Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)COC([N:7]1[C:19]2[CH2:18][N:17]([S:20]([CH2:23][C:24]3([C:30]([O:32]C)=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)(=[O:22])=[O:21])[CH2:16][CH2:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=O.O.[OH-].[Li+]>O1CCCC1.CO.O>[CH2:18]1[C:19]2[NH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[CH2:15][CH2:16][N:17]1[S:20]([CH2:23][C:24]1([C:30]([OH:32])=[O:31])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1)(=[O:21])=[O:22]
Reactant: COC(=O)C1(CS(=O)(=O)N2CCc3c(n(C(=O)OCC(Cl)(Cl)Cl)c4ccccc34)C2)CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(CS(=O)(=O)N2CCc3c([nH]c4ccccc34)C2)CCOCC1
Reaction time: 8 h
Yield: 80.7 %

Procedure:
2-(4-Methoxycarbonyl-tetrahydro-pyran-4-ylmethanesulfonyl)-1,2,3,4-tetrahydro-β-carboline-9-carboxylic acid 2,2,2-trichloro-ethyl ester (556 mg) and lithium hydroxide monohydrate (206 mg) in tetrahydrofuran (10 ml), methanol (10 ml) and water (10 ml) was heated to reflux for 8 h. The reaction was left to stand at room temperature overnight and then refluxed for a further 4 h. The mixture was evaporated under reduced pressure and the residue dissolved in water (25 ml) and washed with ethyl acetate (2×30 ml). The aqueous was acidified to pH =4 with 5% citric acid solution and extracted with dichloromethane (2×40 ml) followed by ethyl acetate (3×50 ml). The combined extracts were dried (MgSO4) and evaporated under reduced pressure to give the title compound (299 mg, 80%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.Br[CH2:11][CH2:12][CH2:13][O:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:15][O:14][CH2:13][CH2:12][CH2:11][N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1
Reactant: COCCCBr
Reactant: NC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COCCCN1CCC(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 23 h
Yield: 49 %

Procedure:
A mixture of isonipecotamide (10.6 g, 82.3 mmol), 1-bromo-3-(methyloxy)propane (C. A. Grob and A. Waldner, Helv. Chim. Acta, 1980, 63, 2152–2158., 12.6 g, 82.3 mmol), and potassium carbonate (22.8 g, 165 mmol) in ethanol (60 ml) was refluxed with stirring for 23 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was dissolved in water (500 ml), and the aqueous layer was extracted with dichloromethane (300 ml×13). The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo to give 8.04 g (49%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH:18]([NH2:21])[CH2:19][OH:20])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH:18]([NH2:21])[CH2:19][OH:20])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CN1CC=C(c2c[nH]c3ccc(CC(N)CO)cc23)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCC(c2c[nH]c3ccc(CC(N)CO)cc23)CC1

Procedure:
The product from step (e) (0.08 g) was dissolved in ethanol (25 ml) and 10% w/w Pd/C (0.23 g) added. The mixture was stirred under 1 atmos. pressure of hydrogen for 7 hours when uptake was complete. The mixture was filtered through celite and the filtrate evaporated in vacuo to give the desired product as colourless oil which was eluted through a silica column using DCM/EtOH/NH4OH (50:8:1) as eluant.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([N:15]1[CH2:19][CH2:18][CH2:17]C1)[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2].C(N)(=[O:23])C=C>O>[C:1]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]3[CH2:17][CH2:18][C:19](=[O:23])[NH:15][C:10]=3[CH2:9][CH2:8][C:7]=2[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C=CC(N)=O
Reactant: CC(C)(C)c1ccc2c(c1)CCC(N1CCCC1)=C2
Solvent: O
Product: CC(C)(C)c1ccc2c(c1)CCC1=C2CCC(=O)N1
Temperature: 89 °C
Reaction time: 8 h

Procedure:
To 6-t-butyl-2-pyrrolidinyl-3,4-dihydronaphthalene (7.25 g; 28.37 mmol) was added 3.0 equiv. of acrylamide (6.05 g; 85.11 mmol). The reaction mixture was stirred at 89° C. overnight. The temperature was then increased to 130° C. and held there for 20 minutes. Water (100 ml) was cautiously added and the reaction mixture was cooled to room temperature. The resulting solid was triturated with water and collected on a filter to afford a brown solid. The solid was recrystallized twice from dimethyl formamide (DMF)/H2O to afford the subtitle compound. Melting point 265°-268° C. decomp.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:12]=[C:11](Cl)[N:10]=1.[C:24]1([CH:31]=[CH:30][CH:29]=[C:27]([OH:28])[CH:26]=1)[OH:25]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[N:12]=[C:11]([C:29]2[CH:30]=[CH:31][C:24]([OH:25])=[CH:26][C:27]=2[OH:28])[N:10]=1
Reactant: Cc1ccc(-c2nc(Cl)nc(-c3ccc(C)cc3C)n2)c(C)c1
Reactant: Oc1cccc(O)c1
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(O)cc3O)n2)c(C)c1
Temperature: 180 °C
Reaction time: 5 h

