Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4](I)[N:3]=1.[C:11](B(O)O)([CH3:13])=[CH2:12].COCCOC.C([O-])([O-])=O.[Na+].[Na+]>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.CCO>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([C:11]([CH3:13])=[CH2:12])[N:3]=1
Reactant: C=C(C)B(O)O
Reactant: COc1ccc(I)nc1Br
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: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: C=C(C)c1ccc(OC)c(Br)n1
Temperature: 80 °C

Procedure:
In a tube were placed 2-bromo-6-iodo-3-methoxypyridine (700 mg, 2.236 mmol), isopropenylboronic acid (212 mg, 2.460 mmol), DME (7.5 mL), EtOH (2.8 mL), and 1M aq. Na2CO3 (5.6 mL). The mixture was degassed with N2. Next, Pd(PPh3)4 (206 mg, 0.179 mmol) was added and the mixture was degassed again with N2. The tube was sealed and heated at 80° C. for 16 hours. The reaction was then cooled to room temperature, diluted with EtOAc (100 mL), and washed with saturated NaHCO3 and brine (50 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (0 to 15% EtOAc/hexanes) afforded 2-bromo-6-isopropenyl-3-methoxypyridine. Rf=0.38 (25% EtOAc/hexanes). LCMS=230.0 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.36 (d, J=8.5 Hz, 1H), 7.07 (d, J=9.4 Hz, 1H), 5.81 (s, 1H), 5.21 (s, 1H), 3.92 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: O1CCOCC1.[O:7]1[CH2:11][CH2:10][O:9][CH:8]1[C:12]1[CH:13]=[C:14](B(O)O)[C:15]([F:18])=[N:16][CH:17]=1.Cl[C:23]1[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([S:30][CH3:31])[N:24]=1.C([O-])([O-])=O.[Na+].[Na+]>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.O>[O:7]1[CH2:11][CH2:10][O:9][CH:8]1[C:12]1[CH:13]=[C:14]([C:23]2[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([S:30][CH3:31])[N:24]=2)[C:15]([F:18])=[N:16][CH:17]=1
Reactant: CSc1nc(C)nc(Cl)n1
Reactant: OB(O)c1cc(C2OCCO2)cnc1F
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CSc1nc(C)nc(-c2cc(C3OCCO3)cnc2F)n1
Temperature: 90 °C
Yield: 48.3 %

Procedure:
1,4-Dioxane (16 mL) and water (3.3 mL) were added to a mixture of 5-(1,3-dioxolan-2-yl)-2-fluoropyridin-3-ylboronic acid (0.715 g, 3.53 mmol), 2-chloro-4-methyl-6-(methylthio)-1,3,5-triazine (0.682 g, 3.88 mmol), Pd(PPh3)4 (0.408 g, 0.353 mmol), and Na2CO3 (0.935 g, 8.82 mmol) and the suspension was heated at 90° C. for 2 h. After cooling, the mixture was filtered, washed with EtOAc (2×20 mL), and the combined organic phases were concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (hexanes to 30% ethyl acetate in hexanes) to give 2-(5-(1,3-dioxolan-2-yl)-2-fluoropyridin-3-yl)-4-methyl-6-(methylthio)-1,3,5-triazine (0.5259 g, 1.706 mmol, 48.3% yield) as a white solid. LCMS (API-ES) m/z 309 (M+H)+.
Reaction SMILES: [CH:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.CN(CCN(C)C)C.[Li]CCCC.[Br:25]C(F)(F)C(F)(F)Br.C(OC(=O)C)(=O)C.[OH-].[K+]>O.CN(C1C=CN=CC=1)C.C(N(CC)CC)C.CCCCC>[Br:25][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:1]([OH:11])[CH2:2][CH2:3][CH2:4]2
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: OC1CCCc2ccccc21
Agent: CN(C)CCN(C)C
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CCCCC
Solvent: O
Product: OC1CCCc2cccc(Br)c21
Temperature: -20 °C
Reaction time: 12 h

