Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:13]C)(=O)[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:15]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24]([CH3:29])([CH3:28])[CH2:23][CH2:22][C:21]2([CH3:31])[CH3:30])(=[O:17])[CH3:16].[H-].[Na+].Cl>C1(C)C=CC=CC=1.C(COC)OC.O>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([C:1](=[O:13])[CH2:16][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:24]([CH3:29])([CH3:28])[CH2:23][CH2:22][C:21]([CH3:31])([CH3:30])[C:20]=3[CH:19]=2)=[O:17])=[CH:11][CH:10]=1)([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: COC(=O)c1ccc(C(=O)CC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 56.3 %

Procedure:
A solution of 19.4 g (0.1 mol) of dimethyl terephthalate and 23 g (0.1 mol) of 6-acetyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene in 80 ml of toluene and 20 ml of dimethoxyethane was added dropwise under nitrogen to a suspension of 3.6 g (0.15 mol) of sodium hydride in 21 ml of toluene at 100° C. The mixture was refluxed for 5 h and, after cooling, 50 ml of water were added, and the mixture was acidified with 50% concentrated hydrochloric acid, poured into 500 ml of water and extracted with chloroform. The precipitated product was filtered off with suction, and the chloroform phase was dried over sodium sulfate and concentrated. The residue and crude product were mixed and washed several times with hot methanol. Drying of the crystals resulted in 22.1 g of the title compound of melting point 128° C.
Reaction SMILES: [C:1]([C:3]1([OH:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[CH:2].[F:10][C:11]1[C:12](I)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>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.CN(C=O)C.CCN(CC)CC>[F:10][C:11]1[C:12]([C:2]#[C:1][C:3]2([OH:9])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CC1(O)CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC3(O)CCOCC3)c21

Procedure:
Using Method C above, 4-ethynyl-tetrahydro-pyran-4-ol (41.1 mg, 0.33 mmol) (Example 85A) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg) and Cul (2.5 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 85° C. for 7 h to yield (Z)-1,3-Dihydro-5-fluoro-4-[(4-hydroxy-tetrahydro-pyran-4-yl)ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 36 mg, 75%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:9][C:10](=[O:16])[CH2:11][C:12](=[O:15])[CH2:13][CH3:14])[CH:6]=[CH:7][CH:8]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>>[CH3:21][N:22]1[CH:24]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:17])([F:18])[F:1])[CH:4]=2)[C:10](=[O:16])[C:11]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:23]1
Reactant: COC(OC)N(C)C
Reactant: CCC(=O)CC(=O)Cc1cccc(C(F)(F)F)c1
Product: CCC(=O)c1cn(C)cc(-c2cccc(C(F)(F)F)c2)c1=O
Reaction time: 60 h

Procedure:
A 29.1 g. portion of 1-(3-trifluoromethylphenyl)-2,4-hexanedione was combined with 120 ml. of N,N-dimethylformamide dimethyl acetal and the mixture was stirred under reflux overnight. The mixture was then evaporated to a thick dark brown oil under vacuum, and the residue was dissolved in 250 ml. of methanol. Forty g. of methylamine hydrochloride was added and the mixture was stirred under reflux for 2 hours, and at ambient temperature for 60 hours. The mixture was then evaporated under vacuum to dryness, and the residue was taken up in water and diethyl ether. The organic layer was dried over magnesium sulfate and evaporated under dryness to a dark brown solid, which was chromatographed on a 500 g. silica gel column with ethyl acetate as the eluting solvent. The product-containing fractions were combined and evaporated under vacuum to obtain a light orange solid, which was crystallized from diisopropyl ether to obtain 3.04 g. of the desired product, m.p. 136°-138°. Nmr analysis in DMSOd6 showed peaks at δ7.6-8.3 (m, 6H, aromatic); 3.8 (s, 3H, N--CH3); 2.9-3.3 (q, 2H, COCH2CH3); 0.9-1.1 (t, 3H, COCH2CH3).
