Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][Si:8]([CH3:18])([CH3:17])[C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1.[Cl:19][C:20]1[C:21](=[O:29])[N:22]([CH2:27][CH3:28])[N:23]=[CH:24][C:25]=1[OH:26].O>CN(C)C=O>[Cl:19][C:20]1[C:21](=[O:29])[N:22]([CH2:27][CH3:28])[N:23]=[CH:24][C:25]=1[O:26][CH2:13][C:12]1[CH:15]=[CH:16][C:9]([Si:8]([CH3:18])([CH3:17])[CH3:7])=[CH:10][CH:11]=1
Reactant: C[Si](C)(C)c1ccc(CBr)cc1
Reactant: CCn1ncc(O)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ncc(OCc2ccc([Si](C)(C)C)cc2)c(Cl)c1=O
Temperature: 25 °C
Yield: 58.7 %

Procedure:
1.8 g of anhydrous potassium carbonate and 2.1 g of p-trimethylsilylbenzylbromide were added to 1.5 g of 4-chloro-2-ethyl-5-hydroxy-3(2H)-pyridazinone dissolved in 10 ml of N,N-dimethylformamide, and the resulting mixture was heated in an oil bath of 120°-130° C. for 2 hours. After the reaction mixture was allowed to cool to room temperature, 100 ml of water was added thereto and the mixture was stirred vigorously. Precipitate was filtered, washed with water and dried to obtain 1.7 g of a crude product. The product was recrystallized from a mixed solvent of isopropyl ether and ethyl acetate to obtain the intended compound (Compound No. 4.6) having m.p. 122°-125° C. (yield: 44.8%).
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1.Br[C:35]1[CH:36]=[CH:37][C:38]([F:45])=[C:39]([CH2:41][C:42]([OH:44])=[O:43])[CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:45][C:38]1[CH:37]=[CH:36][C:35]([C:16]2[CH:17]=[CH:18][C:19]([C:21]([F:23])([F:22])[F:24])=[CH:20][C:15]=2[CH2:14][N:3]2[C@@H:2]([CH3:1])[C@@H:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:5][C:4]2=[O:13])=[CH:40][C:39]=1[CH2:41][C:42]([OH:44])=[O:43]
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(O)Cc1cc(Br)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1ccc(F)c(CC(=O)O)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
(4S,5R)-4-Methyl-5-phenyl-3-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-oxazolidin-2-one (0.080 g, 0.17 mmol), 5-bromo-2-fluorophenylacetic acid (0.061 g, 0.26 mmol), potassium carbonate (0.084 g, 0.61 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.021 g, 0.02 mmol) were combined in DME:H2O (2:1; 3 mL), and the mixture was purged with N2 for 5 minutes. The reaction was stirred under N2 at 90° C. overnight. After work-up with EtOAc and brine, the crude material was purified by silica gel chromatography (0-5% MeOH in CH2Cl2) to give the title compound. M+H is 488.
Reaction SMILES: [C:1]1(=[O:34])[N:5]([CH2:6][C:7]([N:9]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2OC(F)(F)F)=[O:8])[C:4](=[O:29])[C:3]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:2]12.[CH2:35]([O:37][C:38](C1C=CC=CC=1NC(=O)CN1C(=O)C2=CC=CC=C2C1=O)=[O:39])[CH3:36].[H-].[Na+].BrCC(OC(C)(C)C)=O>>[CH2:35]([O:37][C:38]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[N:9]([CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:7](=[O:8])[CH2:6][N:5]1[C:4](=[O:29])[C:3]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:2]2[C:1]1=[O:34])=[O:39])[CH3:36]
Reactant: CCOC(=O)c1ccccc1NC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccccc1OC(F)(F)F
Agent: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1ccccc1N(CC(=O)OC(C)(C)C)C(=O)CN1C(=O)c2ccccc2C1=O

