Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][CH2:5][O:6][C:7](=[C:15]1[CH:22]2[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:24][CH:16]1[CH2:17]3)[CH2:21]2)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1.C(OCC)(=O)C.CCCCCC>CC(C)=O>[OH:14][C:10]1[CH:9]=[C:8]([C:7](=[C:15]2[CH:22]3[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:24][CH:16]2[CH2:17]4)[CH2:21]3)[O:6][CH2:5][CH2:4][I:1])[CH:13]=[CH:12][CH:11]=1
Reactant: Oc1cccc(C(OCCCl)=C2C3CC4CC(C3)CC2C4)c1
Reactant: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: Oc1cccc(C(OCCI)=C2C3CC4CC(C3)CC2C4)c1
Yield: 102.9 %

Procedure:
Sodium iodide (14.0 g, 0.09 mol) and [(2-chloroethoxy)(3-hydroxyphenyl)methylene]adamantane (3.0 g, 0.009 mol) were dissolved in dry acetone and refluxed for 6 days. The reaction was followed by TLC analysis (silica gel, 10% ethyl acetate/hexane) and after the completion of reaction, solvent was evaporated to obtain a white solid. This solid was washed with methylene chloride several times and the combined organic layers were again washed with water. The organic layer was dried over MgSO4 and concentrated to give 3.8 g (100%) of product as an oily material: 1H NMR (CDCl3) δ 1.78-1.97 (m, 12H), 2.64 (bs, 1H), 3.19 (t, 2H, J=7.1 MHz), 3.35 (bs, 1H), 3.69 (t, 2H, J=7.1 MHz), 6.75-7.21 (m, 4H); 13C NMR (CDCl3) δ 2.40, 28.13, 30.41, 32.33, 36.99, 38.86, 39.09, 69.74, 114.86, 116.00, 121.79, 129.28, 133.37, 136.42, 140.51, 155.66. MS m/e (rel intensity) 410 (42), 256 (19), 227 (75), 155 (18), 121 (100), 107 (32), 93 (28), 79 (14), 65 (16); Exact mass: calcd 410.0744, found: 410.0744. ##STR31##
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[C:15]1([CH2:14][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(OCc2ccccc2)cc1
Reaction time: 2 h
Yield: 58.8 %

Procedure:
To a solution of ice-cooled methyl 4-hydroxybenzenepropanoate (0.70 g, 3.9 mmol), benzyl alcohol (0.48 mL, 4.7 mmol) and triphenylphosphine (1.2 g, 4.7 mmol) in tetrahydrofuran (5 mL) was added dropwise diethyl azodicarboxylate (0.73 mL, 4.7 mmol), and the mixture was stirred for 2 hours with ice cooling. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was washed with water, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=17:3) to give the title compound (0.62 g, yield 59%) as powders.
Reaction SMILES: Br.[NH2:2][C:3]1[CH:4]=[CH:5][C:6](/[C:11](/[C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[CH:12]/[C@@H:13]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14]2)=[N:7][C:8]=1[O:9]C.O>O1CCOCC1>[NH2:2][C:3]1[C:8](=[O:9])[NH:7][C:6](/[C:11](/[C:19]2[CH:20]=[CH:21][C:22]([C:25]([CH3:27])([CH3:26])[CH3:28])=[CH:23][CH:24]=2)=[CH:12]/[C@H:13]2[CH2:14][CH2:15][C:16](=[O:18])[NH:17]2)=[CH:5][CH:4]=1
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)ccc1N
Agent: Br
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(/C(=C\[C@H]2CCC(=O)N2)c2ccc(N)c(=O)[nH]2)cc1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
48% hydrobromic acid (0.5 mL) was added to a solution of (5R)-5-[(E)-2-(5-amino-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]pyrrolidin-2-one (20 mg) in 1,4-dioxane (1 mL), and the mixture was stirred at 65° C. for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:0→4:1) and crystallized from chloroform-ethyl acetate to give the title compound as a light brown powder (8 mg, 44%).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([CH3:21])[CH:13]=[CH:12][C:11]([NH:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1.[CH2:22]1[C:27]2([CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH2:26][CH2:25][O:24][CH:23]1O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(N(CC)CC)C>[C:8]1([CH3:21])[CH:9]=[CH:10][C:11]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:31][CH2:32][C:27]3([CH2:28][CH2:29][OH:30])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH2:17][CH2:16]2)=[CH:12][CH:13]=1
Reactant: OC1CC2(CCOCC2)CCO1
Reactant: Cc1ccc(NC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC2CCN(CCC3(CCO)CCOCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a suspension of 4-(p-toluidino)piperidine trifluoroacetate (synthesized in Preparation Example 4-5) (656 mg) in tetrahydrofuran (5 mL) was added triethylamine (0.44 mL). The solution was stirred at room temperature for 25 minutes. Then, 3,9-dioxaspiro[5.5]undecan-2-ol (synthesized in Example 79) (135 mg) in tetrahydrofuran (3 mL) was added to the solution and it was stirred at room temperature for additional 5 minutes. The reaction solution was ice-cooled and sodium triacetoxyborohydride (333 mg) was added thereto. After allowing the reaction solution for its temperature rise to room temperature, it was stirred for additional 26 hours. To the reaction solution was added a 3N aqueous sodium hydroxide solution (10 mL) and it was extracted with ethyl acetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:15]([O:17]C)=[O:16])=[CH:12][S:13][CH:14]=1.[OH-].[Li+]>O1CCCC1.CO.O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:15]([OH:17])=[O:16])=[CH:12][S:13][CH:14]=1
Reactant: COC(=O)c1cscc1Nc1ccc(I)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cscc1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.3 %

Procedure:
Methyl 4-(2-Fluoro-4-iodo-phenylamino)-thiophene-3-carboxylate (270 mg, 0.72 mmol) was dissolved in a mixture of tetrahydrofuran:methanol (6:1, 3 mL) and a solution of lithium hydroxide (0.1 g, 4.2 mmol) in 1 mL of water was added. The solution was stirred at room temperature for 18 hours and the solvent was concentrated. The residue was dissolved in 5 mL of water and the solution was acidified to pH 1 with 1N HCl. The resulting solid was filtered and dried in vacuo to provide 210 mg (79% yield) of 4-(2-fluoro-4-iodo-phenylamino)-thiophene-3-carboxylic acid. MS (EI) for C11H7FINO2S: 364 (MH+).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][C:21]([N:23]2[CH2:29][CH:28]3[CH2:30][CH2:31][CH:25]([CH2:26][CH2:27]3)[CH2:24]2)=[O:22])[C:3]1=[O:32].[OH:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](O)=[O:38].CCN=C=NCCCN(C)C.Cl.C(OCC)(=O)C>C(Cl)Cl.Cl>[CH:25]12[CH2:31][CH2:30][CH:28]([CH2:27][CH2:26]1)[CH2:29][N:23]([C:21]([CH2:20][N:4]1[C:5]3[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=3[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])=[N:8][CH:2]([NH:1][C:37]([C:36]3[CH:40]=[CH:41][CH:42]=[C:34]([OH:33])[CH:35]=3)=[O:38])[C:3]1=[O:32])=[O:22])[CH2:24]2
Reactant: NC1N=C(c2ccccc2F)c2ccccc2N(CC(=O)N2CC3CCC(CC3)C2)C1=O
Reactant: O=C(O)c1cccc(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NC1N=C(c2ccccc2F)c2ccccc2N(CC(=O)N2CC3CCC(CC3)C2)C1=O)c1cccc(O)c1

Procedure:
A mixture of (3RS)-3-amino-1-[(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl]-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one, 3-hydroxybenzoic acid, and WSC-HCl was stirred in CH2Cl2 at room temperature overnight. Ethyl acetate and iN HCl were added in the reaction mixture and organic layer was separated, and washed with water and brine, and dried over magnesium sulfate, evaporated in vacuo. The colorless powder was washed with isopropyl ether to afford (3RS)-1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-3-(3-hydroxyphenyl)carbonylamino-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[H-].[Na+].[Cl:9][C:10]1(C(F)=O)[N:15]=[C:14]([NH:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:13]=[CH:12][NH:11]1.Cl.CN([CH:29]=[O:30])C>O>[NH2:2][C:1]1[N:16]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)[C:14]2[N:15]=[C:10]([Cl:9])[N:11]=[CH:12][C:13]=2[C:29](=[O:30])[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: N#CCC(N)=O
Reactant: CN(C)C=O
Reactant: O=C(F)C1(Cl)N=C(NC2CCCC2)C=CN1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: NC(=O)c1c(N)n(C2CCCC2)c2nc(Cl)ncc2c1=O
Temperature: 3.5 °C
Reaction time: 0.25 h
Yield: 9 %

Procedure:
To a solution, cooled to 2-5°C. on an ice bath, of 1.88 g (22.41 mmol) of cyanoacetamide in 20 mL of anhydrous DMF are added portionwise 1.8 g (44.82 mmol) of 60% sodium hydride. The mixture is stirred for 15 minutes at 2-5°C., and this suspension is then added rapidly to a solution of 5.2 g (21.34 mmol) of the acid fluoride prepared in step 3.2 in 20 mL of anhydrous DMF precooled to 2-5°C. The mixture is stirred overnight at room temperature and then cooled to 2-5°C. on an ice bath, and 0.90 g (22.41 mmol) of 60% sodium hydride is added portionwise. The reaction mixture is stirred for 3 hours at room temperature and then poured into a mixture of ice, 100 mL of water and 150 mL of aqueous 1N HCl. The yellow precipitate formed is isolated by filtration, rinsed with water and then dried in an oven, after which it is rinsed with pentane. 5.4 g of a mixture containing the expected cyclized product and the non-cyclized product are finally obtained in the form of an orange powder. The mixture is purified by chromatography on a column of silica, eluting with a dichloromethane/methanol gradient (99/1 to 96/4). 0.6 g of the expected product is finally obtained in the form of a pale yellow solid. Yield=9%.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:32])=[C:16]([NH:21][C:22](=O)[C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:34])[CH3:33])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CCCCCC>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[C:15]([CH3:32])=[C:16]([NH:21][CH2:22][C:23]4[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:34])[CH3:33])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Solvent: CCCCCC
Product: COc1ccc(CNc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Yield: 80 %

Procedure:
By using N-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-4-methoxybenzamide, the title compound was synthesized according to Example 2b. Yield: 80%. Melting point: 95-96° C. (Hexane)
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]([O:18]C(C)C)=[O:17])[CH:3]=1.C(O)(C)C.[OH-].[K+]>O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[N:5]=[C:4]([C:16]([OH:18])=[O:17])[CH:3]=1
Reactant: CC(C)OC(=O)c1cc(Cl)c(Cl)c(-c2ccc(Cl)cc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)c1cc(Cl)c(Cl)c(-c2ccc(Cl)cc2)n1
Temperature: 40 °C
Yield: 109.2 %

Procedure:
To a 125 mL 3-neck round bottom flask fitted with a condenser, nitrogen inlet, overhead stirrer, thermometer and heating mantle was charged isopropyl 4,5-dichloro-6-(4-chlorophenyl)picolinate (7.6 g, 22.1 mmol) and isopropyl alcohol (70 mL). Reaction mixture was heated to 40° C. and potassium hydroxide (85%, 5.1 g, 77.4 mmol) and water (5 mL) were added. Solids precipitated from the mixture, and it became difficult to stir. The mixture was diluted with water (250 mL) to dissolve most of the solids and allowed to stir at room temperature. Concentrated HCl (12 N, 5.6 mL) was added dropwise to the reaction mixture to achieve a pH of ˜2 and solids precipitated from the mixture. The solids were isolated by vacuum filtration and washed with water (2×100 mL), then allowed to dry to give 7.3 g (108% yield by weight) of 4,5-dichloro-6-(4-chlorophenyl)picolinic acid as a white solid. 1H NMR (400 MHz, THF-d8/D2O) δ 8.19 (d, J=11.2 Hz, 1H), 7.84-7.73 (m, 2H), 7.50 (dd, J=10.3, 3.5 Hz, 2H); 13C NMR (101 MHz, THF-d8/D2O) δ 167.70, 156.03, 152.40, 143.60, 136.49, 134.76, 131.22, 129.24, 128.04, 124.71; mp=229° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][CH2:9][C:8]([C:16]([O:18][CH3:19])=[O:17])=[CH:7][C:6]=2[CH:20]=1.B([O-])([O-])O[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[CH2:12]([N:11]1[C:5]2[CH:4]=[CH:3][C:2]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35])=[CH:25][CH:24]=3)=[CH:20][C:6]=2[CH:7]=[C:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][CH2:10]1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: CCCCN1CCC(C(=O)OC)=Cc2cc(Br)ccc21
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: Cc1ccccc1
Solvent: CCO
Product: CCCCN1CCC(C(=O)OC)=Cc2cc(-c3ccc(OCCOCCC)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
A mixture of methyl 7-bromo-1-butyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.45 g), 4-(2-propoxyethoxy)phenyl borate (0.66 g), 1M potassium carbonate solution (4 ml), ethanol (4 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakis(triphenylphosphine)palladium (0.12 g), and the mixture was refluxed overnight under argon atmosphere and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane) to give methyl 1-butyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.5 g) as pale yellow oil.
Reaction SMILES: [NH2:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:11]([O:13][CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])=[C:6]([CH2:9]Cl)[CH2:7][S:8][C@H:3]12.[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[I-:37].[Na+].[C:39]1([P:45]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(OC(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[I-:37].[CH:14]([O:13][C:11]([C:5]1[N:4]2[C:27](=[O:28])[CH:2]([N:1]=[CH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@H:3]2[S:8][CH2:7][C:6]=1[CH2:9][P+:45]([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:12])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: O=Cc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CS[C@@H]2C(N=Cc3ccccc3)C(=O)N12
Temperature: 40 °C
Reaction time: 0.67 h
Yield: 102.3 %