Reaction SMILES: [C:1]1([C:7]2([CH2:13][O:14][CH2:15][C:16]3[CH:17]=[C:18]([C:25]([F:28])([F:27])[F:26])[CH:19]=[C:20]4[C:24]=3[NH:23][N:22]=[CH:21]4)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([BH3-])#N.[Na+].C=O.C(O)(=O)C>C(#N)C.C(O)(=O)C>[CH3:29][N:10]1[CH2:11][CH2:12][C:7]([CH2:13][O:14][CH2:15][C:16]2[CH:17]=[C:18]([C:25]([F:27])([F:26])[F:28])[CH:19]=[C:20]3[C:24]=2[NH:23][N:22]=[CH:21]3)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1
Reactant: FC(F)(F)c1cc(COCC2(c3ccccc3)CCNCC2)c2[nH]ncc2c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CCC(COCc2cc(C(F)(F)F)cc3cn[nH]c23)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 7-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)-1H-indazole (62 mg, 0.159 mmol) and sodium cyanoborohydride (10 mg, 0.159 mmol) in acetonitrile (1 mL) at room temperature was added formalin (25 μL). To this was added 1 drop of acetic acid. After 5 min, a second drop of acetic acid was added and the reaction stirred at room temperature for 15 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated. The product was purified by preparative HPLC. The trifluoroacetic acid salt was loaded onto a strong cation exchange cartridge in methanol. The cartridge was washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 37 mg (58%). 1H-NMR (CDCl3, 500 MHz) δ 9.60 (bs, 1H), 8.02 (s, 1H), 7.91 (s, 1H), 7.49 (m, 2H), 7.41 (m, 3H), 7.25 (s, 1H), 4.71 (s, 2H), 3.61 (s, 2H), 2.57 (m, 2H), 2.10-2.40 (m, 4H), 2.22 (s, 3H), 1.96 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 143.9, 139.5, 135.2, 129.0, 127.1, 126.9, 124.7 (q, J=272 Hz), 123.2 (q, J=32 Hz), 121.9, 120.1, 118.3, 80.8, 72.0, 52.0, 46.3, 40.7, 32.9. Mass spec.: 404.01 (MH)+. Accurate mass spec.: m/z [MH]+, Δ=4.4 ppm.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([NH:33][C@H:34]([C:39]([OH:41])=[O:40])[CH2:35][CH2:36][S:37][CH3:38])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:49][CH:50]([CH2:53][OH:54])[CH2:51][OH:52].[C:55](O)([C:57]([F:60])([F:59])[F:58])=[O:56].C(Cl)Cl>>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([NH:33][C@H:34]([C:39]([OH:41])=[O:40])[CH2:35][CH2:36][S:37][CH3:38])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])=[O:17])[CH3:15])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1.[F:58][C:57]([F:60])([F:59])[C:55]([O:52][CH2:51][C@@H:50]([CH2:53][OH:54])[NH2:49])=[O:56]
Reactant: NC(CO)CO
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](C)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O
Product: N[C@H](CO)COC(=O)C(F)(F)F
Reaction time: 0.5 h

Procedure:
2 g of Boc-Tyr-(D)-Ala-Gly-Phe-Met-serinol are dissolved at room temperature in 10 ml of CF3COOH/CH2Cl2 (1:1 v/v). After 30 minutes, the mixture is concentrated under vacuum and the residue triturated with ether. The solid product is recrystallized from methanol/ether to yield the title compound. M.P. 200° (decomp.). [α]D20 =+2.1° (C=1.0 in DMF).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]([CH2:13]O)[CH2:10][C:9]2=[O:15])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:36]>N1C=CC=CC=1>[Br:36][CH2:13][CH:11]1[CH2:12][N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9](=[O:15])[CH2:10]1
Reactant: BrC(Br)(Br)Br
