Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH2:6][CH:5]([C:8]2[S:26][C:11]3[N:12]=[C:13]([CH3:25])[N:14]=[C:15]([CH2:16][NH:17][C:18]4([CH3:24])[CH2:23][CH2:22]S[CH2:20][CH2:19]4)[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.[ClH:28].OO.[O-:31][S:32]([O-:35])(=S)=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>CO.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[ClH:28].[CH3:27][C:2]1([CH3:1])[CH2:7][CH2:6][CH:5]([C:8]2[S:26][C:11]3[N:12]=[C:13]([CH3:25])[N:14]=[C:15]([CH2:16][NH:17][C:18]4([CH3:24])[CH2:23][CH2:22][S:32](=[O:35])(=[O:31])[CH2:20][CH2:19]4)[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=S([O-])([O-])=S
Reactant: Cc1nc(CNC2(C)CCSCC2)c2cc(C3CCC(C)(C)CC3)sc2n1
Agent: O=[W](=O)([O-])[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: Cc1nc(CNC2(C)CCS(=O)(=O)CC2)c2cc(C3CCC(C)(C)CC3)sc2n1
Reaction time: 0.17 h

Procedure:
To a suspension of N-{[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}-4-methyltetrahydro-2H-thiopyran-4-amine (55 mg) and sodium tungstate (IV) dihydrate (9.0 mg) in MeOH (1.1 mL) were sequentially added dropwise 1 M hydrochloric acid (313 μL) and a 35% hydrogen peroxide solution (56 μL) under ice-cooling, followed by stirring at the same temperature for 10 minutes, and further stirring at room temperature for 6 hours. To the reaction mixture that had been ice-cooled was added an aqueous Na2S2O3 solution, followed by stirring at room temperature for 30 minutes. Then, saturated aqueous sodium bicarbonate was added thereto, followed by extraction with chloroform. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column. The obtained purified product was dissolved in EtOAc, and 4 M HCl/dioxane was added dropwise thereto. The precipitate was collected by filtration and then dried under reduced pressure to obtain N-{[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}-4-methyltetrahydro-2H-thiopyran-4-amine-1,1-dioxidehydrochloride (22 mg).
Reaction SMILES: [C:1]1([C:7]2([C:11]([OH:13])=O)[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O.[N+:19]([O-])([O-:21])=[O:20].[K+].[BH4-].[Na+].B(F)(F)F.CCOCC>C(O)(=O)C>[N+:19]([C:4]1[CH:5]=[CH:6][C:1]([C:7]2([CH2:11][OH:13])[CH2:10][CH2:9][CH2:8]2)=[CH:2][CH:3]=1)([O-:21])=[O:20]
Reactant: O=C(O)C1(c2ccccc2)CCC1
Reactant: O=[N+]([O-])[O-]
Agent: FB(F)F
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(C2(CO)CCC2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of 1-phenylcyclobutanecarboxylic acid (10) and acetic acid (20 ml) and H2SO4 (20 ml) and KNO3 (1.1 eq) was stirred at 0° C. for 20 min. The mixture was warmed to RT and stirred overnight. The mixture was poured on ice and stirred until all ice melted. The precipitate was filtered and used for next step without further purification. The above product (5 g) was dissolved into THF and stirred at 0° C., NaBH4 (3 eq) was added slowly to the reaction followed by slowly addition of BF3.Et2O (3 eq). The reaction was stirred at RT overnight and quenched with 1 N NaOH slowly until bubble ceased. The solution was extracted with EtOAc and washed with H2O followed by brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography to give [(4-nitrophenyl)cyclobutyl]methane-1-ol as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([OH:18])=O)[C:13](=[O:19])[C:12]([CH3:21])([CH3:20])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:46](=[CH:47][CH:48]=1)[CH2:45][C@:27]1([C:35]3[C:30](=[N:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:28]1=[O:44])[CH2:26]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([NH:22][C:23]3[CH:24]=[C:25]4[C:46](=[CH:47][CH:48]=3)[CH2:45][C@:27]3([C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:42])[CH3:43])[C:28]3=[O:44])[CH2:26]4)=[O:18])[C:13](=[O:19])[C:12]([CH3:21])([CH3:20])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@@]2(Cc3ccc(N)cc3C2)c2cccnc21
