Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].C([Li])CCC.[CH2:13]([CH:15]1[CH2:19][CH:18]([CH3:20])[N:17]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:16]1=[O:30])[CH3:14].ICC.[Cl-].[NH4+]>O1CCCC1>[CH2:13]([C:15]1([CH2:1][CH3:2])[CH2:19][CH:18]([CH3:20])[N:17]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C:16]1=[O:30])[CH3:14]
Reactant: CCC1CC(C)N(Cc2ccc(OC)cc2)C1=O
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCI
Product: CCC1(CC)CC(C)N(Cc2ccc(OC)cc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
To a solution of diisopropylamine (2.1 g) in tetrahydrofuran (20 mL) was added dropwise n-butyllithium (1.6 M hexane solution, 13 mL) at −78° C. under nitrogen atmosphere, and the mixture was warmed to 0° C., and stirred for 30 min. The reaction mixture was cooled to −78° C., a solution of 3-ethyl-1-(4-methoxybenzyl)-5-methylpyrrolidin-2-one (2.5 g) obtained in Step B in tetrahydrofuran (10 mL) was added thereto, and the mixture was stirred at the same temperature for 1 hr. Iodoethane (2.5 mL) was added thereto, and the mixture was stirred overnight while it was allowed to be warmed. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.3 g).
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][N:5]1[CH:9]=[C:8]([N:10]2[C:22]3[C:21]4[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=4[N:15]=[CH:14][C:13]=3[N:12]([CH3:24])[C:11]2=[O:25])[C:7]([CH3:26])=[N:6]1.[N:28]1([C:33]2[N:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][N:34]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:26][C:7]1[C:8]([N:10]2[C:22]3[C:21]4[CH:20]=[C:19]([C:36]5[CH:37]=[N:38][C:33]([N:28]6[CH2:29][CH2:30][CH2:31][CH2:32]6)=[N:34][CH:35]=5)[CH:18]=[CH:17][C:16]=4[N:15]=[CH:14][C:13]=3[N:12]([CH3:24])[C:11]2=[O:25])=[CH:9][N:5]([CH2:4][C:3]([OH:2])=[O:27])[N:6]=1
Reactant: CC1(C)OB(c2cnc(N3CCCC3)nc2)OC1(C)C
Reactant: COC(=O)Cn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(C)n1
Product: Cc1nn(CC(=O)O)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(N5CCCC5)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using [4-(8-bromo-3-methyl-2-oxo-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-3-methyl-pyrazol-1-yl]-acetic acid methyl ester (stage 247.1.2) and 2-(pyrrolidin-1-yl)pyrimidine-5-boronic acid pinacol ester (Frontier Scientific, Logan, USA) to give the title compound as a yellow hydrochloride salt after evaporation of the fractions containing pure product and exchange of the trifluoroacetate to the chlorure. (HPLC: tR 2.29 min (Method A); M+H=485, M−H=483 MS-ES)
Reaction SMILES: [Se](=O)=[O:2].[CH3:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6]>O1CCOCC1.O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]([CH:4]=[O:2])=[O:6])=[CH:8][CH:9]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: O=CC(=O)c1ccc(F)cc1
Reaction time: 12 h
Yield: 71.1 %

Procedure:
Selenium dioxide (6.70 g, 61.0 mmol) was added to a solution of 4-fluoroacetophenone (8.43 g, 61.0 mmol) in dioxane (100 mL) and water (3 mL), and the resulting mixture was heated at 55° C. until complete dissolution of selenium dioxide had occurred. The reaction mass was then refluxed for 5-6 hrs. After completion of the reaction (TLC), the mixture was filtered and the filtrate was concentrated in vacuo affording a viscous oil. Water (50 mL) was added and the resulting mixture was stirred for 12 hrs, after which time the solid was collected on a filter, washed with water (25 mL) and dried in vacuo, affording 4-fluorophenylglyoxal (6.60 g, 85%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([I:11])[CH:5]=1.[NH2:13][NH2:14]>>[I:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[CH3:10])[C:3]([NH:13][NH2:14])=[O:2]
Reactant: NN
Reactant: COC(=O)c1ccc(C)c(I)c1
Product: Cc1ccc(C(=O)NN)cc1I

Procedure:
3-Iodo-4-methyl benzoic acid methyl ester was treated with hydrazine to form 3-Iodo-4-methyl benzoic acid hydrazide. 2-(3-Iodo-4-methyl-phenyl)-[1,3,4]oxadiazole was prepared from 3-iodo-4-methyl benzoic acid hydrazide according to a method analogous to that described in J. of Medicinal Chemistry (2001), 44(8):1268-85, the entire teachings of which are incorporated herein by reference. Compounds 46, 68, 69, 70, and 71 were prepared via an amide coupling reaction analogous to that described in step A of the synthesis of Compound 1, followed by a Suzuki coupling reaction analogous to that described in step B of the synthesis of Compound 1. The amide coupling reaction and Suzuki coupling reaction are shown for Compound 69 in Scheme XX below:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][NH:7][C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:10][N:9]=1.[H-].[Na+].[Br:36][C:37]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[C:40]([O:47][CH3:48])=[CH:39][C:38]=1[CH2:49]Br.O>CN(C)C=O.C(OCC)(=O)C>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=1)[CH2:6][N:7]([CH2:49][C:38]1[CH:39]=[C:40]([O:47][CH3:48])[C:41]([C:43]([F:44])([F:46])[F:45])=[CH:42][C:37]=1[Br:36])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:12][N:13]=1
Reactant: COc1cc(CBr)c(Br)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CCCOc1cnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(OCCCC(=O)OC(C)(C)C)cn2)c(Br)cc1C(F)(F)F
Reaction time: 0.25 h
Yield: 54.8 %

Procedure:
Tert-butyl 4-[2-(3,5-bis-trifluoromethyl-benzylamino)-pyrimidin-5-yloxy]-butyrate (300 mg) is dissolved in N,N-dimethylformamide (4 ml) and thereto is added sodium hydride (60%) (33 mg) under ice-cooling, and the mixture is stirred for 15 minutes and thereto is added 1-bromo-2-bromomethyl-4-methoxy-5-trifluoromethyl-benzene (327 mg) and the mixture is stirred at room temperature overnight. Thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→17:3) to give tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-bromo-5-methoxy-4-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (256 mg). MS (m/z): 746/748 [M+H]+
Reaction SMILES: C1(C)C=CC=CC=1.Cl[CH2:9][CH2:10][CH2:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=1[NH2:21].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O>[O:26]1[CH2:27][CH2:28][N:23]([CH2:9][CH2:10][CH2:11][O:12][C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[NH2:21])[CH2:24][CH2:25]1
Reactant: C1COCCN1
Reactant: Nc1ccc(C(=O)OCCCCl)c(N)c1
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1ccc(C(=O)OCCCN2CCOCC2)c(N)c1
Temperature: 25 °C
Yield: 46.3 %

Procedure:
A mixture of 35 ml of toluene, 4.6 g of (3-chloropropyl)-2,4-diaminobenzoate and 3.5 g of morpholine was refluxed for 10 hrs, cooled to room temperature, and poured into 70 ml of water with stirring. The precipitate was filtered, washed with hexane and dried. Recrystallization from toluene gave 2.6 g (3-morpholinopropyl)-2,4-diaminobenzoate, a white solid, mp 96° C.
Reaction SMILES: [NH2:1]/[C:2](/[C:10]([F:13])([F:12])[F:11])=[C:3](/[CH3:9])\[C:4]([O:6]CC)=O.C[O-].[Na+].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=O)[O:26]CC)=[C:20]([F:30])[CH:19]=1>CN(C=O)C>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:4](=[O:6])[C:3]([CH3:9])=[C:2]([C:10]([F:11])([F:12])[F:13])[NH:1][C:25]2=[O:26])=[C:20]([F:30])[CH:19]=1
Reactant: CCOC(=O)/C(C)=C(\N)C(F)(F)F
Reactant: CCOC(=O)Nc1ccc(Br)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(C(F)(F)F)[nH]c(=O)n(-c2ccc(Br)cc2F)c1=O
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
Ethyl 3-amino-4,4,4-trifluoro-2-methylcrotonate (26.0 g) was dissolved in DMF (123 ml). To this solution, a suspension of sodium methoxide in DNF (7.78 g) was added dropwise at 0° C., and the mixture was stirred at 5° C. for 30 minutes. Then, a DMF solution of ethyl N-(4-bromo-2-fluoro-phenyl)carbamate (31.44 g) was added dropwise thereto, and the mixture was stirred at 130° C. for 5 hours. After the reaction, DMF was distilled off under reduced pressure, and the residue was acidified by adding diluted hydrochloric acid thereto. This was extracted with ethyl acetate, washed with water, and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off, and the resulting residue was crystallized from ethyl acetate-n-hexane (1:3 v/v) to obtain the objective 3-(4-bromo-2-fluorophenyl)-5-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (18.78 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[C:10]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:6][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccc(Br)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1
Reaction time: 8 h
Yield: 93.1 %

Procedure:
14 g of 3-Bromobenzyl alcohol was dissolved in 200 ml of N,N-dimethylformamide, and 15 g of t-butylchlorodimethyl silane and 10 g of imidazole were added. After stirring was continued at room temperature overnight, the solution was diluted with ethyl acetate, and washed successively with 1N hydrochloric acid and saturated brine. After drying the organic layer over anhydrous magnesium sulfate, the solvent was evaporated. The residue was purified by silica gel column chromatography, and 21 g of [(3-bromobenzyl)oxy] (t-butyl)dimethylsilane was obtained in the 4:1 hexane-ethyl acetate fraction. Then, the obtained 21 g of [(3-bromobenzyl)oxy] (t-butyl)dimethylsilane was dissolved in 300 ml of tetrahydrofuran, and the mixture was cooled to −78° C. under nitrogen atmosphere. 55 ml of butyl lithium (1.52 M solution in hexane) was added thereto, and the mixture was stirred for 30 minutes. A solution of 11.5 g of 4-formylmorpholine solution in 20 ml of tetrahydrofuran was added. After stirring was continued at −78° C. for 1 hour, 1N-hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 14.7 g of the title compound in the 4:1 hexane-ethyl acetate fraction.
Reaction SMILES: [O-:1][C:2]#N.[K+].[C:5]([C:7]1([NH:23][CH3:24])[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:9][CH2:8]1)#[N:6].[OH2:25]>C(O)(=O)C>[CH3:24][N:23]1[C:7]2([CH2:8][CH2:9][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:14])[CH2:11][CH2:12]2)[C:5](=[O:25])[NH:6][C:2]1=[O:1]
Reactant: CNC1(C#N)CCN(C(=O)OCc2ccccc2)CC1
Reactant: N#C[O-]
Reactant: O
Agent: [K+]
Solvent: CC(=O)O
Product: CN1C(=O)NC(=O)C12CCN(C(=O)OCc1ccccc1)CC2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of potassium cyanate (5.74 g, 70.8 mmol) in water (9 mL) was added dropwise to a solution of the hydrochloride salt of benzyl 4-cyano-4-(methylamino)piperidine-1-carboxylate (9.68 g, 35.4 mmol) in acetic acid (27 mL). The reaction mixture was heated at 50° C. After 1 h, the mixture was poured into cold water (200 mL). The mixture was extracted with ethyl acetate (4×), and the combined organic extracts were dried over magnesium sulfate and concentrated. A solution of HCl (10% in water; 40 mL) was added and the mixture was heated at 50° C. After 15 min, the reaction mixture was cooled to ambient temperature. The precipitated solid was filtered, washed with water, and dried under reduced pressure to give the title compound. MS 318.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:28][C:27]3[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=3)[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2c(CC(F)(F)F)nc3cc(Cl)c(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (301 mg) in DMF (5 mL) was added potassium carbonate powder (298 mg) and 4-fluorobenzyl bromide (841 mg). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as a peach colored solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:20]=2[N:21]=1.[H-].[Na+].CN(C=O)C>C1COCC1.O>[C:1]([O:5][C:6](=[O:15])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([O:14][C:17]2[S:18][C:19]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:20]=3[N:21]=2)[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: COc1cccc2sc(Cl)nc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cccc2sc(O[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
trans-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester (2.15 g, 10 mmol) and 2-chloro-4-methoxybenzothiazole (1.99 g, 10 mmol) were dissolved in THF (50 ml) and cooled to 0° C. At this temperature, NaH dispersion (960 mg, 2.2 eq) was added portionwise and the mixture was heated at 60° C. for 2 h. DMF (20 ml) was added and heating was continued for 1 h. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. Purification by chromatograpy on SiO2 (hex/EtOAc 4:1, 2:1) gave 1 g (26%) of a beige solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([CH3:16])([CH3:15])[O:9][SiH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1.C([Li])CCC.[F:22][C:23]1[CH:34]=[CH:33][C:26]([C:27](N(OC)C)=[O:28])=[CH:25][CH:24]=1>CCOCC>[C:11]([SiH2:10][O:9][C:8]([CH3:16])([CH3:15])[C:6]1[CH:7]=[C:2]([C:27]([C:26]2[CH:33]=[CH:34][C:23]([F:22])=[CH:24][CH:25]=2)=[O:28])[CH:3]=[N:4][CH:5]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cncc(Br)c1
Reactant: CON(C)C(=O)c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)[SiH2]OC(C)(C)c1cncc(C(=O)c2ccc(F)cc2)c1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a solution of 3-bromo-5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridine (1G) (1.0 g, 3.3 mmol) in 15 mL of ether at −75° C., is added n-butyl lithium (1.4 mL, 3.6 mmol, 2.5M in hexane) drop wise. After being stirred at −75° C. for 30 minutes, a solution of 4-fluoro-N-methoxy-N-methyl-benzamide (0.69 g, 3.8 mmol) in 5 mL of ether is added to the reaction solution drop wise. After being stirred at −75° C. for 1 hour, the reaction solution is warmed to room temperature in 1 hour, and quenched by addition of 10 mL of water. The mixture is extracted with 2×15 mL of EtOAc. After concentration, the crude product is purified by chromatography (heptane 90%, EtOAc 10%) to give [5-(tert-butyl-dimethyl-silanyloxymethyl)-pyridin-3-yl]-(4-fluoro-phenyl)-methanone (1H) (0.79 g, Yield 69%) as colorless liquid. MS (ESI) m/e 346 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].CN(C=O)C.[H-].[Na+].Cl[CH2:20][S:21][C:22]#[N:23]>O>[NH2:6][C:5]1[CH:7]=[C:8]([S:11][CH2:20][S:21][C:22]#[N:23])[CH:9]=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: N#CSCCl
Reactant: Nc1cc(S)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CSCSc1ccc([N+](=O)[O-])c(N)c1
Reaction time: 0.5 h