Reactant: O=C1CC(CO)CN1c1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Product: O=C1CC(CBr)CN1c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a cooled solution of 1-(4-fluorophenyl)-4-(hydroxymethyl)pyrrolidin-2-one (0.05 g, 0.25 mmol) in pyridine (3 ml) was added triphenylphosphine (0.130 g, 0.5 mmol). The solution was stirred and carbon tetrabromide (0.08 g, 0.25 mmol) was added in 3 separate portions. The reaction mixture was then allowed to warm to room temperature and stirred for three hours. The reaction was quenched with methanol and the solvent removed. The residue was dissolved in EtOAc (75 ml) and sequentially washed with ammonium chloride (sat, 2×25 ml) and water (25 ml). The organic layer was concentrated and purified using preparative tlc (1:1 EtOac:Hexanes) to yield 4-(bromomethyl)-1-(4-fluorophenyl)pyrrolidin-2-one (HNMR).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.C[Si]([N-:15][Si](C)(C)C)(C)C.[Na+].O>C1COCC1>[NH2:15][CH2:10][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[OH:9]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Clc1cccc([C@@H]2CO2)c1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NC[C@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-2-(3-chlorophenyl)oxirane (13 g, 84 mmol) in THF (84 mL) was added NaHMDS (1 M in THF) (252 mL, 252 mmol) slowly at 0° C. The reaction mixture was warmed up to room temperature and stirred for overnight. To the reaction mixture, water (33 mL, 2.5 mL/g) added. After stirring for 5 h at room temperature, solvent was removed in vacuo to about ¼ and partitioned by DCM. The bottom layer is a little cloudy and the top layer was a brown solution. Both layers were concentrated, which contained the desired (R)-2-amino-1-(3-chlorophenyl)ethanol (14 g, 97%). The combined products were used in next step without further purification. LCMS (m/z): 172.1 (MH+), 0.37 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]#[C:15][C:16]2[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][N:19]=[C:18]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH:33]4[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34]4)=[CH:29][CH:28]=3)[N:17]=2)[CH2:7][CH2:6]1)=[O:4].CCN(CC)CC.[H][H]>CN(C=O)C.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][CH2:15][C:16]2[C:21]([C:22]([F:23])([F:25])[F:24])=[CH:20][N:19]=[C:18]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH:33]4[CH2:34][N:35]([C:37]([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38])[CH2:36]4)=[CH:29][CH:28]=3)[N:17]=2)[CH2:6][CH2:7]1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)C1(c2ccccc2C#Cc2nc(Nc3ccc(C4CN(C(=O)OC(C)(C)C)C4)cc3)ncc2C(F)(F)F)CC1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CN(C(=O)OC(C)(C)C)C4)cc3)ncc2C(F)(F)F)CC1
Yield: 99.3 %

Procedure:
A suspension of 10% Pd/C (200 mg), tert-butyl 3-(4-((4-((2-(1-(methoxycarbonyl)cyclopropyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate (A7) (353 mg, 0.596 mmol) and Et3N (1.5 mL) in DMF (10 mL) was stirred with under a hydrogen atmosphere for 16 hours. The resulting mixture was diluted with EtOAc (60 mL), filtered through Celite and the volatiles were removed under reduced pressure. The residue was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 0-40% EtOAc in petroleum benzine 40-60° C.) to give the title compound A8 as yellow oil (353 mg, 99%); 1H NMR (400 MHz, d6-DMSO) δ 10.22 (s, 1H), 8.69 (s, 1H), 7.74 (d, J=8.6 Hz, 2H), 7.32-7.26 (m, 5H), 7.22-7.16 (m, 1H), 4.24 (t, J=7.4 Hz, 2H), 3.87-3.71 (m, 3H), 3.49 (s, 3H), 3.17-2.98 (m, 4H), 1.58 (d, J=3.3 Hz, 2H), 1.40 (s, 9H), 1.19 (s, 2H). LCMS-A: rt 6.650 min; m/z 595 [M−H]−.
