Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:20][CH2:21][CH:22]([OH:44])[CH2:23][O:24][C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:45][C:46]1[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[I:45][C:46]1[CH:51]=[CH:50][C:49]([O:44][CH:22]([CH2:21][O:20][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:23][O:24][C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:48][CH:47]=1
Reactant: Oc1ccc(I)cc1
Reactant: OC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Ic1ccc(OC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 8 h
Yield: 89.9 %

Procedure:
Compound 1 (5.0 g, 8.67 mmol), 4-iodophenol (2.10 g, 9.54 mmol) and triphenyl phosphine (2.5 g, 9.5 mmol) were dissolved in dry THF (35 mL). Diisopropyl azodicarboxylate (1.88 mL, 9.5 mmol) was added dropwise during 15 min, and the reaction was allowed to proceed overnight at RT. All volatiles were removed in vacuo. Purification on silica gel (eluent, petroleum ether, bp 40-60° C.: dichloromethane, 1:1, v/v) yielded 6.07 g of the title compound. 1H NMR (CDCl3): 7.49 (2H, d, J 9.1); 7.37-7.21 (30H); 6.62 (2H, d, J 9.1). 4.43 (1H, m); 3.40 (4H, m).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C-:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)=[CH:5][CH:4]=1)#[CH:2].[CH-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[Fe+2:19].I[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1>[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-:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:21]3[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=3)=[CH:4][CH:5]=2)[CH:13]=[CH:12][CH:11]=[CH:10]1.[CH-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[Fe+2:19]
Reactant: C#Cc1ccc(-[c-]2cccc2)cc1
Reactant: O=Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Fe+2]
Product: O=Cc1ccc(C#Cc2ccc(-[c-]3cccc3)cc2)cc1
Reaction time: 0.05 h

Procedure:
Samples of 4 (500 mg, 1.75 mmol), 4-iodobenzaldehyde (406 mg, 1.75 mmol), CuI (18 mg, 94 μmol) and Pd(PPh3)2Cl2 (8 mg, 11 μmol) were placed in a Schlenk flask. The flask was evacuated for 3 min and then the flask was backflushed with argon for 3 min. The process of evacuation and flushing was repeated 3 times. At this point flow rate was increased and the threaded stopcock was removed. Deaerated THF (5 mL) and DIEA (5.0 mL) were added in succession to the flask by gas-tight syringe. The threaded stopcock was replaced, the argon flow rate was reduced and the flask was immersed in an oil bath thermostated at 40° C. The reaction was stopped after 40 h. The mixture was then evaporated and the resulting orange solid was chromatographed (silica, CH2Cl2/hexanes, 1:1). The second orange band comprising the title compound was collected (579 mg, 84.9%). mp 219-220° C.; 1H NMR δ 4.10 (s, 5H), 4.42 (s, 2H), 4.73 (s, 2H), 7.52 (s, 4H), 7.72, 7.92 (AA′BB′, 4H), 10.07 (s, 1H); 13C NMR δ 67.3, 70.3, 70.5, 84.6, 89.4, 94.8, 120.2, 126.6, 130.4, 130.6, 132.6, 132.7, 135.9, 141.6, 192.2; EI-MS obsd 390.0696 (M+), calcd exact mass 390.0707; Anal. Calcd for C25H18FeO: C, 76.94; H, 4.65. Found: C, 76.75; H, 4.68.
Reaction SMILES: C([O:8][N:9]1[C:13](=[O:14])[CH2:12][CH:11]([NH:15][S:16]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:21][CH2:20]2)(=[O:18])=[O:17])[C:10]1=[O:32])C1C=CC=CC=1>C(O)C.[Pd]>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH:22]2[CH2:23][CH2:24][N:19]([S:16]([NH:15][C@H:11]3[CH2:12][C:13](=[O:14])[N:9]([OH:8])[C:10]3=[O:32])(=[O:17])=[O:18])[CH2:20][CH2:21]2)=[CH:26][CH:27]=1
Reactant: O=C1CC(NS(=O)(=O)N2CCC(c3ccc(F)cc3)CC2)C(=O)N1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C1C[C@H](NS(=O)(=O)N2CCC(c3ccc(F)cc3)CC2)C(=O)N1O

Procedure:
N-[1-(benzyloxy)-2,5-dioxo-3-pyrrolidinyl]4-(4fluorophenyl)-1-piperidinesulfonamide was hydrogenated over 10% Pd on charcoal in ethanol+10% AcOH under normal atmospteric pressure in the standard hydrogenation apparatus and the reaction progress was monitored by TLC. Then, the catalysator was filtered, washed with ethanol and the title compound was purified by silica gel chromatography (EtOAc+10% MeOH+1% AcOH).
Reaction SMILES: Br.[N:2]1([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]3)=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.O>CN(C=O)C>[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([N:5]2[CH2:6][CH2:7][N:2]([C:8]3[CH:17]=[C:16]4[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]4)=[CH:10][CH:9]=3)[CH2:3][CH2:4]2)=[O:32])=[CH:29][CH:28]=1
Reactant: O=C1CCc2ccc(N3CCNCC3)cc2N1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Br
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCc2ccc(N3CCN(C(=O)c4ccc(Cl)cc4)CC3)cc2N1
Yield: 73.9 %

Procedure:
To a solution of 800 mg of 7-(1-piperazinyl)-3,4-dihydrocarbostyril hydrobromide in 10 ml of DMF was added 1.2 ml of triethylamine, and then a solution of 730 mg of 4-chlorobenzoyl chloride in 2 ml of DMF was added dropwise to the mixture while stirring. After completion of addition, the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into a large amount of water. Crystals which formed were collected by filtration, washed with water and dried. The crystals were purified through silica gel column chromatography and recrystallized from chloroform-methanol to give 700 mg of 7-[4-(4-chlorobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 289°-291° C., colorless powders.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:29](I)=[C:11]2[N:12]=[C:13]([CH3:28])[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][C:19]([NH:25][CH2:26][CH3:27])([C:22]([NH2:24])=[O:23])[CH2:18][CH2:17]3)[N:10]2[N:9]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>C(O)C.C1(C)C=CC=CC=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>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:29]([C:35]2[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=2)=[C:11]2[N:12]=[C:13]([CH3:28])[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][C:19]([NH:25][CH2:26][CH3:27])([C:22]([NH2:24])=[O:23])[CH2:18][CH2:17]3)[N:10]2[N:9]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCNC1(C(N)=O)CCN(c2nc(C)nc3c(I)c(-c4ccccc4Cl)nn23)CC1
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: Cc1ccccc1
Solvent: CCO
Product: CCNC1(C(N)=O)CCN(c2nc(C)nc3c(-c4ccc(F)cc4)c(-c4ccccc4Cl)nn23)CC1
Temperature: 80 °C
Yield: 266 %

Procedure:
A mixture of 1-[7-(2-chlorophenyl)-8-iodo-2-methylpyrazolo[1,5-a][1,3,5]triazin-4-yl]4-ethylaminopiperidine-4-carboxylic acid amide (I-1A-1i; 20 mg, 0.037 mmol) and 4-fluorophenylboronic acid (7.8 mg, 0.056 mmol) in ethanol (1.3 ml), toluene (1.3 ml) and 2M aqueous Na2CO3 (0.3 ml) was degassed (3×) by pulling a vacuum followed by refilling with nitrogen gas. Tetrakis(triphenylphosphine)palladium (6 mg, 0.005 mmol) was added and the mixture was heated at 80° C. for 5 hours. After cooling to room temperature, the mixture was extracted from water with ethyl acetate, the combined organic layers were washed with brine, dried (MgSO4), filtered through a 0.45 μm filter disk, and then concentrated, in vacuo, to afford the crude product (50 mg). Purification on a Chromatotron using 0-3% methanol in methylene chloride as eluant afforded a light yellow oil, which was crystallized from diethyl ether, and dried, in vacuo, to afford 1A-1 (11 mg, 58%) as a colorless solid: +ESI MS (M+1) 508.4; 1H NMR (400 MHz, CD3OD) δ 7.46-7.34 (m, 4H), 7.32 (dd, J=8.7, 5.4 Hz, 2H), 6.96 (t, J=8.7 Hz), 4.70-4.58 (br m, 2H), 4.40-4.25 (br m, 2H), 2.51 (q, J=7.1 Hz, 2H), 2.46 (s, 3H), 2.20-2.12 (br m, 2H), 1.83-1.75 (m, 2H), 1.10 (t, J=7.1 Hz, 3H).
Reaction SMILES: NC1C=CN(C)C(=O)N=1.ClCC(CCl)=O.[Cl:16][CH2:17][C:18]1[N:19]=[C:20]2[CH:25]=[CH:24][N:23]([C:26]3C=CC(F)=CC=3)[C:22](=[O:33])[N:21]2[CH:34]=1>>[Cl:16][CH2:17][C:18]1[N:19]=[C:20]2[CH:25]=[CH:24][N:23]([CH3:26])[C:22](=[O:33])[N:21]2[CH:34]=1
Reactant: O=c1n(-c2ccc(F)cc2)ccc2nc(CCl)cn12
Agent: Cn1ccc(N)nc1=O
Agent: O=C(CCl)CCl
Product: Cn1ccc2nc(CCl)cn2c1=O

