Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH:19]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1.[Br:29][CH2:30][CH2:31]Br>C1COCC1>[Br:29][CH2:30][CH2:31][C:19]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: BrCCBr
Reactant: CCOC(=O)C1CCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCBr)CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
To an ice cold solution of diisopropylamine (56 mL, 0.396 mol) in THF (85 mL) was added n-butyl lithium in hexane solution (240 mL, 1.6 M, 0.393 mol) over 20 min. The mixture was stirred at 0° C. for 30 min, cooled to a bath temperature of −65° C. and ethyl cyclopentanecarboxylate (37.4 g, 0.263 mol) in THF (50 mL) was added over 20 min. After 1 h, a solution of 1,2-dibromoethane (47 mL, 0.545 mol) in THF (50 mL) was added, the mixture was held at −65° C. for 3 h and then was allowed to warm to room temperature overnight. After the reaction was quenched by addition of saturated ammonium chloride solution (200 mL), the layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined extracts were washed with 1:1 brine:water (250 mL) and were dried (Na2SO4). The solution was filtered, concentrated in vacuo then the residue was diluted with toluene (100 mL) and concentrated. The dilution and concentration cycle was repeated twice to give ethyl 1-(2-bromoethyl)cyclopentanecarboxylate (52.5 g).
Reaction SMILES: I[C:2]1[N:25]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:10]3[C:11]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=4)=[N:12][N:13]([CH3:15])[CH:14]=3)=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[N:45][C:46]([N:49]3[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]3)=[N:47][CH:48]=2)O1.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:15][N:13]1[CH:14]=[C:10]([C:9]2[CH:8]=[CH:7][N:6]=[C:5]3[N:25]([S:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)(=[O:27])=[O:28])[C:2]([C:43]4[CH:48]=[N:47][C:46]([N:49]5[CH2:50][CH2:51][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:53][CH2:54]5)=[N:45][CH:44]=4)=[CH:3][C:4]=23)[C:11]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:12]1
Reactant: Cn1cc(-c2ccnc3c2cc(I)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Cn1cc(-c2ccnc3c2cc(-c2cnc(N4CCN(C(=O)OC(C)(C)C)CC4)nc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 95 °C

Procedure:
To a solution of 2-iodo-4-[1-methyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.321 mmol) and 1,1-dimethylethyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyrimidinyl]-1-piperazinecarboxylate (0.353 mmol) in 1,4-dioxane (3 ml) was added saturated NaHCO3(aq) (0.85 ml). After degassing with argon for 10 minutes, dichlorobis(triphenylphosphine) palladium(II) (0.0161 mmol) was added and the resulting mixture was heated at 95° C. overnight. Upon cooling, the reaction was concentrated and partitioned between EtOAc and H2O. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated to yield the title compound as a yellow oil (quant.). ESMS [M+H]+: 722.2.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=O)=O.[CH:36](O)([CH3:38])[CH3:37]>O1CCCC1>[CH2:37]([O:4][CH2:3][CH:2]([NH2:1])[CH2:5][O:6][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])[CH2:36][CH2:38][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: CCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: NC(CO)CO
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOCC(N)COCCCCCCCCCCCCCCCC
Temperature: 25 °C

Procedure:
A solution of 2-amino-1,3-propanediol (Serinol: Aldrich Chem. Co., Milwaukee, Wis.; Catalog No. 35,789-8) in tetrahydrofuran (THF) is added dropwise with vigorous stirring to a slurry of sodium hydride in THF over a period of 1-2 hrs. The reaction mixture is stirred for an additional 30 minutes to 1 hr at room temperature. Hexadecyl tosylate in THF is added dropwise to the mixture with vigorous stirring over a period of 1-1.5 hrs. The reaction mixture is stirred at room temperature for 1 hr and worked up by addition of isopropanol to destroy excess sodium hydride. The reaction mixture is extracted with chloroform (3×100 mL) and the combined chloroform layers are washed with water (2×50 mL), saturated NaCl (1×50 mL) and dried (MgSO4). The dried chloroform layer is evaporated under vacuum to afford the product as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:10][CH2:9][CH2:8][N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2].[CH3:30][N:31](C)C=O>C1(C)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N>[CH2:1]([O:3][C:4]([C:6]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:10][CH2:9][CH2:8][N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:30]#[N:31])=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc(Br)cc2)nc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc(C#N)cc2)nc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of 1-[6-(4-bromo-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.28 g, 0.53 mmol), zinc cyanide (0.037 g, 0.32 mmol), tetrakistriphenylphosphine palladium (0) (0.024 g, 0.021 mmol) and 0.66 mL of dimethylformamide was heated to 80° C. for 24 hours. An additional 37 mg of zinc cyanide and 24 mg of tetrakistriphenylphosphine palladium (0) was added and the mixture was stirred at 80° C. for an additional 48 hours. After cooling to room temperature, the mixture was diluted with toluene and was washed with 2M ammonium hydroxide (twice), brine, dried over sodium sulphate, filtered and concentrated in vacuo. Purification by radial chromatography (ethyl acetate-hexanes, then methanol) afforded 58 mg of 1-[6-(4-Cyano-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester as a colorless syrup. 1H NMR (CDCl3, 500 MHz): 8.07 (d, 1H, J=3.5 Hz), 7.80 (dd, 1H, J=2.5, 9.0 Hz), 7.69 (d, 2H, J=9.0 Hz), 7.25 (d, 2H, J=9.0 Hz), 7.02 (d, 1H, J=9.0 Hz), 4.21 (q, 4H, J=7.5 Hz), 2.74 (m, 2H), 2.66 (m, 2H), 1.19 (t, 6H, J=7.0 Hz) ppm. MS (APCl, m/z): 424 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[N:34]=[C:33]([C:35]([N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)=[O:36])[CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[CH:31][CH:32]=[C:33]([C:35]([N:37]5[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]5)=[O:36])[N:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CN1CCN(C(=O)c2cccc(Br)n2)CC1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(C(=O)N5CCN(C)CC5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 290, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and (6-bromo-pyridin-2-yl)-(4-methyl-piperazin-1-yl)-methanone.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCCl.[Br:20]Br.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Br:20][C:8]([CH3:9])=[C:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrBr
Reactant: CC=C(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(Br)=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
Into a reactor were introduced 19.4 g (100 mmol) of the 1,1-diphenylpropene and 78 mL of 1,2-dichloroethane under a nitrogen atmosphere. The contents were cooled to 0° C., and 15.9 g (100 mmol) of bromine was gradually added dropwise thereto. The resultant mixture was stirred at room temperature for 1 hour. Thereafter, 32.4 mL (400 mmol) of pyridine and 156 mL of toluene were added thereto and this mixture was stirred at 80° C. for 3 hours. After being cooled, the reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. Thereafter, the solvent was removed under reduced pressure. The concentrate was purified by column chromatography and then recrystallized from methanol to obtain 14.5 g (53%) of the target compound as white crystals.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:14]=3[O:13][CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[C:30](#[N:32])[CH3:31]>CC(N(C)C)=O.O>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:16][C:15]3[CH:17]=[C:18]([C:31]4[CH:30]=[N:32][C:8]([NH2:10])=[N:5][CH:4]=4)[CH:19]=[CH:20][C:14]=3[O:13][CH2:12][CH2:11]2)=[O:9])[CH2:4][CH2:3]1
