Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:16](Br)(Br)[C:15](=[O:19])[N:14]([CH3:20])[C:11]2=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:23])C>[Zn]>[C:1]([C:8]1[CH:9]=[C:10]2[CH2:16][C:15](=[O:19])[N:14]([CH3:20])[C:11]2=[N:12][CH:13]=1)(=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1C(=O)C(Br)(Br)c2cc(Cc3ccccc3)cnc21
Reactant: CC(=O)O
Agent: [Zn]
Product: CN1C(=O)Cc2cc(C(=O)c3ccccc3)cnc21
Reaction time: 0.5 h
Yield: 60 %

Procedure:
Add a spatula tip of zinc to a solution of 40 mg of the compound of Step 2 in acetic acid. After 30 minutes' stirring, concentrate to dryness under reduced pressure, take up in water and extract with dichloromethane. The crude product obtained by concentrating to dryness is purified by chromatography on a silica column (eluant: petroleum ether/ethyl acetate, 6/4). The title product is obtained in the form of an oil in a yield of 60%. ##STR63##
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]1=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[C:3]2=[O:18])=[O:28])=[CH:22][CH:21]=1
Reactant: Nn1nc(-c2ccccc2)c2c(c1=O)CCCC2
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(-c2ccccc2)c2c(c1=O)CCCC2

Procedure:
The product from Example 185A and 2-(4-chlorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.64 (s, 1H), 7.29-7.51 (m, 9H), 3.65 (s, 2H), 2.50-2.55 (m, 2H), 2.36-2.40 (m, 2H), 1.68-1.76 (m, 2H), 1.57-1.65 (m, 2H); MS (APCI+) M/Z 394 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:5]2.C([N:21]1[CH2:25][CH2:24][NH:23][C:22]1=O)(=O)C>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:5]2[C:22]1[NH:23][CH2:24][CH2:25][N:21]=1
Reactant: Clc1ccc2[nH]c(Cc3ccccc3)cc2c1
Reactant: CC(=O)N1CCNC1=O
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc2[nH]c(Cc3ccccc3)c(C3=NCCN3)c2c1
Temperature: 60 °C

Procedure:
A mixture of 2.42 g (10 mmol) 5-chloro-2-benzylindole and 1.28 g (10 mmol) 1-acetyl-imidazolidine-2-one (0.1 mol) is added to phosphorus oxychloride (10 ml) and heated to 60° C. for 5 hours. After evaporation of phosphorus oxychloride the residue is treated with ethanol (14 ml) and heated to reflux for 3.5 hours. Ethanol is evaporated. The residue is purified by chromatography to obtain the hydrochloride. The base is obtainable by treatment with 2N sodium hydroxide to pH 11. The solid is filtered off and dried in vacuo. Hydrochloride, m.p. 299-300° C., M.S. (Ei 70 ev) m/Z M=309.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C@H:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C@H:8]([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[C:22](C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.O(C)S(C(F)(F)F)(=O)=O.[Cl-].[NH4+]>ClCCl>[C:1]([O:5][C:6](=[O:21])[C@H:7]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C@H:8]([O:15][CH3:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)n1
Reactant: CCCCCC[C@@H](O)[C@@H](CCCCC)C(=O)OC(C)(C)C
Agent: COS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CCCCCC[C@@H](OC)[C@@H](CCCCC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95.4 %