Reaction SMILES: CO[C@H:3]1[C@@H:8](C)[CH2:7][O:6][C@@H:5](/C=C/CCCCCCC)[C@@H:4]1[OH:19].C([NH:30][CH2:31][P:32](=[O:35])([OH:34])O)(OCC1C=CC=CC=1)=O.[CH2:36](C1C=CC=CC=1S(Cl)(=O)=O)CC>N1C=CC=CC=1.CO.[Pd].CN(C1C=CC=CN=1)C>[NH2:30][CH2:31][P:32](=[O:35])([O:34][CH3:36])[O:19][CH:4]1[CH2:3][CH2:8][CH2:7][O:6][CH2:5]1
Reactant: CCCCCCC/C=C/[C@@H]1OC[C@H](C)[C@H](OC)[C@H]1O
Reactant: CCCc1ccccc1S(=O)(=O)Cl
Reactant: O=C(NCP(=O)(O)O)OCc1ccccc1
Agent: [Pd]
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: CO
Product: COP(=O)(CN)OC1CCCOC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 138.1 %

Procedure:
To a solution of (2S,3R,4S,5S)-4-methoxy-5-methyl-2-[(E)-1-nonenyl]tetrahydro-2H-pyran-3-ol (0.5 g), dimethylamino-pyridine (0.03 g) and (N-carbobenzoxy-amino)methylphosphonic acid (0.7 g) in dry pyridine (30 ml) there was added 2,4,6-triiso=propyl benzenesulfonyl chloride (0.74 g). The reaction mixture was stirred for 12 hr at room temperature and evaporated to dryness under reduced pressure. The residue was partitioned between ether (50 ml) and 0.1N-HCl (50 ml). The ether layer was dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure. The resultant yellow oil was dissolved in ether (30 ml) and methanol (5 ml). 10%-trimethylsilyldiazomethane solution in hexane was added to the solution until the evolution of gas ceased. The reaction mixture was evaporated to dryness and purified by silica gel chromatography eluted with CH2Cl2 /AcOEt (7:3) to give (2S,3R,4S,5S)-4-methoxy-5-methyl-2-[(E)-1-nonenyl]tetrahydro-2H-pyran-3-yl methyl (benzyloxy=carbonylamino)methylphosphonate (0.8 g, y. 84%) as a colorless oil; EI-MS: m/z 511 (M+) b) A solution of (2S,3R,4S,5S)-4-methoxy-5-methyl-2-[(E)-1 -nonenyl]tetrahydro-2H-pyran-3-yl methyl (benzyloxycarbonyl=amino)methylphosphonate (0.8 g) in methanol (20 ml) was stirred under hydrogen atmosphere in the presence of Pd-black (50 mg) at room temperature for 4 hr. The catalyst was removed by filtration and washed with methanol (10 ml×2). The combined filtrate and washings were evaporated to dryness under reduced pressure to give (2S,3R,4S,5S)-4-methoxy-5-methyl-2-nonyl=tetrahydro-2H-pyran-3-yl methyl (aminomethyl)phosphonate (0.534 g, y. 90%) as colorless oil; FAB-MS: m/z 380 (MH+); 1H-NMR (CDCl3)d: 0.88 (3H,t,J=6 Hz), 1.0 (3H,d,J=6.3 Hz), 1.24 (14H,br.s), 1.54 (1H,m), 1.7 (1H,m), 2.31 (1H,m), 3.1-3.3 (5H,br.m), 3.37 (1.5H,s), 3.40 (1.5H, s), 3.47-3.54 (2H,m), 3.79 (1H,m), 3.85 (1.5 H, d,J=12 Hz), 3.91 (1.5H,d,J=12 Hz), 4.2 (1H,m). (2S,3R,4S,5S)-4-Methoxy-5-methyl-2-nonyltetrahydro-2H-pyran-3-yl (aminomethyl)phosphonate could also be obtained by the same manner as Example 57 without O-methylation.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:24]=1[CH2:25]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[C:5]([N:12]([CH2:25][C:24]2[CH:27]=[CH:28][C:29]([O:31][CH3:32])=[CH:30][C:23]=2[O:22][CH3:21])[C:13](=[O:17])[O:14][CH2:15][CH3:16])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: CCOC(=O)Nc1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Reactant: COc1ccc(CO)c(OC)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1ccc(OC)cc1OC)c1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
To a solution of ethyl 4-bromo-2-nitro-6-(trifluoromethyl)phenylcarbamate (1049.3 mg), 2,4-dimethoxybenzyl alcohol (1.7217 g) and triphenylphosphine (3.0183 g) in tetrahydrofuran (15 ml) was added diethyl azodicarboxylate (2.2505 g). The mixture was stirred at room temperature for 8 hours, and then concentrated in vacuo. The resultant residue was purified by silica gel column (110 g, hexane:ethyl acetate=20:1→10:1) to give the title compound (796.8 mg, 53%) and recovered ethyl 4-bromo-2-nitro-6-(trifluoromethyl)phenylcarbamate (489.2 mg, 47%).