Reactant: CC#N
Reactant: CC1CCN(C(=O)N2CCOc3ccc(B(O)O)cc3C2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC1CCN(C(=O)N2CCOc3ccc(-c4cnc(N)nc4)cc3C2)CC1
Temperature: 95 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 2-amino-5-bromopryimidine (65 mg, 0.37 mmol), {4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-yl}boronic acid (100 mg, 0.31 mmol) and potassium carbonate (215 mg, 1.6 mmol) in DMA (5.0 mL) and water (0.5 mL) was added dichloro[1,1-bis(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (23 mg, 0.03 mmol). The reaction mixture was stirred at 95° C. for 2.5 hours and then partitioned between dichloromethane (10 mL) and 1M aqueous sodium hydroxide (10 mL). The organic layer was separated and washed with brine (10 mL) then dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was chromatographed on silica gel using 2% methanol in dichloromethane as eluent and the combined product containing fractions were concentrated. The residue thus obtained was taken into a minimum of acetonitrile and purified by preparative reverse phase HPLC to afford 5-{4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}pyrimidin-2-amine (24 mg) as an amorphous solid. 1H NMR (400 mHz, DSMO-d6): 8.51 (s, 2H), 7.47 (d, 1H), 7.42 (dd, 1H), 6.98 (d, 1H), 6.75 (s, 2H), 4.39 (s, 2H), 4.12-4.18 (m, 2H), 3.46-3.59 (m, 4H), 2.70 (t, 2H), 1.42-1.61 (m, 3H), 1.04-1.18 (m, 2H), 0.91 (d, 3H); MS (EI) for C20H25N5O2: 368 (MH+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:7][C:6]=1[N+:17]([O-])=O.[H][H]>[Ni].C(O)C>[F:1][C:2]([F:20])([F:21])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:7][C:6]=1[NH2:17]
Reactant: O=[N+]([O-])c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reaction time: 5 h

Procedure:
a mixture of 59 g. (0.185 mole) of 2,5-bis-(2,2,2-trifluoroethoxy)nitrobenzene, about 15 g. of Raney nickel and 1200 ml. of ethanol is hydrogenated by shaking on a Parr hydrogenation apparatus with a hydrogen pressure of 40 to 50 p.s.i. for about five hours. The mixture is filtered, and the filtrate is evaporated to a liquid residue. The residue is distilled to provide 2,5-bis(2,2,2-trifluoroethoxy)aniline as a clear, colorless liquid, b.p. 95°-98° C/0.35 mm Hg.
Reaction SMILES: C(OC1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6]C=1Br)C.[Mg].II.[Cl:15][C:16]1[CH:27]=[CH:26][C:19]2[N:20]=[C:21]([CH3:25])[O:22][C:23](=[O:24])[C:18]=2[CH:17]=1.[CH2:28]1[CH2:32][O:31][CH2:30][CH2:29]1>>[Cl:15][C:16]1[CH:27]=[CH:26][C:19]([NH:20][C:21](=[O:22])[CH3:25])=[C:18]([C:23](=[O:24])[C:6]2[CH:7]=[C:8]([F:10])[CH:9]=[CH:29][C:30]=2[O:31][CH2:32][CH3:28])[CH:17]=1
Reactant: C1CCOC1
Reactant: CCOc1cc(F)ccc1Br
Reactant: Cc1nc2ccc(Cl)cc2c(=O)o1
Agent: II
Agent: [Mg]
Product: CCOc1ccc(F)cc1C(=O)c1cc(Cl)ccc1NC(C)=O
Temperature: -20 °C
Yield: 58 %

Procedure:
Making Grignard reagent: A solution of 2-ethoxy-4-fluorophenyl bromide (30 g, 138 mmol) in THF (140 ml) was added dropwisely into a stirred mixture of magnesium flake and catalytically amount of iodine under nitrogen. The result mixture was heated to reflux for 15 minutes and cooled to room temperature (Grignard reagent). In a separated flask, 6-chloro-2-methyl-4H-benzo[d][1,3]oxazin-4-one (25 g, 128 mmole) was dissolved into THF (200 ml) and stirred under nitrogen. The Grignard reagent was transferred slowly into the flask during 30 minutes. The reaction temperature was kept below 55° C. during addition. The result mixture was stirred for further 2 hours under nitrogen. The reaction was quenched by slowly addition of aqueous solution of ammonium chloride (30 g/300 ml). The reaction was extracted into MTBE (500 ml). The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated on a rotary evaporator to solid. The solid was sonicated for 5 minutes in ethyl acetate (250 ml) and filtered. The filtrate was concentrated on a rotary evaporator to about 70 ml and cooled at −20° C. for 4 hours. During this time, crystallized product came out and was collected by filtration (25 g, yield: 58%). 