Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2Cl)=[O:4].[CH3:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[NH2:24]>ClCCCl.C(O)(C)(C)C.C(OCC)(=O)C>[Cl:1][CH2:2][C:3]([NH:5][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2[NH:24][C:23]1[CH:25]=[CH:26][C:27]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:21]([CH3:20])[CH:22]=1)=[O:4]
Reactant: Cc1cc(N)ccc1Oc1ccccc1
Reactant: O=C(CCl)NCC#Cc1ccc2ncnc(Cl)c2c1
Solvent: CC(C)(C)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2ncnc3ccc(C#CCNC(=O)CCl)cc23)ccc1Oc1ccccc1
Temperature: 25 °C
Yield: 94 %

Procedure:
A solution of 2-Chloro-N-[3-(4-chloro-quinazolin-6-yl)-prop-2-ynyl]-acetamide (50 mg; 0.17mmol) and 3-methyl-4-phenoxyaniline (36 mg; 0.9 equiv.) in 1,2-dichloroethane (1 ml) and t-butanol (1 ml) was heated at 87° C. for 30 minutes. The mixture was then cooled to room temperature and diluted with ethyl acetate to further facilitate precipitation. The solution was then filtered to give the coupled product as a yellow powder (73 mg; 90%). 2.28 (3H, s), 4.10 (2H, s), 4.30 (2H, s), 6.93 (3H, d), 7.09 (1H, t), 7.34 (2H, t), 7.50-7.53 (1H, dd, J=2.6, 6 Hz), 7.63 (1H, d, J=2.4 Hz), 7.78 (I H, d, J=8 Hz), 8.06-8.08 (1H, dd, J=1.4, 7.2 Hz), 8.68 (1H, d, J=1.2 Hz), 8.75 (1H, s). Irms(M+): 457.0, 4.59.1; (M−): 455.7, 419.6
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:16][CH3:17])=[C:4]([C:11]([CH2:14][CH3:15])=[CH:12][CH:13]=1)[CH2:5][C:6]1[NH:7][CH2:8][CH2:9][N:10]=1.C1(N(Cl)C(=O)N(Cl)C(=O)N1Cl)=O.C1CCN2C(=NCCC2)CC1>>[Cl:1][C:2]1[C:3]([CH2:16][CH3:17])=[C:4]([C:11]([CH2:14][CH3:15])=[CH:12][CH:13]=1)[CH2:5][C:6]1[NH:10][CH:9]=[CH:8][N:7]=1
Reactant: CCc1ccc(Cl)c(CC)c1CC1=NCCN1
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1ccc(Cl)c(CC)c1Cc1ncc[nH]1

Procedure:
2-(3-Chloro-2,6-diethyl-benzyl)-1H-imidazole was prepared from 2-(3-chloro-2,6-diethyl-benzyl)-4,5-dihydro-1H-imidazole (Example 196), TCCA and DBU in analogy to Example 194e): light yellow crystals; MS (ISP): 251.3 ([M+H]+, 39%), 249.2 ([M+H]+, 100%).
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=O)[C:10]=2[S:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C([N:21](CC)CC)C.N.O1CCOCC1>S(Cl)(Cl)(=O)=O.CO>[O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH2:21])=[O:18])[C:10]=2[S:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: O=C(O)c1cccc2c(=O)c3ccccc3sc12
Reactant: CCN(CC)CC
Agent: N
Solvent: O=S(=O)(Cl)Cl
Solvent: CO
Solvent: C1COCCO1
Product: NC(=O)c1cccc2c(=O)c3ccccc3sc12
Yield: 23.4 %

Procedure:
A sample of 9-oxo-9H-thioxanthene-4-carboxylic acid 1r (15 g, 58.7 mmol) was heated in sulfonyl chloride (70 mL) for 2 h. Excess sulfonyl chloride was removed via evaporation. The residue was dissolved in tetrahydrofuran (200 mL), and triethylamine (16.4 mL, 117.4 mmol) and a 0.5 M solution of ammonia in dioxane (176 mL, 88.5 mmol) were added. Methanol (20 mL) was added, and the mixture was evaporated. Water and chloroform were added, and a precipitate formed. The precipitate was isolated via filtration, and yielded 3.5 g (25%) of title compound 2r. The organic layer was separated, dried, filtered, and evaporated to yield 11 g of recovered 1r.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[OH-].[CH2:14]([N+:18]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>CO>[NH2:12][CH2:11][C:4]1([CH2:7][C:8]([O-:10])=[O:9])[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]1.[CH2:27]([N+:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:28][CH2:29][CH3:30]
Reactant: NCC1(CC(=O)O)CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Product: NCC1(CC(=O)[O-])CCCCC1

Procedure:
A solution containing gabapentin (34.4 g, 200 mmol), a 1 M solution of tetrabutylammonium hydroxide in methanol (200 mL, 200 mmol), and additional methanol (200 mL) was stirred at ambient temperature for 14 h. The solvent was removed in vacuo, then toluene (200 mL) was added and evaporated under reduced pressure two times. The title compound (11) was obtained as a thick syrup, and was further dried under high vacuum and used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13](SC)[N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=O)C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]2[N:4]([C:8]([C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[CH:13][N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CSc1ncc(C#N)c(-c2cnc3c(C)cccn23)n1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cccn2c(-c3ncncc3C#N)cnc12
Reaction time: 0.5 h

Procedure:
300 mg of the compound [1-6] was dissolved in 6 mL of chloroform, and 368 mg of m-chloroperbenzoic acid was added thereto under an ice-cold condition. After the 30 minutes stirring at the same temperature, to the reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with chloroform. The resulting organic layer was dried over anhydrous sodium sulfate, then the insolubles were filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 3 mL of chloroform, poured onto 3 mL of a tetrahydrofuran solution containing 257 mg of S-(−)-1-(4-bromophenyl)ethylamine and 224 μL of triethylamine, and the mixture was stirred overnight at room temperature. To the reaction mixture was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with chloroform. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1), to obtain 252 mg of 2-{[(1S)-1-(4-bromophenyl)ethyl]amino})-4-(8-methylimidazo[1,2-a]pyridin-3-yl)pyrimidine-5-carbonitrile [3-1] (hereinafter, referred to as the compound [3-1]) as a pale yellow oily product.
Reaction SMILES: [H-].[Na+].ClC1C=C(O)C=CC=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1.CCOC(C)=O>C1COCC1>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH3:25])[N:15]=[CH:14][N:13]=[CH:12]2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Oc1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2cncnc2cc1OC
Temperature: 25 °C

Procedure:
THF (5 ml) and NaH (60% disp in oil, approx. 28 mg) is added to a dry flask maintained under inert atmosphere at room temperature. m-Chlorophenol (0.09 g) is added as a soin. In THF (1 mL) and stirring Is continued until the solution became clear. 4-Chloro-6,7-dimethoxyquinazoline is added all at once (as the solid) and stirring was maintained overnight at RT. The solution is partitioned between CH2CL2 and 5% NaOH. The organic layer is washed with brine, dried (Na2SO4) and concentrated. Flash column chromatography (40% EtOAc/Hex) provided the pure compound. An analytical sample is obtained by recrystallization from EtOAc/Hex to provide 4-m-chlorophenoxy)-6,7-dimethoxyquinazoline (0.05 g, white needles, m.p. 152°-153° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Reactant: c1cn[nH]c1
Product: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-ethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-ethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.ClC1C=CC(NN)=CC=1.Cl.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[C:15]([F:21])[CH:14]=1.ClC1C=CC(N2[C:37](=[O:38])[C:36]3[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=3N2)=CC=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:37](=[O:38])[C:36]3[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=3[NH:20]2)=[C:15]([F:21])[CH:14]=1
Reactant: O=c1c2c([nH]n1-c1ccc(Cl)cc1)CCCC2
Reactant: NNc1ccc(Cl)cc1F
Agent: Cl
Agent: NNc1ccc(Cl)cc1
Product: O=c1c2c([nH]n1-c1ccc(Cl)cc1F)CCCC2