Procedure:
The (2R,3R)-3-hydroxy-2-pentylnonanoic acid t-butyl ester (500 mg, 1.66 mmol) obtained in Production Example C-3 was dissolved in anhydrous dichloromethane (5.0 ml). Then, 2,6-di-t-butylpyridine (476 mg, 2.49 mmol) was added thereto to be stirred for 5 minutes at room temperature. Methyl triflate (328 mg, 1.99 mmol) was added to the obtained mixture, which was heated to 40° C. and stirred for 20 hours. An aqueous saturated ammonium chloride solution was added to the reaction solution, which was extracted 3 times with dichloromethane. The resulting organic layer was dried with anhydrous magnesium sulfate, filtered, and condensed. The obtained residue was purified by column chromatography (silica gel: 25 g, n-hexane/ethyl acetate=20/1) to produce the target compound (498 mg, 95%).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]=[C:13]2[N:19]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[C:7]([NH:9][C:21]([CH3:22])=[O:23])[CH:6]=[CH:5][C:4]=1[C:10]1[N:19]=[C:13]2[NH:14][C:15](=[O:18])[CH2:16][CH:17]=[C:12]2[N:11]=1
Reactant: CN(C)c1cc(N)ccc1C1=NC2=NC(=O)C=CC2=N1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc(C2=NC3=CCC(=O)NC3=N2)c(N(C)C)c1

Procedure:
A quantity of 0.6 gm of 2-(2-dimethylamino-4-amino-phenyl)imidazo[4,5-b]pyridin-5-one is refluxed with 20 ml of acetic anhydride for 30 minutes. After evaporation, 10 ml of concentrated ammnoia and then 20 ml of ice are added. The product precipitated is suction filtered and washed with water.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([O:27]N4C5C=CC=CC=5N=N4)[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])=[N:9]2)[CH2:4][O:3]1.[C:39]1(O)[C:48]2[CH2:47][CH2:46][CH2:45][CH2:44][C:43]=2[CH:42]=[CH:41][CH:40]=1>>[CH3:1][C:2]1([CH3:38])[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:37])[CH:15]([N:20]3[C:25](=[O:26])[CH:24]=[C:23]([O:27][C:47]4[C:48]5[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=5[CH:44]=[CH:45][CH:46]=4)[CH:22]=[N:21]3)[CH2:16][CH:17]([CH3:18])[CH3:19])=[N:9]2)[CH2:4][O:3]1
Reactant: Oc1cccc2c1CCCC2
Reactant: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(On2nnc3ccccc32)cc1=O
Product: CC(C)CC(C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)n1ncc(Oc2cccc3c2CCCC3)cc1=O

Procedure:
Using the method described in Example 109, Step 2, 2-[4-(benzotriazol-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (Example 109, Step 1) and 5,6,7,8-tetrahydro-naphthalen-1-ol afforded 4-methyl-2-[6-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-6H-pyridazin-1-yl]-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide as a white solid as a mixture of diastereomers (197.3 mg, 77%).
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:21]1[CH2:26][N:25](C(OC(C)(C)C)=O)[C@H:24]([CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])[CH:23]=[CH:22]1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19])(=[O:8])=[O:7])[CH:2]=[CH2:3]>C(Cl)Cl.[Br-].[Zn+2].[Br-]>[CH2:1]([O:4][N:5]([C@@H:21]1[CH:22]=[CH:23][C@@H:24]([CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:37])[CH3:38])[NH:25][CH2:26]1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@@H]1C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: C=CCON([C@@H]1C=C[C@@H](CO[Si](C)(C)C(C)(C)C)NC1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 106.7 %

Procedure:
To a stirred solution of (2S,5R)-tert-butyl 5-(N-(allyloxy)-2,4-dinitrophenylsulfonamido)-2-((tert-butyldimethylsilyloxy)methyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 126, 19.5 g, 31.01 mmol) in DCM (250 mL) under nitrogen at rt, zinc bromide (20.95 g, 93.04 mmol) was added. The reaction mixture was stirred at rt for 6 hs, (lcms indicated the reaction was a clean one) and diluted with 50 mL DCM and washed with sat. NaHCO3, brine, dried over MgSO4, filtered and concentrated to give the desired product as an orange oil (17.5 g).
Reaction SMILES: CS[C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]=[CH:13]3)[C:6](=[O:8])[N:7]=1.[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[C:23]([O:28][CH3:29])[CH:22]=1.CCN(C(C)C)C(C)C>>[F:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][N:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)=[C:23]([O:28][CH3:29])[CH:22]=1
Reactant: CSC1=NC(=O)C(=Cc2ccc3ncncc3c2)S1
Reactant: COc1cc(F)ccc1N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(F)ccc1NC1=NC(=O)/C(=C/c2ccc3ncncc3c2)S1

