Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O(CC([NH:11][C@@H:12]1[C:23](=[O:24])[N:14]2[C:15]([C:20]([OH:22])=[S:21])=[C:16]([CH3:19])[CH2:17][S:18][C@H:13]12)=O)C1C=CC=CC=1.CN(C)C1C=CC=CC=1.C[Si](C)(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl.O.O1CCOCC1.C(O)CCC>[NH2:11][C@@H:12]1[C:23](=[O:24])[N:14]2[C:15]([C:20]([OH:22])=[S:21])=[C:16]([CH3:19])[CH2:17][S:18][C@H:13]12
Reactant: CC1=C(C(O)=S)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Agent: C[Si](C)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC1=C(C(O)=S)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A suspension of 3.80 g (10 mmols) of 7β-phenoxyacetamido-3-methylthio-ceph-3-em-4-carboxylic acid in 38 ml of absolute methylene chloride is stirred with 4.45 ml of dimethylaniline and 1.50 ml of dimethyldichlorosilane for 30 minutes at room temperature. The reaction mixture is cooled to -20° C., 2.60 g of phosphorus pentachloride are added, the mixture is stirred for 30 minutes at -20° C. and is then added dropwise to a mixture, cooled to -20° C., of 15.5 ml of n-butanol and 1.47 ml of dimethylaniline. The temperature is allowed to rise to -10° C. and 15.5 ml of dioxane and 0.53 ml of water are added. When crystallisation starts, the pH value is adjusted to 4.1 with tributylamine and crystallisation is brought to completion by stirring for 2 hours at 0°-5° C. The precipitate is filtered off, washed with 10 ml of dioxane and 5 ml of methylene chloride and dried in a high vacuum. 7β-Amino-3-methylthio-ceph-3-em-4-carboxylic acid of melting point 205° C. (decomposition) is obtained; UV spectrum (0.1 N NaHCO3): λmax =293 (ε=7600); IR spectrum (nujol): characteristic bands at 3.15, 5.55 6.17 and 6.53μ.
Reaction SMILES: [Li+].[BH4-].C[O:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[C:13]#[N:14].Cl>C1COCC1.[Cl-].[Cl-].[Zn+2]>[NH2:14][CH2:13][C:7]1[C:8]([Cl:12])=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][OH:4]
Reactant: COC(=O)c1cccc(Cl)c1C#N
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: NCc1c(Cl)cccc1CO
Temperature: 50 °C

Procedure:
To a slurry of ZnCl2 (0.77 mmol) in 5 mL THF was added LiBH4 (1.64 mmol, 2M in THF) at RT. After heating to 50° C. for 90 min, a solution of 3-chloro-2-cyanobenzoic acid methyl ester (0.81 mmol) in 5 mL THF was slowly added and the mixture was heated to 60° C. overnight. The reaction mixture was then cooled to 5° C., acidified with 2M HCl solution and extracted with EtOAc. The aq. phase was basified with 1M NaOH solution, extracted twice with EtOAc, dried over MgSO4 and concentrated in vacuo to give the desired product as yellowish oil.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([O:20][C@@H]2O[C@@H](C)[C@H](O)[C@@](OC)(C)C2)[C@H:13]([CH3:32])[C@@H:12]([O:33][C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@@:4]1(O)[CH3:50].C[C@H]1O[C@@H](O[C@@H]2[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](C)C(=O)O[C@H](C)[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@@]3(OC3)C[C@@H]2C)[C@H](O)[C@@H](N(C)C)C1>>[CH3:1][CH2:2][C@H:3]1[O:18][C:16](=[O:17])[C@H:15]([CH3:19])[C@@H:14]([OH:20])[C@H:13]([CH3:32])[C@@H:12]([OH:33])[C@@:11]([OH:46])([CH3:45])[CH2:10][C@@H:9]([CH3:47])[C:7](=[O:8])[C@H:6]([CH3:48])[C@@H:5]([OH:49])[C@H:4]1[CH3:50]
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Agent: CO[C@H]1C[C@H](O[C@H]2[C@H](C)[C@@H](O[C@@H]3O[C@H](C)C[C@H](N(C)C)[C@H]3O)[C@@H](C)C[C@@]3(CO3)C(=O)[C@H](C)[C@@H](O)[C@@H](C)[C@@H](C)OC(=O)[C@@H]2C)O[C@@H](C)[C@@H]1O
Product: CC[C@H]1OC(=O)[C@H](C)[C@@H](O)[C@H](C)[C@@H](O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@H]1C