Reactant: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C1=O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)N(COCC[Si](C)(C)C)c3ncccc32)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]acetic acid (21 mg, 0.07 mmol, described in Intermediate 49), (R)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (26 mg, 0.07 mmol, described in Intermediate 9, step B), HOBT (15 mg, 0.10 mmol), and EDC (19 mg, 0.10 mmol) in DMF (0.5 mL) was stirred at ambient temperature for 18 h. The reaction mixture was partitioned between saturated aqueous NaHCO3 (10 mL) and EtOAc (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=661 (M+1).
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[CH3:17][CH:18]1[CH2:23][CH:22]([CH3:24])[CH2:21][N:20]([CH2:25][CH2:26][NH2:27])[CH2:19]1>>[CH3:17][CH:18]1[CH2:23][CH:22]([CH3:24])[CH2:21][N:20]([CH2:25][CH2:26][NH:27][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)[CH2:19]1
Reactant: CC1CC(C)CN(CCN)C1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Product: CC1CC(C)CN(CCNc2ccc3c(=O)[nH]c4ncccc4c3c2)C1
Yield: 8.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 456 using 6 (171 mg, 0.74 mmol) and 2-(3,5-dimethylpiperidin-1-yl)ethanamine (464 mg, 2.97 mmol) to provide 478 (23 mg, 9% yield) as a white powder. LC-MS (M+H=351, obsd.=351). 1H NMR (400 MHz, DMSO-D6) δ 11.58 (s, 1H), 9.48 (s, 1H), 8.73 (d, J=6.7, 1H), 8.46 (dd, J=1.6, 4.7, 1H), 8.06 (d, J=8.7, 1H), 7.42 (d, J=2.1, 1H), 7.29 (dd, J=4.7, 7.9, 1H), 6.96 (dd, J=2.1, 8.8, 1H), 3.70 (s, 2H), 3.52 (d, J=11.1, 2H), 3.30 (d, J=5.3, 2H), 2.56 (dt, J=8.1, 16.4, 2H), 1.89 (s, 2H), 1.77 (d, J=13.0, 1H), 0.91 (t, J=8.4, 6H), 0.80 (dd, J=12.3, 24.8, 1H).
Reaction SMILES: [C:1]([C:3]([OH:21])([CH2:5][CH2:6][C:7]1[C:12]([CH3:13])=[C:11]([O:14]C(=O)C)[C:10]([CH3:18])=[C:9]([CH3:19])[C:8]=1O)[CH3:4])#[N:2].S(=O)(=O)(O)O>CO>[C:1]([C:3]1([CH3:4])[CH2:5][CH2:6][C:7]2[C:8](=[C:9]([CH3:19])[C:10]([CH3:18])=[C:11]([OH:14])[C:12]=2[CH3:13])[O:21]1)#[N:2]
Reactant: CC(=O)Oc1c(C)c(C)c(O)c(CCC(C)(O)C#N)c1C
Agent: O=S(=O)(O)O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#N)O2
Reaction time: 72 h

Procedure:
A solution of 5.31 g. of (±)-2-cyano-4-(5-acetoxy-2-hydroxy-3,4,6-trimethylphenyl)butan-2-ol in 60 ml. of methanol was cooled in an ice bath under N2. Sulfuric acid (3.8 ml.) was added over 5 minutes. The light yellow solution was stirred at 23° for 72 hours and then at reflux for 5 hours, cooled, poured into ice-H2O and filtered. The solid was washed with H2O and crystallized from ether- 30°-60° petroleum ether to give (±)-2-cyano-6-hydroxy-2,5,7,8-tetramethylchroman as a white needle, m.p. 152.5°-153°.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[C:10](#[N:14])[CH2:11][C:12]#[N:13].[CH3:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)=O>C(O)(=O)C>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([C:16](=[C:11]([C:10]#[N:14])[C:12]#[N:13])[CH3:15])[CH:23]=[CH:22][CH:21]=1
Reactant: N#CCC#N
Reactant: COc1cccc(C(C)=O)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC(=O)O
Product: COc1cccc(C(C)=C(C#N)C#N)c1
Temperature: 70 °C
Yield: 100.9 %

