Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[N:6]=[CH:5]2.C([Li])CCC.[C:26]([C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=[O:31])#[N:27]>O1CCCC1>[OH:31][CH:30]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([CH:12]([CH3:14])[CH3:13])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:16])[CH3:17])[N:6]=[CH:5]2)[C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[C:26]#[N:27]
Reactant: N#Cc1ccccc1C=O
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ncc2cc(I)ccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ncc2cc(C(O)c3ccccc3C#N)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 9.1 %

Procedure:
A solution of 5-iodo-1-[tris(1-methylethyl)silyl]-1H-indazole (1.8 g, 4.6 mmol) in tetrahydrofuran (9.2 mL) was cooled to −78° C., and n-butyllithium was added (1.6M in hexanes, 3.4 mL, 5.5 mmol). After 15 min., 2-cyanobenzaldehyde (0.78 g, 6.0 mmol) in 2.0 mL tetrahydrofuran was added quickly and the solution was allowed to warm to room temperature. The reaction mixture was quenched with an excess of saturated aqueous ammonium chloride solution, then partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted (2×100 mL ethyl acetate). The combined organic layers were dried (sodium sulfate), filtered and concentrated in vacuo. Column chromatography (silica gel, 3:1 hexanes/ethyl acetate) gave 0.17 g (9%) of 2-(hydroxy{1-[tris(1-methylethyl)silyl]-1H-indazol-5-yl}methyl)benzonitrile. 1H NMR (400 MHz, CDCl3): 8.20 (s, 1H), 7.95 (m, 1H), 7.69 (s, 1H), 7.51 (m, 3H), 7.23 (m, 1H), 7.09 (m, 1H), 6.50 (s, 1H), 1.77 (m, 3H), 1.06 (m, 18H); MS (EI) for C24H31N3OSi: 250 (M−SiiPr3).
Reaction SMILES: C[O-].[Na+].[Na].[CH3:5][SH:6].Cl[C:8]1[N:13]=[C:12]([CH:14]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][CH:9]=1>CS(C)=O.CO>[CH3:5][S:6][C:8]1[N:13]=[C:12]([CH:14]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: CS
Reactant: Clc1cccc(C(Oc2ccccc2)Oc2ccccc2)n1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CS(C)=O
Product: CSc1cccc(C(Oc2ccccc2)Oc2ccccc2)n1
Temperature: 13 °C

Procedure:
To a mixture of sodium methoxide (made from 100 ml (2.47 m) of methanol and 1.50 g (0.652 m) of sodium metal) which had been cooled to 13° C. was added 7.0 ml (0.126 m) of methylmercaptan. The mixture was allowed to warm to room temperature and then 20.0 g of 6-chloro-2-(diphenoxymethyl)pyridine and 150 ml of dimethylsulfoxide was added thereto. The mixture was heated to 90° C. and after 4 days at this temperature, the reaction mixture was cooled to room temperature and poured into 300 ml of ice. The solution was extracted with methylene chloride and the extract was dried over magnesium sulfate and the solvent stripped off under reduced pressure. The residue was further purified using preparative high pressure liquid chromatography with a 2:98 mixture of ethylacetate and hexane. The oil thus obtained crystallized in n-hexane and was purified by recrystallization from n-hexane leaving the above named compound as a white solid in a yield of 49 g (98 percent pure). The product melted at 58°-59° C. and its structure was confirmed by its NMR spectrum. Upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 70.42, 5.19 and 4.20 percent, respectively, as compared with the theoretical contents of 70.59, 5.26 and 4.33 percent, respectively, as calculated for the above named compound (Compound 3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[CH2:19]([N:26]1[CH:34]=[C:33]2[C:28]([CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=[CH:32]2)=[N:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:26]1[CH:34]=[C:33]2[C:28]([CH:29]=[C:30]([C:2]3[CH:3]=[C:4]([C:12]4[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=4)[N:5]4[C:10]=3[C:9]([NH2:11])=[N:8][CH:7]=[N:6]4)[CH:31]=[CH:32]2)=[N:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: Nc1ncnn2c(-c3ccnc(Cl)c3)cc(Br)c12
Product: Nc1ncnn2c(-c3ccnc(Cl)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 28 %