Procedure:
Similar procedure as described in example 1d was used, starting from 2-methylsulfanyl-5-quinazolin-6-ylmethylene-thiazol-4-one, 4-fluoro-2-methoxy-aniline and DIEA to give 2-(4-fluoro-2-methoxy-phenylamino)-5-[1-quinazolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one: LC-MS m/e observed. LC-MS m/e 381 (MH+).
Reaction SMILES: Cl[CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([N:13]3[C:17](=[O:18])[N:16]([CH2:19][CH2:20][CH2:21][F:22])[N:15]=[N:14]3)=[C:8]([F:12])[CH:9]=2)[NH:4][C:3]1=[O:23].C(=O)([O-])[O-].[K+].[K+].I[CH2:31][CH3:32]>CN(C)C=O>[CH2:31]([N:4]1[C:5]2[C:10](=[CH:9][C:8]([F:12])=[C:7]([N:13]3[C:17](=[O:18])[N:16]([CH2:19][CH2:20][CH2:21][F:22])[N:15]=[N:14]3)[CH:6]=2)[CH:11]=[CH:2][C:3]1=[O:23])[CH3:32]
Reactant: CCI
Reactant: O=C1Nc2cc(-n3nnn(CCCF)c3=O)c(F)cc2CC1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(=O)ccc2cc(F)c(-n3nnn(CCCF)c3=O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
A solution of 1.8 g (0.0052 mole) of 1-(3-chloro-6-fluoro-3,4-dihydroquinolin-2(1H)-one-7-yl)-4-(3-fluoropropyl)-1,4-dihydro-5H-tetrazol-5-one and 1.1 g (0.0079 mole) of potassium carbonate in 50 mL of dimethylformamide was stirred at room temperature for 30 minutes. To this solution was added 1.6 g (0.011 mole) of 2-iodoethane, and the reaction mixture was stirred at room temperature for one hour, then was heated at 40° C. for two days. The reaction mixture was heated at 70° C. for four hours, then was cooled and poured into icewater. This mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure leaving a residue. This residue was purified by column chromatography on silica gel, eluting with ethyl acetate:n-hexane (75:25), to yield 0.77 g of 1[1 -ethyl-6-fluoroquinolin-2(1H)-one-7-yl]-4-(3-fluoropropyl)-1,4-dihydro-5H-tetrazol-5-one as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]=[C:9]1[S:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[S:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][CH:18]([F:21])[S:19]Cl.C(SC(F)F)C1C=CC=CC=1.ClCl>ClCCl.N1C=CC=CC=1>[C:1]([O:5][C:6]([C:8](=[C:9]1[S:12][CH:11]([C:13]([O:15][CH3:16])=[O:14])[S:10]1)[S:19][CH:18]([F:21])[F:17])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C1SC(=CC(=O)OC(C)(C)C)S1
Reactant: FC(F)SCl
Agent: ClCl
Agent: FC(F)SCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1SC(=C(SC(F)F)C(=O)OC(C)(C)C)S1