Procedure:
To a mixture of 78.5 g (530 mmol) of 1,2,3,4-tetrahydronaphthalen-1-ol, 160 ml (1.06 mol) of TMEDA, and 3000 ml of pentane cooled to −20° C. 435 ml (1.09 mol) of 2.5M nBuLi in hexanes was added dropwise. The obtained mixture was refluxed for 12 h. To the resulting mixture cooled to −80° C. 160 ml (1.33 mol) of 1,2-dibromotetrafluoroethane was added, and this mixture was allowed to warm to room temperature and then stirred for 12 h at this temperature. After that 100 ml of water was added. The resulting mixture was diluted with 2000 ml of water, and the organic layer was separated. The aqueous layer was extracted with 3×400 ml of toluene. The combined organic extract was dried over Na2SO4 and evaporated to dryness. The residue was distilled using the Kugelrohr apparatus, b.p. 150-160° C./1 mbar. The resulting yellow oil was dissolved in 100 ml of triethylamine, and the obtained solution was added dropwise to a stirred solution of 71.0 ml (750 mmol) of acetic anhydride and 3.00 g (25.0 mmol) of DMAP in 105 ml of triethylamine. The resulting mixture was stirred for 5 min, then 1000 ml of water was added, and the obtained mixture was stirred for 12 h. After that the reaction mixture was extracted with 3×200 ml of ethyl acetate. The combined organic extract was washed with aqueous Na2CO3, dried over Na2SO4, and evaporated to dryness. The residue was purified by flash chromatography on silica gel 60 (40-63 um, eluent: hexane-ethyl acetate=30:1, vol.). The resulting acetate was dissolved in 1500 ml of methanol, 81.0 g (1.45 mol) of KOH was added, and the obtained mixture was refluxed for 3 h. The reaction mixture was then cooled to room temperature and poured into 4000 ml of water, and the title product was extracted with 3×300 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and then evaporated to dryness. Yield 56.0 g (47%) of a white crystalline solid. Anal. Calc for C10H11BrO: C, 52.89; H, 4.88. Found: C, 53.01; H, 4.75. 1H NMR (CDCl3): δ 7.38-7.41 (m, 1H, 7-H); 7.03-7.10 (m, 2H, 5,6-H); 5.00 (m, 1H, 1-H), 2.81-2.87 (m, 1H, 4- or 4′-H), 2.70-2.74 (m, 1H, 4′- or 4-H), 2.56 (br.s., 1H, OH), 2.17-2.21 (m, 1H, 2- or 2′-H), 1.74-1.79 (m, 2H, 3,3′-H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](N)[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].N([O-])=[O:12].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1ccc(N)cc1Br
Reactant: O=N[O-]
Agent: [Na+]
Product: CCc1ccc(O)cc1Br

Procedure:
In a manner similar to that of Example 1(d), by reacting 27 g (135 mmol) of 3-bromo-4-ethylphenylamine with 11 g (162 mmol) of sodium nitrite, and after purification by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (90/10), 13 g (49%) of the expected product are obtained in the form of a brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:23][C@@H:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:31][C@@H:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](Nc1c([N+](=O)[O-])c(Cl)nc2ccccc12)c1ccccc1
Yield: 87.3 %

