Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:6][CH:5]=1)[CH3:3].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([O:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:13]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])=[CH:6][CH:5]=1)[CH3:3])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)c1ccc(CCNC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)c1ccc(CCNC(=O)OC(C)(C)C)cc1
Reaction time: 4 h

Procedure:
tert-Butyl [2-[4-(1-hydroxyethyl)phenyl]ethyl]carbamate (606 mg) was dissolved in dichloromethane (20 ml), triethylamine (0.38 ml) and then methanesulfonyl chloride (0.195 ml) were added at 0° C., and the mixture was stirred for 4 hr. The reaction mixture was diluted with dichloromethane, and washed with saturated aqueous sodium hydrogen carbonate solution and then saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give 1-[4-[2-[(tert-butoxycarbonyl)amino]ethyl]phenyl]ethyl methanesulfonate. The obtained compound, (3S)-3-fluoropyrrolidine hydrochloride (287 mg) and N,N-diisopropylethylamine (1.18 g) were mixed with DMF (10 ml), and the mixture was stirred at 50° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, and washed with water and then saturated brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1 (volume ratio)→ethyl acetate→ethyl acetate:methanol=9:1 (volume ratio)) to give tert-butyl [2-[4-[1-[(3S)-3-fluoropyrrolidin-1-yl]ethyl]phenyl]ethyl]carbamate (133 mg) as a crude oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([I:8])=[N:6][CH:7]=1.[CH:9]([Si:12](Cl)([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])([CH3:11])[CH3:10].N1C=CN=C1>C(#N)C>[I:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][Si:12]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:9]([CH3:11])[CH3:10])=[CH:7][N:6]=1
Reactant: Oc1ccc(I)nc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CC#N
Product: CC(C)[Si](Oc1ccc(I)nc1)(C(C)C)C(C)C
Temperature: 25 °C
Yield: 98 %

Procedure:
5 g (22.6 mM) of 5-hydroxy-2-iodopyridine and 6.42 ml (30.09 mM) of triisopropylsilyl chloride in 35 ml of acetonitrile are stirred at room temperature for 10 minutes. After the addition of 4.62 g (67.87 mM) of imidazole, stirring is maintained for 4 h 20 min at room temperature. The acetonitrile is evaporated off and the reaction mixture is taken up with three 150 ml portions of pentane. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The evaporation residue is passed through a silica plug using petroleum ether as the eluent to give the desired product in the form of a light yellow oil with a yield of 98%.
Reaction SMILES: [CH2:1]([Cl:4])[CH2:2][OH:3].CCOCC.[CH2:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]([CH3:13])[CH3:12]>C(N(CC)CC)C>[CH2:10]([S:14]([O:3][CH2:2][CH2:1][Cl:4])(=[O:16])=[O:15])[CH:11]([CH3:13])[CH3:12]
Reactant: OCCCl
Reactant: CC(C)CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)CS(=O)(=O)OCCCl
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
A mixture was formed containing 6.7 ml. of ethylene chlorohydrin, 70 ml. of ether and 15.6 g. of isobutane sulfonyl chloride. Then, 14 ml. of triethylamine was added dropwise to the mixture with stirring in an ice bath over a period of 30 minutes at 12°-14° C. While stirring the mixture was allowed to warm to 23° C. (1 hour) and was then washed with water (100 ml.), dried over magnesium sulfate and evaporated to yield 19.7 g. of a colorless oil. nD30 1.4502.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[OH-].[Na+]>C1C=CC=CC=1>[CH2:10]([O:9][C:8]([NH:7][C@H:3]1[CH2:4][CH2:5][CH2:6][C@@H:2]1[O:1][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(N[C@H]1CCC[C@@H]1O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)CO[C@H]1CCC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 67.3 %