Procedure:
To a 50 mL round-bottomed flask equipped with a magnetic stirrer, condenser and nitrogen atmosphere are charged 1.00 g (3.10 mmol) of 4,6-bis-(2,4-dimethylphenyl)-2-chloro-s-triazine and 1.70 g (15.5 mmol) of resorcinol. The mixture is stirred at 180° C. for five hours at which point 1H nmr (CDCI3) of an aliquot reveals a 72% overall conversion to the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[S:11][CH:12]=1.Cl>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[S:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccccc3F)cs2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccccc1-c1csc(C2CCNCC2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.5 %

Procedure:
To a solution of tert-butyl 4-[4-(2-fluorophenyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (390 mg, 1.07 mmol) in ethyl acetate (10 ml) was added a 4N solution (10 ml) of hydrogen chloride in ethyl acetate, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in water. The solution was neutralized with 1N aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the desired product (181 mg, 64.3%) as a solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[CH:20]1([NH:23][C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:26]=2)[CH2:22][CH2:21]1>>[CH:20]1([NH:23][C:24]([C:25]2[CH:30]=[C:29]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][C:11]([CH2:13][N:14]5[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]5)=[N:10][N:9]=4)=[CH:4][CH:3]=3)[C:28]([CH3:31])=[CH:27][CH:26]=2)=[O:41])[CH2:21][CH2:22]1
Reactant: Ic1ccc(-c2nnc(CN3CCCCC3)o2)cc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN3CCCCC3)o2)cc1

Procedure:
Example 13 was prepared from 1-[5-(4-iodophenyl)-[1,3,4]oxadiazol-2-ylmethyl]-piperidine (intermediate 9) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)benzamide (Intermediate 17).
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([C@@H:13]([C:15]2[CH:16]=[C:17]3[C:26](=[CH:27][C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[O:25][CH2:24][C:23]2[N:18]3[C@H:19]([CH3:37])[C:20](=[O:36])[NH:21][N:22]=2)[CH3:14])([CH3:12])[CH2:9]1)=O)(C)(C)C>Cl>[F:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:28]1[CH:27]=[C:26]2[C:17]([N:18]3[C:23]([CH2:24][O:25]2)=[N:22][NH:21][C:20](=[O:36])[C@H:19]3[CH3:37])=[CH:16][C:15]=1[C@H:13]([C:10]1([CH3:12])[CH2:11][NH:8][CH2:9]1)[CH3:14]
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c([C@@H](C)C4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: Cl
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c([C@@H](C)C4(C)CNC4)cc3N21
Yield: 102 %

Procedure:
A solution of 3-{(R)-1-[(R)-7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-ethyl}-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.073 g, 0.144 mmol) in HCl (4M in EtOAc, 1 mL) was stirred at ambient temperature for 1 h. The reaction mixture was concentrated in vacuo to give (R)-7-(2-fluoro-phenyl)-4-methyl-6-[(R)-1-(3-methyl-azetidin-3-yl)-ethyl]-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.06 g, 100%), which was used directly in the next step without further purification. 1H NMR (CD3OD, 400 MHz): δ 7.45 (m, 1H), 7.16-7.34 (m, 3H), 6.90-6.96 (m, 1H), 6.86 (s, 1H), 4.92-4.98 (m, 1H), 4.57-4.68 (m, 2H), 4.24 (m, 1H), 3.69-3.76 (m, 1H), 3.46-3.55 (m, 1H), 3.38 (m, 1H), 2.97 (m, 1H), 1.36-1.51 (m, 6H), 1.20-1.27 (m, 3H). LC/MS (Table 1, Method 25) Rt=0.673 min; MS (ESI): m/z 409 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:11]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=2)[NH:3]1.N1C=CC=CC=1.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30]>ClCCl>[N:12]1([C:11]2[C:2]([O:1][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:30])=[O:28])=[N:3][C:4]3[C:9]([N:10]=2)=[CH:8][C:7]([C:18]([O:20][CH3:21])=[O:19])=[CH:6][CH:5]=3)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCCC3)nc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCCC3)nc2c1
Temperature: 0 °C

Procedure:
To a solution of methyl 2-oxo-3-(piperidin-1-yl)-1,2-dihydroquinoxaline-6-carboxylate (200 mg, 0.70 mmol) in dichloromethane (30 mL) was added pyridine (220 mg, 2.8 mmol) and then Tf2O (393 mg, 1.4 mmol) was added dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature and then quenched by the addition of water (50 mL), extracted with dichloromethane (3×10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford methyl 3-(piperidin-1-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as red solid (280 mg, crude).
Reaction SMILES: O[C:2]1[C:3]2[CH:10]=[C:9]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)(Cl)(Cl)[Cl:41]>ClCCCl>[Cl:41][C:2]1[C:3]2[CH:10]=[C:9]([CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)NCCc1cc2c(O)ncnc2s1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCc1cc2c(Cl)ncnc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
To a solution of tert-butyl N-(2-[4-hydroxythieno[2,3-d]pyrimidin-6-yl]ethyl)carbamate (2.3 g, 7.79 mmol, 1.00 equiv) in DCE (300 mL) was added PPh3 (4.1 g, 15.63 mmol, 2.00 equiv). The solution was stirred for 1 h at room temperature under nitrogen. Then CCl4 (3.6 g, 23.38 mmol, 3.00 equiv) was added and the resulting solution was stirred at 72° C. overnight. After cooling, the resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5 to 1:3) to give tert-butyl N-(2-[4-chlorothieno[2,3-d]pyrimidin-6-yl]ethyl)carbamate (1.0 g) as a light yellow solid. MS (ES): m/z 314 and 316 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[SH:24]>>[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[S:24][CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(CCl)N1CCCc2ccccc21
Reactant: Sc1nc2ccccc2[nH]1
Product: O=C(CSc1nc2ccccc2[nH]1)N1CCCc2ccccc21
Yield: 82 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 1H-benzo[d]imidazole-2-thiol as the nucleophile to yield 16 as a white solid (82%): MS m/z: 324 (M+H)+. Anal. Calcd. For, C18H17N3OS: C, 66.85; H, 5.30; N, 12.99; S, 9.91. Found: C, 66.78; H, 5.41; N, 12.90; S, 9.72.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12].[OH-].[K+].[CH2:15](Br)[CH:16]=[CH:17][CH3:18]>CO>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:15][CH:16]=[CH:17][CH3:18])=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:12]
Reactant: CC=CCBr
Reactant: Cc1ccc(O)c2c1CCC2=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC=CCOc1ccc(C)c2c1C(=O)CC2