Procedure:
tert-Butyl 2-[N-(2-ethoxycarbonylphenyl)-2-phthalimidoacetamido] acetate may be prepared in a manner similar to that described in Example 4 for the preparation of tert-butyl 2-[2-phthalimido-N-(2-trifluoromethoxyphenyl)acetamido]acetate, but starting with N-(2-ethoxycarbonylphenyl)-2-phthalimidoacetamide (7.7 g), an oily suspension (50% by weight) (1.26 g) of sodium hydride and tert-butyl bromoacetate (4.3 g). After recrystallisation in diisopropyl ether, tert-butyl 2-[N-(2-ethoxycarbonylphenyl)-2-phthalimidoacetamido]acetate (6.1 g), m.p. 127° C., is thereby obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.[Li]CCCC.[B:17](OC)([O:20]C)[O:18]C.Cl>C1COCC1>[CH3:11][O:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([B:17]([OH:20])[OH:18])=[CH:3][CH:4]=1
Reactant: COB(OC)OC
Reactant: COCCc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCc1ccc(B(O)O)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-bromo-4-(2-methoxyethyl)benzene (1 g, 4.6 mmole) in THF (15 mL) at −78° C. was added dropwise BuLi (2.5M in hexane) (2.4 mL, 6 mmole). After stirring at −78° C. for 20 min, trimethyl borate (0.62 g, 6 mmole) was added to the mixture at −78° C. The mixture was slowly warmed to room temperature and stirred at room temperature for 1 h. 2N HCl was added to the reaction mixture and stirred for 2 h. The mixture was extracted with ether, washed with water, dried over MgSO4, and filtered. Hexane was added to the ether solution. Solid was precipitated and collected by filtration. The solid was used in the next step without purification. MS (ESI) m/z: Calc: 180.0 (M+). Found: 181.3 (M++1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: BrCCCCCBr
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccc(OCCCCCBr)c1
Temperature: 90 °C
Reaction time: 6 h
Yield: 59 %

Procedure:
To a stirred solution of 3-nitrophenol (4.17 g, 30.0 mmol) and 1,5-dibromo-pentane (7.59 g, 33.0 mmol) in N-methylpyrolidinone (100 mL) was added potassium carbonate (6.21 g, 45.0 mmol), and the resulting mixture was stirred at 90° C. for 6 hours. The reaction mixture was quenched with water (30 mL) followed by extraction with ethyl acetate (30 mL×3). The combined organic layers were washed with brine and then concentrated under vacuum. The residue was purified by silica gel column chromatography to give 1-(5-bromo-pentyloxy)-3-nitro-benzene (5.10 g, 17.7 mmol, 59%) as a yellow liquid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH:13]=[CH:14][CH2:15][NH2:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[C:28]1[S:32][C:31]([NH2:33])=[N:30][N:29]=1>C1COCC1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH:13]=[CH:14][CH2:15][NH:16][C:28]2[S:32][C:31]([NH2:33])=[N:30][N:29]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nnc(Br)s1
Reactant: NCC=CCOc1cccc(CN2CCCCC2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1nnc(NCC=CCOc2cccc(CN3CCCCC3)c2)s1

Procedure:
0.6 g (2.3 mmol) of 4-[3-(1-piperidinylmethyl)phenoxy]2-butene-1-amine, 0.35 ml of triethylamine and 0.42 g (2.3 mmol) of 5-bromo-1,3,4-thiadiazole-2-amin are heated under reflux in 20 ml of THF for 3 hours. Solid triethylammonium bromide is filtered off, the filtrate is concentrated by evaporation and the oily residue is purified by preparative layer chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]Br)[CH:10]=1)[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:6]=[CH:5]2.[C:21]([O-:24])(=[O:23])[CH3:22].[K+]>CN(C)C=O.C(OCC)C>[C:21]([O:24][CH2:11][C:9]1[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]2[C:8]=1[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:6]=[CH:5]2)(=[O:23])[CH3:22]
Reactant: C[Si](C)(C)CCOCn1ncc2cc(Br)cc(CBr)c21
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(Br)cc2cnn(COCC[Si](C)(C)C)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-bromo-7-(bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (940 mg, 2.237 mmol) in dimethylformamide (10 mL) at room temperature was added potassium acetate (659 mg, 6.71 mmol). After 10 min, the reaction was placed in a 40° C. bath and stirred for 1 h. The reaction was cooled to room temperature, diluted with diethyl ether, washed with water (2×), then brine, dried over magnesium sulfate, and concentrated to give 1.04 g (quant.) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 7.95 (s, 1H), 7.86 (d, J=1.8, 1H), 7.55 (d, J=1.2, 1H), 5.81 (s, 2H), 5.52 (s, 2H), 3.49 (m, 2H), 2.08 (s, 3H), 0.84 (m, 2H), −0.09 (s, 9H; 13C NMR (126 MHz, CDCl3) δ ppm 170.2, 137.1, 133.4, 132.2, 128.1, 124.1, 120.9, 114.1, 79.6, 66.3, 63.0, 21.1, 17.8, −1.4.
Reaction SMILES: C1(N[C:8]2[C:9]3[S:33][CH2:32][CH2:31][C:10]=3[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][N:17](C4C=CC(C(OCC)=O)=CC=4)[CH2:16][CH2:15]3)[N:13]=2)CCCCC1.[C:34]1([N:40]=C=O)C=CC=[CH:36][CH:35]=1>O1CCCC1>[N:14]1([C:12]2[N:13]=[C:8]([CH2:36][CH2:35][CH2:34][NH2:40])[C:9]3[S:33][CH2:32][CH2:31][C:10]=3[N:11]=2)[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)c1ccc(N2CCN(c3nc4c(c(NC5CCCCC5)n3)SCC4)CC2)cc1
Solvent: C1CCOC1
Product: NCCCc1nc(N2CCNCC2)nc2c1SCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
0.330 g (1.0 mmol) of cyclohexyl-(2-piperazin-1-yl-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amine (VI) and 0.115 mL (1.0 mmol) of phenyl isocyanate are placed in 12.5 mL of tetrahydrofuran, then stirred for 1 hour at ambient temperature. Then the reaction mixture is concentrated by evaporation. The residue is stirred with water, suction filtered, washed with water and petroleum ether, then dried. The crude product is purified by chromatography through a 25 g silica gel cartridge with a solvent mixture of petroleum ether/ethyl acetate 1/1. 0.240 g of product VII (53%) is obtained as a powder (m.p. 207-210° C.). 1H NMR (400 MHz, DMSO): 8.51 (1H, s); 7.47 (2H, d); 7.23 (2H, t); 6.92 (1H, t); 6.11 (1H, d); 3.91-3.78 (1H, m); 3.69-3.59 (4H, m); 3.53-3.44 (4H, m); 3.22 (2H, t); 2.98 (2H, t); 1.92-1.78 (2H, m); 1.79-1.67 (2H, m); 1.65-1.56 (1H, m); 1.37-1.21 (4H, m); 1.18-1.04 (1H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[C:16]1([CH:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:24]1[CH2:25][CH2:26][CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23]1)=[O:15]
Reactant: c1ccc(C2CCNC2)cc1
Reactant: Cc1ccccc1-c1oncc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1oncc1C(=O)N1CCC(c2ccccc2)C1
Temperature: 25 °C

