Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[CH3:12][CH:13]([CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1)=[O:15].C(N(C(C)C)CC)(C)C.N>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)Cl.O1CCOCC1>[OH:5][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:2][N:26]1[CH2:27][CH2:28][CH:23]([C:19]2[CH:18]=[C:17]([NH:16][C:14](=[O:15])[CH:13]([CH3:12])[CH3:29])[CH:22]=[CH:21][CH:20]=2)[CH2:24][CH2:25]1
Reactant: O[C@@H](CCCl)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Temperature: 90 °C
Reaction time: 72 h
Yield: 40.2 %

Procedure:
A mixture of (S)-(−)-3-chloro-1-phenyl-1-propanol (0.426 g, 2.50 mmol, 99%ee), 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (0.565 g, 2.00 mmol), diisopropylethylamine (1.29 g, 10.0 mmol), dioxane (5.0 mL) and catalytic amount of tetrabutylammonium iodide was stirred at 90° C. for 72 hrs. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (306 mg, 39.3% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.42 (d, 4H, J=8.1 Hz), 7.35 (m, 1H), 7.30 (d, 1H, J=8.0 Hz), 7.23 (t, 1H, J=8.1 Hz), 7.12 (s, 1H), 6.96 (apparent dd, 1H, J=8.0 Hz), 5.0 (apparent dd, 1H, J=4.4, 8.3 Hz), 3.18 (apparent dd, 2H, J=2.5, 12.5 Hz), 2.74 (m, 2H), 2.50 (m, 2H), 2.3-2.1 (m, 6H), 1.8 (m, 2H), 1.25 (d, 6H, J=7.1 Hz); ESMS m/e: 389.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])=[C:11]3[CH2:22][CH2:23][CH2:24][C:10]3=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27](=[O:37])[C:28]1[CH:33]=[C:32]([CH3:34])[C:31](O)=[C:30]([CH3:36])[CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:25][O:26][C:27](=[O:37])[C:28]1[CH:29]=[C:30]([CH3:36])[C:31]([O:15][CH2:14][CH:13]([C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=[C:10]3[CH2:24][CH2:23][CH2:22][C:11]=23)[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:32]([CH3:34])[CH:33]=1
Reactant: COC(=O)c1cc(C)c(O)c(C)c1
Reactant: OCC(c1c2c(nn1-c1ccc(Cl)cc1)CCC2)C1CCCCC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(OCC(c2c3c(nn2-c2ccc(Cl)cc2)CCC3)C2CCCCC2)c(C)c1
Temperature: 0 °C
Reaction time: 48 h
Yield: 13 %

Procedure:
To a solution of 2-[2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-2-cyclohexyl-ethanol (100 mg, 290 umol) in THF (2 ml) was added 4-hydroxy-3,5-dimethyl-benzoic acid methyl ester (57 mg, 319 umol; CAS Reg. No. 34137-14-9) and tri-phenylphosphine (91 mg, 348 umol) at ambient temperature under an argon atmosphere. The mixture was cooled to 0° C., di-tert-butyl azodicarboxylate (80 mg, 348 umol) was added and the suspension was stirred for 48 h at ambient temperature. The solvent was removed under reduced pressure to give a solid which was purified by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water to obtain the title compound (19 mg, 37 umol; 13%) as yellow solid. MS: m/e=507.2 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25]CC)=[O:24])=[C:16]3[N:15]=2)[C:5]([CH3:8])=[N:6][CH:7]=1.C1COCC1.CO.O.[OH-].[Li+]>O>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[C:16]3[N:15]=2)[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3C)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
To a solution of (R)-ethyl 5-(2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (480 mg, 1.3 mmol) in a 1:1:1 mixture of THF:MeOH:water (30 mL) was added lithium hydroxide monohydrate (164 mg, 3.9 mmol). The mixture was stirred at ambient temperature for 16 hours then concentrated to ⅓ volume, acidified to pH 3 with 1N HCl and extracted with EtOAc (3×30 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated to afford the title product as a white solid (381 mg, 86% yield). MS (apci) m/z=342.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([CH3:13])([CH3:12])[C:10]#[N:11].[OH-:14].[Na+].OO>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([CH3:13])([CH3:12])[C:10]([NH2:11])=[O:14]
Reactant: CC(C)(C#N)c1c(F)cccc1F
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Product: CC(C)(C(N)=O)c1c(F)cccc1F