Procedure:
A solution of 3.4 g. of 2-nitro-5-mercaptoaniline in 20 ml. of DMF is treated with 0.5 g. of 100% sodium hydride, and 2.2 g. of chloromethylthiocyanate is added to the solution. After 30 minutes at 20°-25° C., the solution is diluted with water and extracted with chloroform. Removal of the chloroform leaves 1-amino-2-nitro-5-(thiocyanatomethylthio)benzene.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=O)[CH2:4][OH:5].[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=C.Cl>CCOCC.C(OCC)(=O)C.CCCCCC>[CH3:14][O:13][C:9]([CH:10]1[C:4](=[O:5])[CH2:3][O:7][CH2:8]1)=[O:12]
Reactant: COC(=O)CO
Reactant: C=CC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)C1COCC1=O
Yield: 53.6 %

Procedure:
To a suspension of NaH (6.66 g, 166.5 mmol) in ether (500 mL) add methyl glycolate (15.0 g, 166.5 mmol) drop wise. Stir the reaction until evolution of H2 gas ceases. Concentrate and dissolve the solid in DMSO (300 mL). Cool the reaction to 0° C. and add methyl acrylate (16.6 mL, 183.17 mmol) drop wise. Warm the reaction to room temperature and stir overnight. Acidify the reaction with 10% HCl and extract with ether (3×). Combine organic extracts and wash with brine. Dry the organic solution (Na2SO4), filter, and concentrate in vacuo. Purify by flash chromatography (250 g SiO2, 40 mL/min, 0-50% ethyl acetate/hexane for 20 minutes and then 50% ethyl acetate/hexane for 13 minutes) to yield 4-oxo-tetrahydro-furan-3-carboxylic acid methyl ester 4a (12.9 g, 89.2 mmol, 54%) as a colorless oil. 1H NMR (δ, 400 MHz, CDCl3): 4.50 (dd, 1H, J=8.4, 9.6 Hz), 4.46 (dd, 1H, J=8.4, 9.6 Hz), 4.05 (d, 1H, J=16.8 Hz), 3.79, (s, 3H), 3.97 (d, 1H, J=16.8, Hz), 3.54 (t, 1H, J=8.4Hz). MS calcd. 144; found (EI) 144.
Reaction SMILES: N[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:20][CH:19]=2)[N:3]=1.N([O-])=[O:32].[Na+].C(=O)([O-])O.[Na+]>Cl.O1CCOCC1.O>[CH2:11]([O:10][C:8]([C:7]1[C:2](=[O:32])[NH:3][C:4]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:20][CH:19]=2)=[CH:5][C:6]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])[CH3:12]
Reactant: O=N[O-]
Reactant: CCOC(=O)c1cc(-c2ccc(OCOCCOC)cc2)nc(N)c1C(=O)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(OCOCCOC)cc2)[nH]c(=O)c1C(=O)OCC
Reaction time: 1 h