Procedure:
Under HPLC the peak corresponding to P 15153 has a retention time with respect to erythromycin A of 0.64 and with respect to oleandomycin of 0.99. For the above four antibiotics, which are obtained in admixture from erythronolide B, after 100 hours of fermentation and before the isolation, the total antibiotic activity, expressed as activity of erythromycin A, is about 120-150 mcg/ml.
Reaction SMILES: [H-].[Na+].O.[NH2:4][C:5]1[C:14]2[N:15]=[C:16]([CH:22]([CH2:24][CH2:25][CH2:26][CH3:27])[OH:23])[N:17]([CH2:18][CH:19]([CH3:21])[CH3:20])[C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1.N[C:29]1C2N=C(C(CCCC)O)N(CC(C)C)C=2C2C=CC=CC=2N=1.CI>>[CH3:29][O:23][CH:22]([C:16]1[N:17]([CH2:18][CH:19]([CH3:20])[CH3:21])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]([NH2:4])[C:14]=2[N:15]=1)[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCC(O)c1nc2c(N)nc3ccccc3c2n1CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCCCC(OC)c1nc2c(N)nc3ccccc3c2n1CC(C)C
Reaction time: 2 h
Yield: 16 %

Procedure:
Sodium hydride (0.32 g; 10.1 mmol) was added to a suspension of 4-amino-α-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanol (3 g; 9.2 mmol, Example 60) and the resulting mixture was stirred for about 2 hours. Methyl iodide (0.82 mL; 13.8 mmol) was added to the mixture and stirring was continued overnight. Thin layer chromatography indicated that the reaction was incomplete so sodium hydride (0.25 g) was added followed two hours later by methyl iodide (1 mL). The reaction was stirred for several additional hours then quenched with water and diluted with ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and concentrated under vacuum to provide an oil. The oil was purified by silica gel chromatography (1-3% methanol in methylene chloride as eluent) to provide 0.5 g of a solid, m.p. 125-128° C. Analysis: Calculated: C, 70.55; H, 8.3; %N, 16.5; Found: C, 70.2; H, 8.3; N, 16.0.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=1)(C)C.[OH-].[K+]>C(O)(C)C>[C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:6]#[CH:5])=[CH:12][CH:11]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1ccc(C#C[Si](C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: C#Cc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
To a stirred solution of 1.44 g (6.23 mmol) of trimethylsilyl (4-tert-butyl) phenylethyne (Compound 21) in 5 ml of isopropanol was added 10 ml of 1N aqueous KOH and the mixture then stirred at room temperature for 6.5 hours. The isopropanol was removed under vacuum and the residue extracted with ether. The ether extract was washed with dilute HCl until the washings were acidic. The ether solution was then successively washed with water, saturated NaCl and NaHCO3 solutions and then dried (MgSO4) Solvent was then removed in-vacuo to give the title compound as a colorless oil. PMR (CDCl3) & 1.34 (9H, s), 3.05 (1H, s), 7.37 (2H, d, J~8.2 Hz), 7.46 (2H, d, J~8.2 Hz).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:8])[C:5]([OH:7])=O.[NH2:9][C:10]1[C:15](=[O:16])[C:14]2[CH:17]=[C:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH:19]=[CH:20][C:13]=2[S:12][CH:11]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:2][O:3][C:4](=[O:8])[C:5]([NH:9][C:10]1[C:15](=[O:16])[C:14]2[CH:17]=[C:18]([CH2:21][CH2:22][CH2:23][CH3:24])[CH:19]=[CH:20][C:13]=2[S:12][CH:11]=1)=[O:7]
Reactant: CCCCc1ccc2scc(N)c(=O)c2c1
Reactant: COC(=O)C(=O)O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCc1ccc2scc(NC(=O)C(=O)OC)c(=O)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.94 g (0.024 mol) of oxalic acid monomethyl ester chloride are added to a solution of 5.05 g (0.0216 mol) of 3-amino-6-(n-butyl)-4H-1-benzothiopyran-4-one and 2.4 g (0.024 mol) of triethylamine in 325 ml of chloroform, the temperature of the reaction mixture rising to 30°. The mixture is then stirred for one hour at room temperature. The mixture is then concentrated to dryness by evaporation and the crystalline residue is stirred with ethanol, filtered with suction and washed first with ethanol and then with ether. After drying, N-[6-(n-butyl)-4H-1-benzothiopyran-4-on-3-yl]-oxalic acid amide methyl ester having a melting point of 192°-193.5° is obtained.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][CH:6](OCC)OCC)C.Cl.[Cl:17][C:18]1[CH:19]=[C:20]([CH3:26])[CH:21]=[CH:22][C:23]=1[NH:24][NH2:25]>CO.Cl>[Cl:17][C:18]1[CH:19]=[C:20]([CH3:26])[CH:21]=[CH:22][C:23]=1[N:24]1[CH:6]=[CH:5][CH:4]=[N:25]1
Reactant: Cc1ccc(NN)c(Cl)c1
Reactant: CCOC(CC(OCC)OCC)OCC
Agent: Cl
Solvent: CO
Product: Cc1ccc(-n2cccn2)c(Cl)c1
Yield: 87.1 %