Procedure:
The method described in Part A of Example 1 was used to treat 2,4-dichloro-3-nitroquinoline (20.6 g, 85.1 mmol) in DMF (100 mL) with triethylamine (35 mL, 0.225 mol) and (R)-(+)-α-methylbenzylamine (13.3 mL, 102 mmol). After the precipitate was isolated by filtration, it was washed with water and diethyl ether to provide 24.35 g of 2-chloro-3-nitro-N-[(1R)-1-phenylethyl]quinolin-4-amine as an orange solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])([CH3:3])[CH3:2].[C:22](Cl)(=[O:24])[CH3:23].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[CH:1]([C:4]1[C:5]([S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:13])=[O:14])=[CH:6][C:7]([C:22](=[O:24])[CH3:23])=[C:8]([O:10][CH3:11])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1ccc(S(=O)(=O)c2ccc(C)cc2)c(C(C)C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1cc(C(C)C)c(S(=O)(=O)c2ccc(C)cc2)cc1C(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
To a clear solution of 2-Isopropyl-4-methoxy-1-(toluene-4-sulfonyl)-benzene (5.3 g, 16.56 mmol) in DCE (50 ml) was added acetyl chloride (2.0 g, 24.84 mmol) and AlCl3 (3.3 g, 24.84 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hrs and quenched by H2O (10 ml). Ten minutes after quenching, the aqueous solution was extracted into CH2Cl2. The combined extracts was washed with H2O, dried over Na2SO4, filtered and concentrated. Flashed chromatography on silica gel (0 to 30% EtOAc in Hex) gave 1-[4-Isopropyl-2-methoxy-5-(toluene-4-sulfonyl)-phenyl]-ethanone (4.7 g, 79%) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][NH2:10].[Br:11][C:12]1[S:16][C:15]2=[N:17][C:18]([C:20](O)=[O:21])=[CH:19][N:14]2[CH:13]=1>>[Br:11][C:12]1[S:16][C:15]2=[N:17][C:18]([C:20]([NH:10][CH2:9][C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[O:21])=[CH:19][N:14]2[CH:13]=1
Reactant: NCc1c(F)cccc1Cl
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Product: O=C(NCc1c(F)cccc1Cl)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using (2-chloro-6-fluorophenyl)methanamine and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9](S(C3C=CC(C)=CC=3)(=O)=O)[CH:8]=[CH:7][C:6]=2[C:5]([C:21]([C:23]2[N:27](COCC[Si](C)(C)C)[C:26]3[CH:36]=[CH:37][C:38]([C:40]#[N:41])=[CH:39][C:25]=3[N:24]=2)=[O:22])=[C:4]([C:42]([F:45])([F:44])[F:43])[CH:3]=1.[CH3:46]C1C2N(S(C3C=CC(C)=CC=3)(=O)=O)C=CC=2C(C(C2N(COCC[Si](C)(C)C)C3C=C(C#N)C=CC=3N=2)=O)=C(C(F)(F)F)C=1>>[OH:22][C:21]([C:23]1[NH:27][C:26]2[CH:36]=[CH:37][C:38]([C:40]#[N:41])=[CH:39][C:25]=2[N:24]=1)([C:5]1[C:4]([C:42]([F:43])([F:44])[F:45])=[CH:3][C:2]([CH3:1])=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2)[CH3:46]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(=O)c4nc5cc(C#N)ccc5n4COCC[Si](C)(C)C)c(C(F)(F)F)cc(C)c32)cc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(=O)c4nc5ccc(C#N)cc5n4COCC[Si](C)(C)C)c(C(F)(F)F)cc(C)c32)cc1
Product: Cc1cc(C(F)(F)F)c(C(C)(O)c2nc3cc(C#N)ccc3[nH]2)c2cc[nH]c12

Procedure:
The title compound was synthesized from a mixture of 2-(7-methyl-1-tosyl-5-(trifluoromethyl)-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile and 2-(7-methyl-1-tosyl-5-(trifluoromethyl)-1H-indole-4-carbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile using the same procedures as described in Example 64-B and 64-C. 1H NMR (400 MHz, DICHLOROMETHANE-d2 with 5% of METHANOL-d4) δ ppm 9.24 (br. s., 1H) 7.92 (s, 1H) 7.57-7.65 (m, 1H) 7.51-7.55 (m, 1H) 7.47 (s, 1H) 6.99-7.12 (m, 1H) 5.96 (dd, J=3.41, 1.89 Hz, 1H) 2.53 (s, 3H) 2.34 (s, 3H). HRMS calcd. for C20H15F3N4O (M+H)+ 385.1271. found 385.1277.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1.[C:23]1([C:29]#[C:30][CH2:31][CH2:32]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([C:29]#[C:30][CH2:31][CH2:32][N:8]2[CH2:12][CH2:11][CH:10]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:9]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)OCCC#Cc2ccccc2)cc1
Reactant: O=S(=O)(c1ccc(O)cc1)C1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc(O)cc1)C1CCN(CCC#Cc2ccccc2)C1