Procedure:
To a solution of benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate (8.0 g) in N,N-dimethylformamide (40 ml) were added molecular sieve (10 g) and benzaldehyde (2.1 g), followed by stirring at 40° C. for 40 minutes. Thereto were added sodium iodide (2.9 g) and triphenylphosphine (10.1 g), followed by stirring at 40° C. for an hour. The reaction mixture was added dropwise to a mixture of diisopropyl ether (200 ml) and ethyl acetate (100 ml), and the precipitated crystals were collected by filtration and then dried to obtain [4-benzhydryloxycarbonyl-7-benzylideneamino-3-cephem-3-yl]methyl-triphenyl-phosphonium iodide (16.9 g), mp 150°-158° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4]([Cl:6])=[O:5])[CH3:2].[C:7]1([C:13]#[C:14][C:15]2[CH:16]=[C:17]([CH2:21][NH2:22])[CH:18]=[N:19][CH:20]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[ClH:6].[CH2:1]([O:3][C:4](=[O:5])[NH:22][CH2:21][C:17]1[CH:18]=[N:19][CH:20]=[C:15]([C:14]#[C:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:16]=1)[CH3:2]
Reactant: NCc1cncc(C#Cc2ccccc2)c1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NCc1cncc(C#Cc2ccccc2)c1
Product: Cl
Reaction time: 8 h

Procedure:
Add ethylchloroformate (0.18 g, 1.63 mmol) to a solution of C-(5-phenylethynyl-pyridin -3-yl)-methylamine, (prepared as described in EXAMPLE 167), (0.20 g, 0.82 mmol) and triethylamine (0.33 g, 3.27 mmol) in dichloromethane (1.6 mL). Stir overnight, and dilute with dichloromethane. Wash with an aqueous saturated solution of sodium bicarbonate, dry (magnesium sulfate), filter and concentrate. Purify by silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes, to give the free base of the title compound. Dissolve the free base in diethyl ether and add a 1 M solution of hydrogen chloride (1.1 eq.) in diethyl ether. Stir for 2 h and collect the precipitated solid by filtration to give the title compound (0.18 g, 70%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.Br[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[CH3:22][C:7]1([CH3:21])[C:8]2[NH:9][C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=3)[C:16]=2[C:17](=[O:18])[C:5]2[CH:4]=[CH:3][C:2]([O:1][C:25]3[N:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:23][C:6]1=2
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: Brc1ncccn1
Product: CC1(C)c2cc(Oc3ncccn3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound A7-17, the title compound was prepared from Compound A6 and 2-bromopyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].I[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=C(C)C=C(C)C=1.O1CCCC1.C(OCC)(=O)C.[Cu]I>[N+:26]([C:22]1[CH:21]=[C:20]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:25]=[CH:24][CH:23]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1cc(C)cc(C)c1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1Nc1cccc([N+](=O)[O-])c1
Reaction time: 48 h
Yield: 6.2 %