Procedure:
By substituting 4-chlorophenylhydrazine hydrochloride in the above procedure for 4-chloro-2fluorophenylhydrazine hydrochloride, 2-(4-chlorophenyl)-1,2,4,5,6,7-hexahydro-3H-indazol-3-one was prepared, m.p. 183.5°-185° (Lit 186°-187°, Chem. Abs., 67, 11452h).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[CH:18]1([CH2:21]Br)[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][N:12]2[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]2[CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[CH2:20][CH2:19]1
Reactant: BrCC1CC1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1CC1CC1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and cyclopropylmethyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:13](Br)([CH3:15])[CH3:14].[I-].[Na+].O>CN(C)C=O>[CH:13]([O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:15])[CH3:14]
Reactant: CC(C)Br
Reactant: CCOC(=O)c1cccc(O)c1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(OC(C)C)c1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
To a solution of ethyl 3-hydroxybenzoate (15.2 g, 0.10 mol) in N,N-dimethylformamide (100 ml) were added isopropyl bromide (12.1 ml, 0.13 mol) and sodium iodide (19.5 g, 0.13 mol), and the mixture was stirred at 70° C. for 15 hrs. To the reaction solution was added water (500 ml), and the mixture was extracted with ethyl acetate (500,200 ml). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1) to give the objective substance (12.4 g, 64%) as an oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.C(N(CC1C=CC=CC=1)[C:17](=[O:22])[CH2:18][O:19][CH2:20][CH3:21])C.[BH4-].[Na+]>C1COCC1>[Br:13][C:9]1[N:8]=[C:7]([CH:17]([OH:22])[CH2:18][O:19][CH2:20][CH3:21])[CH:12]=[CH:11][CH:10]=1
Reactant: CCOCC(=O)N(CC)Cc1ccccc1
Reactant: Brc1cccc(Br)n1
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCC(O)c1cccc(Br)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 37.1 %

Procedure:
To a solution of n-butyllithium (1.6M in hexanes, 4.19 mL, 6.70 mmol) in anhydrous THF (4.0 mL) under nitrogen at −78° C. was added a solution of 2,6-dibromopyridine (1.59 g, 6.71 mmol) in anhydrous THF (9.5 mL) drop-wise over 1 h. The resulting dark green solution was stirred at −78° C. for 15 min and then treated with N-ethyl-2-(ethyloxy)-N-(phenylmethyl)acetamide (1.93 g, 8.70 mmol), washing in with anhydrous THF (1.0 mL). The resulting green solution was stirred at −78° C. for 15 min and was then treated with a solution of AcOH (0.42 mL) in MeOH (7.00 mL) to give a orange solution which was then treated with NaBH4 (0.38 g, 10.04 mmol). This mixture was removed from the cooling bath and allowed to warm to room temperature over 2 h. The mixture was then treated with saturated aqueous. NH4Cl (50 mL) and the products extracted with EtOAc (2×50 mL). The combined organic layer was then washed with brine (100 mL), dried (MgSO4) and the reduced in vacuo to give a yellow oil. Purification by SPE (silica, 20 g cartridge) eluting with cyclohexane:EtOAc (gradient 50:1 to 1:1) afforded the title compound as a white solid (612 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[N:15]=[C:14]3[C:17](=[O:26])[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[CH2:20][CH2:21][C:13]3=[C:12](O)[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)([Br:30])=O.P(Cl)(Cl)(Cl)=O>>[CH2:1]([N:8]1[C:16]2[N:15]=[C:14]3[C:17](=[O:26])[C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[CH2:20][CH2:21][C:13]3=[C:12]([Br:30])[C:11]=2[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=C1c2ccccc2CCc2c1nc1c(cnn1Cc1ccccc1)c2O
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1c2ccccc2CCc2c1nc1c(cnn1Cc1ccccc1)c2Br