Procedure:
Into a solution of 10 g of 4-methyl-7-hydroxy-1-indanone and 5.3 g of potassium hydroxide in 200 ml of methanol was added 8.2 ml of crotyl bromide, and the mixture was refluxed by heating for 4 hours. The insoluble matters in the reaction mixture were removed by filtration, then the solvent was removed by evaporation. The residue obtained was extracted with chloroform-water, and the chloroform layer was washed with a diluted sodium hydroxide aqueous solution, then washed with water, dried with anhydrous magnesium sulfate, and the solvent was removed by evaporation. The residue obtained was purified by means of a silica gel column chromatography (eluent: n-hexane: dichloromethane=1:1) to obtain 8.72 g of 4-methyl-7-crotyloxy-1-indanone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Br:13]N1C(=O)CCC1=O>FC(C1C=CC=CC=1)(F)F.C(OCC)(=O)C.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][Br:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(Br)ccc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: FC(F)(F)c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)ccc1CBr
Temperature: 90 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
To a solution of methyl 5-bromo-2-methylbenzoate (5.27 g) in trifluoromethylbenzene (50.0 mL) were added AIBN (0.04 g) and N-bromosuccinimide (4.50 g), and the mixture was stirred at 90° C. for 4 hr under argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.89 g).
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:62]=[CH:61][C:15]([O:16][CH2:17][C:18]3([O:42][P:43]([O:53]CC4C=CC=CC=4)([O:45]CC4C=CC=CC=4)=[O:44])[CH2:23][CH2:22][N:21]([C:24]4[CH:33]=[C:32]5[C:27]([C:28](=[O:40])[C:29]([C:37]([OH:39])=[O:38])=[CH:30][N:31]5[CH:34]5[CH2:36][CH2:35]5)=[CH:26][C:25]=4[F:41])[CH2:20][CH2:19]3)=[C:14]([F:63])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2].Br.O>C(#N)C.C(O)(=O)C>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:62]=[CH:61][C:15]([O:16][CH2:17][C:18]3([O:42][P:43]([OH:53])([OH:45])=[O:44])[CH2:23][CH2:22][N:21]([C:24]4[CH:33]=[C:32]5[C:27]([C:28](=[O:40])[C:29]([C:37]([OH:39])=[O:38])=[CH:30][N:31]5[CH:34]5[CH2:35][CH2:36]5)=[CH:26][C:25]=4[F:41])[CH2:20][CH2:19]3)=[C:14]([F:63])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OP(=O)(OCc4ccccc4)OCc4ccccc4)CCN(c4cc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1
Agent: Br
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OP(=O)(O)O)CCN(c4cc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
27 g 7-[4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxymethyl}-4-(bis-benzyloxy-phosphoryloxy)-piperidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (MW: 886.85, 30.44 mmol) were suspended in 600 ml acetonitrile and treated with 53 ml of a 33% solution of anhydrous hydrobromic acid in acetic acid. The yellow suspension was diluted with 150 ml of acetic acid and was heated to 45° C. The reaction was monitored by HPLC/MS and was complete after 3 hours. The sticky suspension was added to 1.5 L of water under stirring. The off white crystals were collected, washed with 300 ml water, 150 ml ethanol and 150 ml ether. The solid was suspended in 1.3 L water and treated with 35 ml (35 mmol) of a 1M aqueous sodium hydroxide solution. The solid dissolved, and the brown-yellow solution was treated with 15 g of activated charcoal and filtered. The filtrate was extracted with 3 portions of 200 ml of a 95/5 dichloromethane/methanol mixture. The water layer was treated with 40 ml of 1 M HCl solution and the product crystallized by stirring. The solid was collected and dried. Yield: 17.3-g, 80.4%. MS: 609.7 (M+H)+, 607.8 (M+H)−, Method ESI+, ESI−.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2O)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>P(OCC)(OCC)OCC.C(OCC)C>[CH3:1][S:2]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc2ccn(O)c2c1
Agent: CCOP(OCC)OCC
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc2cc[nH]c2c1
Temperature: 25 °C

Procedure:
Dissolve 6-Methanesulfonyl-indol-1-ol (5.0 g, 23.7 mmol) in triethyl phosphite (35 ml) and heat at 160° for 5 hours. Cool the solution to ambient temperature and dilute with diethyl ether. Wash the ether solution with brine and water followed by drying (sodium sulfate) and reducing to residue. Crystallize the residue from warm ethyl acetate to give the title compound as colorless cubes: mp 149-152° C. MS (ACPI): m/e 196.0 (M+1). Analysis for C9H9NO2S: Calcd: C, 55.37; H, 4.65; N, 7.17. found: C, 55.14; H, 4.71; N, 7.20.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1)#[CH:2].C(NC(C)C)(C)C.[C:18]([C:22]1[CH:27]=[CH:26][C:25](/[C:28](/[C:45]2[CH:50]=[CH:49][C:48](I)=[CH:47][CH:46]=2)=[CH:29]/[CH2:30][O:31][C:32]2[CH:43]=[CH:42][C:35]([O:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[C:34]([CH3:44])[CH:33]=2)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>O1CCCC1.[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:18]([C:22]1[CH:23]=[CH:24][C:25](/[C:28](/[C:45]2[CH:50]=[CH:49][C:48]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=3)=[CH:47][CH:46]=2)=[CH:29]/[CH2:30][O:31][C:32]2[CH:43]=[CH:42][C:35]([O:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[C:34]([CH3:44])[CH:33]=2)=[CH:26][CH:27]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: C#Cc1ccc(CO)cc1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(C)(C)C)cc2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#Cc3ccc(CO)cc3)cc2)c2ccc(C(C)(C)C)cc2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Ethynyl-4-(hydroxymethyl)benzene (169 mg, 1.28 mmol) and diisopropylamine (0.40 mL, 2.85 mmol) were added to a solution of methyl (Z)-[4-[3-(4-tert-butylphenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (364 mg, 0.638 mmol; prepared as described in example 30) in tetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide (10 mg, 0.053 mmol) and bis(triphenylphosphine)palladium(II) dichloride (22 mg, 0.031 mmol) were added. The reaction mixture was stirred at ambient temperature overnight, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, dichloromethane/methanol 99:1) yielding methyl (Z)-[4-[3-(4-tert-butylphenyl)-3-[4-[4-(hydroxymethyl)phenylethynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetate as brown oil.
Reaction SMILES: C(O)C.[O:4]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]4[C:33]5[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=5)[C:27](/[CH:36]=[CH:37]/[C:38]([O:40]CC)=[O:39])=[CH:26][C:25]4=[O:43])[CH2:18][CH2:17]3)=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1.[OH-].[Na+]>O>[O:4]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][NH:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][N:24]4[C:33]5[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[CH:32]=5)[C:27](/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39])=[CH:26][C:25]4=[O:43])[CH2:20][CH2:21]3)=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1
Reactant: CCOC(=O)/C=C/c1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(OC)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(/C=C/C(=O)O)cc(=O)n(CCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To 1 mL of an ethanol solution containing 65 mg of ethyl (2E)-3-(1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-4-yl)acrylate, 0.2 mL of water and 0.11 mL of 5 mol/L aqueous sodium hydroxide solution were added and stirred for 1 hour. 2 mL of water was added, removed ethanol under reduced pressure, adjusted to pH 6.0 with 1 mol/L hydrochloric acid, and the resulting solid was filtered to afford 48 mg of (2E)-3-(1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-4-yl)acrylic acid as a yellow solid.
Reaction SMILES: CC([O-])(C)C.[K+].F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[Cl:17][CH2:18][CH2:19][CH2:20][SH:21]>CS(C)=O.O>[Cl:17][CH2:18][CH2:19][CH2:20][S:21][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1
Reactant: SCCCCl
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(SCCCCl)cc1
Temperature: 10 °C
Yield: 33.4 %