Procedure:
Methyl 2-(t-butoxycarbonylmethylene)-1,3-dithietane-4-carboxylate (1.05 g) is reacted with difluoromethylsulphenyl chloride, which was synthesized from difluoromethyl benzyl thioether (1.74 g) and chlorine, in dichloromethane (5 ml) at room temperature in the presence of pyridine (0.65 ml) until no starting carboxylate is detected in the reaction mixture. The mixture is then washed with a 5% sodium thiosulfate solution and 10% HCl, dried, and concentrated in vacuo to give methyl 2-(1-t-butoxycarbonyl-1-difluoromethylthiomethylene)-1,3-dithietane-4-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=1)[CH:5]=[O:6]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=Cc1ccc(O)c(F)c1
Product: O=Cc1ccc(Oc2ccc(C(F)(F)F)cn2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D1 starting from 3-fluoro-4-hydroxybenzaldehyde and 2-chloro-5-(trifluoromethyl)pyridine, LC-MS (ESI): m/z 286 [M+H]+; 3.37 min (ret time).
Reaction SMILES: [K].[SH:2][C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=1.Br[CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15]([OH:17])=[O:16]>CC(C)=O>[CH3:8][N:7]1[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=[C:3]1[S:2][CH:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15]([OH:17])=[O:16]
Reactant: Cn1c(S)nc2ccccc21
Reactant: O=C(O)C(Br)c1ccccc1
Agent: [K]
Solvent: CC(C)=O
Product: Cn1c(SC(C(=O)O)c2ccccc2)nc2ccccc21
Yield: 87 %

Procedure:
An acetone solution of 6.5 g (0.032M) of the potassium salt of 2-mercapto-1-methyl-benzimidazole and 9.7 g (0.045M) of α-bromophenylacetic acid is stirred at room temperature overnight. The solid which is collected is washed with water and the filtrate is concentrated to remove the solvent. The combined materials are recrystallized from acetonitrile. The recrystallized material weighs 8.3 g (87% yield) and melts at 157°-9° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]([N+:10]([O-])=O)=[CH:8][N:7]([CH3:13])[N:6]=1)=[O:4]>CO.[Pd]>[NH2:10][C:9]1[C:5]([C:3]([NH:2][CH3:1])=[O:4])=[N:6][N:7]([CH3:13])[CH:8]=1
Reactant: CNC(=O)c1nn(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1nn(C)cc1N
Reaction time: 8 h

Procedure:
N,1-Dimethyl-4-nitropyrazole-3-carboxamide (1.23 g) was dissolved in MeOH (30 ml) and 10% Pd/C (0.3 g, 50% wet) was added. The mixture was stirred under a hydrogen atmosphere overnight and the catalyst filtered off. The solvent was removed in vacuo to yield 4-amino-N,1-dimethylpyrazole-3-carboxamide, 1.1 g. NMR Spectrum: (CDCl3) 2.93 (s, 3H), 3.76 (s, 3H), 4.41 (m, 2H), 6.62 (m, 1H), 6.89 (s, 1H); Mass spectrum: MH+ 155
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:6][C:5]=1[C:18]([F:21])([F:20])[F:19])([O-:3])=[O:2].CC([O-])=O.[Na+]>C(OC(=O)C)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:11](=[O:17])[CH2:12][CH2:13][C:14]2=[O:16])=[CH:6][C:5]=1[C:18]([F:21])([F:20])[F:19])([O-:3])=[O:2]
Reactant: O=C(O)CCC(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C1CCC(=O)N1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Yield: 38.6 %

Procedure:
A solution of 4-(4-nitro-3-(trifluoromethyl)phenylamino)-4-oxobutanoic acid (1.1 g, 3.6 mmol) and NaOAc (1.6 g, 19.7 mmol) in acetic anhydride (15 mL) was stirred for 16 h at 80° C. The reaction was cooled and filtered. The filtrate was diluted with water and extracted with dichloromethane. The combined organic layers were washed with 1 N NaOH, dried over MgSO4, filtered, and concentrated in vacuo to provide 1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine-2,5-dione (0.4 g, 39% yield). M+H m/z 289.1.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C[Si](CC(N)=O)(C)C.[NH2:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH:26]([CH3:28])[CH3:27])[C:21]([OH:23])=O)[N:19]=1.[NH2:29][CH:30]1[C:50](=[O:51])[N:32]2[C:33]([C:37]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=3)=[O:38])=[CH:34][CH2:35][S:36][C@H:31]12.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>O1CCCC1.O.CN(C)C=O>[NH2:14][C:15]1[S:16][CH:17]=[C:18]([C:20](=[N:24][O:25][CH:26]([CH3:28])[CH3:27])[C:21]([NH:29][CH:30]2[C:50](=[O:51])[N:32]3[C:33]([C:37]([O:39][CH2:40][C:41]4[CH:42]=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45][CH:46]=4)=[O:38])=[CH:34][CH2:35][S:36][C@H:31]23)=[O:23])[N:19]=1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: CC(C)ON=C(C(=O)O)c1csc(N)n1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.4 %