Procedure:
To a stirred solution of acetic acid (60 mL) was added hexamethyldisilazane (26.2 mL, 125 mmol) dropwise over 30 min with temperature kept below 40° C. throughout addition. This resulting solution was subsequently added to a stirred solution of malononitrile (13.50 g, 204 mmol) and 3-methoxyacetophenone (13.71 mL, 100 mmol) in acetic acid (30 mL). The final reaction mixture heated to 70° C. under nitrogen for 16 h. The reaction mixture was cooled to RT, partitioned between toluene and water (150 mL each). The aqueous layer was separated and re-extracted with toluene (2×60 mL). The combined organic layer was dried over Na2SO4 and solvent removed in vacuo, to afford the title compound (20 g). LCMS (A) m/z: 199 [M+1]+, Rt 1.20 min (acidic).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH3:21])[CH2:17][CH:18]=1.Cl>[Pd]>[F:1][C:2]1[C:7]([O:8][C:9]([F:10])([F:11])[F:12])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH3:21])[CH2:17][CH2:18]1
Reactant: CCCN1CC=C(c2cccc(OC(F)(F)F)c2F)CC1
Agent: [Pd]
Agent: Cl
Product: CCCN1CCC(c2cccc(OC(F)(F)F)c2F)CC1

Procedure:
Preparation according to preparation 18: 4-[2-fluoro-3-(trifluoromethoxy)phenyl]-1-propyl-1,2,3,6-tetrahydro-pyridine (0.55 g, 1.8 mmol), palladium on carbon (0.09 g) and hydrochloric acid (0.5 ml, conc). Yield: 0.22 g (40%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 221-222° C. MS m/z (relative intensity, 70 eV) 305 (M+, 3), 277 (14), 276 (bp), 233 (6) 193 (8).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:12])[C:5]=2[O:4][CH2:3]1.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O1CCCC1>[CH2:24]([O:23][C:21]([O:12][C:11]1[C:5]2[O:4][CH2:3][CH:2]([OH:1])[CH2:7][C:6]=2[CH:8]=[CH:9][CH:10]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: Oc1cccc2c1OCC(O)C2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)Oc1cccc2c1OCC(O)C2
Yield: 100.2 %

Procedure:
23.05 g of 3,4-dihydro-3,8-dihydroxy-2H-1-benzopyran was dissolved in 320 ml of tetrahydrofuran, and 16.7 g of triethylamine was added. With stirring under cooling, a solution of 17.9 g of ethyl chloroformate in 100 ml of tetrahydrofuran was added dropwise. The mixture was worked up in the same way as in Example 1 to give 33.1 g (yield 100%) of 3,4-dihydro-8-ethoxycarbonyloxy-3-hydroxy-2H-1-benzopyran.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH2:10][C:11]#[N:12].[NH2:13][C:14]1[N:19]=[C:18]([NH2:20])[C:17]([CH:21]=O)=[CH:16][N:15]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C:10]1[C:11]([NH2:12])=[N:20][C:18]2[N:19]=[C:14]([NH2:13])[N:15]=[CH:16][C:17]=2[CH:21]=1
Reactant: Nc1ncc(C=O)c(N)n1
Reactant: N#CCc1c(Cl)ccc(Cl)c1Cl
Product: Nc1ncc2cc(-c3c(Cl)ccc(Cl)c3Cl)c(N)nc2n1