Procedure:
Hydrolysis of 2-(2,6-difluorophenyl)-2-methylpropionitrile was performed according to the procedure of Example 10 using sodium hydroxide in the presence of hydrogen peroxide to provide 2-(2,6-difluorophenyl)isobutyramide [1H-NMR (CDCl3): δ 7.34-7.29 (m, 1H), 6.91-6.85 (m, 2H), 6.43 (br s, 1H), 5.73 (br s, 1H), 1.68-1.66 (m, 6H)].
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][CH:5]([CH3:25])[C:6]([C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[F:21])[N:11]=[C:10]([CH3:22])[C:9]=1[C:23]#[N:24])=[O:7].C(O)(C(F)(F)F)=O.O>C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+].C(Cl)Cl>[F:21][C:14]1[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=1[N:12]1[C:8]([C:6](=[O:7])[CH:5]([CH3:25])[CH2:4][CH:3]=[O:2])=[C:9]([C:23]#[N:24])[C:10]([CH3:22])=[N:11]1
Reactant: COc1ccc(-n2nc(C)c(C#N)c2C(=O)C(C)CC(OC)OC)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-n2nc(C)c(C#N)c2C(=O)C(C)CC=O)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
A solution of 5-(4,4-dimethoxy-2-methylbutanoyl)-1-(2-fluoro-4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (33 mg, 0.09 mmol) in CHCl3 (1.5 mL) was added TFA (0.4 mL) and water (0.4 mL) and the reaction was stirred 3 h at room temperature. The mixture was diluted with saturated aqueous solution of NaHCO3 and CH2Cl2. The organic phase was separated and the aqueous phase was extracted with CH2Cl2. The organic phase was then washed with saturated aqueous solution of NaHCO3. The combined extracts were dried with a phase separator and concentrated. The desired 1-(2-fluoro-4-methoxyphenyl)-3-methyl-5-(2-methyl-4-oxobutanoyl)-1H-pyrazole-4-carbonitrile (29 mg, 100%) was obtained and used immediately in the next step.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][C:6]1[N:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.Br[C:15]1[C:16](=[O:23])[N:17]([CH3:22])[N:18]=[C:19]([Cl:21])[CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.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]>[Cl:21][C:19]1[CH:20]=[C:15]([NH:12][C:9]2[CH:8]=[N:7][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:13])[CH3:1])=[CH:11][N:10]=2)[C:16](=[O:23])[N:17]([CH3:22])[N:18]=1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: CN(C)CCOc1cnc(N)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN(C)CCOc1cnc(Nc2cc(Cl)nn(C)c2=O)cn1
Temperature: 105 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
In a 15 mL microwave reaction vial was added a solution of 5-(2-(dimethylamino)ethoxy)pyrazin-2-amine (190 mg, 1.04 mmol, Eq: 1.00) in dioxane (7 ml) under argon. 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (303 mg, 1.36 mmol, Eq: 1.3), Cs2CO3 (1.02 g, 3.13 mmol, Eq: 3), xantphos (90.5 mg, 156 μmol, Eq: 0.15) and bis(dibenzylideneacetone)palladium (45.0 mg, 78.2 μmol, Eq: 0.075) were added and the reaction tube was heated in an oil bath at 105° C. (bath temp) for 7 hrs followed by stirring at room temperature overnight. The reaction mixture was filtered and the solid was washed with dioxane (20 mL) and DCM (5 mL). The combined filtrate and washes was concentrated. The residue was purified by LC chromatography eluting with 0-10% (10% NH4OH in MeOH) in (1/1) EtOAc/heptane to afford 339 mg (67%) of the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH2:21]([NH2:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:21]([NH:27][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Reactant: CCCCCCN
Product: CCCCCCNCc1ccc(Oc2ccc(C(N)=O)cn2)c(OC)c1
Yield: 72.8 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and hexylamine (0.0186 g, 0.184 mmol) gives the title compound (0.0479 g, 73.0%): TOF MS ES+ 358.2 (M+H)+, HRMS calcd for C20H28N3O3 358.2131 (M+H)+, found 358.2124, time 0.41 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=7.4 min, 100% purity.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6](O)[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([NH:16]N)[CH:13]=[CH:14][CH:15]=1>C1(OC2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]2[C:7]3[C:2](=[O:1])[NH:3][CH:4]=[CH:5][C:6]=3[NH:16][C:12]=2[CH:11]=1
Reactant: Oc1ccnc(O)c1
Reactant: NNc1cccc(Cl)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=c1[nH]ccc2[nH]c3cc(Cl)ccc3c12
Temperature: 175 °C
Reaction time: 3 h

