off-white solid: m.p. 150.0-151.5° C.; 1H NMR (300 MHz, d6-DMSO) δ 3.93 (s, 3H), 7.23 (app t, J=7.8 Hz, 1H), 7.41 (d, J=1.8 Hz, 1H), 7.57 (d, J=8.7 Hz, 2H), 7.68 (d, J=7.8 Hz, 1H), 7.75 (dd, J=7.5, 0.9 Hz, 1H), 7.95 (d, J=8.7 Hz, 2H), 11.99 (br s, 1H). HRMS (MALDI, MH+) Calcd for C16H12ClNO2: 286.0635. Found: 286.0631.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6](O)([C:17]([F:20])([F:19])[F:18])[CH2:7][CH:8]1[CH:10]([C:11]([O:13][CH3:14])=[O:12])[C:9]1([CH3:16])[CH3:15]>O>[CH3:15][C:9]1([CH3:16])[CH:8](/[CH:7]=[C:6](\[CH3:5])/[C:17]([F:18])([F:19])[F:20])[CH:10]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C1C(CC(C)(O)C(F)(F)F)C1(C)C
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)C1C(/C=C(\C)C(F)(F)F)C1(C)C

Procedure:
160 ml of thionyl chloride were added at 0° C. to 80.5 g of methyl 2,2-dimethyl-3-(2-methyl-2-hydroxy-3,3,3-trifluoropropylcyclopropane carboxylate of Stage C. The mixture was refluxed for 48 hours, cooled, poured into ice-cooled water and extracted with isopropyl ether. The organic phases were washed with water and after drying over magnesium sulfate and evaporation to dryness, the crude product was chromatographed on silica with a hexane-AcOEt mixture (9-1), then rechromatographed with a hexane--acetone mixture (99-1) to obtain 22.02 g of the starting alcohol, 11.71 g of the exo+Z isomer mixture and 23.31 g of the expected product.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]([N+:11]([O-])=O)=[N:3]1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:11][C:4]1[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[N:2]([CH3:1])[N:3]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])nn1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)nn1C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
In a 250 mL Parr hydrogenation flask was placed methyl 1-methyl-3-nitro-1H-pyrazole-5-carboxylate, (530 mg, 2.9 mmol) dissolved in ethyl acetate (15 mL) and ethanol (15 mL), to which was added 10% Pd/C (Degussa type) (100 mg). The mixture was placed on the Parr apparatus and pressurized with hydrogen to 50 PSI and shaken for 2.5 hrs. The reaction was filtered through a pad of celite which was washed with ethyl acetate. The solvent was removed under vacuum to give 119a as a white solid (450 mg, 2.9 mmol, quantitative yield).
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1>C1COCC1>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][N:34]2[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]2)=[O:29])[S:14][N:13]=1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Reactant: CN1CCN(CCCN)CC1
Solvent: C1CCOC1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCN3CCN(C)CC3)c2C(N)=O)c(F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
To a suspension of [4-Carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester (125 mg, 0.298 mmol) in THF (1 mL) was added 1-(3-aminopropyl)-4-methylpiperazine (70 mg, 0.45 mmol). The mixture was shaken at 50° C. overnight, cooled to ambient temperature, and loaded directly onto a radial chromatograph followed by elution with chloroform/methanol/concentrated ammonium hydroxide (50/5/1) to afford a white solid (121 mg, 0.251 mmol, 84%). 1H NMR (400 MHz, CDCl3) δ1.72 (t, J=5.81 Hz, 2H), 2.20-2.85 (m, 10H), 2.28 (s, 3H superimposed on multiplet from 2.20-2.85), 2.35 (s, 3H superimposed on multiplet from 2.20-2.85), 3.39 (t, J=5.4 Hz, 2H), 5.51 (s, 2H), 5.74 (broad s, 1H), 6.74 (d, J=8.3 Hz, 2H), 7.05 (s, 1H), 7.58 (broad s, 1H), 11.01 (broad s, 1H) ppm; MS (APCI, m/z): 483 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[OH:10].[C:11](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[O:10][CH3:11]
Reactant: Oc1c(Br)cc(F)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(Br)cc(F)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To a stirred solution of 2,6-dibromo-4-fluorophenol (214.5 g, 0.794 mol) in acetone (4.3 L), potassium carbonate (120.6 g, 0.874 mol) and methyl iodide (54.4 mL, 0.874 mol) were added at room temperature. The mixture was heated to reflux for 1.5 hours cooled to 25° C. and filtered, washing the filter cake with dichloromethane (2×1.5 L). The filtrate was concentrated in vacuo at 40° C. The crude product was slurred in dichloromethane (1 L) for 30 minutes at 25° C., filtered and concentrated in vacuo at 40° C. to give 1,3-Dibromo-5-fluoro-2-methoxybenzene as an off-white crystalline solid (223.3 g, 98.9%).