Procedure:
To a mixture of benzyl [(1S,2S)-2-hydroxycyclopentyl]carbamate (1.3 g) and benzene (13 ml) were added, tert-butyl bromoacetate (3.2 g), hydrogen tetrabutyl ammonium sulfate (0.46 g), and a 50% aqueous NaOH solution (13 ml) under ice-cooling, followed by stirring under ice-cooling for 1 hour and further at room temperature for 2 hours. The reaction mixture was poured into ice-water, extracted with ethyl acetate, then washed with water and saturated brine in this order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1→7:1→5:1) to obtain tert-butyl {[(1S,2S)-2-{[(benzyloxy)carbonyl]amino}cyclopentyl]oxy}acetate (1.3 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.IC.[C:12](=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5](=[O:8])[N:6]([CH3:12])[CH:7]=1
Reactant: Cc1cc(=O)[nH]cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: Cc1cc(=O)n(C)cc1Br
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of 5-bromo-4-methylpyridin-2(1H)-one (164 mg, 0.872 mmol) and iodomethane (124 mg, 0.872 mmol) in DMSO (3 mL) was added potassium carbonate (121 mg, 0.872 mmol). The mixture was stirred at 60° C. overnight, filtered, and purified via preparative HPLC, eluting with a gradient of 20-70% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA) to give the title compound.
Reaction SMILES: [Br:1][C:2]([Br:14])=[CH:3][C:4]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:5]=1[NH2:6].Br[CH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]([Br:14])=[CH:3][C:4]1[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:5]=1[NH:6][CH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CCOc1ccc(N)c(C=C(Br)Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(NCc2cccc(C(=O)OC)c2)c(C=C(Br)Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A suspension of 2-(2,2-dibromovinyl)-4-ethoxyaniline (240 mg), methyl 3-(bromomethyl)benzoate (180 mg) and potassium carbonate (124 mg) in N,N-dimethylformamide (2 mL) was stirred overnight at room temperature. Water was added to the reaction mixture and this resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (258 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C@@H:6]2[CH2:8][C@H:3]1[CH2:4][N:5]2[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][NH:13][C:12]2=[O:19].[H-].[Na+].Br[CH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[O:26][N:25]=1>CN(C)C=O>[CH3:1][N:2]1[CH2:7][C@@H:6]2[CH2:8][C@H:3]1[CH2:4][N:5]2[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]([CH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[O:26][N:25]=1)[C:12]2=[O:19]
Reactant: CN1C[C@@H]2C[C@H]1CN2c1ccc2nc[nH]c(=O)c2c1
Reactant: Cc1cc(CBr)no1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Cn2cnc3ccc(N4C[C@@H]5C[C@H]4CN5C)cc3c2=O)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
To a solution of 6-((1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)quinazolin-4(3H)-one (Example 10A) (150 mg, 0.583 mmol) in dimethylformamide was cooled to 0° C. added and sodium hydride (21 mg, 0.875 mmol) was added, after 5 minutes 3-bromomethyl-5-methylisoxazole (75 mg, 0.426 mmol) was added and the reaction stirred at room temp for 1 h. The reaction was quenched with ammonium chloride and the dimethylformamide evaporated off. The residue was dissolved in 10% methanol in dichloromethane and dried over sodium sulphate before evaporation to dryness. The product was purified by silica chromatography, elueting with 10% methanol in dichloromethane to afford 6-((1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-((5-methylisoxazol-3-yl)methyl)quinazolin-4(3H)-one (0.10 g, 0.284 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:27])[CH:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[C:28]([O:32]CC)(=[O:31])[CH:29]=[CH2:30].C(O)(=O)C.[OH-].[Na+]>CO.C(COC)OC.O>[CH2:12]([C:11]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:10](=[O:27])[CH:9]=[CH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:30][CH2:29][C:28]([OH:32])=[O:31])[CH:13]=[CH:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=CC(=O)OCC
Reactant: O=C(C=Cc1ccc(Cl)cc1)C(CC=Cc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CCC(CC=Cc1ccccc1)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Reaction time: 24 h

Procedure:
Triton B (0.2 ml., 40% in MeOH) is added to a stirred solution of 1-(p-chlorophenyl)4,7-diphenyl-1,6-heptadien-3-one (3.72 g., 0.01 mole) in glyme (25 ml.), followed by addition of ethyl acrylate (1.11 g., >0.01 mole). After stirring for 24 hours, glacial acetic acid (0.5 ml.) is added and the solvent removed under reduced pressure. The residue is mixed with a solution of sodium hydroxide (0.80 g., 0.02 mole) in water (15 ml.) and methanol (150 ml.) and stirred for 24 hours. The methanol is removed in vacuo and the residue is dissolved in water (200 ml.). Extraction with ether removes unreacted ketone. Ether is expelled from the aqueous phase and it is acidified to Congo Red with dilute hydrochloric acid. The off-white solid that separates is collected, washed well with water, and air-dried, yield 3 g. Recrystallization from benzene-hexane gives material with m.p. 135°-140°C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.[I:14]I>CCO.S([O-])([O-])(=O)=O.[Ag+2]>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][C:10]([F:11])([F:12])[F:13])[C:5]([NH2:6])=[C:7]([I:14])[CH:8]=1
Reactant: II
Reactant: Nc1ccc(Cl)cc1OC(F)(F)F
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1c(I)cc(Cl)cc1OC(F)(F)F
Temperature: 50 °C
Reaction time: 24 h
Yield: 100.9 %

Procedure:
To a stirred solution of 4-chloro-2-(trifluoromethoxy)aniline (1.0 g, 4.7 mmol) in EtOH (50 mL) at 50° C. was added a slurry of iodine (1.2 g, 9.6 mmol) and silver sulfate (2.6 g, 8.4 mmol) in EtOH (30 mL). The reaction mixture was stirred in darkness at 50° C. for 24 h, then cooled to r.t. and filtered through Celite®. The filtrate was concentrated in vacuo. Purification by column chromatography (SiO2, 0-55% ethyl acetate/hexanes) gave the title compound (1.6 g, quantitative) as a pale brown solid. δH (CDCl3) 7.59 (1H, d, J 1.7 Hz), 7.18 (1H, d, J 1.7 Hz), 4.35 (2H, br. s). LCMS (ES+) 337.8 (M+H)+, RT 3.81 minutes (Method 5).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:43][N:44]1[C:53]2[C:48](=[CH:49][N:50]=[C:51]([CH3:54])[CH:52]=2)[CH:47]=[C:46]([C:55]2[CH:56]=[C:57]([NH:62]/[C:63](/[NH2:66])=[N:64]/O)[CH:58]=[CH:59][C:60]=2[CH3:61])[C:45]1=[O:67].[BH4-].[Na+]>CN(C=O)C>[OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[O:9][N:64]=[C:63]([NH:62][C:57]3[CH:58]=[CH:59][C:60]([CH3:61])=[C:55]([C:46]4[C:45](=[O:67])[N:44]([CH3:43])[C:53]5[C:48]([CH:47]=4)=[CH:49][N:50]=[C:51]([CH3:54])[CH:52]=5)[CH:56]=3)[N:66]=2)[CH2:3]1
Reactant: O=C1CCC(C(=O)O)C1
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [BH4-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(C4CCC(O)C4)n3)ccc1C)c(=O)n2C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
3-Oxocyclopentanecarboxylic acid (16.6 mg, 0.12 mmol), HATU (50 mg, 0.12 mmol), and DIPEA (0.023 mL, 0.12 mmol) were stirred in dry DMF (3 mL) for 1 h before 17 (40 mg, 0.118 mmol) was added at rt. The stirring was continued for 1 h before it was heated at 100° C. for 5 h. After cooling NaBH4 (20 mg) was added and stirred for 5 h at rt. After filtration, the mixture was purified by preparative LC/MS to give 3-(5-(5-(3-hydroxycyclopentyl)-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-di methyl-1,6-naphthyridin-2(1H)-one (A73) as a solid. MS m/z 431.5, 432.6 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.I[CH2:12][CH:13]([O:15][CH2:16][CH2:17]I)[CH3:14].FC1C=C(CC#N)C=C(F)C=1.ClCCOCCCl>>[C:9]([C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=2)[CH2:17][CH2:16][O:15][CH:13]([CH3:14])[CH2:12]1)#[N:10]
Reactant: CC(CI)OCCI
Reactant: N#CCc1cccc(I)c1
Agent: N#CCc1cc(F)cc(F)c1
Solvent: ClCCOCCCl
Product: CC1CC(C#N)(c2cccc(I)c2)CCO1

Procedure:
The titled compounds were prepared according to the procedure described in Example 25A except that 3-iodophenyacetonitrile and 1-iodo-2-(2-iodoethoxy)propane were used in place of 3,5-difluorophenylacetonitrile and bis-(2-chloroethyl)ether. The diastereomers were separated by silica gel column chromatography to afford 1.46 g (38%) of a less polar isomer, (2SR, 4RS)-4-cyano-4-(3-iodophenyl)-2-methyl-3,4,5,6-tetrahydro-2H-pyran; and 1.31 g (34%) of a more polar isomer, (2SR, 4SR)-4-cyano-4-(3-iodophenyl)-2-methyl-3,4,5,6-tetrahydro-2H-pyran.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1)=[CH2:5])C>C1COCC1.Cl>[C:4]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1)(=[O:3])[CH3:5]
Reactant: C=C(OCC)c1ccc(C#N)cn1
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C#N)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.5 %