Procedure:
A mixture of 3-amino-4-methoxy-N-phenyl-benzamide (2.0 g, 8 mmol), 1-iodo-3-nitrobenzene (2.5 g, 10 mmol), potassium carbonate (2.8 g, 20 mmol), and copper(I) iodide (0.4 g, 2 mmol) in mesitylene (20 mL) was stirred under an inert atmosphere and heated to reflux. After 48 hours, the mixture was allowed to cool and was then diluted with tetrahydrofuran (100 mL) and filtered through Celite. The filtrate was stripped of solvent under reduced pressure to leave an oily residue which was dissolved in ethyl acetate (250 mL) and extracted successively with 2N hydrochloric acid (2×200 mL), water, 0.5 M aqueous potassium carbonate, water, and saturated aqueous sodium chloride, then dried over MgSO4. The solution was filtered and the filtrate stripped of solvent under reduced pressure. The resulting residue was subjected to chromatography on a column of silica gel in chloroform to afford the product (0.18 g); m.p. 220-221° C. after recrystallization from acetonitrile.
Reaction SMILES: [CH2:1]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=CC=1)[CH2:2][CH2:3]CCCCCCCCC.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.C(Cl)(=O)C=C.C([O-])(O)=O.[Na+].C([N:37](CC)CC)C>C1COCC1.ClCCl>[CH2:13]1[CH2:1][CH2:2][CH2:3][N:17]([CH2:24][CH2:23][N:22]=[C:21]([NH2:37])[NH2:20])[CH2:16][CH2:18][CH2:19]1
Reactant: c1c[nH]cn1
Reactant: CCCCCCCCCCCCc1ccc(N)cc1
Reactant: CCN(CC)CC
Agent: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC(N)=NCCN1CCCCCCC1
Yield: 95 %

Procedure:
Firstly, p-dodecylaniline (12 g, 0.046 mol) was dissolved in THF solvent (100 mL). The solution was poured into a 100 mL three-mouthed round flask, and an acid eliminator was added dropwise through a funnel for 10 minutes, where the acid eliminator contained imidazole and triethyl amine at the same mole fraction (0.023 mol). Under the nitrogen atmosphere, a solution containing acryloyl chloride (3.8 mL, 0.047 mol) in THF (20 mL) was gradually added dropwise to the mixed solution through a dropping funnel for 20 minutes. Meanwhile, the solution was cooled on ice bath to prevent the temperature of the reaction mixture from rising above 5° C. After 6 hours of reaction at 0° C., the solution was kept at 25° C. for more 9 hours of reaction. Upon completion of the reaction, the solution was passed through a filter paper to eliminate precipitated salts, and the solvent was evaporated from the filtrate on an evaporator. The solid thus obtained was dissolved in dichloromethane (100 mL) and added to a separatory funnel along with 10% aqueous NaHCO3 solution (50 mL). The funnel was shaken vigorously and set aside to allow for the complete separation of the aqueous phase and thereby to remove unreacted acryloyl chloride. Magnesium sulfate (1.0 g) was added to the separated dichloromethane solution. After stirred for 5 hours, the solution was subjected to filtration to remove a trace amount of water dissolved in the solvent. The dichloromethane solution thus obtained was kept on the evaporator, and n-hexane (100 mL) was added. The solution was stirred for 2 hours, and unreacted p-dodecyl aniline was filtered out from the solution. The filtrate was then removed of the solvent on the evaporator to yield a white solid DOPAM product (yield 95%). The chemical structure of the DOPAM product was identified by hydrogen nuclear magnetic resonance (1H-NMR) spectrum. The results were as follows.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.O=[S:10](Cl)Cl.S(=NS(C)(=O)=O)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[N:1]1[S:10][CH:8]=[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: Cc1ccccc1N
Reactant: O=S(Cl)Cl
Agent: CS(=O)(=O)N=S=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: c1ccc2nscc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of o-toluidine (10 g, 93.4 mmol) in 50 mL toluene was added SOCl2 (12.1 g, 102 mmol) dropwise at 0° C. After the addition was complete, the reaction mixture was heated to reflux and stirred overnight. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure to give a yellow oil. The oil was dissolved in toluene (100 mL), then a solution of N-sulfinylmethanesulfonamide (20.6 g, 146 mmol) was added dropwise, followed by pyridine (7.3 g, 93.4 mmol). The mixture was heated to reflux and stirred at that temperature overnight. Toluene was then removed under reduced pressure, the residue was dissolved in EtOAc (200 mL) and washed with water (2×200 mL). The organic layer was washed with brine, dried and evaporated to give the crude product. The crude product was purified by column chromatography (3% EtOAc/PE) to afford 6.2 g title compound as colorless oil. 1H NMR (CHLOROFORM-d) δ 9.22 (s, 1H), 7.88 (d, J=9.7 Hz, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.46 (ddd, J=8.9, 6.5, 1.2 Hz, 1H), 7.26 (dd, J=7.9, 6.6 Hz, 1H).