Procedure:
2-Chloromethyl-6-methyl-6H-imidazo[1,2-c]pyrimidin-5-one was prepared from 4-amino-1-methyl-1H-pyrimidin-2-one and 1,3-dichloroacetone using the methods described above for the preparation of 2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[C:12]([C:19]([NH:21][O:22][CH2:23][CH2:24][O:25]C=C)=[O:20])=[N:13][N:14]([CH3:18])[C:15](=[O:17])[CH:16]=1.Cl>CCO.C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[C:12]([C:19]([NH:21][O:22][CH2:23][CH2:24][OH:25])=[O:20])=[N:13][N:14]([CH3:18])[C:15](=[O:17])[CH:16]=1
Reactant: C=COCCONC(=O)c1nn(C)c(=O)cc1Nc1ccc(SC)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: CSc1ccc(Nc2cc(=O)n(C)nc2C(=O)NOCCO)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
To a solution of 4-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridazine-3-carboxamide (30 mg, 0.077 mmol) in EtOH/THF (2 mL/2 mL) was added 1 N aqueous HCl (0.15 mL, 0.15 mmol, 1 N aqueous solution) at room temperature. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was neutralized to pH 7, diluted with EtOAc (3×), washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (100% EtOAc to 100% CH2Cl2 to 2.5 to 3 to 5% MeOH in CH2Cl2) to afford 6 mg (22%) of the desired product. MS APCI (−) m/z 367 (M−1) detected; −1H NMR (400 MHz, CD3OD) δ 7.35 (t, 1H), 7.18 (dd, 1H), 7.14 (dd, 1H), 5.92 (s, 1H), 4.06 (t, 2H), 3.79 (t, 2H), 3.74 (s, 3H), 2.51 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[CH3:35]>>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:51]2[CH2:52][CH2:53][CH2:54][N:48]([C:40]3[N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:49][CH2:50]2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8]1)=[O:6]
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reactant: COc1cc(OC)c(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc1OC
Agent: I
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)cc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 7.6 using 1-(2,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl) pyrrolidine and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt to give the title compound: Rf=0.42 (silica gel, 9/1/0/1 dichloromethane/methanol/concentrated aqueous ammonia).
Reaction SMILES: [C:1]([S:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH:16]OS([O-])=O.[K+]>CO>[C:1]([S:5]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S([O-])OO
Reactant: CC(C)(C)Sc1ccc(C(=O)O)cc1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)S(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 156.7 %

Procedure:
4-(tert-Butylthio)benzoic acid (3.18 g, 15.1 mmol) was dissolved in methanol (78.70 mL) followed by the addition of water (7.9 mL) and OXONE (4.65 g, 7.56 mmol). The reaction mixture was stirred at room temperature for 45 minutes before it was filtered using methanol. The solvent was evaporated under reduced pressure. Water (35 mL) was added to the residue and the mixture was basified using solid NaOH and was washed with ethyl acetate (3×50 mL). The aqueous layer was acidified with 1N HCl before it was extracted with ethyl acetate (3×100 mL). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to yield 4-(tert-butylsulfinyl)benzoic acid (2.68 g, 78%) as a white solid. 1H NMR (400 MHz, DMSO) δ 13.29 (s, 1H), 8.12-8.08 (m, 2H), 7.73-7.69 (m, 2H), 1.09 (s, 9H). ESI-MS m/z calc. 226.1, found 227.3 (M+1)+; Retention time: 1.05 minutes (3 min run).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)(=[O:4])[CH3:3].C(N(CC)CC)C.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>ClCCl>[C:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:10][S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=2)(=[O:29])=[O:28])=[CH:7][CH:6]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)c1ccc(CN)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1ccc(CNS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 4 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension under argon of 4-acetylbenzylamine hydrochloride (700 mg) in dichloromethane (20 ml) was added triethylamine (1.15 ml) and stirring continued for 15 minutes. The mixture was cooled to 4° C., then 4-methylphenylsulphonyl chloride (790 mg) in dichloromethane (5 ml) added dropwise over 30 minutes. The reaction mixture was stirred for 18 hours at ambient temperature, then diluted with further dichloromethane (50 ml), washed with water, dried (MgSO4) and evaporated. Trituration of the residue gave N-([4-acetylphenyl]methyl)4-methylphenylsulphonamide (A), 1.02 g., as an off-white solid: m.p. 125°-128° C.; NMR (d6DMSO) δ8.13(1H,t), 7.86(2H,d), 7.68(2H,d), 7.37(4H,dd), 4.03(2H,d), 2.55(3H,s), 2.39(3H,s); m/e304(M+H)+.
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[C:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[NH:19][C:20]3=[O:23])=[CH:15][CH:14]=2)[CH2:8]1)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+].O>CN(C)C=O>[N:34]([CH2:6][CH:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[C:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:31])([F:32])[F:33])[NH:19][C:20]3=[O:23])=[CH:15][CH:14]=2)[CH2:8]1)=[N+:35]=[N-:36]
Reactant: CS(=O)(=O)OCC1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCC1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Temperature: 65 °C
Reaction time: 4 h
Yield: 92.6 %