Procedure:
Phosphoryl chloride (4.6 g.), trimethylsilylacetamide (0.95 g.) and N,N-dimethylformamide (1.2 g.) were added to a stirred suspension of 2-(2-amino-4-thiazolyl)-2-isopropoxyiminoacetic acid (syn isomer, 2.8 g.) in tetrahydrofuran (25 ml.) below 5° C. for 30 minutes [Solution A]. On the other hand, trimethylsilylacetamide (10.5 g.) was added to a suspension of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (3.9 g.) in tetrahydrofuran (50 ml.), and stirred at room temperature for 1.5 hours. To the solution was added the above solution A at -20° C. all at once, and the solution was stirred at -5° to 0° C. for 40 minutes. Water (70 ml.) and tetrahydrofuran (100 ml.) were added to the resultant solution at -20° C. The solution was adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate and stirred for an hour. After a saturated aqueous solution of sodium chloride (200 ml.) was added, the organic layer was separated. The remaining aqueous layer was extracted with tetrahydrofuran, and the extract and the above organic layer were combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was triturated with diisopropyl ether and the precipitates were collected by filtration to give 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-isopropoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 6.0 g.).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[C:12]2[OH:17].Cl[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][CH:2]([CH3:18])[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[C:12]2[O:17][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=1
Reactant: CC(C)CCNCc1cccc2c(O)cccc12
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CCNCc1cccc2c(Oc3ccc(C#N)cn3)cccc12
Temperature: 70 °C

Procedure:
To a solution of 5-[(3-methylbutylamino)methyl]naphthalen-1-ol (Preparation 14) (85 mg, 0.35 mmol) in DMF (10 mL), was added 6-chloronicotinonitrile (43 mg, 0.62 mmol) and K2CO3 (86 mg, 0.62 mmol). The reaction mixture was heated at 70° C. for 16 h. Solvent was removed in vacuo and residue partitioned between EtOAc (50 mL) and water (20 mL). The aqueous phase was extracted with EtOAc (50 mL) and the organic phase washed with NaHCO3 (20 mL), brine (20 mL) and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (DCM:MeOH:NH4OH, 95:5:0.5) to give the title compound: RT=2.83 min; m/z (ES+)=346.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:20]2[S:24][C:23]3[CH:25]=[CH:26][C:27]([N+:29]([O-])=O)=[CH:28][C:22]=3[CH:21]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]2=[O:19])=[N:6][CH:7]=1.C(O)C.[In]>O>[NH2:29][C:27]1[CH:26]=[CH:25][C:23]2[S:24][C:20]([C:3]3[C:2]([Br:1])=[CH:7][N:6]=[C:5]([NH:8][CH2:9][CH2:10][N:11]4[C:15]([CH3:17])([CH3:16])[C:14](=[O:18])[NH:13][C:12]4=[O:19])[N:4]=3)=[CH:21][C:22]=2[CH:28]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc3cc([N+](=O)[O-])ccc3s2)n1
Agent: [In]
Solvent: O
Solvent: CCO
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc3cc(N)ccc3s2)n1
Temperature: 25 °C
Yield: 15.2 %