Procedure:
5-(2-methylphenyl)-isoxazole-4-carboxylic acid (46.9 mg, 0.231 mmol), 3-phenylpyrrolidine (40 mg, 0.271 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (92.6 mg, 0.288 mmol) and diisopropylethylamine (49.7 mg, 0.384 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature over night. Solvent was evaporated in vacuo (0.5-1.0 mL) and the residue was taken up in dichloromethane (1 mL), filtered and purified by normal-phase chromatography (20-50% EtOAc:petroleum ether). The combined fractions were partitioned between H2O/acetic acid (pH 4) and ethyl acetate. The organic fractions were washed with H2O/brine and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H20N2O2: 332.1525, found 332.1531.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]2[NH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]2=[CH:5][C:4]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][C:48]1([F:54])[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[N:8]=[C:7]2[NH:9][C:10]([C:12]([N:51]3[CH2:52][CH2:53][C:48]([F:54])([F:47])[CH2:49][CH2:50]3)=[O:14])=[CH:11][C:6]2=[CH:5][C:4]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)O)[nH]c3nc2Cl)CC1
Reactant: FC1(F)CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCC(F)(F)CC4)[nH]c3nc2Cl)CC1
Yield: 40 %

Procedure:
The title compound was synthesized in analogy to example 1 from 6-chloro-5-(1-isopropyl-piperidin-4-yloxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, 4,4-difluoro-piperidine and N,N-diisopropylethylamine in DMF to give the desired product as a light yellow foam (40%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].CCN(C(C)C)C(C)C.[CH3:24][C:25]([SH:28])([CH3:27])[CH3:26]>CN(C=O)C>[C:25]([S:28][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14])([CH3:27])([CH3:26])[CH3:24]
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Reactant: CC(C)(C)S
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)Sc1c(C#N)cnc2ccc(I)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.7 %

Procedure:
To the solution of 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c, 1.0 g, 3.18 mmol) in anhydrous DMF (1 mL) and DIEA (1.67 mL, 9.54 mmol) was added 2-methyl-2-propanethiol (0.72 ul, 6.4 mmol). The mixture was stirred at room temperature for 4 h. The reaction was extracted with methylene chloride (2×100 mL). The combined organic layers were successively washed with water (3×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 0%-50% ethyl acetate in hexanes in 30 min) afforded 4-tert-butylsulfanyl-6-iodo-quinoline-3-carbonitrile (0.57 g, 48%) as a white solid. LC-MS m/e 369 (MH+).
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](OC(C)(C)C)(=[O:25])[C:18](OC(C)(C)C)=[O:19].CC(C)([O-])C.[K+]>C1COCC1>[OH:25][C:17]1[C:18](=[O:19])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][C:9]=1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)CCNc1ccccc1
Reactant: CC(C)(C)OC(=O)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1=C(O)C(=O)N(c2ccccc2)C1
Yield: 52.1 %

Procedure:
To a solution of the title compound of Example B (29.37 g, 0.133 mol) and di-tert-butyl oxalate (26.90 g, 0.133 mol) in dry THF (350 ml) was added potassium tert-butoxide (29.84 g, 0.266 mol) and the resulting solution was heated under reflux for 24 h. The mixture was then cooled and the solvent removed in vacuo. The resulting solid was suspended in CH2Cl2 and 1N aqueous HCl was added. The resulting suspension was filtered and the organic filtrate was dried over MgSO4 and concentrated in vacuo. The residue was then chromatographed on silica gel eluting with 1/1/98 HOAc/EtOH/CH2Cl2 to give the title compound (19.06 g, 52%) as a solid. Anal calcd for C15H17NO4 : C, 65.44; H, 6.22; N, 5.09. Found: C, 65.05; H, 6.33; N, 4.86. MS M+1 calcd for C15H17NO4 276, found 276.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].[C:16]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>C(Cl)Cl>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([NH:24][C:8]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])=[CH:25][CH:26]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C(Cl)c1cccnc1F
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)c2cccnc2F)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 2-fluoropyridine-3-carbonyl chloride (3.2 g, 20 mmol, Step D) and NaHCO3 (4 g, 48 mmol) in CH2Cl2 added in dropwise a solution of 4-tert butylaniline (3.0 g, 20 mmol). After the addition, the suspension was stirred at RT for 5 h. Solid inorganic salts were removed via filtration. The filtrate was concentrated to afford a brown solid as desired compound. MS: 273 (M+H). Calc'd. for C16H17FN2O—272.33.
Reaction SMILES: [BrH:1].C(O)(=O)C.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14](=O)[CH2:15][S:16][C:17]#[N:18].O>C(O)(=O)C>[Br:1][C:17]1[S:16][CH:15]=[C:14]([C:8]2[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=2[F:6])[N:18]=1
Reactant: Br
Reactant: N#CSCC(=O)c1ccc(F)cc1F
Solvent: O
Solvent: CC(=O)O
Product: Fc1ccc(-c2csc(Br)n2)c(F)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
A 25% hydrogen bromide/acetic acid (25 ml) solution was added to a solution of 2-(2,4-difluorophenyl)-2-oxoethyl thiocyanate (3.39 g, 15.9 mmol) in acetic acid (25 ml), and the mixture was stirred at 130° C. for 2 hours and stirred at room temperature for 1 hour. Water was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 3.23 g (73.6%) of the desired product as a solid.
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[F:11][C:12]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:13]=1[CH2:14]Cl>>[NH2:2][C:3]1[N:4]=[C:5]([S:10][CH2:14][C:13]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:12]=2[F:11])[NH:6][C:7](=[O:9])[CH:8]=1
Reactant: COc1ccc(CCl)c(F)c1
Reactant: Nc1cc(O)nc(S)n1
Solvent: O
Product: COc1ccc(CSc2nc(N)cc(=O)[nH]2)c(F)c1

Procedure:
The subtitle compound was prepared according to the procedure of Example 1 step i) treating 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate (1.86 g) with 2-fluoro-4-methoxybenzyl chloride (2.00 g) to afford the subtitle compound as a white solid. Yield: 2.64 g.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[N+:19]([O-])=O)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.C(O)C.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].[OH-].[Na+]>O>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[NH2:19])[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Agent: [S-2]
Solvent: CCO
Solvent: O
Product: Nc1cccc2c1C(=O)c1c(N)cccc1C2=O
Reaction time: 8 h
Yield: 73 %