Procedure:
To a cooled (10° C.), stirred suspension of KOtBu (8.9 g, 0.080 mol) in DMSO (40 mL) was added a solution of 4-fluoronitrobenzene (11.2 g, 0.080 mol) and 3-chloropropanethiol (8.8 g, 0.080 mol) in DMSO (40 mL) over 10 minutes. The mixture was stirred at room temperature for 3.5 hours, diluted with water (1000 ml), and extracted with ether. The extracts were washed with brine, dried (MgSO4), and concentrated. Purification by flash chromatography (10% EtOAc/hexane) gave 6.2 g (34%) of product as a yellow solid m.p. 45°-48° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([F:9])[C:3]=1[OH:10].C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.O>[Br:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([O:10][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:4]([F:9])[CH:5]=1
Reactant: Oc1c(F)cc(Br)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(Br)cc(F)c1OCc1ccccc1
Reaction time: 12 h
Yield: 87.8 %

Procedure:
To a solution of 5.0 g (24.0 mmol) of 2,6 difluoro-4-bromophenol in 20 ml of DMF at rt was added 5 g (36.0 mmol) of K2CO3 followed by 4.5 g (26.3 mmol) of benzyl bromide. The mixture was stirred for 12 h, diluted with H2O, the organic phase washed with sat'd NaCl, and the aqueous phase was then extracted 3× with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated. Flash chromatography with a gradient of 0-15% ethyl acetate/hexanes (v/v) afforded 6.3 g (88%) of the title compound: 1H NMR (500 MHz) δ 5.17 (s, 21), 7.06-7.11 (2H). 7.34-7.45 (5H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:14].[C:15]1(C)C=CC=CC=1>CO>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([O:13][CH3:15])=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:14]
Reactant: Cc1ccccc1
Reactant: Cc1nc2cc(C(=O)O)ccc2n1C
Solvent: CO
Product: COC(=O)c1ccc2c(c1)nc(C)n2C
Reaction time: 1 h

Procedure:
To a suspension of 1,2-Dimethyl-1H-benzo[d]imidazole-5-carboxylic acid (crude, 2.54 g, approx. 9.35 mmol) in MeOH (15.5 ml)/toluene (78 ml) Trimethylsilyldiazomethane (2 M solution in hexane, 7.0 ml, 14 mmol) was added at 0-10° C. The reaction mixture was stirred at it for 1 hour. The reaction mixture was evaporated under reduced pressure. The residue was taken up in DCM, Remaining insoluble solid was filtered off. The filtrate was evaporated again to dryness to afford crude Methyl 1,2-dimethyl-1H-benzo[d]imidazole-5-carboxylate