Procedure:
Using a procedure similar to that of Example 4 with 5-bromo-7-(2-chloro-pyridin-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and 2-benzyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-2H-indazole as starting materials, 60 mg (28%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1 H), 8.5 (d, 2 H), 8.0 (m, 2 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 3 H), 7.25-7.15 (m, 4 H), 7.20 (s, 1 H), 5.70 (s, 2 H); ES-MS m/z 45224 [M+H]+, HPLC RT (min) 3.33.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([C:11](=O)[CH3:12])[CH:9]=[CH:10][C:5]=2[C:4]([CH3:15])([CH3:14])[O:3]1.[NH2:16][OH:17].Cl.CC([O-])=O.[Na+].O>CO>[OH:1][B:2]1[C:6]2[CH:7]=[C:8](/[C:11](=[N:16]/[OH:17])/[CH3:12])[CH:9]=[CH:10][C:5]=2[C:4]([CH3:15])([CH3:14])[O:3]1
Reactant: CC(=O)c1ccc2c(c1)B(O)OC2(C)C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C/C(=N\O)c1ccc2c(c1)B(O)OC2(C)C
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]-oxaborol-6-yl)ethanone (190 mg, 0.93 mmol), NH2OH HCl (77 mg, 1.12 mmol) and NaOAc (114 mg, 1.4 mmol) in MeOH (15 mL) was heated to 65° C. and stirred for 3 h. Water was added and the mixture was extracted with DCM. The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give (E)-1-(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)ethanone oxime as a white solid. It was used in the next step without further purification. MS: m/z=220.1 (M+1, ESI+).
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].[CH2:12]([N:14]([CH2:18][CH3:19])[C:15](=[S:17])[S-:16])[CH3:13].C([NH2+]CC)C>C(=S)=S>[CH2:12]([N:14]([CH2:18][CH3:19])[C:15](=[S:16])[S:17][CH:5]([CH2:4][N+:1]([O-:3])=[O:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:13]
Reactant: CCN(CC)C(=S)[S-]
Reactant: O=[N+]([O-])C=Cc1ccccc1
Agent: CC[NH2+]CC
Solvent: S=C=S
Product: CCN(CC)C(=S)SC(C[N+](=O)[O-])c1ccccc1

Procedure:
As in Example 17, reaction of β-nitrostyrene with diethylammonium diethyldithiocarbamate in the presence of carbon disulfide gave α-(nitromethyl)benzyl diethyldithiocarbamate melting at 81° C.-82.5° C. when recrystallized without heating from acetone-2-propanol solution.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:9])=[CH:5][C:6]=1[C:7]#[N:8].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].[OH-].[K+]>CS(C)=O.O>[CH3:9][C:4]1[S:3][C:2]([NH:1][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])=[C:6]([C:7]#[N:8])[CH:5]=1
Reactant: Cc1cc(C#N)c(N)s1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C#N)c(Nc2ccccc2[N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-5-methylthiophene-3-carbonitrile (13.8 g, 100 mmol) and 1-fluoro-2-nitrobenzene (16.92 g, 120 mmol) in dimethylsulfoxide was added potassium hydroxide (11.2 g, 200 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water, and the resulting suspension was filtered. The filtered cake was dried to give 5-methyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile as a red solid used without further purification. 1H NMR: (400 MHz, CDCl3) δ 9.69 (s, 1H), 8.27-8.25 (m, 1H), 7.56-7.52 (m, 1H), 7.23-7.20 (m, 1H), 7.0-6.96 (m, 1H), 6.80 (s, 1H), 2.49 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:15]=NC2C(Br)=CC=CC=2Br)[C:6]=1[OH:25])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:28]=1[NH2:29].C(C1C(O)=C(C=C(C(C)(C)C)C=1)C=O)(C)(C)C>>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([CH:15]=[N:29][C:28]2[C:27]([Cl:26])=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:34])[C:6]=1[OH:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=Nc2c(Br)cccc2Br)c(O)c(C(C)(C)C)c1
Reactant: Nc1c(Cl)cccc1Cl
Agent: CC(C)(C)c1cc(C=O)c(O)c(C(C)(C)C)c1
Product: CC(C)(C)c1cc(C=Nc2c(Cl)cccc2Cl)c(O)c(C(C)(C)C)c1

