Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.C([Li])CCC.[CH2:15]([N:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)C>[CH2:15]([N:22]1[CH2:26][CH2:25][C:24]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=2)([OH:27])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: Fc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: OC1(c2ccc(F)c(F)c2)CCN(Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
To a solution of 1-bromo-3,4-difluorobenzene (5.0 g, 25.9 mmol) in dry diethyl ether (40 mL), under nitrogen, was added dropwise at −78° C., n-butyllithium (2.5 M in hexane, 10.36 mL, 25.9 mmol). The mixture was stirred for 1 h after which a solution of 1-benzylpyrrolidin-3-one (3.63 g, 20.7 mmol) in dry diethyl ether (20 mL) was added drop wise. The resulting mixture was stirred for 1 h at −78° C. and then brought to ambient temperature. Aqueous sodium carbonate (10%, 50 mL) was added and the aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with brine, dried (MgSO4) and evaporated. Purification by flash column chromatography on silica gel (ethyl acetate/isooctane, 1:1) gave the title compound (3.6 g). MS m/z (rel. intensity, 70 eV) 289 (M+, 3), 198 (74), 133 (44), 132 (38), 91 (bp).
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:19]([O:21]C)=[O:20])[CH:15]=3)[CH:10]=2)[CH:3]=1>Cl>[ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:19]([OH:21])=[O:20])[CH:15]=3)[CH:10]=2)[CH:3]=1
Reactant: COC(=O)c1ccc2cc(Cc3cccnc3)ccc2c1
Agent: Cl
Product: O=C(O)c1ccc2cc(Cc3cccnc3)ccc2c1
Temperature: 25 °C

Procedure:
A solution of 205 mg of methyl 2-(3-pyridylmethyl)naphthalene-6-carboxylate hydrochloride in 15 ml of 6N hydrochloric acid was refluxed for 18 hours. The solution was cooled to room temperature and the precipitate filtered off, washed with cold 6N hydrochloric acid followed by acetone and air dried to give 2-(3-pyridylmethyl)naphthalene-6-carboxylic acid hydrochloride, m.p. 265°-270° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C@H:10]([C@@H:14]([N:16]([CH:24]=[O:25])[O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH3:15])[C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH3:70][NH:71][C:72](=[O:79])[C@@H:73]([NH2:78])[C:74]([CH3:77])([CH3:76])[CH3:75]>CN(C=O)C>[CH3:75][C:74]([CH3:77])([CH3:76])[C@H:73]([NH:78][C:11](=[O:13])[C@H:10]([CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C@@H:14]([N:16]([CH:24]=[O:25])[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[CH3:15])[C:72](=[O:79])[NH:71][CH3:70]
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: C[C@@H]([C@@H](CCCc1ccccc1)C(=O)O)N(C=O)OC1CCCCO1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H](NC(=O)[C@H](CCCc1ccccc1)[C@H](C)N(C=O)OC1CCCCO1)C(C)(C)C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a solution of (2R,3S)-2-(3-phenyl-1-propyl)-3-(formyl-2-tetrahydropyranyloxyamino)buta noic acid (5.5 g, 15.76 mmol) in DMF (20 mL) is added BOP reagent (7.66 g, 17.34 mmol), HOBt (2.34 g, 17.34 mmol), and NMM (4.78 g, 47.28 mmol). After 30 min, addition of (2S)-2-Amino-3,3-dimethylbutanoic acid methylamide (3.4 g, 23.64) occurs and the resulting solution is stirred at 25.degree. C. for 20 h. The reaction mixture is poured into ethyl acetate/hexanes (1:1, 200 mL) and washed sequentially with 1 M hydrochloric acid, 1 M aqueous sodium carbonate, and saturated aqueous sodium chloride. The organic layer is dried over magnesium sulfate, concentrated in vacuo, and purified by silica gel chromatography (elution with 2:1 ethyl acetate-hexane) to provide (2R,3S)-3-(Formyl-2-tetrahydropyranyloxyamino)-2-(3-phenyl-1-propyl)butanoic acid [(1S)-2,2-dimethyl-1-(methylcarbamoyl)-1-propyl]amide as a white solid (2.7 g, 36% yield).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]4[C:24]([O:26][C:27](=O)[C:20]=4[CH:19]=3)=[O:25])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:29]1([CH:36]=[CH:35][C:33]([OH:34])=[CH:32][CH:31]=1)[OH:30].C(O)(=O)C(O)=O>>[OH:30][C:29]1[C:36]2[C:24](=[O:25])[C:21]3[C:20](=[CH:19][C:18]([C:15]4[CH:14]=[CH:13][C:12]([C@H:9]5[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][CH2:8]5)=[CH:17][CH:16]=4)=[CH:23][CH:22]=3)[C:27](=[O:26])[C:35]=2[C:33]([OH:34])=[CH:32][CH:31]=1
Reactant: Oc1ccc(O)cc1
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc4c(c3)C(=O)OC4=O)cc2)CC1
Agent: O=C(O)C(=O)O
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc4c(c3)C(=O)c3c(O)ccc(O)c3C4=O)cc2)CC1