Procedure:
Add 1,8-dinitroanthraquinone (1.49 g, 5 mmol) into 56 ml ethanol and stir the mixture. Then add a reductive solution containing sodium sulfide nonahydrate (5.4 g, 22.5 mmol), sodium hydroxide (2.14 g, 53.5 mmol) dissolved in 95 ml water. The mixed solution is reflux heated for 6 hours, standing overnight, and filter the precipitate. The precipitate is recrystallized from ethanol to get red compound 2.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([N+:15]([O-])=O)[CH:9]=1)(C)(C)C.[S:19]1[CH:23]=[C:22]([C:24](O)=O)[N:21]=[CH:20]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C=O>[S:19]1[CH:23]=[C:22]([C:24]2[NH:15][C:10]3[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][C:11]=3[N:14]=2)[N:21]=[CH:20]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(O)c1cscn1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc2nc(-c3cscn3)[nH]c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (4-Amino-3-nitro-phenyl)-carbamic acid tert-butyl ester (1-3, 0.409 g, 1.832 mmol), thiazole 4-carboxylic acid (0.226 g, 1.832 mmol) and diisopropylethylamine (0.81 mL, 4.03 mmol) in N,N-dimethylformamide (10 mL) was reacted at the ambient temperature with benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBop, 1.05 g, 2.02 mmmol). After 3 h stirring at the same temperature, the reaction mixture was concentrated under the reduced pressure and the residue was partitioned between ethyl acetate (100 mL) and aqueous 0.5N-NaOH solution (70 mL). The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo. The resulting crude product was triturated with ethyl acetate (5 mL), collected by filtration, and dried under the reduced pressure. The mixture of the intermediate products (1-4a and 1-4b) was dissolved in aqueous 20%(v/v)-acetic acid (50 mL) and heated at reflux for 2 h. The reaction mixture was cooled to the ambient temperature and concentrated in vacuo. The resulting crude thick oil was partitioned between ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution (70 mL). The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo. The crude product was triturated with ethyl acetate (15 mL) and hexanes (2 mL). The resulting solid, 2-thiazol-4-yl-3H-benzoimidazol-5-ylamine (1-5), was collected by filtration and dried under the reduced pressure; 1H NMR (500 MHz, DMSO-d6) δ 12.34 (s, 1H), 9.27 (s, 1H), 8.24 (s, 1H), 7.27 (bs, 1H), 6.66 (s, 1H), 6.54 (d, 1H, J=7.5 Hz), 4.96 (bs, 2H).
Reaction SMILES: S1(CCCC1)(=O)=O.C[C:9]([O:11][CH2:12][C:13]1[CH2:22][S:21][C@@H:16]2[C@H:17]([NH2:20])[C:18](=[O:19])[N:15]2[C:14]=1[C:23]([OH:25])=[O:24])=O.[Bi](Cl)(Cl)Cl>CO>[NH2:20][CH:17]1[C:18](=[O:19])[N:15]2[C:14]([C:23]([OH:25])=[O:24])=[C:13]([CH2:12][O:11][CH3:9])[CH2:22][S:21][C@H:16]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl[Bi](Cl)Cl
Solvent: CO
Solvent: O=S1(=O)CCCC1
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 60 °C

Procedure:
To 10 ml of sulfolane were added 2.72 g of 7-ACA, 19 g of bismuth trichloride and 1.1 g of methanol. The mixture was heated at 60° C. for 35 min to advance a reaction. After completion of the reaction, the reaction mixture was cooled to 5° C. The resulting precipitate was filtered off. To the filtrate was added 30 ml of water while cooling on ice. Then, the filtrate was adjusted to pH 3.5 with sodium bicarbonate at a temperature of from 0° C. to 5° C., thereby to form a white crystalline precipitate. The resulting precipitate was collected by filtration, and washed with 10 ml of cold water and, then, with 10 ml of cold methanol to obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.76 g. The yield of the desired product was 31 %.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[N:12]2[N:13]=[C:14]([CH3:16])[CH:15]=[C:11]2[N:10]=[C:9]([NH:17][C:18](=[O:30])[C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])=[CH:21][CH:20]=2)[CH:8]=1>CO>[OH:27][CH2:26][C:25]([C:22]1[CH:21]=[CH:20][C:19]([C:18]([NH:17][C:9]2[CH:8]=[C:7]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:12]3[N:13]=[C:14]([CH3:16])[CH:15]=[C:11]3[N:10]=2)=[O:30])=[CH:24][CH:23]=1)([CH3:29])[CH3:28]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)CO)cc3)cc(Cl)n2n1
Reactant: C1CCNC1
Solvent: CO
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)CO)cc3)cc(N3CCCC3)n2n1
Yield: 76 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(1-hydroxy-2-methylpropan-2-yl)benzamide (4G, 44 mg, 1.0 equivalent) and pyrrolidine (4.0 equivalents) in DMF (0.10 M with respect to 4G) was stirred at 80° C. for 1 h. After cooling, the mixture was diluted with methanol and purified by preparative LC-MS to afford the titled compound (76%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (s, 6H), 1.85-2.07 (m, 4H), 2.33 (s, 3H), 3.47 (s, 2H), 3.96 (br. s., 4H), 6.13 (s, 1H), 6.75 (s, 1H), 7.53 (d, J=8.59 Hz, 2H), 7.97 (d, J=8.59 Hz, 2H), 10.89 (s, 1H). ESI-MS: m/z 394.3 (M+H)+.