Procedure:
In 250 ml of 1N hydrochloric acid and 100 ml of dioxane was dissolved 32.2 g of 2-amino-3,4-diethoxycarbonyl-6-(4-methoxyethoxymethoxyphenyl)pyridine, whereto a solution of 6.9 g (1.3 eq.) of sodium nitrite dissolved in 30 ml of water was added dropwise under ice-cooling. The mixture was stirred for 1 hour and left standing in a refrigerator overnight. The mixture was neutralized with sodium hydrogencarbonate, and dioxane was distilled off, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried. Then, the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent:dichloromethane→ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].S([O-])(O)=O.[Na+].[CH:18](=O)[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[N:6]([CH3:7])[C:4](=[O:5])[C:3]3[C:2](=[C:11]([CH3:12])[CH:10]=[CH:9][CH:8]=3)[N:1]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CNC(=O)c1cccc(C)c1N
Agent: O=S([O-])O
Agent: [Na+]
Product: COc1ccc(-c2nc3c(C)cccc3c(=O)n2C)cc1
Temperature: 150 °C
Reaction time: 5 h
Yield: 48.8 %

Procedure:
2-Amino-N,3-dimethylbenzamide (4.10 g, 25.0 mmol), sodium hydrogensulfite (2.93 g, 27.5 mmol) and para-anisaldehyde (3.4 g, 25 mmol) were mixed in N,N′-dimethylacetamide (20 ml), stirred at 150° C. for 5 hours, then cooled to room temperature, and distilled water (100 ml) was added thereto and stirred at that temperature for 1 hour. The precipitated solid was taken out through filtration, dried, and recrystallized from hot ethanol to obtain the intended compound (3.42 g, 49%) as a white solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH3:20])[C:15]([OH:17])=O)[N:13]=1)=[O:7].[CH3:21][N+:22]([CH3:25])=[CH:23][Cl:24].[Cl-].C[Si](C)(C)NC(=O)C.[NH2:35][CH:36]1[C:67](=[O:68])[N:38]2[C:39]([C:51]([O:53][CH:54]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)=[O:52])=[C:40]([CH:43]=[CH:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)[CH2:41][S:42][C@H:37]12>C(OCC)(=O)C.O1CCCC1.O>[CH3:21][N+:22]([CH3:25])=[CH:23][Cl:24].[Cl-:3].[CH3:20][O:19][N:18]=[C:14]([C:12]1[N:13]=[C:9]([NH:8][CH:6]=[O:7])[S:10][CH:11]=1)[C:15]([NH:35][CH:36]1[C:67](=[O:68])[N:38]2[C:39]([C:51]([O:53][CH:54]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)=[O:52])=[C:40]([CH:43]=[CH:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)[CH2:41][S:42][C@H:37]12)=[O:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3ccccn3)CS[C@H]12
Reactant: CON=C(C(=O)O)c1csc(NC=O)n1
Agent: CC(=O)N[Si](C)(C)C
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3ccccn3)CS[C@H]12)c1csc(NC=O)n1
Reaction time: 0.5 h

Procedure:
Vilsmeier reagent was prepared from phosphorus oxychloride (1.29 g) and dimethylformamido (0.62 g) in ethyl acetate (30 ml) in a usual manner. 2-(2-Formamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer) (1.6 g) was added to the stirred suspension of the Vilsmeier reagent in ethyl acetate (2 ml) and tetrahydrofuran (10 ml) under ice-cooling and stirred at the same temperature for 0.5 hours to produce an activated acid solution. N-(Trimethylsilyl)acetamide (5.0 g) was added to the stirred suspension of benzhydryl 7-amino-3-[2-(2-pyridyl)vinyl]-3-cephem-4-carboxylate (trans isomer) (3 g) in ethyl acetate (30 ml) and stirred at 40° to 43° C. for 30 minutes. To the clear solution was added the activated acid solution prepared above at -20° C. and stirred at the same temperature for 30 minutes. Water (30 ml) was added to the resulting solution, and separated organic layer was washed with 5% aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated to give benzhydryl 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[2-(2-pyridyl)vinyl]-3-cephem-4-carboxylate (syn isomer) (trans isomer) (4.1 g).