Procedure:
41.0 g (186 mmoles) of 1,1,3,3-tetraethoxypropane are added dropwise at 40° C. to 30 g (155 mmoles) of 3-chloro-p-tolylhydrazine hydrochloride in 180 ml of methanol and 15.6 ml of concentrated hydrochloric acid and heated to the boil for 1.5 hours. The resulting solution is concentrated in a vacuum; the thus-prepared concentrate is dissolved in benzene. The obtained benzene solution is washed with water and sodium hydrogen carbonate solution, dried and evaporated to dryness to yield 26 g (87% of theory) of 1-(3-chloro-p-tolyl)pyrazole (m.p. 61° to 62° C.).
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([NH:10][C:11](=[O:32])[NH:12][C:13]2[N:14]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24]C(=O)OC(C)(C)C)=[CH:20][CH:19]=3)[S:16][CH:17]=2)[CH:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3].C1(SC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[S:16][CH:17]=[C:13]([NH:12][C:11]([NH:10][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[N:9]=3)=[O:32])[N:14]=2)=[CH:19][CH:20]=1
Reactant: CCCc1cccc(NC(=O)Nc2csc(-c3ccc(NC(=O)OC(C)(C)C)cc3)n2)n1
Solvent: CSc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cccc(NC(=O)Nc2csc(-c3ccc(N)cc3)n2)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In an oven-dried, 25-mL, round-bottomed flask were placed N-[6-propylpyridine]-N′-[4-[N-Bocamino]pheny]-4-thiazolyl]urea (55 mg, 0.12 mmol, Example 187), thioanisole (0.35 mL) in CH2Cl2 (10 mL). TFA (0.35 mL) was added, the mixture was stirred at RT for 6 h then concentrated in vacuo. Purification by flash chromatography on silica gel [EtOAc/hexane (extracted with aq. NH4OH), 40:60] afforded the title compound. MS m/z: 354.0 (M+H). Calc'd for C18H19N50S: 353.13.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[F:11].O.C(O)(=O)C>[Fe].C(O)C>[Br:1][C:2]1[C:3]([F:11])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(Br)c1F
Agent: [Fe]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cccc(Br)c1F