Reaction SMILES: [ClH:1].C([O:6][C:7]([CH2:9][O:10][N:11]=[C:12]([C:43]1[N:44]=[C:45]([NH2:48])[S:46][CH:47]=1)[C:13]([NH:15][CH:16]1[C:41](=[O:42])[N:18]2[C:19]([C:25]([O:27]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:26])=[C:20]([CH:23]=[CH2:24])[CH2:21][S:22][C@H:17]12)=[O:14])=[O:8])(C)(C)C.C(OC(C)C)(C)C>C(O)=O>[ClH:1].[C:7]([CH2:9][O:10][N:11]=[C:12]([C:43]1[N:44]=[C:45]([NH2:48])[S:46][CH:47]=1)[C:13]([NH:15][CH:16]1[C:41](=[O:42])[N:18]2[C:19]([C:25]([OH:27])=[O:26])=[C:20]([CH:23]=[CH2:24])[CH2:21][S:22][C@H:17]12)=[O:14])([OH:8])=[O:6]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(N)n3)[C@H]2SC1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: O=CO
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 73.6 %

Procedure:
Conc. hydrochloric acid (0.18 g) was added to a solution of benzhydryl 7-[2-(tert-butoxycarbonylmethoxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (3.0 g) in formic acid (12 ml) at 10° C. and stirred for 2.5 hours at ambient temperature. The reaction mixture was poured into diisopropyl ether (100 ml). The precipitates were collected by filtration, washed with diisopropyl ether and dried to give 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid mono-hydrochloride (syn isomer) (1.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18](O)=[O:19])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[NH:25]1[CH2:30][CH2:29][CH:28]([CH2:31][OH:32])[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18]([N:25]2[CH2:30][CH2:29][CH:28]([CH2:31][OH:32])[CH2:27][CH2:26]2)=[O:19])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: OCC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCC(=O)N1CCC(CO)CC1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 2-(5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxamido)acetic acid (200 mg, 0.49 mmol) from example 210 and piperidin-4-ylmethanol (89.0 mg, 0.59 mmol). The title compound was obtained as a solid (25.0 mg, 8% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.02 (1H, m), 8.98 (1H, s), 8.50 (1H, s), 4.47 (1H, m), 4.32 (1H, m), 4.06 (2H, m), 3.83 (1H, m), 3.24 (2H, m), 2.96 (1H, m), 2.51 (1H, m), 1.66 (2H, m), 1.60 (1H, m), 1.11 (1H, m), 1.05 (1H, m), 0.92 (1H, m). MS m/z: 505.31, 507.27 [M+H]+.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][N:6]=[CH:5][CH:4]=1.C(OC([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH2:21][CH2:20]1)=O)(C)(C)C>>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([N:25]([CH:22]2[CH2:23][CH2:24][NH:19][CH2:20][CH2:21]2)[C:9](=[O:11])[C:8]2[C:3]([CH3:2])=[CH:4][CH:5]=[N:6][CH:7]=2)=[CH:27][CH:28]=1
Reactant: Cc1ccncc1C(=O)O
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Product: COc1ccc(N(C(=O)c2cnccc2C)C2CCNCC2)cc1

Procedure:
Using general procedure F with 4-methylnicotinic acid hydrochloride (277 mg, 1.60 mmol) and 4-(4-methoxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 119) (350 mg, 1.14 mmol) and then using general procedure C afforded N-(4-methoxy-phenyl)-4-methyl-N-piperidin-4-yl-nicotinamide as a white solid (181 mg, 49% over 2 steps).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[O:27][C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)/[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([OH:23])=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+].