Procedure:
An analogous procedure was employed to that described above for the synthesis of 2,4-bis(tert-butyl)-6-[[(2,6-dibromophenyl)imino]methyl]phenol, using 2,6-dichloroaniline (1.03 g, 6.4 mmol) and 3,5-di-tert-butyl-2-hydroxybenzaldehyde (1.5 g, 6.4 mmol). The product was purified by recrystallisation from hot ethanol and the product isolated as yellow crystals. Yield 1.87 g, 77%.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C1(C)C(C)=CC=CC=1.[C:18]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](Cl)[CH:24]=1)(=[O:20])[CH3:19]>C1(C)C=CC=CC=1>[C:18]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:24]=1)(=[O:20])[CH3:19]
Reactant: Oc1ccccc1
Reactant: CC(=O)OCc1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: CC(=O)OCc1cccc(Oc2ccccc2)c1
Yield: 73 %

Procedure:
18.07 g. (0.192 mole) of phenol, 8.42 g. (0.15 mole) of potassium hydroxide and 20 cm3 of xylene are weighed together. The water is azeotropically distilled with stirring and boiling then the xylene is also distilled. To the reaction mixture 1.0 g. of copper(I) chloride and 1.0 g. of activated copper are added and in oil bath of 160° C. 18.07 g. (0.1 mole) of 3-chlorobenzyl acetate are dropped during 70 minutes then stirred at the same temperature for four hours. After cooling 25 cm3. of toluene are added to the reaction mixture, then the reaction mixture is filtered off and washed with 25 cm3. of toluene. The filtrate is washed with a mixture of 30 cm3. 15% sodium chloride solution and 2 cm3. 40% sodium hydroxide solution. The organic phase is evaporated and the residue is distilled in vacuo. 17.68 g. of 3-phenoxybenzyl acetate are obtained. Boiling point 138°-144° C./40 Pa, nD20 : 1.562, yield 73%.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.[Cl:7][C:8]1[CH:9]=[C:10]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[O:33][C@@H:34]([CH3:38])[CH2:35][NH:36][CH3:37])[N:26]=[CH:25][N:24]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[Cl:7][C:8]1[CH:9]=[C:10]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[O:33][C@@H:34]([CH3:38])[CH2:35][N:36]([CH3:37])[C:4](=[O:6])[CH2:3][O:2][CH3:1])[N:26]=[CH:25][N:24]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CNC[C@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: COCC(=O)O
Product: COCC(=O)N(C)C[C@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 39 %

Procedure:
The procedure described in Example 1 was repeated using methoxyacetic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(1S)-1-methyl-2-(methylamino) ethoxy]quinazolin-4-amine (obtained as described for the R-antipode in Example 2.3, preparation of starting materials) to give the title compound in 39% yield; NMR spectrum (DMSO-d6) 1.38 (d, 3H), 2.99 (s, 3H), 3.16 (s, 3H), 3.27 (1H obscured by H2O), 4.03 (s, 2H), 4.23 (m, 1H), 5.11 (m, 1H), 5.29 (s, 2H), 7.24 (m, 2H), 7.30 (d, 1H), 7.35 (m, 1H), 7.57 (d, 1H), 7.65, (dd, 1H), 7.71 (t, 1H), 7.86 (dt, 1H), 8.12 (d, 1H), 8.44 (s, 1H), 8.58 (d, 1H), 9.90 (s, 1H); Mass Spectrum MH+ 522.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH:10]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH3:24])=[CH:17][CH:16]=1)[C:11]([O:13][CH3:14])=[O:12]>>[CH3:14][O:13][C:11](=[O:12])[CH:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)[CH3:24])=[CH:17][CH:16]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: COC(=O)C(Br)c1ccc(OCC(C)Oc2ccc(Cl)cc2)cc1
Product: COC(=O)C(Oc1ccc(Cl)cc1)c1ccc(OCC(C)Oc2ccc(Cl)cc2)cc1
Yield: 79.4 %