Procedure:
1-Bromo-2-fluoro-3-nitro-benzene (3 g, 13.64 mmol), iron (2.28 g, 40.91 mmol), water (34.39 ml, 1909 mmol) and acetic acid (11.7 ml, 204.55 mmol) were added to ethanol (60 ml) and heated to reflux for 2 h. The reaction mixture was then filtered through Celite and evaporated. Water was added and the solution was made basic by the addition of 2 N NaOH, followed by extraction with DCM. The organic layers were washed with water and brine, dried with Na2SO4 evaporated to dryness and the crude product was obtained and used without further purification. Yield: 1.46 g, 56%
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:46][C:47]1[CH:54]=[CH:53][C:50]([C:51]#[N:52])=[CH:49][N:48]=1.N1C=CC=CC=1>C(Cl)Cl.O>[C:51]([C:50]1[CH:53]=[CH:54][C:47]([NH:46][C:35](=[O:37])[CH:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[CH2:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[N:48][CH:49]=1)#[N:52]
Reactant: N#Cc1ccc(N)nc1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)nc1
Temperature: 0 °C
Yield: 72.6 %

Procedure:
A solution of triphenylphosphine (1.23 g, 4.70 mmol) in methylene chloride (26 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (948 mg, 5.33 mmol). The reaction mixture was stirred at 0° C. until it was completely dissolved and became light purple in color. The reaction mixture was then treated with 3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionic acid (prepared as in Example 38A, 900 mg, 3.13 mmol). The reaction mixture was stirred at 0° C. for 20 min and then warmed to 25° C. where it stirred for 30 min. After such time, the reaction mixture was treated with 6-amino-nicotinonitrile (560 mg, 4.70 mmol) and pyridine (0.46 mL, 5.64 mmol), and the reaction mixture was stirred at 25° C. for 16 h. The reaction was then diluted with water (25 mL) and then extracted with methylene chloride (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 85/15 hexanes/ethyl acetate) afforded N-(5-cyano-pyridin-2-yl)-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide (882 mg, 73%) as a pink foam: EI-HRMS m/e calcd for C20H19Cl2N3O (M+) 387.0905, found 387.0905.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:10][C:11]([F:19])(S(F)(=O)=O)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+].O>C(#N)C>[Br:1][C:2]1[C:3]([O:9][CH:11]([F:19])[F:10])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: Cc1cnc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cnc(OC(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a solution of 3-bromo-5-methylpyridin-2-ol (25.0 g, 0.13 mol) in ACN (100 mL) was added 2,2-difluoro-2-(fluorosulfonyl)acetic acid (23.7 g, 0.13 mol) and sodium carbonate (28.2 g, 0.270 mol). The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the reaction mixture was extracted with DCM. The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification (FCC, SiO2, 0-10%, EtOAc/hexanes) afforded the title compound as an off-white solid (22 g, 70%). M+H]=238.09240.09.
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(CO)=CC=2)=O)C(=O)C=1)C1C=CC=CC=1.[CH2:27]([O:34][C:35]1[CH:40]=[N:39][NH:38][C:37](=[O:41])[CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl[CH2:43][C:44]([C:46]1[CH:55]=[C:54]2[C:49]([CH2:50][CH2:51][N:52]([C:56](=[O:61])[C:57]([F:60])([F:59])[F:58])[CH2:53]2)=[CH:48][CH:47]=1)=[O:45]>>[CH2:27]([O:34][C:35]1[CH:40]=[N:39][N:38]([CH2:43][C:44](=[O:45])[C:46]2[CH:55]=[C:54]3[C:49]([CH2:50][CH2:51][N:52]([C:56](=[O:61])[C:57]([F:60])([F:58])[F:59])[CH2:53]3)=[CH:48][CH:47]=2)[C:37](=[O:41])[CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(CCl)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Reactant: O=c1cc(OCc2ccccc2)cn[nH]1
Agent: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CO)cc1
Product: O=C(Cn1ncc(OCc2ccccc2)cc1=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2