Procedure:
1.2 g of 4'-(trans-4-n-pentylcyclohexyl)-biphenyl-3,4-dicarboxylic acid anhydride, 2.0 g of hydroquinone and 10 g of oxalic acid are heated for 2 hours to 220°. After cooling, the 1,4-dihydroxy-6-[4-(trans-4-n-pentylcyclo-hexyl)-phenyl]-anthraquinone obtained is purified by recrystallization from ethanol.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:29]N1C(=O)CCC1=O.O>C(#N)C>[Br:29][C:18]1[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[CH3:19]
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of N-(3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (1.0 g, 2.63 mmol) obtained in Example 3 in acetonitrile (30 mL) was added N-bromosuccinimide (468 mg, 2.63 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The solvent was distilled off under reduced pressure. The obtained residue was recrystallized from ethanol to obtain 1.10 g (yield: 91%) of the title compound. Melting point: 191-193° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21]([OH:23])=[O:22])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]O)[CH:33]=1>>[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][O:22][C:21]([C:20]2[N:11]([CH2:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[C:12](=[O:31])[C:13]3[C:18]([C:19]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:17][C:16]([Br:30])=[CH:15][CH:14]=3)=[O:23])[CH:33]=1
Reactant: OCc1cccnc1
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Product: O=C(OCc1cccnc1)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2

Procedure:
The present compound was synthesized by a method similar to that in Example 200 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (300 mg) and 3-pyridinemethanol. Colorless crystals (288 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4([CH:25]([OH:27])[CH3:26])[CH2:24][CH2:23][NH:22][CH2:21]4)=[O:19])[CH:15]=3)[N:10]([C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl[CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57]2[CH:62]=[CH:61][C:60]([C:63]3[N:68]=[CH:67][CH:66]=[CH:65][N:64]=3)=[CH:59][N:58]=2)[CH2:53][CH:52]1[CH3:69])=[O:50]>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C:20]4([CH:25]([OH:27])[CH3:26])[CH2:24][CH2:23][N:22]([CH2:48][C:49]([N:51]5[CH2:56][CH2:55][N:54]([C:57]6[CH:62]=[CH:61][C:60]([C:63]7[N:64]=[CH:65][CH:66]=[CH:67][N:68]=7)=[CH:59][N:58]=6)[CH2:53][CH:52]5[CH3:69])=[O:50])[CH2:21]4)=[O:19])[CH:15]=3)[N:10]([C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(O)C1(C(=O)Nc2ccc3c(c2)c(-c2ccc(F)cc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)CCNC1
Reactant: CC1CN(c2ccc(-c3ncccn3)cn2)CCN1C(=O)CCl
Solvent: CN(C)C=O
Product: CC1CN(c2ccc(-c3ncccn3)cn2)CCN1C(=O)CN1CCC(C(=O)Nc2ccc3c(c2)c(-c2ccc(F)cc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)(C(C)O)C1
Yield: 84.5 %