1H NMR (CDCl3): 11.2 (br, 1H), 8.73 (d, J=22 Hz, 1H), 7.49 (dd, J=24 Hz, 7 Hz, 1H), 7.38 (d, J=6 Hz, 1H), 7.2 (m, 1H), 7.07 (dd, J=20 Hz, 8 Hz, 1H), 6.93 (m, 1H), 3.97 (q, J=17 Hz, 2H), 2.27 (s, 1H), 1.13 (tr, J=17 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.C(O)(=O)C>O>[OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:3]=1[C:8](=[O:9])[N:20]([CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)[C:5]2=[O:7]
Reactant: COc1ccc(CN)cc1
Reactant: O=C1OC(=O)c2c(O)cccc21
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)c3cccc(O)c3C2=O)cc1
Temperature: 100 °C
Yield: 81.1 %

Procedure:
A mixture of 3-hydroxyphthalic anhydride (543 mg, 3.31 mmol), 4-methoxybenzylamine (0.43 mL, 3.31 mmol) and acetic acid (3 mL) was heated at 100° C. for 4 hours. The mixture was allowed to cool and diluted with water (20 mL). The white solid was collected by filtration, washed well with water and dried to give the title compound (760 mg, 81%). 1H NMR (DMSO-d6) 11.03 (1H, s), 7.61 (1H, dd), 7.28 (1H, d), 7.23-7.19 (3H, m), 6.89-6.86 (2H, m), 4.63 (2H, s), 3.71 (3H, s). MS: [M−H+] 282.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18]O)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].Cl.[CH3:27][N:28]([CH3:37])[CH2:29][CH2:30][N:31]1[C:35]([SH:36])=[N:34][N:33]=[N:32]1.P(OC)(OC)OC.Cl>C(N)=O.O.CCOCC>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH2:18][S:36][C:35]4[N:31]([CH2:30][CH2:29][N:28]([CH3:37])[CH3:27])[N:32]=[N:33][N:34]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(CC(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(CO)CS[C@H]23)cs1
Reactant: CN(C)CCn1nnnc1S
Agent: COP(OC)OC
Agent: Cl
Agent: [Na+]
Solvent: NC=O
Solvent: O
Solvent: CCOCC
Product: CN(C)CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3csc(N)n3)[C@H]2SC1
Reaction time: 1.5 h

Procedure:
In a mixture of 4 ml of formamide and 4 ml of acetonitrole was suspended 423 mg of sodium 7β-[2-(2-aminothiazol-4-yl)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylate.dihydrate. To the suspension were added in sequence 315 mg of 1-(2-dimethylaminoethyl)-5-mercapto-1H-tetrazole hydrochloride, 0.45 ml of trimethyl phosphite and 0.20 ml of ether solution of hydrogen chloride (5 mol./l). The mixture was stirred at 20~25° C. for 1.5 hour, and there was added 5 ml of water, followed by concentration under reduced pressure at 20 to 25° C. To the concentrated solution was added 50 ml of water, whose pH was adjusted to 5.8 with 1N NaOH, followed by subjecting the resultant to an Amberlite XAD-2 column chromatography, eluting with a mixture of water and acetone (4:1,v/v). Fractions containing the end product were combined, concentrated under reduced pressure and then freeze-dried to give 7β-[ 2-(2-aminothiazol-4-yl) acetamido]-3-[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid.
Reaction SMILES: CC([N:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9])C.[CH2:10]([Li])[CH2:11][CH2:12]C.CCCCCC.[C:21]1([CH2:27][CH2:28][C:29](Cl)=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[C:21]1([CH2:27][CH2:28][C:29]([N:4]2[C@H:8]([CH:11]([CH3:12])[CH3:10])[CH2:7][O:6][C:5]2=[O:9])=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [Li]CCCC
Reactant: CC(C)N1CCOC1=O
Reactant: O=C(Cl)CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)[C@@H]1COC(=O)N1C(=O)CCc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 82 %

Procedure:
To a stirred solution of 4 (2-propyl)-oxazo-lidine-2-one in anhydrous tetrahydrofuran (250 mL) under a nitrogen atmosphere at -78° C. were added in a dropwise fashion a solution of butyllithium in hexane (50 mL, 77.4 mmol) over 5 to 10 min. After stirring an additional 20 min at -78° C. 3-phenylpropionyl chloride (12.7 mL, 85.2 mmol) was added neat. The reaction was warmed to room temperature and stirred 1 to 2 h at the temperature. The reaction was quenched by adding 100 mL of saturated aqueous ammonium chloride and the volatiles removed by rotary evaporation. The resulting aqueous residue was extracted three times with ether and the combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Recrystallization from hexanes/ethyl acetate provided the title compound (16.6 g, 82%). mp =86.5 to 87.5° C. Mass spectrum: (M+NH4)+ =279, (M+H)+=262. Mass spectrum: (M+NH4)
Reaction SMILES: FC1[CH:3]=[C:4]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])C=1)[C:5]([N:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[O:22][CH3:23])[CH3:8])=[O:6].[F:31][C:32]([F:47])([F:46])[C:33]1C=C(C=C(C(F)(F)F)[N:41]=1)C(O)=O>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:7]([CH3:8])[C:5](=[O:6])[C:4]2[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[N:41]=[C:33]([C:32]([F:47])([F:46])[F:31])[CH:3]=2)=[C:16]([O:22][CH3:23])[CH:17]=1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-methyl-amine (example 129, intermediate) and 2,6-bis(trifluoromethyl) isonicotinic acid (Key Organics Ltd.) after a reaction time of 22 hours. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown solid (73%). MS (ESI): m/z=474.11 [M+H]+.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=[CH:11]2.[BrH:19]>OS(O)(=O)=O.CC(O)=O.O>[Br:19][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=[CH:11]2
Reactant: Nc1cccc2ccc(C(=O)O)cc12
Reactant: Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc2cccc(Br)c2c1
Temperature: 10 °C
Yield: 55 %

Procedure:
According to the procedure of W. Adcock, et al. Aust. J. Chem. 18, 1351 (1965) and H. H. Hodgson, et al. J. Chem. Soc., 1620 (1933), to a cooled (10° C.), stirred solution of NaNO2 (1.24 g, 0.0179 mol) in H2SO4 (16.1 mL) and HOAc (14.9 mL) [prepared by adding NaNO2 to cooled (10° C.) H2SO4, heating to dissolve, recooling, and adding HOAc] was added a solution of 8-amino-2-naphthoic acid (2.80 g, 0.0150 mol) in HOAc (50 mL) over 10 minutes. The resulting solution was added slowly (over 10 minutes) to a heated (60° C.), stirred solution of CuBr (9.44 g, 0.0658 mol) in concentrated HBr (90 mL). The mixture was warmed to 90° C. for 10 minutes, cooled, diluted with H2O (200 mL) and filtered to give a green solid, 3.4 g. The crude product was combined with similarly prepared material (450 mg) and recrystallized from EtOH to give an off-white solid (2.3 g, 55%), m.p. 265°-266° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([OH:28])=O)[N:9]=2)[CH:7]=1.Cl.[CH3:34][N:35]([CH3:45])[C:36](=[O:44])[CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:41]3[CH2:40][CH2:39][N:38]([CH2:37][C:36](=[O:44])[N:35]([CH3:34])[CH3:45])[CH2:43][CH2:42]3)=[O:28])[N:9]=2)[CH:7]=1
Reactant: CN(C)C(=O)CN1CCNCC1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid (100 mg) in DMF (4 mL) was added N,N-dimethyl-2-(piperazin-1-yl)acetamide hydrochloride (72 mg, 0.35 mmol), DIEA (67.2 mg, 0.52 mmol), HATU (79.2 mg, 0.21 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-005): Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% FA and MeCN (27.0% up to 36.0% in 10 min, up to 95.0% in 1 min, hold 95.0% in 1 min, down to 27.0% in 2 min); Detector, UV 254/220 nm. This resulted in 73.4 mg (64%) of the formic acid salt of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[(dimethylcarbamoyl)methyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 20) [M+H]+=616.3, RT=2.41 min. 1H NMR (400 MHz, CD3OD-d4) δ: (ppm) 9.09 (dd, 1H, J=1.6, 7.2 Hz), 8.66-8.64 (m, 2H), 8.37 (s, 1H), 8.11 (s, 1H), 7.68 (d, 1H, J=2.8 Hz), 7.57 (dd, 1H, J=2.8, 8.8 Hz), 7.42 (d, 1H, J=8.8 Hz), 7.21 (dd, 1H, J=4.4, 7.2 Hz), 6.63 (t, 1H, J=73.6 Hz), 5.29 (s, 2H), 3.84-3.77 (m, 4H), 3.75 (s, 2H), 3.08 (s, 3H), 3.06-2.96 (m, 7H).