Procedure:
The title compound, MS: m/e=355.1 (M+) was prepared from (RS)-4-(pyrrolidine-3-sulfonyl)-phenol trifluoroacetic acid salt and toluene-4-sulfonic acid 4-phenyl-but-3-ynyl ester.
Reaction SMILES: [NH2:1][CH:2]1[C:13](=[O:14])[N:4]2[C:5](C(O)=O)=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12.P(Cl)(Cl)Cl.[C:19]1([OH:25])C=CC=CC=1>CN(C)C=O.O>[CH:19]([NH:1][C@@H:2]1[C:13](=[O:14])[N:4]2[CH:5]=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12)=[O:25]
Reactant: Oc1ccccc1
Reactant: NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12
Solvent: CN(C)C=O
Solvent: O
Solvent: ClP(Cl)Cl
Product: O=CN[C@@H]1C(=O)N2C=C(Cl)CS[C@H]12

Procedure:
This invention relates to a process for the preparation of 7-amino-3-chloro-3-cephem-4-carboxylic acid and esters thereof and to useful intermediates. In particular, it relates to a process for preparing the 3-chloro nucleus which comprises reacting a 7-amino-3-hydroxy-3-cephem ester with a chlorinating agent, for example phosphorus trichloride, in dimethylformamide to produce a 7β-[(dimethylaminomethylene)amino]-3-chloro-3-cephem ester which, on reaction with a carboxylic acid, a percarboxylic acid, or a phenol having a pH in water of between about 2.0 and about 5, forms the corresponding 7β-formamido-3-chloro ester. The product is obtained as an isomeric mixture of 7β-formamido-3-chloro-3-cephem and the corresponding 2-cephem when the 7-amidino-3-chloro intermediate is reacted with a weakly acidic carboxylic acid or with a phenol.
Reaction SMILES: [CH3:1]N(C)C1C=CC=CC=1.[C:10]([O:13][CH2:14][C:15]1[N:29]=[C:18]2[N:19]=[C:20]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH:21]=[C:22]([OH:23])[N:17]2[N:16]=1)(=[O:12])[CH3:11].C(Cl)(Cl)Cl>P(Cl)(Cl)(Cl)=O>[C:10]([O:13][CH2:14][C:15]1([CH3:1])[N:29]=[C:18]2[N:19]=[C:20]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH:21]=[C:22]([OH:23])[N:17]2[NH:16]1)(=[O:12])[CH3:11]
Reactant: CN(C)c1ccccc1
Reactant: CC(=O)OCc1cc(O)n2nc(COC(C)=O)nc2n1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)OCC1=NC2=NC(C)(COC(C)=O)NN2C(O)=C1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
In 300 ml of phosphorus oxychloride was added dropwise 28 ml of N,N-dimethylaniline, and 30.5 g of 2,5-bis(acetoxymethyl)-7-hydroxy-s-triazolo[1,5-a]pyrimidine was added to the mixture and the mixture was stirred at 50 ° C. for 1.5 hours. An oily residue obtained by removing phosphorus oxychloride was dissolved in 500 ml of chloroform and ice-cooled. After addition of crushed ice and water to the mixture and stirring thereof, a chloroform layer was separated, washed with water and dried over anhydrous magnesium sulfate. Then, the mixture was condensed. This was applied to a silica gel column chromatography (eluent chloroform) and fractions containing the title compound were condensed to obtain 14 g of the title compound as an oily product.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([O:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1)=[N+]=[N-]>[Pd]>[NH2:1][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([O:20][C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCN=[N+]=[N-])cc1)Oc1ccc(F)cc1
Agent: [Pd]
Product: CCOC(=O)C(Cc1ccc(OCCN)cc1)Oc1ccc(F)cc1
Yield: 95.1 %