Procedure:
To 2,4-dihydroxypyridine (25.0 g, 225 mmol) in phenyl ether (400 mL) in a three neck flask fitted with a Dean-Stark trap was added 3-chlorophenylhydrazine. The reaction mixture was heated to 175° C. for 1 h, and to 230° C. for 3 h. The reaction mixture was allowed to cool to room temperature and diluted with toluene. The mixture was filtered, washed with MeOH, and dried. The collected solids were ground to fine power, slurried in MeOH, and sonicated for 5 min. The slurry was filtered, washed with MeOH, and dried to give the title compound. 1H NMR (600 MHz, CD3SOCD3) δ 11.83 (s, 1H); 11.19 (s, 1H); 8.05 (d, 1H); 7.53 (d, 1H); 7.32 (t, 1H); 7.21 (dd, 1H); 6.52 (d, 1H). LRMS (APCI) calc'd for (C11H7ClN2O) [M+H]+, 219.0. found 219.1.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2.[C:15]([O-:18])(=[S:17])[CH3:16].[K+]>CC(C)=O>[N:11]1[C:12]2[C:7](=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][S:17][C:15](=[O:18])[CH3:16])=[CH:14][CH:13]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: ClCCCc1ccc2ncccc2c1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)SCCCc1ccc2ncccc2c1
Yield: 71.9 %

Procedure:
A solution of 0.41 g (2.0 mmol) 6-(3-chloro-propyl)-quinoline and 287 mg (2.5 mmol) potassium thioacetate in 8 ml acetone was heated to reflux for 8 hours. The mixture was concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, gradient of 0 to 2% methanol in DCM) to afford 353 mg (71%) of dark orange oil. MS(ISP): 246.3 [MH]+
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:10]=[C:9]([S:11][CH3:12])[N:8]([CH3:13])[N:7]=1.O.O.Cl[Sn]Cl.[OH-].[Na+]>O.Cl>[NH:5]([C:6]1[CH:10]=[C:9]([S:11][CH3:12])[N:8]([CH3:13])[N:7]=1)[NH2:1]
Reactant: CSc1cc(N)nn1C
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CSc1cc(NN)nn1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
1.1 g (15.8 mmol) sodium nitrite in 4 ml water was added dropwise to 1.9 g (13.1 mmol) 3-amino-1-methyl-5-methylmercaptopyrazole in 28 ml concentrated hydrochloric acid at 0° C. and the mixture stirred for 2 hours at 0° C. Then, at -30° C., a solution of 7.4 g (32.8 mmol) SnCl2.2H2O in 5.5 ml concentrated hydrochloric acid was added dropwise and the mixture stirred for 3 hours at this temperature. The reaction mixture was then made basic with 32% caustic soda and extracted with methylene chloride. The organic phase was dried over sodium sulfate and concentrated. 2.0 g of product was obtained which was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[CH2:23]([S:25]([N:28]1[CH2:31][C:30](=[CH:32][C:33]#[N:34])[CH2:29]1)(=[O:27])=[O:26])[CH3:24].C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:23]([S:25]([N:28]1[CH2:29][C:30]([CH2:32][C:33]#[N:34])([N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)[CH2:31]1)(=[O:26])=[O:27])[CH3:24]
Reactant: CCS(=O)(=O)N1CC(=CC#N)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a suspension of 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 440 g, 1.395 mol) and 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (11, 312.4 g, 1.68 mol, 1.2 equiv) in acetonitrile (4.4 L) was added DBU (249.8 mL, 1.67 mol, 1.2 equiv) drop wise to keep the reaction temperature between 15-25° C. After adding DBU, the reaction mixture became homogeneous, but a precipitate appeared in 30 min. The reaction mixture was stirred for 3 h at room temperature. When HPLC showed that the reaction was deemed complete, the reaction mixture was quenched with water (11 L). The resulting mixture was stirred at room temperature for additional 30 min and then filtered. The solid cake was washed with water (4 L), MTBE (2 L) and dried in vacuum oven at 35° C. for 24 h to afford crude 2-(1-(ethylsulfonyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (12, 681 g, 699.8 g theoretical, 97.3% yield) as white solids, which was found to be sufficiently pure for the subsequent reaction without further purification. For 12: 1HNMR (CDCl3, 300 MHz), δ 8.86 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 7.43 (d, 1H), 6.80 (d, 1H), 5.68 (s, 2H), 4.65 (d, 2H), 4.27 (d, 2H), 3.55 (s, 2H), 3.4 (t, 2H), 3.07 (m, 2H), 1.42 (m, 3H), 0.92 (m, 2H), −0.05 (s, 9H) ppm; C22H31N7O3SSi (MW, 501.68), LCMS (EI) m/e 502 (M++H).
Reaction SMILES: BrC(Br)C.[F:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Br)=[CH:8][CH:7]=1.Br[C:15]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]>O1CCCC1.[Zn].C[Si](Cl)(C)C>[N+:25]([C:22]1[CH:21]=[C:16]([C:15]([CH2:10][C:9]2[CH:12]=[CH:13][C:6]([F:5])=[CH:7][CH:8]=2)=[CH:24][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])([O-:27])=[O:26]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: Fc1ccc(CBr)cc1
Agent: CC(Br)Br
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: COC(=O)c1cc([N+](=O)[O-])ccc1Cc1ccc(F)cc1
Temperature: 67 °C
Reaction time: 0.5 h
Yield: 132.2 %