Procedure:
5-Benzyloxy-2-{2-oxo-2-[2-(2,2,2-trifluoro-acetyl)-1,2,3,4-tetrahydro-isoquinolin-7-yl]-ethyl}-2H-pyridazin-3-one is prepared following preparation 15b (DMSO as solvent; purification via HPLC) from 3.00 g (14.8 mmol) 5-benzyloxy-2H-pyridazin-3-one (preparation 5c) and 4.54 g (14.8 mmol) 1-[7-(2-chloro-acetyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoro-ethanone.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.[Li]CCCC.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(NC1C(C([O-])=O)=CC=C(F)N=1)(=O)C(C)(C)C>C1COCC1.O>[F:1][C:2]1[C:3]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:4][CH:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[N:7]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(F)n1
Reactant: CCOC(=O)Cl
Agent: CC(C)(C)C(=O)Nc1nc(F)ccc1C(=O)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc(NC(=O)C(C)(C)C)nc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 6-fluoro-2-pivaloylaminopyridine (2 g) in THF (30 ml) was cooled to -78° C. and BuLi (15 mL of 1.6M in hexane) was added and the reaction stirred at 0° C. for 2 h. On re-cooling to -78° C., ethyl chloroformate (2 mL) was added and the reaction allowed to warm slowly to room temperature over 1 h. Water (10 ml) was added and the products extracted into Et2O (3×50 ml) and dried (Na2 SO4). Concentration afforded an oil which was triturated with petrol to give a solid, the isomeric 2-pivaloylamino-6-fluoropyridine-3-carboxylate (1H NMR [CDCl3 ] δ1.36 (s, 9H), 1.43 (t, 3H), 4.41 (q, 2H), 6.64 (dd, 1H), 8.45 (t, 1H), 11.34 (brs, 1H). The mother liquors were concentrated and purified by flash column chromatography (SiO2, Petrol to 5% Et2O/petrol to give ethyl 2-fluoro-6-pivaloylaminopyridine-3-carboxylate (1.2 g).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[C:18]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([CH2:26][N:12]2[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]2[CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)=[CH:28][CH:29]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: CC(C)(C)c1ccc(CBr)cc1
Product: CC(C)(C)c1ccc(CN2N(C3C4CC5CC(C4)CC3C5)C(=O)C2(C)C)cc1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 4-t-butylbenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[C:9]2[C:10]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:12]([O:14]C)=[CH:13][C:8]=2[S:7][CH:6]=1.CC(O)=O.Br>[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[C:9]2[C:10]([C:16]([F:19])([F:17])[F:18])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: COC(=O)Cc1csc2cc(OC)cc(C(F)(F)F)c12
Agent: Br
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)Cc1csc2cc(O)cc(C(F)(F)F)c12
Temperature: 130 °C
Reaction time: 0.67 h

Procedure:
To a mixture of methyl(6-methoxy-4-(trifluoromethyl)-1-benzothiophen-3-yl)acetate obtained above (405 mg) and AcOH (1.5 mL) was added 48% hydrobromic acid (3 mL) at room temperature. The mixture was stirred at 130° C. for 40 min under microwave irradiation. The mixture was poured into brine at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. A mixture of the residue, MeOH and conc. H2SO4 (0.071 mL) was refluxed for 1 h. The mixture was poured into brine at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine twice, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (232 mg).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:5][N:4]=1)[NH2:2].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([O:27][CH3:28])[CH:19]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>C(Cl)Cl>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:2][NH:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)=[CH:5][N:4]=2)=[O:23])=[C:20]([O:27][CH3:28])[CH:19]=1
Reactant: COc1ccc(-c2ccc(NN)nc2)cc1
Reactant: COc1cc(Cl)ccc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(-c2ccc(NNC(=O)c3ccc(Cl)cc3OC)nc2)cc1
Yield: 81.2 %