Procedure:
A mixture of 1-(2-(5-bromo-4-(5-nitrobenzo[b]thiophen-2-yl)pyrimidin-2-ylamino)ethyl)-5,5-dimethylimidazolidine-2,4-dione (996 mg, 1.97 mmol), ethanol (100 mL) and indium powder, 100 mesh (1.13 g, 9.85 mmol) was heated to reflux with stirring. After 1.5 h the reaction mixture was cooled to r.t., diluted with water (40 mL) and filtered through a pad of celite. The yellow precipitate (collected on the celite) was purified by reverse phase chromatography (0.1% TFA in AcCN:H20/10:90 to 95:5). The product fractions were combined, then passed through a 1 g SCX cartridge. The fully loaded cartridge was then washed with MeOH (4 mL) and 2 M ammonia in MeOH (8 mL). Elution of the desired compound was brought about by washing the cartridge finally with DMSO (4 mL). The solvent was removed in vacuo, employing a Genevac, to yield the title compound (142 mg, 15%) as a yellow amorphous solid. 1H NMR: δ (d6-DMSO, 400 MHz) 1.29 (s, 6H), 3.39-3.54 (m, 4H), 5.20 (s, 2H), 6.83 (d, J=8.61 Hz, 1H), 7.02 (s, 1H), 7.62 (d, J=8.61 Hz, 1H), 7.68 (s, 1H), 8.38 (s, 1H), 8.48 (s, 1H), 10.82 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:25]2[CH2:26][CH2:27][N:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24]2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Product: Cc1ccc(-c2oncc2C(=O)N2CCN(c3ccccc3)CC2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 1-phenylpiperazine (9.7 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (11.5 mg). Calcd for C21H21N3O2: 347.1634, found 347.1628.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[CH3:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1.CCN(C(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOC(C)=O.CC(O)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[CH3:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: CC(F)(F)Oc1ccc(NC(=O)c2cnc(Cl)c(Br)c2)cc1
Reactant: O[C@@H]1CCNC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(F)(F)Oc1ccc(NC(=O)c2cnc(N3CC[C@@H](O)C3)c(Br)c2)cc1
Temperature: 120 °C

Procedure:
A mixture of 5-bromo-6-chloro-N-(4-(1,1-difluoroethoxy)phenyl)nicotinamide (Stage 30.2, 700 mg, 1.752 mmol), (R)-pyrrolidin-3-ol (0.170 mL, 2.102 mmol) and DIPEA (0.673 mL, 3.85 mmol) and iPrOH (2 mL) in a sealed vial was heated to 120° C. for 1 h. The RM was diluted with EtOAc (80 mL), treated with citric acid 10% (40 mL; ˜pH4) and extracted with EtOAc. The combined extracts were washed with brine (2×40 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was washed with Et2O and n-hexane and the crystals were dried to give the title product as a beige solid. HPLC (Condition 5) tR=6.4 min, UPLC-MS (Condition 3) tR=1.02 min, m/z=442.1/444.0 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=3)[C:15]=2[CH3:16])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:33]([O:37][C:38]([N:40]1[CH2:45][CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].O1CCOCC1>O>[C:33]([O:37][C:38]([N:40]1[CH2:41][CH:42]=[C:43]([C:2]2[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[CH:12]=[N:13][N:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=4)[C:15]=3[CH3:16])=[O:10])=[CH:4][CH:3]=2)[CH2:44][CH2:45]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1c(C(=O)Nc2ccc(Br)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 110 °C
Reaction time: 6.5 h
Yield: 94.9 %

Procedure:
To N-(6-bromopyridin-3-yl)-5-methyl-1-[5-(tri fluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (3.0 g), cesium carbonate (6.4 g), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloridedichloromethane complex (287 mg), and N-tert-butyloxycarbonyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (2.28 g) were added 1,4-dioxane (26 ml) and water (7 ml), and stirred at 110° C. for 6.5 hours. To the reaction solution was added water, and the obtained solid was washed with a mixed solution of n-hexane and ethyl acetate to give N-[6-(1-tert-butyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (3.53 g) as a brown solid.