Procedure:
Dissolve crude 6-(1-ethoxy-vinyl)-nicotinonitrile (14.5 g, ca. 80%) in THF (120 mL) and 2.5 N hydrochloric acid (40 mL). Stir the solution for 16 h at room temperature. Quench the reaction with saturated aqueous NaHCO3 (pH to 7.5). Extract the mixture with EtOAc (200 mL). Dry the organic layer over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel (120 g) eluting with hexane/EtOAc (9:1 to 3:1 gradient) to obtain the desired intermediate (4.2 g, 65%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2].[Cl:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:37]3[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(N(CC)CC)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(Cl)cc3)ccc2n1-c1ccc(N(CC)CC)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 1-(4-diethylaminophenyl)-2-ethoxycarbonylmethyl-5-hydroxyindole-3-carboxylic acid ethyl ester (150 mg, 0.35 mmol, see step (b) Example 1) and 4-chlorophenylboronic acid (83 mg, 0.53 mmol). Yield 107 mg (57%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[O:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.ClC1C=C(C2N=C(CCC(O)=O)OC=2)C=C(C(F)(F)F)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])[O:15][CH:16]=2)[CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=1
Reactant: COC(=O)CCc1nc(-c2cc(Br)cc(C(F)(F)F)c2)co1
Agent: O=C(O)CCc1nc(-c2cc(Cl)cc(C(F)(F)F)c2)co1
Product: O=C(O)CCc1nc(-c2cc(Br)cc(C(F)(F)F)c2)co1
Yield: 85 %

Procedure:
The title compound was prepared from methyl 3-(4-(3-bromo-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoate (Reference Example 44) by a procedure similar to the one described for 3-(4-(3-chloro-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoic acid (Reference Example 52) to provide 3-(4-(3-bromo-5-(trifluoromethyl)phenyl)oxazol-2-yl)propanoic acid (0.316 g, 85%) as an off-white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C@H:10]([NH:19][C:20]([C:22]2([CH2:27]CC(C(OCC)=O)CC(O)=O)[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[C:9]1=[O:39])([CH3:4])([CH3:3])[CH3:2].C[C@@H]1[O:47][C@@H:46]([O:48][C@@H:49]2[C:54]3=C(O)C4C(=O)C5C(=CC=CC=5OC)C(=O)C=4C(O)=C3C[C@@](O)(C(CO)=O)C2)[CH2:45][C@H:44](N)[C@@H:43]1[OH:79].Cl>CO>[C:1]([O:5][C:6](=[O:40])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C@H:10]([NH:19][C:20]([C:22]2([CH2:27][CH:45]([CH2:44][C:43]([NH:8][CH:14]([CH3:15])[CH3:13])=[O:79])[C:46]([O:48][CH2:49][CH3:54])=[O:47])[CH2:23][CH2:24][CH2:25][CH2:26]2)=[O:21])[C:9]1=[O:39])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Reactant: CCOC(=O)C(CCC1(C(=O)N[C@H]2CCc3ccccc3N(CC(=O)OC(C)(C)C)C2=O)CCCC1)CC(=O)O
Agent: Cl
Solvent: CO
Product: CCOC(=O)C(CC(=O)NC(C)C)CC1(C(=O)N[C@H]2CCc3ccccc3N(CC(=O)OC(C)(C)C)C2=O)CCCC1

Procedure:
With a retention time of 6.5 min., there was obtained 33 g of the second stereoisomer, which was assigned the designation “rel2” in relation to the chiral center “*Ca” bearing the group “—COOR1”, as (2“rel2”)-3-{[1-({[(3S)-1-(2-tert. butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]ethyl}4-ethoxy-4-oxobutyric acid, 1H-NMR (CDCl3): 7.31-7.17, m, [3]; 7.11, d, [2]; 6.81, d, [1]; 4.60, 4.56, 4.35, 4.31, AB-Q. [2]; 4.48, m, [1]; 4.10, m, [1]; [α]D=−136° (1% in methanol).
Reaction SMILES: [Cl-].[NH4+].[CH2:3]([S:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O>[Fe].CO>[CH2:3]([S:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCSCc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCCCCSCc1ccc(N)cc1
Temperature: 50 °C
Yield: 95.2 %