Procedure:
As described in Example 71, 2.19 g of p-chlorophenol is reacted with 7.0 g of methyl bromo{p-[2-(p-chlorophenoxy)propoxy]phenyl}acetate to give 6.2 g of product as a gum.
Reaction SMILES: [C:1]([NH:9][NH:10][C:11](=O)[C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1.C(OCC)(=O)C>CCCCCCC>[C:2]1([C:1]2[S:32][C:11]([C@@H:12]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH3:13])=[N:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OC(C)(C)C)c1nnc(-c2ccccc2)s1
Yield: 75.1 %

Procedure:
To a solution of (S)-tert-butyl (1-(2-benzoylhydrazinyl)-1-oxopropan-2-yl)carbamate (155 mg, 0.5 mmol, 1.0 equv. in 5 ml of THF) was added Lawesson's reagent (36.4 mg, 0.5 mmol, 1.0 equv.) the reaction mixture was stirred at reflux for 3 hours, the reaction mixture was filtered and the solvent was removed to yield the crude product. Silica gel column chromatography (ethyl acetate in heptane 10 to 50%) to provide (S)-tert-butyl (1-(5-phenyl-1,3,4-thiadiazol-2-yl)ethyl)carbamate (114.6 mg, white solid) in 70.7% yield. 1H NMR (400 MHz, CD2Cl2) δ 7.94-7.72 (m, 2H), 7.52-7.26 (m, 3H), 5.59 (b, 1H), 5.11 (b, 1H), 1.57 (d, J=7.0 Hz, 3H), 1.34 (s, 9H).
Reaction SMILES: O1CCCCC1OC1C=C(C23CCC(CCCCC#[N:27])(CC2)CO3)C=CC=1.[O:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[O:34][C:35]1[CH:36]=[C:37]([C:41]23[CH2:48][CH2:47][C:44]([CH2:49][CH2:50][CH2:51]CO)([CH2:45][CH2:46]2)[CH2:43][O:42]3)[CH:38]=[CH:39][CH:40]=1.O1CCCCC1OC1C=C(C23CCC(CCO)(CC2)CO3)C=CC=1>>[O:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[O:34][C:35]1[CH:36]=[C:37]([C:41]23[CH2:48][CH2:47][C:44]([CH2:49][CH2:50][C:51]#[N:27])([CH2:45][CH2:46]2)[CH2:43][O:42]3)[CH:38]=[CH:39][CH:40]=1
Reactant: N#CCCCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Reactant: OCCCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Agent: OCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Product: N#CCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2

Procedure:
3-(1-(3-(Tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)propanenitrile was prepared using a procedure analogous to 5-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)pentanenitrile except that 4-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)butan-1-ol was replaced with 2-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethanol. The title compound was obtained (490 mg, 1.435 mmol, 87% yield) as a white solid. LCMS, [M+NH4]+=359.2. 1H NMR (500 MHz, CDCl3) δ 7.24 (t, J=8.0 Hz, 1H), 7.14-7.10 (m, 1H), 7.03-6.99 (m, 1H), 6.96 (ddd, J=8.2, 2.5, 0.8 Hz, 1H), 5.45 (t, J=3.2 Hz, 1H), 3.94 (ddd, J=11.3, 9.7, 3.2 Hz, 1H), 3.85 (s, 2H), 3.62 (m, 1H), 2.36-2.30 (m, 2H), 2.11-1.98 (m, 5H), 1.90-1.84 (m, 2H), 1.77-1.59 (m, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[N:6][C:5]=1Cl.[CH2:14]([Sn](CCCC)(CCCC)C=C)[CH2:15]CC>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[N:6][C:5]=1[CH:14]=[CH2:15]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(OC)nc1Cl
Agent: Cl[Pd]Cl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1nc(OC)ccc1C(=O)OC
Temperature: 80 °C
Reaction time: 16 h
Yield: 53.2 %