Procedure:
Added N—N-Diisopropylethylamine (0.3 ml, 1.72 mmol) to a mixture of 3-(1-Hydroxy-ethyl)-pyrrolidine-3-carboxylic acid [3-(4-fluoro-phenyl)-1Trityl-indazol-5-yl]-amide (6N) (600 mg, 0.98 mmol) and 2-Chloro-1-[2-methyl-4-(5-pyrimidin-2-yl-pyridin-2-yl)-piperazin-1-yl]-ethanone (360 mg, 1.15 mmol) in DMF (10 ml) at room temperature. The solvent was evaporated and the residue extracted with MeCl2 (100 ml) and H2O (50 ml). The organic layer was separated, washed with saturated NaCl solution (20 ml), dried over MgSO4, filtered and solvent evaporated yielding 9N as a solid (750 mg, 84%) ESMS (MH, 906).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([N:7]([CH3:20])[C:8]1[N:9]=[C:10]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]2[C:16]=1[C:17](O)=[O:18])=[O:6].CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.[CH2:45]([NH2:55])[C:46]1[CH:54]=[CH:53][C:52]2[O:51][CH2:50][O:49][C:48]=2[CH:47]=1>C(Cl)Cl>[O:51]1[C:52]2[CH:53]=[CH:54][C:46]([CH2:45][NH:55][C:17]([C:16]3[N:11]4[CH2:12][CH2:13][CH2:14][CH2:15][C:10]4=[N:9][C:8]=3[N:7]([C:5](=[O:6])[C:4]3[CH:21]=[CH:22][CH:23]=[C:2]([Cl:1])[CH:3]=3)[CH3:20])=[O:18])=[CH:47][C:48]=2[O:49][CH2:50]1
Reactant: CN(C(=O)c1cccc(Cl)c1)c1nc2n(c1C(=O)O)CCCC2
Reactant: NCc1ccc2c(c1)OCO2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CN(C(=O)c1cccc(Cl)c1)c1nc2n(c1C(=O)NCc1ccc3c(c1)OCO3)CCCC2
Yield: 35.7 %

Procedure:
2-[(3-chloro-benzoyl)-methyl-amino]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-3-carboxylic acid (232 mg, 0.70 mmol), EDCI (146.6 mg, 0.76 mmol, 1.1 eq.) and HOAt (9.5 mg, 0.07 mmol, 0.1 eq.) were dissolved in DCM (10 mL). Piperonylamine (96 μL, 0.77 mmol, 1.1 eq.) was then added thereto. The reaction mixture was stirred over night and the solvent was then removed. EtOAc (70 mL) was added thereto and the reaction mixture was washed in succession with 0.5 M KHSO4 in water (70 mL) and saturated aqueous NaHCO3 solution (70 mL). The aqueous phases were extracted with EtOAc (30 mL). The combined organic phases were washed with saturated aqueous NaCl solution (70 mL), dried over sodium sulphate, and the solvent was removed under vacuum. The untreated product was purified by column chromatography (SiO2, DCM→DCM/2% MeOH). 116.8 mg (36%) of the desired product 2-[(3-chloro-benzoyl)-methyl-amino]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-3-carboxylic acid(benzo[1,3]dioxol-5-ylmethyl)-amide were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[F:14][C:15]([F:33])([F:32])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[F:14][C:15]([F:32])([F:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: FC(F)(F)CCCCCCCCCCCCCCCBr
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)Cc1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A solution of 8.2 g. of 4-aminophenylacetic acid, 150 ml. of absolute ethanol, and 3 ml. of boron trifluoride etherate is heated to reflux for 15 hours. The solution is concentrated by distillation and then evaporated to dryness in vacuo. The residue is dissolved in ethyl ether, washed with aqueous sodium bicarbonate dried and evaporated to yield ethyl 4-aminophenylacetate. A mixture of 5.0 g. of this amine, 9.4 g. of 15-(trifluoromethyl)pentadecyl bromide, 4.2 g. of anhydrous potassium carbonate and 40 ml. of hexamethylphosphoramide is heated at 80° C. for 7 hours. The mixture is then cooled, diluted with water, and extracted with ethyl ether. The ether extracts are washed with water, dried and evaporated. The residue is recrystallized from a mixture of chloroform and hexane, yielding ethyl 4-[15-(trifluoromethyl)pentadecylamino]phenylacetate. A mixture of 6.0 g. of this ester, 7.0 g. of potassium hydroxide and 100 ml. of ethanol-water is heated to reflux for 4 hours. While hot, the mixture is adjusted to pH 7 with concentrated hydrochloric acid. The mixture is diluted with water, cooled and filtered. Recrystallization of the precipitate yields the product as a white solid.
Reaction SMILES: [CH:1]1([N:4]([CH:31]2[CH2:33][CH2:32]2)[C:5]([C:7]2[N:28]([CH2:29][CH3:30])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][CH:22]=[C:23]([C:25]([OH:27])=O)[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:34][N:35](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:36].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CNC>CN(C=O)C>[CH:1]1([N:4]([CH:31]2[CH2:32][CH2:33]2)[C:5]([C:7]2[N:28]([CH2:29][CH3:30])[C:10]3=[N:11][C:12]([NH:19][C:20]4[S:21][CH:22]=[C:23]([C:25]([N:35]([CH3:36])[CH3:34])=[O:27])[N:24]=4)=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C(=O)O)cs3)nc21
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3nc(C(=O)N(C)C)cs3)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.4 %