Procedure:
Ammonium chloride (152.9 g, 2.858 mol), 1 (225.0 g, 0.572 mol), water (2.8 L), methanol (3.8 L) were combined and mechanically stirred at 50° C., then powdered iron (95.9 g, 1.715 mol) was added portionwise over ten minutes. The suspension was vigorously stirred at reflux for 2.5 hours, then hot filtered through a celite pad. The pad was rinsed with water (3×700 mL) and CH2Cl2 (5×700 mL). The aqueous layer was extracted with CH2Cl2 (3×1 L), then concentrated to remove methanol and again extracted with CH2Cl2 (3×500 ml). The combined organics were washed with water (2×3 L), dried (Na2SO4), filtered, and spin-evaporated to give 198.1 g (95.3% yield) of 2 as a pale yellow solid. TLC (7:1 hexanes/EtOAc) indicated a single spot. This lot was combined with that of a 100 mmol run to give a total of 231 g of 2 (94.3% yield) which was suitable for further transformation.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:29](=[O:30])[N:11]2[C:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[C:13]([C:16]([O:18]CC=C)=[O:17])[CH2:14][CH2:15][C@H:10]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[SnH](CCCC)(CCCC)CCCC.Cl>CC#N.CCOCC.O.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:29](=[O:30])[N:11]2[C:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[C:13]([C:16]([OH:18])=[O:17])[CH2:14][CH2:15][C@H:10]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCOC(=O)C1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2CC1
Agent: CCCC[SnH](CCCC)CCCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)(C)C)=C(C(=O)O)CC[C@H]12
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
To 700 mg (1.657 mMol) of 4-t-butyl 7β-t-butyloxycarbonylamino-3-allyloxycarbonyl-1-carba-3-cephem-4-carboxylate, dissolved in 12 ml of (1:1) CH3CN/(CH3CH2)2O, was added 174 mg (0.663 mMol) of triphenylphosphine and 20.34 mg (0.0829 mMol) of ##STR153## The reaction mixture was stirred for approximately 20 minutes and then cooled to 0° C. and treated with 0.464 ml (1.724 l) of (CH3CH2CH2CH2)3SnH. The reaction mixture was then allowed to cool and stirring was continued for 50 minutes. The crude reaction mixture was then treated with 1N HCl. This mixture was then poured into 100 ml of CHCl3 and 25 ml of H2O. The organic layer was separated, dried over anhydrous MgSO4, filtered, and concentrated, under reduced pressure to provide an oily solid. The crude product was recrystallized from CH2Cl2 /hexane to yield 570 mg (90%) of the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][N+:9]([O-])=[C:8]([CH3:13])[C:7]=1[CH3:14])[CH2:2][CH2:3][CH3:4].[C:15]([O:18]C(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:18][CH2:13][C:8]1[C:7]([CH3:14])=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:11]=[CH:10][N:9]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCOc1cc[n+]([O-])c(C)c1C
Product: CCCCOc1ccnc(COC(C)=O)c1C
Yield: 45.8 %

Procedure:
To 24.1 g of 4-butoxy-2,3-dimethylpyridine-1-oxide, 44.0 g (4.0 eq.) of acetic anhydride was added, and the mixture was allowed to react for 4 hours at 90° C. Acetic anhydride was distilled off, and then the resulting concentrated residue was purified on a silica gel column, to obtain 13.4 g of 2-acetoxymethyl-3-methyl-4-butoxy-pyridine as an oily matter.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[N:9][N:8]=2)[CH:7]=1
Reactant: CN1CCN(CC(=O)NNc2ccc(F)cn2)CC1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(Cc2nnc3ccc(F)cn23)CC1
Reaction time: 18 h
Yield: 88.7 %

Procedure:
Intermediate 14a (570 mg, 2.13 mmol) was dissolved in THF (20.0 mL) and cooled in an ice/water bath. Triphenylphosphine (1.12 g, 4.27 mmol) was added followed by triethylamine (1.19 mL, 8.54 mmol) and hexachloroethane (1.01 g, 4.27 mmol). The reaction was stirred for 18 h. The mixture was loaded onto an SCX-2 cartridge, washing with MeOH and eluting with 2M NH3 in MeOH. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (470 mg, 1.89 mmol, 89%). LCMS (Method 1): Rt 0.36 min, m/z 250 [MH+].
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]\1.[NH2:11][NH2:12]>CO>[NH:11]1[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:3]=2[CH:2]=[N:12]1
Reactant: NN
Reactant: O=C1CCCCC/C1=C/O
Solvent: CO
Product: c1n[nH]c2c1CCCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a solution of 2-[1-hydroxy-meth-(Z)-ylidene]-cycloheptanone (1.35 g, 9.63 mmol) in MeOH (10 mL) at 0° C. was added hydrazine (0.30 mL, 9.63 mmol) dropwise. The yellow reaction mixture was stirred at room temperature for 30 min then concentrated. The residue was dissolved in CH2Cl2 and washed with water. The organic layer was dried over MgSO4 and concentrated to provide 1.24 g (95%) of 1,4,5,6,7,8-hexahydrocycloheptapyrazole as a pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.28 (s, 1H), 2.75-2.82 (m, 2H), 2.54-2.62 (m, 2H), 1.80-1.91 (m, 2H), 1.60-1.75 (m, 4H).