Procedure:
The 2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethyl methanesulfonate (169.1 mg, 0.351 mmol) obtained in step C was dissolved in N,N-dimethylformamide (1.3 ml). Thereafter, sodium azide (96.2 mg, 1.33 mmol) was added to the obtained solution, and the mixture was then stirred at 65° C. for 4 hours. Thereafter, water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with a saturated saline solution, and was then dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1 to 3:1), so as to obtain 7-(5-azidomethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (139.6 mg; yield: 93%) in the form of a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=O)[NH:6]2.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>C(#N)C.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[NH:6]2
Reactant: C1CCNC1
Reactant: O=C(O)c1cc2c(Br)cccc2[nH]1
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc2c(Br)cccc2[nH]1)N1CCCC1
Temperature: 25 °C
Reaction time: 18.25 h
Yield: 67.2 %

Procedure:
A mixture of 4-bromo-1H-indole-2-carboxylic acid (250 mg, 1.04 mmol), pyrrolidine (0.129 mL, 1.56 mmol), and HOAT (213 mg, 1.56 mmol) in acetonitrile (5 mL) was treated with DIEA (0.364 mL, 2.08 mmol) and EDC (399 mg, 2.08 mmol) and the mixture was stirred at rt. After 18.25 h, the mixture was diluted with EtOAc, filtered to remove some tan solid, and washed sequentially with 1 M hydrochloric acid and NaHCO3 (aq), and dried and concentrated to provide (4-bromo-1H-indol-2-yl)(pyrrolidin-1-yl)methanone as a tan solid (205 mg, 67%). 1H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H) 7.46 (d, J=7.9 Hz, 1H) 7.27 (d, J=7.5 Hz, 1H) 7.06-7.17 (m, 1H) 6.82 (s, 1H) 3.85 (t, J=6.8 Hz, 2H) 3.55 (t, J=6.8 Hz, 2H) 1.93-2.04 (m, 2H) 1.81-1.92 (m, 2H). Mass spectrum m/z 293, 295 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([O:21][CH3:22])[CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20])=[O:8].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:22][O:21][C:12]1[CH:13]=[C:14]2[C:19](=[C:10]([NH:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:27]3[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]3)[CH:11]=1)[N:18]=[CH:17][CH:16]=[C:15]2[CH3:20]
Reactant: CN1CCNCC1
Reactant: COc1cc(NC(=O)CCCCCBr)c2nccc(C)c2c1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1cc(NC(=O)CCCCCN2CCN(C)CC2)c2nccc(C)c2c1
Yield: 53.7 %