Procedure:
To 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)thiazole-4-carboxylic acid (example 12A, 44 mg, 0.095 mmol) in DMF (2 ml) was added HATU (108 mg, 0.284 mmol), DIPEA (0.066 mL, 0.378 mmol), and dimethylamine (0.013 mL, 0.189 mmol). The reaction was stirred at rt for 3 h, then the solvent was removed in vacuo. The residue was purified by preparative HPLC to give 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-4-ylamino)-N,N-dimethylthiazole-4-carboxamide (10 mg, 21% yield) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]([O:30]C)=[O:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)(O)[O-].[Na+].C(O)(=O)C>O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]([OH:30])=[O:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC)c3csc(N)n3)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Reaction time: 7 h
Yield: 46.4 %

Procedure:
A mixture of 7-[2-(2-aminothiazol-4-yl)-2-methoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (2.0 g) and sodium bicarbonate (1.8 g) in water (40 ml) was stirred at 40° to 45° C. for 7 hours. The reaction mixture was adjusted to pH 5.0 with acetic acid. This solution was subjected to column chromatography on macroporous nonionic adsorption resin "Diaion HP-20" (20 ml) and eluted with water. The eluate was acidified to pH 2.2 with 10% hydrochloric acid under ice-cooling. The precipitates were collected by filtration and dried to give 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (0.9 g), which was identified by comparing the physico-chemical data with those of the object compound in Example 90.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[Cl:10].[C:11]([S:15][C:16](=[O:21])[CH2:17][C:18](=[O:20])[CH3:19])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([S:15][C:16](=[O:21])[CH:17]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[Cl:10])[C:18](=[O:20])[CH3:19])([CH3:14])([CH3:12])[CH3:13]
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: CC(=O)CC(=O)SC(C)(C)C
Product: CC(=O)C(Cc1ccc(F)cc1Cl)C(=O)SC(C)(C)C

Procedure:
The title compound was prepared by the method of Preparation 34a using 1-bromomethyl-2-chloro-4-fluorobenzene and 3-oxothiobutyric acid S-tert-butyl ester.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:8][OH:9].[C:10]([C@@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH:14]1[CH2:16][CH2:15]1)#[N:11]>O.C(O)C>[NH2:11]/[C:10](=[N:8]\[OH:9])/[C@@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:13][CH:14]1[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N[C@H](C#N)CC1CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CC1)/C(N)=N/O
Reaction time: 72 h
Yield: 92.7 %