Procedure:
The title compound was prepared according to Example 1, starting from 1.0 g of (2,3,6-trichloro)-phenyl-acetonitrile and 0.6 g of 2,4-diamino-5-pyrimidine-carboxaldehyde; mp 320°-322° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]1([CH3:12])[CH2:11][CH2:10][CH2:9][NH:8]1)=[O:4].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC#N.O>[CH3:12][C:7]12[CH2:11][CH2:10][CH2:9][N:8]1[CH2:2][C:3](=[O:4])[NH:5][CH2:6]2
Reactant: CC1(CNC(=O)CCl)CCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC12CCCN1CC(=O)NC2
Temperature: 25 °C
Yield: 49.5 %

Procedure:
A solution of 2-chloro-N-((2-methylpyrrolidin-2-yl)methyl)acetamide (˜300 mg), K2CO3 (1.0 g, 7.2 mmol) and a catalytic amount of NaI in CH3CN was stirred at 80° C. for about 3 h. The reaction was monitored by LC-MS. After cooling to room temperature, the suspension was diluted with water (30 mL) and extracted with DCM (8×100 mL). Then the combined organic layers were concentrated to give 120 mg of the desired product, which was directly used for the next step without further purification. MS (ESI): 155 (MH+).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[OH:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][N:32]=1)[C:27](O)=[O:28]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:27]([C:26]3[CH:30]=[CH:31][N:32]=[C:24]([OH:23])[CH:25]=3)=[O:28])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: O=C(O)c1ccnc(O)c1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCCN3C(=O)c3ccnc(O)c3)c21

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 2-hydroxyisonicotinic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.41 (m, 1H), 1.52-1.74 (m, 4H), 1.81 (m, 1H), 3.22 (m, 1H), 3.43 (m, 1H), 4.19 (dd, 1H, J=10.1, 3.8 Hz), 4.62 (t, 1H, J=10.5 Hz), 5.16 (m, 1H), 6.06 (d, 1H, J=7.0 Hz), 6.23 (s, 1H), 6.61 (d, 1H, J=8.0 Hz,), 6.87 (d, 1H, J=8.7 Hz), 7.45 (m, 2H), 7.75 (br s, 1H), 8.36 (br s, 1H), 10.92 (s, 1H), 11.73 (br s, 1H). MS 432 (MH+).
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](=O)([O-])[O-].[K+].[K+].IC.Cl>O.CN(C=O)C>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Yield: 90 %