Procedure:
In a similar manner to that described in Reference example 1(d), a reaction was carried out using ethyl 3-[4-(2-azidoethoxy)phenyl]-2-(4-fluorophenoxy)propionate (2.60 g), which is the product of Reference example 37(f), and palladium on carbon (5%, 250 mg) and the reaction mixture was treated to afford the title compound (2.30 g) as a colorless oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]1[C:15]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:16][N:17]=[C:10]1[N:9]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:8]2=[O:30])(=[O:3])[CH3:2].[CH2:31](Br)[CH:32]=CC1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(NC1C=C2C(=CC=1)N1C(N3CCCC3)=NN=C1NC2=O)(=O)C.CN(C=O)C.[Pd]>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]1[C:15]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[N:16][N:17]=[C:10]1[N:9]([CH2:23]/[CH:24]=[CH:29]/[C:28]1[CH:27]=[CH:26][CH:25]=[CH:32][CH:31]=1)[C:8]2=[O:30])(=[O:3])[CH3:2]
Reactant: BrCC=Cc1ccccc1
Reactant: CC(=O)Nc1ccc2c(c1)c(=O)n(Cc1ccccc1)c1nnc(N3CCCC3)n21
Agent: [Pd]
Agent: CC(=O)Nc1ccc2c(c1)c(=O)[nH]c1nnc(N3CCCC3)n12
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc2c(c1)c(=O)n(C/C=C/c1ccccc1)c1nnc(N3CCCC3)n21

Procedure:
From 1.2 g (3.0 mmol) of 7-acetamido-4-benzyl-1-(pyrrolidin-1yl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (described in example 221) debenzylated in 7-acetamido-1-(pyrrolidin-1yl)-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one by Palladium/C method described in example 257, then directly treated with 0.59 g of cinnamyl bromide in the presence of 0.98 g cesium carbonate, in 15 ml of DMF, according to a method described in example 3. We obtain, after purification by chromatography on silica column and recrystallization in ethanol, 0.4 g of pure compound from example 222.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:9][C:10]=2[NH2:12])[CH:5]=[C:4]([S:17]([OH:20])(=[O:19])=[O:18])[CH:3]=1.[Cl:21][C:22]1[N:27]=[C:26](Cl)[N:25]=[C:24]([Cl:29])[N:23]=1>O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:9][C:10]=2[NH:12][C:26]2[N:25]=[C:24]([Cl:29])[N:23]=[C:22]([Cl:21])[N:27]=2)[CH:5]=[C:4]([S:17]([OH:20])(=[O:19])=[O:18])[CH:3]=1
Reactant: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(O)c12
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Product: O=S(=O)(O)c1cc(O)c2c(Nc3nc(Cl)nc(Cl)n3)cc(S(=O)(=O)O)cc2c1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
An ice cold neutral solution of 1-hydroxy-8-aminonaphthalene-3,6-disulphonic acid (31.9 parts) in water (120 parts) was added, with stirring, to a freshly prepared suspension of 2,4,6-trichloro-s-triazine (18.5 parts) in ice and water (140 parts). The mixture was stirred for 3 hours at 0 to 5° C. to give a solution of 1-hydroxy-8-(2,4-dichloro-s-triazin-6-ylamino-)naphthalene-3,6-disulphonic acid (solution 1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=[O:25])=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.C1(C)C=CC(S([CH2:46][N+:47]#[C-:48])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].CO>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([C:24]4[O:25][CH:48]=[N:47][CH:46]=4)=[CH:22][N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(COc2nn(-c3ccccc3)cc2-c2cnco2)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 52.4 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.60 g), p-toluenesulfonylmethylisocyanide (0.25 g), potassium carbonate (0.17 g) and methanol (30 mL) was heated under reflux for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-(2-furyl)-4-{[2-methoxy-4-({[4-(1,3-oxazol-5-yl)-1-phenyl-1H-pyrazol-3-yl]oxy}methyl)phenoxy]methyl}-5-methyl-1,3-oxazole as colorless crystals (0.34 g, yield 54%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 153-154° C.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)=[C:18]([CH:38]=O)[CH:17]=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][CH:48]=2)=[CH:43][CH:42]=1.CC(O)=O>CCOC(C)=O.C1COCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:29])=[N:26][CH:27]=2)=[C:18]([CH2:38][NH:53][C:50]2[CH:49]=[CH:48][C:47]([C:44]3[CH:45]=[CH:46][C:41]([Cl:40])=[CH:42][CH:43]=3)=[CH:52][CH:51]=2)[CH:17]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2ccc(Cl)cc2C=O)cn1
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2ccc(Cl)cc2CNc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Temperature: 25 °C