Procedure:
Potassium carbonate (2.18 g, 16 mmol) was dissolved in water (8 mL) and hydroxylamine hydrochloride (1.1 g, 16 mmol) was added. A solution of (S)-tert-butyl 1-cyano-2-cyclopropylethylcarbamate (3.31 g, 16 mmol) in ethanol (24 mL) was added thereto and the resulting reaction mixture was stirred for 72 h. After evaporation of solvents, the residue was dissolved with ethyl acetate (20 mL) and then filtered. The filtrate was concentrated to yield crude product as yellow solid (3.61 g, 94%); MS (EI): m/e 244.2 [M+H]+.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][C:17]([O:30][P:31]([CH:34]([NH:38][C:39](=[O:48])[CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:35]([CH3:37])[CH3:36])([OH:33])=[O:32])([C:20]([O:22]CC2C=CC=CC=2)=[O:21])[CH2:16][CH2:15]1)=O)C1C=CC=CC=1>O1CCOCC1.O.[OH-].[Pd+2].[OH-]>[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][C:17]([O:30][P:31]([CH:34]([NH:38][C:39](=[O:48])[CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:35]([CH3:36])[CH3:37])([OH:33])=[O:32])([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]1
Reactant: CC(C)C(NC(=O)CCc1ccccc1)P(=O)(O)OC1(C(=O)OCc2ccccc2)CCN(CCNC(=O)OCc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C(NC(=O)CCc1ccccc1)P(=O)(O)OC1(C(=O)O)CCN(CCN)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The benzyl 1-(2-benzyloxycarbonylaminoethyl)-4-((2-methyl-1-(3-phenylpropanoylamino)propyl)(hydroxyphosphinoyl)oxy)piperidine-4-carboxylate (56 mg) obtained in the above step (f) was dissolved in a mixed solvent of dioxane (1.5 ml) and water (0.5 ml), and then the solution was added with palladium hydroxide (13 mg). The mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. The reaction mixture was filtered with celite, and then the solvent was evaporated. The residue was purified with HP-20 (Diaion, 40 cc, methanol:water=1:1 to acetone:water=1:4)) to obtain the title compound:1-(2-aminoethyl)-4-((2-methyl-1-(3-phenylpropionylamino)propyl)(hydroxyphosphinoyl)oxy)piperidine-4-carboxylic acid (32 mg, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1[S:30](Cl)(=[O:32])=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:30]([C:23]2[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=2[O:21][CH3:20])(=[O:32])=[O:31])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Product: COc1ccc(OC)c(S(=O)(=O)Nc2cnc(Oc3cc4ccccc4cn3)c(Cl)c2)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 2,5-dimethoxybenzene-1-sulfonylchloride.
Reaction SMILES: [NH2:1][C@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@H:2]([NH:1][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[C:3]1=[O:20]
Reactant: CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N[C@H]1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Reaction time: 0.17 h

Procedure:
Equimolar amounts of 3(S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, isobutyryl chloride, and triethylamine were mixed in CH2Cl2 at room temperature and stirred 10 minutes. Flash chromatography of the reaction solution on silica gel (10% Et2O in CH2Cl2) provided the title compound as a white foam upon removal of the solvent: m.p. 87°-107° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[C:14]1([N:20]2[CH:24]=[C:23]([CH:25]=O)[CH:22]=[N:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]([N:8]2[CH2:9][CH2:10][N:11]([CH2:25][C:23]3[CH:22]=[N:21][N:20]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:24]=3)[CH2:12][CH2:13]2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=Cc1cnn(-c2ccccc2)c1
Reactant: Clc1nccnc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1nccnc1N1CCN(Cc2cnn(-c3ccccc3)c2)CC1
Yield: 75.2 %

Procedure:
Stir together 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (1.6 g, 8.43 mmol) and 1-phenyl-1H-pyrazole-4-carbaldehyde (2.17 g, 12.6 mmol) in dry tetrahydrofuran (10 mL) at room temperature for 15 min., under nitrogen. Add sodium triacetoxyborohydride (2.68 g, 12.6 mmol) and stir reaction for 1 hr. Quench reaction mixture with saturated aq. sodium bicarbonate (50 mL), then extract with DCM (3×50 mL) and pass through an IST Phase Separator Frit®. Concentrate and purify (silica gel chromatography, eluting with 5:95 methanol:DCM) and concentrate all fractions containing product. Pass the mixture through a CBA column to retain the product, wash with methanol and then elute with 2 M ammonia in methanol. Evaporate the ammonia methanol solution and purify (silica gel chromatography, eluting with 0:100 then 5:95 methanol:DCM). Concentrate, wash with diethyl ether and dry in vacuum oven to give 3′-chloro-4-(1-phenyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl as brown powder (2.25 g, 76%). MS (ES): m/z=355 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][CH2:21][C:22]1[O:23][C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:27]([C:25]3[N:26]=[C:22]([CH2:21][O:20][CH3:19])[O:23][C:24]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COCc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: COCc1nc(C(=O)Nc2ccn(Cc3ccc(C(C)=O)o3)n2)c(-c2ccccc2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-methoxymethyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.99 min; [M+H]+=421.61.