Procedure:
Zinc dust (14.2 g, 217.2 mmol) and tetrahydrofuran (17 ml) were sonicated under argon for 30 minutes. Dibromoethane (2.1 ml, 24.38 mmol) was added and the mixture heated to 67° C. for 1 minute, cooled to 25° C. and trimethylsilyl chloride (2.5 ml, 19.58 mmol) added. After initial effervescence and exotherm, the mixture was stirred at ambient temperature for 30 minutes. 3M 4-Fluorobenzyl bromide (26 ml, 212 mmol) in tetrahydrofuran (70 ml) was added dropwise with exotherm and stirred at ambient temperature for 1.5 hours. To this a solution of tris(dibenzylideneacetone)palladium(0) (1.3 g, 1.42 mmol) and methyl 2-bromo-5-nitrobenzoate (44 g, 170 mmol) in tetrahydrofuran (550 ml) was added dropwise, under argon, over 30 minutes with exotherm and stirred at ambient for 18 hours. The mixture purified on silica (eluting with ethyl acetate), washed with brine (200 ml) and water (200 ml), dried (magnesium sulphate) and evaporated to give methyl 3-nitro-6-(4-fluorobenzyl)benzoate (65 g) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-Cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A157) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[C:26]([F:29])[C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH2:12][NH:11][C:10]1=[O:36].[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[C:26]([F:29])[C:27]=3[CH3:28])[C:22]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:24])[C:13]=2[CH2:12][NH:11][C:10]1=[O:36]
Reactant: Nc1ccccc1
Reactant: Cc1c(F)cc(C(=O)O)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: Cc1c(F)cc(C(=O)Nc2ccccc2)cc1-c1nc(NCCN(C)C)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 34.7 %

Procedure:
To the solution of 3-(8-(2,6-difluorophenyl)-2-{[2-(dimethylamino)ethyl]-amino}-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl)-5-fluoro-4-methylbenzoic acid (25 mg, 0.05 mmol) in CH2Cl2 (2 mL) were added aniline (0.025 mL, 0.25 mmol) and HBTU (20 mg, 0.053 mmol). The reaction mixture was stirred over night. The reaction mixture was concentrated. Separation via a HPLC with TFA followed by treatment with t-amino SPE cartridge then provided the title compound as a white solid (10 mg, 35%). LC-MS m/z 576 (M+H)+; 1H-NMR (MeOD) δ 2.27 (s, 3H), 2.79 (s, 6H), 3.15 (m, 2H), 3.55 (m, 2H), 4.21 (s, 2H), 7.19 (m, 3H), 7.39 (m, 2H), 7.54 (m, 1H), 7.71 (m, 3H), 7.86 (m, 1H).
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:46]2[N:47]=[C:48]([NH:51]C=O)[S:49][CH:50]=2)[C:7]([NH:9][C@@H:10]2[C:44](=[O:45])[N:12]3[C:13]([C:28]([O:30][CH:31]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:29])=[C:14]([CH2:17][S:18][C:19]4[N:24]([CH3:25])[C:23](=[O:26])[C:22](=[O:27])[NH:21][N:20]=4)[CH2:15][S:16][C@H:11]23)=[O:8])[CH2:3][CH2:2]1.Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CO.O1CCCC1>[NH2:51][C:48]1[S:49][CH:50]=[C:46]([C:6](=[N:5][O:4][CH:1]2[CH2:2][CH2:3]2)[C:7]([NH:9][C@@H:10]2[C:44](=[O:45])[N:12]3[C:13]([C:28]([O:30][CH:31]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[O:29])=[C:14]([CH2:17][S:18][C:19]4[N:24]([CH3:25])[C:23](=[O:26])[C:22](=[O:27])[NH:21][N:20]=4)[CH2:15][S:16][C@H:11]23)=[O:8])[N:47]=1
Reactant: Cn1c(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)C(=NOC4CC4)c4csc(NC=O)n4)[C@H]3SC2)n[nH]c(=O)c1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1c(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)[C@@H](NC(=O)C(=NOC4CC4)c4csc(N)n4)[C@H]3SC2)n[nH]c(=O)c1=O
Temperature: 35 °C
Yield: 33.6 %

Procedure:
To a suspension of benzhydryl 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(5,6-dioxo-4-methyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer) (1.10 g) in a mixture of methanol (7.5 ml) and tetrahydrofuran (4 ml) was added concentrated hydrochloric acid (0.44 ml) and the mixture was stirred at 35° C. for an hour. The mixture was poured into a mixture of ethyl acetate (100 ml) and ice-water (100 ml) and adjusted to pH 7 with saturated aqueous solution of sodium bicarbonate. The organic layer was separated, washed with saturated aqueous solution of sodium chloride and water successively and concentrated in vacuo. The residue was subjected to column chromatography on silica gel (30 g) using a mixture of chloroform and methanol (30:1 V/V) as an eluent to give benzhydryl 7β-[2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetamido]-3-(5,6-dioxo-4-methyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl)thiomethyl-3-cephem-4-carboxylate (syn isomer) (356 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1>C(N(CC)CC)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][N:25]([CH2:8][C:7]3[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1cccc(N2CCN(Cc3ccc([N+](=O)[O-])cc3)CC2)c1

Procedure:
In the manner given in Example 1A, p-nitrobenzyl chloride is reacted with (m-methoxyphenyl)piperazine dihydrochloride in the presence of triethylamine to give 1-(m-methoxyphenyl)-4-(p-nitrobenzyl)piperazine.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[C:8]([CH3:17])=[C:9]([N+:14]([O-:16])=[O:15])[C:10](=[O:13])[NH:11][CH:12]=1)(C)C.[F-]>C1COCC1.C(OCC)(=O)C>[C:6]([C:7]1[C:8]([CH3:17])=[C:9]([N+:14]([O-:16])=[O:15])[C:10](=[O:13])[NH:11][CH:12]=1)#[CH:5]
Reactant: Cc1c(C#C[Si](C)(C)C)c[nH]c(=O)c1[N+](=O)[O-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#Cc1c[nH]c(=O)c([N+](=O)[O-])c1C
Yield: 37.4 %

Procedure:
To a stirred solution of 5-trimethylsilylethynyl-4-methyl-3-nitro-2-pyridone (1.0 g, 2.7 mmol) in THF (10 mL) was added tetrabutylammoniun fluoride (1M in THF, 2 mL). After 30 minutes the mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. Chromatography of the residue over silica gel (40% ethyl acetate/hexane) gave 5-ethynyl-4-methyl-3-nitro-2-pyridone (0.18 g, 22%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([OH:13])[CH3:12])[CH:7]=[CH:8][C:9]=1[Cl:10].[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([O:13][C:19]2[CH:20]=[CH:21][CH:22]=[C:15]([F:14])[C:16]=2[C:17]#[N:18])[CH3:12])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: CC(O)c1ccc(Cl)c(Cl)c1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1cccc(F)c1C#N)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
To a cold (ice water) suspension of sodium hydride (316 mg; 7.9 mmol) in anhydrous DMF (10 mL) is added a solution of 1-(3,4-dichlorophenyl)-ethanol (1.40 g; 7.3 mmol) in anhydrous DMF (5 mL) over 30 minutes. After allowing to room temperature over 30 minutes, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (1.0 g; 7.2 mmol) in anhydrous DMF (15 mL), and allowed to room temperature over 2 hours. The reaction mixture is poured into ice water with vigorous stirring and extracted with ethyl acetate. The organics are separated and dried over magnesium sulfate. The solvent is removed and the resulting oil is dried under vacuum at 30° C. overnight to give 1.93 gm of 2-[1-(3,4-dichlorophenyl)-ethoxy]-6-fluorobenzonitrile.