Procedure:
A solution of 2-hydrazinyl-5-(4-methoxyphenyl)pyridine (200 mg, 0.93 mmol), 4-chloro-2-methoxybenzoic acid (210 mg, 1.12 mmol), BOP (500 mg, 1.12 mmol) and NMM (330 mg, 3.27 mmol) in DCM (9 mL) was stirred at room temperature under Nitrogen overnight. The resulting mixture was filtered, and the solid was washed with DCM, dried to give the title compound as white solids (290 mg, 81.2% yield), which was used for the next reaction without further purification. MS: m/z 384.2 [M+H+].
Reaction SMILES: O=[C:2]1[C:22]2[C:9]3[CH2:10][CH2:11][C:12]4[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][C:13]=4[S:14][C:8]=3[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.Cl>[Zn].C(O)(=O)C>[CH2:2]1[C:22]2[C:9]3[CH2:10][CH2:11][C:12]4[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][C:13]=4[S:14][C:8]=3[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccc3c(c1CC2)C(=O)CC3
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)Sc1ccc3c(c1CC2)CCC3
Yield: 90.7 %

Procedure:
1-Oxo-2,3,11,12-tetrahydro-1H-benzo[b]indeno[4,5-f]thiepin-8-carboxylic acid (50 mg; 0.16 mmole) was added in portions over a 3/4 hour period to a refluxing mixture of acetic acid (4 ml), concentrated hydrochloric acid (0.3 ml) and amalgamated "mossy" zinc (220 mg) under argon. After a further 3 hours under reflux no oxo-acid remained. The reaction mixture was filtered, evaporated to a small volume and diluted with a little water to afford 43 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][C:11](=[O:14])[N:10]([C@@H:15]([CH2:21][CH3:22])[C:16](OCC)=[O:17])[C@@H:9]2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Li+]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:9]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)[N:10]([C@@H:15]([CH2:21][CH3:22])[CH2:16][OH:17])[C:11](=[O:14])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](CC)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cn1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Product: CC[C@@H](CO)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cn1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of 3.95 g (10.0 mmol) of (S)-ethyl 2-((2S,3R)-3-(3-chlorophenyl)-2-(5-chloropyridin-2-yl)-6-oxopiperidin-1-yl)butanoate (Example 121, Step G) in ether (100 mL) was added 486 mg (90%, 20.1 mmol) of lithium borohydride. The resulting light yellow slurry was stirred at 0° C. for 3 h, and then was warmed to room temperature and stirred for an additional 3 h. The reaction was re-cooled to 0° C. and quenched by cautious addition of 1 N HCl until bubbling subsided. The mixture was extracted with EtOAc (3×), and the combined organic layers were washed with saturated aqueous sodium chloride (1×). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (1 to 7% MeOH/DCM, gradient elution) provided the title compound as a white solid.
Reaction SMILES: [I-:1].O1CCC([Zn+:8])CC1.[CH3:9][O:10][CH:11]1[CH2:16][CH2:15][CH:14](O)[CH2:13][CH2:12]1>C1COCC1>[I-:1].[CH3:9][O:10][CH:11]1[CH2:16][CH2:15][CH:14]([Zn+:8])[CH2:13][CH2:12]1
Reactant: COC1CCC(O)CC1
Reactant: [Zn+]C1CCOCC1
Agent: [I-]
Solvent: C1CCOC1
Product: COC1CCC([Zn+])CC1

Procedure:
The title compound was prepared in an analogous manner to (tetrahydro-2H-pyran-4-yl)zinc(II) iodide except that 4-methoxycyclohexanol was used instead of tetrahydro-2H-pyran-4-ol in Step 1 to afford a 0.28M solution of (4-methoxycyclohexyl)zinc(11) iodide in THF.