Procedure:
A mixture of 5.5 g (0.015 mole) of 6-bromo-N-(6-methoxy-4-methyl-8-quinolinyl)hexanamide and 1.8 g (0.018 mole) of N-methylpiperazine in 70 ml of benzene was heated under reflux for 20 hr, treated with 2 ml of triethylamine, and heated for an additional 24 hr. The mixture was allowed to cool, filtered and the filtrate was washed with water, dried and concentrated to dryness in vacuo. The residue was recrystallized twice from n-hexane containing a little toluene and then dried in vacuo at 68° to afford 3.1 g (53%) of the title compound, mp 104°-107°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[NH:10][CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:4].C(Cl)(Cl)Cl.[Br:27]Br>N1C=CC=CC=1>[Br:27][C:8]1[S:7][C:6]([NH:10][CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:9]=1
Reactant: BrBr
Reactant: CCOC(=O)C(=CNc1sccc1C(=O)OC)C(=O)OCC
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(=CNc1sc(Br)cc1C(=O)OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3.3 parts of diethyl (3-methoxycarbonylthienyl)aminomethylenemalonate in a mixture of 20 parts by volume of chloroform and 4 parts by volume of pyridine, 0.6 part by volume of bromine is added dropwise. The solution is further stirred at room temperature for 15 minutes, after which the reaction mixture is washed with dilute hydrochloric acid, an aqueous sodium hydrogen carbonate solution and water, followed by drying over Na2SO4. The solvent is distilled off to give diethyl (5-bromo-3-methoxycarbonylthienyl)aminomethylenemalonate. Recrystallization from ethanol gives light-yellowish needles melting at 129°-130° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[Cl:9][C:10]1[C:18]([Cl:19])=[CH:17][C:16]([S:20](Cl)(=[O:22])=[O:21])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>C(Cl)Cl>[Cl:9][C:10]1[C:18]([Cl:19])=[CH:17][C:16]([S:20]([N:4]2[CH2:5][C@H:6]([CH3:8])[CH2:7][C@H:2]([CH3:1])[CH2:3]2)(=[O:22])=[O:21])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cc(Cl)c1Cl
Reactant: C[C@@H]1CNC[C@H](C)C1
Solvent: ClCCl
Product: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2cc(Cl)c(Cl)c(C(=O)O)c2)C1

Procedure:
To cis-3,5-dimethylpiperidine (374 mg.; 3.3 m moles) in 3 ml. of methylene chloride is added 192 mg. (0.66 m moles) of 2,3-dichloro-5-chlorosulfonylbenzoic acid and the mixture heated to reflux for 1.5 hrs. The solvent is removed under reduced pressure, and the residue is partitioned between 25 ml. of 1N sodium hydroxide solution and diethyl ether. The aqueous layer is separated, acidified with 6N hydrochloric acid and the resulting precipitated product filtered and dried, 230 mg., m.p. 235°-238° C. Recrystallization from acetonitrile gave the purified product, m.p. 244°-245° C.
Reaction SMILES: [CH2:1]([CH:8]([C:14](OCC)=[O:15])[C:9](OCC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>CCOCC>[CH2:1]([CH:8]([CH2:9][OH:10])[CH2:14][OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC(CO)Cc1ccccc1
Yield: 63.6 %

Procedure:
Slowly add a solution of diethyl 2-benzylmalonate (20 g) in Et2O (300 mL) to a slurry of LiAlH4 (6 g) in Et2O (300 mL), then heat the reaction mixture at reflux for 14 h. Carefully add 4N NaOH to the reaction mixture until there is no precipitate, then extract with EtOAc. Concentrate the organic layer and purify the crude product on a silica gel column, eluting with EtOAc to obtain 2-benzyl-1,3-propanediol (8.45 g).
Reaction SMILES: ClS(O)(=O)=O.C1([C:12]2[C:13](=[O:23])[O:14][CH2:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)C=CC=CC=1>ClCCl>[C:17]1([C:16]2[CH2:15][O:14][C:13](=[O:23])[CH:12]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1OCC(c2ccccc2)=C1c1ccccc1
Agent: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=C1C=C(c2ccccc2)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To 20 mL of stirring chlorosulfonic acid cooled to −5° C. was added 3,4-diphenyl-2-(5H )-furanone (Step 1)(3.160 g, 13.4 mmol) portion-wise over 30 minutes. The solution was warmed to room temperature and maintained at that temperature for 16 hours. The reaction mixture was diluted with dichloromethane and quenched into ice water. The phases were separated and the aqueous phase extracted with dichloromethane, the combined dichloromethane extract was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was diluted with dichloromethane and added to excess concentrated NH4OH. The mixture was stirred for 1 hour. The phases were separated and the aqueous phase was extracted with dichloromethane. The organic extract was dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a white solid that was crystallized from aqueous ethanol to afford pure 3-[(4-aminosulfonyl)phenyl)]-4-phenyl-2-(5H )-furanone (2.110 g, 50%): mp 225.5-226.5° C. 1H NMR (CDCl3/300 MHz) 7.79 (d, 2H, J=8.4 Hz), 7.41 (d, 2H, J=8.4 Hz), 6.38 (brs, 2H), 5.09 (s, 2H). FABLRMS m/z 316 (m+H). Anal. Calc'd for C16H13NO4S: C, 60.94; H, 4.16; N, 4.44. Found: C, 60.86; H, 4.18; N, 4.40.