Procedure:
By treating the product of Example 10 according to the procedure of Example 2, but substituting phosphorus oxybromide for the phosphorus oxychloride, 1-benzyl-4-bromo-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)one is obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[C:59]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=1[CH2:67][C:68]([O:70][CH3:71])=[O:69])#[CH:60].C#C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:28]([O:27][C:26]([NH:25][CH:22]1[CH2:23][CH2:24][N:19]([C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:4]3[N:3]=[C:2]([C:60]#[C:59][C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=4[CH2:67][C:68]([O:70][CH3:71])=[O:69])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=3)=[CH:14][CH:15]=2)[CH2:20][CH2:21]1)=[O:32])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1ccccc1CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(N3CCC(NC(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A suspension of tert-butyl (1-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)carbamate (I76) (550 mg, 1.17 mmol), CuI (15 mg, 0.12 mmol), triphenylphosphine (31 mg, 0.117 mmol) and triethylamine (487 μL, 3.50 mmol) in DMF (6 mL) was sonicated for 5 minutes in a 10 mL microwave vial, to this PdCl2(PPh3)2 (54.0 mg, 0.077 mmol) and methyl 2-(2-ethynylphenyl)acetate (I4) (305 mg, 1.75 mmol) were added and the reaction heated to 120° C. for 20 minutes under microwave irradiation. Upon cooling the reaction mixture was chromatographed on silica gel using gradient elution (0-100% ethyl acetate in petroleum benzine 40-60° C.) to yield a mixture of the title compound (I77) and homo-coupled acetylene which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[S:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)(=[O:11])=[O:10].[CH2:18]([O:20]C=C[Sn](CCCC)(CCCC)CCCC)[CH3:19].Cl.C([O-])(O)=O.[Na+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([C:18](=[O:20])[CH3:19])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)(=[O:11])=[O:10]
Reactant: O=S(=O)(c1ccc(Br)cc1Br)N1CCOCC1
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CC#N
Product: CC(=O)c1ccc(S(=O)(=O)N2CCOCC2)c(Br)c1
Reaction time: 0.33 h
Yield: 67.8 %

Procedure:
To a solution of the product obtained in step 1 (4.8 g, 12.5 mmol) in ACN (15 ml) was added Cul (119 mg, 0.62 mmol), PdCl2(PPh3)2 and 1-(ethoxyvinyl)tributyl-stannane (5.4 g, 14.95 mmol). The mixture was refluxed for 3 h. After cooling, the reaction mixture was acidified with 1 N HCl (7 ml) and stirred for 20 min. The reaction mixture was neutralized with saturated aqueous NaHCO3 and extracted with AcOEt. The organic phase was dried over Na2SO4 and evaporated. Purification of the crude product by silica gel chromatography using ethyl acetate/n-heptane gave the desired product (2.95 g, 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9].Cl[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[O:9])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(/C=C/C(=O)O)cc1OC
Reactant: OCCCCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(/C=C/C(=O)OCCCCCCO)cc1OC
Temperature: 80 °C
Reaction time: 19 h

Procedure:
A solution consisting of 0.72 ml of 1,8-diazobicyclo[5.4.0]undec-7-ene (1.5-5) and 5 ml of dimethylformamide was added dropwise to a solution of 1.0 g of (E)-3,4-dimethoxycinnamic acid in 10 ml of dimethylformamide in the course of 10 minutes at room temperature. Thereafter, the reaction mixture was heated to 80° C., 0.18 g of tetrabutylammonium iodide and 0.71 ml of 6-chloro-1-hexanol were then added in succession and the reaction was then allowed to proceed for 19 hours. Thereafter, the reaction mixture was cooled to room temperature and partitioned between diethyl ether and 1 N hydrochloric acid and the organic phase was washed several times with saturated sodium chloride solution. The organic phase was then dried over magnesium sulfate, filtered and evaporated down. Chromatography of the residue over 150 g of silica gel with 3:2 toluene/ethyl acetate gave 1.35 g of 6-hydroxyhexyl 3(E)-(3,4-dimethoxyphenyl)acrylate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[S:12][C:13]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[O:9])=[CH:4][N:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>O1CCOCC1>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]1[N:15]=[C:11]([NH:10][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[N:3][CH:4]=2)=[O:9])[S:12][C:13]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: C1COCCN1
Reactant: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccc(Cl)nc1
Solvent: C1COCCO1
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccc(N2CCOCC2)nc1
Yield: 84.3 %

Procedure:
Compound 32 (391 mg, 1.00 mmol) was dissolved in 1,4-dioxane (10 mL), and morpholine (0.44 mL, 5.00 mmol) was added thereto, followed by stirring under heating and reflux for 10 hours. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of sodium chloride was added to the resulting residue, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=19:1) to afford the entitled Compound 34 (372 mg, 84%).
Reaction SMILES: [Na+:1].Br[CH2:3][C:4]([NH:6][C@@H:7]1[C:14](=[O:15])[N:13]2[C@@H:8]1[S:9][CH2:10][C:11](/[CH:19]=[C:20]1/[C:21](=[O:28])[N:22]([CH:25]3[CH2:27][CH2:26]3)[CH2:23][CH2:24]/1)=[C:12]2[C:16]([O-:18])=[O:17])=[O:5].[Na].[SH:30][C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1>CN(C)C=O>[Na+:1].[NH:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=[C:31]1[S:30][CH2:3][C:4]([NH:6][C@@H:7]1[C:14](=[O:15])[N:13]2[C@@H:8]1[S:9][CH2:10][C:11](/[CH:19]=[C:20]1/[C:21](=[O:28])[N:22]([CH:25]3[CH2:27][CH2:26]3)[CH2:23][CH2:24]/1)=[C:12]2[C:16]([O-:18])=[O:17])=[O:5]
Reactant: O=C(CBr)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(/C=C3\CCN(C4CC4)C3=O)CS[C@H]12
Reactant: Sc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C(CSc1nc2ccccc2[nH]1)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(/C=C3\CCN(C4CC4)C3=O)CS[C@H]12