Procedure:
A mixture of 2-chloro-6-methoxy-nicotinic acid methyl ester (10 g, 49.8 mmol), tributyl(vinyl)tin (15.8 g, 49.8 mmol), 2,6-di-tert-butyl-4-methylphenol (0.3 g, 1.36 mmol) and trans-bis(triphenylphosphine)palladium(II) chloride (0.5 g, 0.71 mmol) was added to DMF (50 mL) under nitrogen. The mixture was stirred at 80° C. for 16 h. The solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; petroleum ether/EtOAc 50/1). The desired fractions were collected and the solvents evaporated in vacuo to yield 6-methoxy-2-vinyl-nicotinic acid methyl ester (5.12 g, 54%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:20](Cl)[C:21]4[CH:22]=[C:23]([C:27]([CH3:30])([CH3:29])[OH:28])[CH:24]=[CH:25][CH:26]=4)[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[SH:32][CH2:33][CH:34]([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36].C([O-])([O-])=O.[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([CH:20]([S:32][CH2:33][CH:34]([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([OH:28])([CH3:30])[CH3:29])[CH:22]=4)[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1cccc(C(Cl)c2cccc(C=Cc3ccc4ccc(Cl)cc4n3)c2)c1
Reactant: CCOC(=O)C(C)CS
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)C(C)CSC(c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1)c1cccc(C(C)(C)O)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 52 %

Procedure:
To the crude chloride of Step 4 dissolved in 10 mL of DNE, ethyl 3-mercapto-2-methylpropanoate (Step 6; 350 μl, approx. 2.4 mmol) and Cs2CO3 (1.61 g, 4.9 mmol) were added and the mixture was stirred at r.t. for 3.5 h. 25% Aq NH4OAc was then added and the reaction mixture was extracted with EtOAc, dried over Na2SO4 and purified by flash chromatography on silica using EtOAc:toluene 7.5:92.5 and 10:90 to yield 347 mg of the title compound as an oil (52% yield for Steps 6 and 7).
Reaction SMILES: [NH2:1][CH:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]3[NH:16][N:15]=[N:14][N:13]=3)[CH3:10])[CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.[CH:30]([NH:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39](=[N:43][O:44][CH3:45])[C:40](O)=[O:41])[N:34]=1)=[O:31]>C(Cl)Cl>[CH:30]([NH:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([C:39](=[N:43][O:44][CH3:45])[C:40]([NH:1][CH:2]2[C:20](=[O:21])[N:4]3[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH:9]([S:11][C:12]4[NH:13][N:14]=[N:15][N:16]=4)[CH3:10])[CH2:7][S:8][C@H:3]23)=[O:41])[N:34]=1)=[O:31]
Reactant: CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1nccc(NC=O)n1
Agent: C[Si](C)(C)CC(N)=O
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1nccc(NC=O)n1
Temperature: 25 °C