Procedure:
Solid NaBH(OAc)3 (110 mg, 0.52 mmol) was added to a THF solution (1.7 mL) of ethyl 3-(5-(4-chloro-2-formylphenyl)picolinamido)propanoate (125 mg, 0.35 mmol), 4′-chloro-[1,1′-biphenyl]-4-amine (106 mg, 0.52 mmol), and AcOH (0.02 mL, 0.35 mmol) and the resulting mixture was stirred at room temperature. After 16 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), dry-packed onto silica gel and purified via column chromatography to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8][CH3:9])=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[N:3]=1.[Cl:23][CH2:24][CH2:25][N:26]=[C:27]=[O:28].C1(C)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([S:8][CH3:9])=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:27](=[O:28])[NH:26][CH2:25][CH2:24][Cl:23])=[CH:18][CH:17]=2)[N:3]=1
Reactant: O=C=NCCCl
Reactant: CSc1c(Cl)nc(-c2ccc(O)cc2)nc1N1CCOCC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CSc1c(Cl)nc(-c2ccc(OC(=O)NCCCl)cc2)nc1N1CCOCC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(4-chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenol (80.0 mg, 0.236 mmol), 1-chloro-2-isocyanato-ethane (43.1 mg, 0.354 mmol, eq=1.5), toluene and CH2Cl2 was added to the reaction vessel and flushed with argon. The reaction mixture was stirred at 80° C. for 16 hrs and then dried, and the solvent was evaporated. The reaction mixture was partitioned between EA and water, the organic layer was washed with brine, dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (Hexane/EtOAc 2:1) to give a gray solid of 58.9 mg (58.1%)
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH2:13][C:12](=[O:15])[NH:11][C:10]=2[CH:16]=1)([O-:5])=[O:4].[CH3:17]I>CN(C=O)C>[CH3:17][N:11]1[C:10]2[CH:16]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[CH:8][C:9]=2[O:14][CH2:13][C:12]1=[O:15]
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)COc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 101.3 %

Procedure:
NaH (0.57 g, 23.75 mmol) was added to a solution of 6-nitro-4H-benzo[1,4]oxazin-3-one (2.3 g, 11.85 mmol) in DMF (50 ml) at 0° C. The mixture was stirred at 0° C. for 10 minutes and then CH3I (1.5 ml, 24.04 mmol) was added. The mixture was stirred at 0° C. for one hour, then at room temperature for one hour. The mixture was partitioned between EtOAc and water. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure to give 2.5 g of 4-methyl-6-nitro-4H-benzo[1,4]oxazin-3-one as a solid, 100%.
Reaction SMILES: [O:1]1[C@@H:7]2[C@H:2]1[C:3]([CH3:15])([CH3:14])[O:4][C:5]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:6]=12.[C:16]([N:18]=[C:19]1[NH:23][CH2:22][CH2:21][S:20]1)#[N:17]>C(N(CC)CC)C>[C:16]([N:18]=[C:19]1[N:23]([C@@H:7]2[C:6]3[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:5]=3[O:4][C:3]([CH3:15])([CH3:14])[C@H:2]2[OH:1])[CH2:22][CH2:21][S:20]1)#[N:17]
Reactant: N#CN=C1NCCS1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H]2O[C@@H]21
Solvent: CCN(CC)CC
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCSC2=NC#N)[C@@H]1O
Yield: 56.9 %

Procedure:
A mixture of (3S,4S)-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.603 g) and 2 -cyanoiminothiazolidine (0.762 g) in triethylamine (4.2 ml) was heated under reflux for 9 hours. The resulting precipitates were collected by filtration, and washed with water, and recrystallized from ethanol to give (3S,4R)-4(2-cyanoiminothiazolidin-3-yl)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.56 g).