Procedure:
(E)-(6R,7R)-7-(2-bromo-acetylamino)-3-(1-cyclopropyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1:1) (see ex. C4a) (200 mg, 0.42 mmol) was dissolved in 4 ml N,N-dimethylformamide and 2-mercaptobenzimidazole sodium salt (79.2 mg, 0.46 mmol) was added in a single portion. After completion of the reaction, the solvent was stripped off at a rotary evaporator. The residue was dissolved in water and chromatographed on MCI gel (75-150μ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitril (10:1, 9:1). The organic solvent was evaporated and the aqueous phase was freeze-dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])[CH2:6][C:5]2([CH3:20])[CH3:19].N1C=CC=CC=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:28]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][S:33]([C:29]1[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34])[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(Cl)cc21
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2cccnc2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)aniline (100 mg, 0.35 mmol) in dichloromethane (5 mL) was added pyridine (0.6 mL) and pyridine-3-sulfonyl chloride (112 mg, 0.35 mmol) at ice-bath. The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was washed with water. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuum. The residue was purified by HPLC to give pyridine-3-sulfonic acid [2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide. LC/MS m/e obsd. (ESI+) [(M+H)+] 427.90.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]1CCN2C(=NCCC2)CC1>>[CH3:16][N:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nc3ccccc3[nH]2)cc1
Reactant: C1CCC2=NCCCN2CC1
Product: Cn1c(-c2ccccc2)nc2ccccc21
Temperature: 90 °C

Procedure:
To a mixture of 2-phenylbenzimidazole (1.02 g, 5.25 mmol) in DMC (10 mL), DBU (0.80 g, 5.25 mmol) was added and the resulting mixture was heated to reflux (90° C.) for 6 hours. The solvent was evaporated under vacuum and the resulting oil was dissolved in methylene chloride (2 mL) and filtered through silica gel (2:1 EtOA/hexane). The solvent was evaporated under vacuum to afford 1-methyl-2-phenylbenzimidazole as a solid. The yield of 1-methyl-2-phenylbenzimiazole as determined by HPLC analysis was 98%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]([OH:17])=O)=[N:4][CH:5]=[C:6]([O:8][CH2:9][C@H:10]2[CH2:12][C:11]2([F:14])[F:13])[CH:7]=1.[NH2:18][C:19]1[C:20]([OH:37])=[CH:21][C:22]([O:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:28])=[N:23][CH:24]=1>>[Cl:1][C:2]1[C:3]([C:15]([NH:18][C:19]2[C:20]([OH:37])=[CH:21][C:22]([O:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH3:28])=[N:23][CH:24]=2)=[O:17])=[N:4][CH:5]=[C:6]([O:8][CH2:9][C@H:10]2[CH2:12][C:11]2([F:13])[F:14])[CH:7]=1
Reactant: C[C@@H](COc1cc(O)c(N)cn1)NC(=O)OC(C)(C)C
Reactant: O=C(O)c1ncc(OC[C@H]2CC2(F)F)cc1Cl
Product: C[C@@H](COc1cc(O)c(NC(=O)c2ncc(OC[C@H]3CC3(F)F)cc2Cl)cn1)NC(=O)OC(C)(C)C

Procedure:
Using 3-chloro-5-(((1R)-2,2-difluorocyclopropyl)methoxy)pyridine-2-carboxylic acid and tert-butyl ((2S)-1-((5-amino-4-hydroxypyridin-2-yl)oxy)propan-2-yl)carbamate, and in the same manner as in Step E of Example 139, the title compound was obtained.