[C:71](=[O:83])([O:79][CH:80](I)[CH3:81])[O:72][CH:73]1[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]1>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[O:27][C:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)/[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O:23][CH:80]([O:79][C:71]([O:72][CH:73]4[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]4)=[O:83])[CH3:81])=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C/C=C\C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Reactant: CC(I)OC(=O)OC1CCCCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C/C=C\C1=C(C(=O)OC(C)OC(=O)OC2CCCCC2)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Reaction time: 1 h
Yield: 61.8 %

Procedure:
To a mixture of the product of Procedure 7 (35 g, 53.7 mmol) 18-crown-6 (4.0 g, 15 mmol) and well ground K2CO3 (9.45 g, 6.84 mmol) in dry DMF (330 ml) was added dropwise the cyclohexyl 1-iodoethyl carbonate (41 g, 138 mmol) at 0° C. under argon and the mixture was stirred for 1 hr. at 2°-4° C. The mixture was diluted with ethyl acetate (1.5 L) and washed well with water. The organic layer was separated, dried and evaporated under reduced pressure. The residue was chromatographed on a column of silica gel (400 g) and the column was eluted with n-hexane-dichloromethane (2:1 to 0:1). The fractions containing the desired product were combined and evaporated under reduced pressure to afford 27.3 g (62%) of the product as an amorphous powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:14][CH:13]=3)=[CH:9][S:8][C:7]=2[CH:27]=1.Br[C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=1.CC(C)(C)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)[S:8][C:7]=2[CH:27]=1
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)OC(C)(C)C)cc3)csc2c1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: CC(C)(C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(Oc3ccc(/C=C/C(=O)OC(C)(C)C)cc3)c(-c3ccc(C(F)(F)F)cc3)sc2c1
Yield: 84.6 %

Procedure:
To a 5 mL microwave vial, added a solution of (E)-tert-butyl 3-(4-((6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (50 mg, 0.13 mmol) in anhydrous DMA (1.5 mL), followed by 1-bromo-4-(trifluoromethyl)benzene (35.3 mg, 0.16 mmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (BrettPhos palladacycle 1st generation, 10.4 mg, 0.013 mmol), trimethylacetic acid (40.1 mg, 0.392 mmol) and potassium carbonate (54.2 mg, 0.392 mmol). The microwave vial was scaled, purged and back-filled with nitrogen. The reaction mixture subjected to microwave irradiation for 2 h at 150° C. Upon completion the reaction was diluted with EtOAc, and washed with water and brine. The combined organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a red brown residue which was purified by column chromatography (SiO2, 0-30% EtOAc/heptane) to afford (E)-tert-butyl 3-(4-((6-methoxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3 yl)oxy)phenyl)acrylate (59.4 mg, 0.11 mmol, 86% yield). 1H NMR (400 MHz, CD3OD) δ ppm=1.42-1.61 (m, 9 H), 3.77-3.98 (m, 3 H), 6.31 (d, J=15.66 Hz, 1 H), 6.87-7.04 (m, 3 H), 7.28 (d, J=9.09 Hz, 1 H), 7.46 (d, J=2.53 Hz, 1 H), 7.47-7.57 (m, 3 H), 7.65 (d, J=8.08 Hz, 2 H), 7.89 (d, J=8.08 Hz, 2 H), LC/MS (m/z, MH+): 471.40.