Procedure:
On the other hand, 7-amino-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid and trimethylsilylacetamide (11 g.) were added to methylene chloride (66 ml.) and the mixture was stirred at ambient temperature for an hour, and to this solution was added all at once the above activated solution of 2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetic acid under cooling at -20° C. with stirring, and the stirring was continued at the same temperature for an hour and at ambient temperature for additional an hour. The reaction mixture was concentrated under reduced pressure and then ethyl acetate and an aqueous solution of sodium bicarbonate were added to adjust the solution to pH 7 to 8. After the aqueous layer was separated out, a proper quantity of ethyl acetate was added thereto. The mixture was adjusted to pH 1 to 2 with dilute hydrochloric acid and then salted out. The ethyl acetate layer was separated out, washed with an aqueous solution of sodium chloride and dried over magnesium sulfate, and then evaporated to dryness under reduced pressure. The resultant foamy substance was pulverized in ethyl ether, collected by filtration and then dried to give 7-[2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (2.9 g.). Thus obtained product (0.6 g.) was dissolved in a mixed solution of methanol and ethyl acetate (5 ml.) (2:1 by volume), and the solution was poured into ethyl ether (40 ml.) and then the mixture was allowed to stand for a while. The precipitates were collected by filtration to give purified pale-yellowish powder of 7-[2-(4-formamidopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (a mixture of syn and anti isomers) (0.5 g.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:13])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C>C(O)C.[Pd]>[F:12][C:8]1[C:7]([F:13])=[C:6]2[C:11]([CH:2]=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1cnc2c(F)c(F)ccc2c1Cl
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc2c(F)c(F)ccc2c1
Yield: 92 %

Procedure:
A solution of 21.9 g of ethyl 4-chloro-7,8-difluoroquinoline-3-carboxylate in 7300 cm3 of ethanol in the presence of 8.8 g of triethylamine and 2.2 g of 5% palladium on carbon was hydrogenated at atmospheric pressure for 1 hour. The solid residue obtained was recrystallized from 300 cm3 of hexane. 17.6 g of ethyl 7,8-difluoroquinoline-3-carboxylate was obtained in the form of white crystals, which melted at 118° C.
Reaction SMILES: C(O)(=O)/C=C\C(O)=[O:5].C(O)(=O)/C=C\C(O)=O.[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][C:18]=1[S:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]([NH:38][C:39]2[C:40]([S:48][CH3:49])=[N:41][C:42]([CH3:47])=[CH:43][C:44]=2[S:45][CH3:46])=[O:37])[CH2:31][CH2:30]1.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl.CO>[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][C:18]=1[S:26][CH2:27][CH2:28][N:29]1[CH2:30][CH2:31][N:32]([CH2:35][C:36]([NH:38][C:39]2[C:40]([S:48]([CH3:49])=[O:5])=[N:41][C:42]([CH3:47])=[CH:43][C:44]=2[S:45][CH3:46])=[O:37])[CH2:33][CH2:34]1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Reactant: O=C(O)/C=C\C(=O)O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CSc1cc(C)nc(S(C)=O)c1NC(=O)CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 26 h
Yield: 40.1 %

Procedure:
To a mixed solution of this amide (500 mg, 0.664 mmol) in chloroform (10 ml) and methanol (2 ml) was added m-chloroperbenzoic acid (213 mg, 1.23 mmol) with ice-cooling, and stirred at room temperature for 26 hours. The reaction solution was diluted with chloroform. The organic layer was washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution successively, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by a silica gel preparative thin layer chromatography (developing solvent; chloroform:sat. ammonia methanol=10:1) to provide 138 mg (yield 40%) of the desired compound as colorless amorphous. IR (neat) cm−1: 3424, 3155, 1695, 1571, 1481. 1H-NMR (d6-DMSO, 120° C.) δ: 2.51 (3H, s), 2.56 (3H, s), 2.73,(3H, s), 2.59-2.68 (6H, m), 2.77 (2H, t, J=7.1 Hz), 2.81-2.92 (2H, br s), 3.11 (1H, d, J=15.8 Hz), 3.17 (1H, d, J=15.8 Hz), 3.41 (2H, t, J=7.1 Hz), 7.07-7.13 (2H, m), 7.30 (1H, S), 7.38-7.44 (2H, m), 9.26 (1H, br s).