Procedure:
A 2 L flask equipped with a dropping funnel and mechanical stirrer was charged with crude 3-cyclohexyl-6-indole carboxylic acid (99.4 g, 0.409 mole) and anhydrous DMF (665 mL) was added followed by anhydrous potassium carbonate (78.13 g, 0.565 mole). Iodomethane (63.72 g, 0.449 mole) was added dropwise over 35 min with stirring to the slurry which was then stirred overnight at room temperature until complete disappearance of starting material (TLC). The resulting suspension was then poured into water (1350 mL) and acidified to pH 4 with 4N HCl (200 mL). The product was extracted into ether (3×1700 mL), washed with water and brine and dried (Na2SO4). Volatiles were removed under reduced pressure and the residue was triturated with hexane (700 mL). The beige solid was filtered and dried under vacuum (94.3 g, 90% yield).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][Si:9]([C:12]#[CH:13])([CH3:11])[CH3:10].[CH2:14]([O:21][C@@H:22]1[C@@H:28]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:27]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@@H:26]([CH2:45][O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[O:25][C@@:23]1([C:54]1[CH:59]=[CH:58][C:57]([CH3:60])=[C:56]([CH2:61][C:62]2[CH:67]=[CH:66][C:65](OS(C(F)(F)F)(=O)=O)=[CH:64][CH:63]=2)[CH:55]=1)[OH:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.[Cu](I)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>[CH2:14]([O:21][C@@H:22]1[C@@H:28]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C@H:27]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@@H:26]([CH2:45][O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[O:25][C@@:23]1([C:54]1[CH:59]=[CH:58][C:57]([CH3:60])=[C:56]([CH2:61][C:62]2[CH:63]=[CH:64][C:65]([C:13]#[C:12][Si:9]([CH3:11])([CH3:10])[CH3:8])=[CH:66][CH:67]=2)[CH:55]=1)[OH:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc([C@@]2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc([C@@]2(O)O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Under argon, 27 mg copper iodide, 49 mg bis-(triphenylphosphine)-palladium dichloride, 0.30 ml triethylamine and finally 0.14 ml of trimethylsilylacetylene are added to a solution of 0.60 g 1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranos-1-yl)-3-[4-(trifluoromethylsulphonyloxy)-benzyl]-4-methyl-benzene in 3 ml of dimethylformamide. The flask is tightly sealed and stirred for 4 h at 90° C. Then another 20 mg of bis-(triphenylphosphine)-palladium dichloride and 0.6 ml trimethylsilylacetylene are added, and the solution is stirred for a further 4 h at 90° C. Then aqueous sodium hydrogen carbonate solution is added, the mixture is extracted three times with ethyl acetate, and the combined organic phases are dried over sodium sulphate. After the solvent has been eliminated the residue is chromatographed through silica gel (cyclohexane/ethyl acetate 40:1->10:1).
Reaction SMILES: [NH2:1][C@H:2]1[C@H:7]([OH:8])[CH2:6][O:5][CH2:4][CH2:3]1.S=[C:10]1[CH2:14][S:13][C:12](=[O:15])[NH:11]1>C(O)C>[O:15]=[C:12]1[N:11]=[C:10]([NH:1][C@H:2]2[C@H:7]([OH:8])[CH2:6][O:5][CH2:4][CH2:3]2)[CH2:14][S:13]1
Reactant: O=C1NC(=S)CS1
Reactant: N[C@@H]1CCOC[C@H]1O
Solvent: CCO
Product: O=C1N=C(N[C@@H]2CCOC[C@H]2O)CS1
Yield: 40 %

Procedure:
To a solution of 3-amino-1,5-anhydro-2,3-dideoxy-threo-pentitol (3.20 g) in ethanol (100 mL) was added 4-thioxo-1,3-thiazolidin-2-one (3.63 g), and the mixture was heated under reflux overnight. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (2.36 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]2[CH:11]=[C:12]([C:14]([OH:16])=O)[NH:13][C:8]2=[CH:7][CH:6]=1)=[O:4].Cl.Cl.[N:19]1([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl.C(N(CC)CC)C>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]2[CH:11]=[C:12]([C:14](=[O:16])[NH:25][CH:22]3[CH2:21][CH2:20][N:19]([C:26]4[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=4)[CH2:24][CH2:23]3)[NH:13][C:8]2=[CH:7][CH:6]=1)=[O:4]
Reactant: NC1CCN(c2ccncc2)CC1
Reactant: COC(=O)c1ccc2[nH]c(C(=O)O)cc2n1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2[nH]c(C(=O)NC3CCN(c4ccncc4)CC3)cc2n1
Reaction time: 2 h

Procedure:
To a solution of 450 mg 1H-pyrrolo[3,2-b]pyridine-2,5-dicarboxylic acid 5-methyl ester in 9 mL dichloromethane and 1.13 mL triethylamine, 614 mg 3,4,5,6-tetrahydro-2H-[1,4′]bipyridyl-4-ylamine dihydrochloride and 520 mg bis(2-oxo-3-oxazolidinyl)phophinic chloride were added at room temperature and the mixture was stirred for 2 hours. After treatment of the reaction mixture with 5 mL saturated aqueous solution of potassium carbonate the precipitate was collected by filtration and coevaporated twice with toluene. The residue was directly subjected to the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH:5]=[CH:6][C:7]1[C:8]([C:13]([OH:15])=[O:14])=[CH:9][CH:10]=[CH:11][CH:12]=1.[C:19](C1C=CC=CC=1CCC1C=C(C)C=CC=1)(O)=O>[Pd].CN(C)C=O>[C:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1[CH:1]=[CH:19][CH:16]=[CH:17][CH:18]=1)([OH:15])=[O:14]
Reactant: Cc1cccc(CCc2ccccc2C(=O)O)c1
Reactant: Cc1cccc(C=Cc2ccccc2C(=O)O)c1
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1CCCCc1ccccc1

Procedure:
A solution of 53.0 gm. of 3'-methylstilbene-2-carboxylic acid in 230 ml. dimethylformamide containing 2.0 gm. of 5% palladium on carbon is hydrogenated in a Parr shaker at 60 p.s.i. for 11/2 hours. The solution is filtered and added to ether and water. The organic layer is washed with water, then dried and evaporated. The product is recrystallized from ether-hexane to give 48 gm., 90%, of 3-(o-carboxyphenethyl)toluene, m.p. 82°-84°C. Use of 3'-ethylenestilbene-2-carboxylic acid gives a similar yield of 3-(o-carboxyphenethyl)ethylbenzene.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]([OH:19])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]#[CH:32]>O>[Cl:1][C:2]1[C:3]([N:9]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]([O:19][CH2:32][C:31]#[CH:30])=[N:10]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C#CCBr
Reactant: CCOC(=O)c1cc(O)nn1-c1ncc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C#CCOc1cc(C(=O)OCC)n(-c2ncc(Cl)cc2Cl)n1
Temperature: 60 °C
Yield: 38 %

Procedure:
To a 100 mL flask, ethyl 1-(3,5-dichloropyridin-2-yl)-3-hydroxy-1H-pyrazole-5-carboxylate (0.7 g, 2.32 mmol), acetonitrile (10 mL), potassium carbonate (0.32 g, 2.32 mmol) and 3-bromoprop-1-yne (0.27 g, 2.32 mmol) were added sequentially. The reaction mixture was heated to 60° C. for 2 hours. Then the reaction mixture was poured into water (100 mL), extracted with ethyl acetate (2×100 mL). The organic layer was washed with saturated sodium carbonate solution (80 mL) and saturated brine (80 mL), dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the compound (0.30 g) as yellow oil in 38% yield.
Reaction SMILES: [C:1](=[O:6])=[N:2][C:3](Cl)=[O:4].[CH:7]1([NH:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](=[O:32])[C:19]([CH2:29][NH:30][OH:31])=[CH:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:16][C:15]=2[F:33])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Cl>C1COCC1>[CH:7]1([NH:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](=[O:32])[C:19]([CH2:29][N:30]4[C:3](=[O:4])[NH:2][C:1](=[O:6])[O:31]4)=[CH:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:16][C:15]=2[F:33])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=c1c(CNO)cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Reactant: O=C=NC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)n(Cc2cn(C3CCCC3)c3cc(NC4CCCCC4)c(F)cc3c2=O)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.14 ml of N-(chlorocarbonyl) isocyanate was added dropwise at −50° C. to a 4 ml THF solution of 110 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-[(hydroxyamino)methyl]quinolin-4(1H)-one, followed by stirring at room temperature for 1 hour. 1 M hydrochloric acid was added to the reaction mixture, followed by extraction with chloroform and washing with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 45 mg of 2-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]methyl}-1,2,4-oxadiazolidine-3,5-dione.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:41]([O:45][C:46]([N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]>CN(C=O)C.O>[C:41]([O:45][C:46]([N:48]1[CH2:54][CH2:53][CH2:52][N:51]([C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[Br:10])[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=C(O)c1ccccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccccc2Br)CC1
Reaction time: 0.03 h
Yield: 277.6 %

Procedure:
DIPEA (460 mg, 0.63 mL, 3.68 mmol) was added dropwise to 2-bromo-benzoic acid (370 mg, 1.84 mmol) in DMF (4 mL). This was followed by the addition of EDCI (423 mg, 2.2 mmol) and HOBT (298 mg, 2.2 mmol). After 2 minutes of stirring, [1,4]diazepane-1-carboxylic acid tert-butyl ester (150 mg, 0.47 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford 500 mg (71.12% yield) of 4-(2-bromo-benzoyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester.