Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH2:12].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=1)(=[O:24])=[O:23]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cc(Br)cc(C)c1N
Product: COC(=O)c1cc(Br)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Temperature: 80 °C
Yield: 84.5 %

Procedure:
To a stirred solution of 24.5 g (100 mmol) of the product of Example 133 in 100 mL of pyrdine was added 21.0 g (100 mmol) of p-methoxybenzenesulfonyl chloride and the resulting mixture was heated to 80° C. for 24 h. The reaction mixture was then quenched with ice cold water and acidified with concentrated HCl. The resulting mixture was extracted with chloroform, washed with water, dried over MgSO4, filtered and concentrated in vacuo. The residue was triteretd with diethyl ether, filtered and dried to provide 35 g (84%) of the desired product as a brown solid. Electrospray Mass Spec 416, (M+H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:2]1.[Li:16]CCCC>CCCCCC>[N:10]1([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:1]([Li:16])[CH:2]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: [Li]CCCC
Reactant: C1=C(N2CCCCC2)c2ccccc2C1
Solvent: CCCCCC
Product: [Li]C1C=C(N2CCCCC2)c2ccccc21
Reaction time: 24 h
Yield: 95 %

Procedure:
1-(1H-inden-3-yl)piperidine (3.00 g, 15.1 mmol) was dissolved in 75 mL of hexane and 7.1 mL of 2.5 M n-BuLi (1.09 eq) was added dropwise via syringe over a 5 minute period. The solution developed a yellow precipitate upon the addition of the first 0.5 mL of n-BuLi. The resulting slurry was allowed to stir 24 hours. After this time the solid was filtered, washed with 50 mL of hexane and allowed to dry in vacuo overnight to afford the desired anion as a yellow solid (2.96 g, 14.3 mmol) in 95 percent yield.
Reaction SMILES: [CH:1]1([C:4]2[CH2:8][CH:7]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=3)NN=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>O>[CH:1]1([CH:4]2[CH2:8][CH:7]2[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH2:3][CH2:2]1
Reactant: Oc1cccc(C2CC(C3CC3)=NN2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1cccc(C2CC2C2CC2)c1
Temperature: 250 °C
Yield: 67.4 %

Procedure:
To a 250 ml round bottom flask equipped with nitrogen inlet, thermometer, and reflux condenser was charged 5.0 g (0.0247 moles) of 3-cyclopropyl-5-(3-hydroxyphenyl)-2-pyrazoline, and 5.0 g of powdered sodium hydroxide (0.125 moles). The two solids were mixed thoroughly, then heated slowly to 250° C., under a rapid stream of nitrogen. The reaction mixture was heated continuously at 250° C. for a total of 2 hours, then cooled to ambient temperature. The resulting residue was the dissolved in 200 mls of water, then acidified to pH 2 with 1 N aqueous hydrochloric acid. The acidic solution was extracted with 3×100 mls of ethyl ether, and the ether extract was washed with 2×100 mls of water, and 100 mls of saturated aqueous sodium chloride solution. The ether extract was the dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure with a rotary evaporator at 45° C. The resulting crude product was chromatographed on silica gel with a 15% ethyl acetate, 85% hexane mobile phase. The pure fractions were combined and concentrated under reduced pressure on a rotary evaporator to afford 2.9 g of the title compound 1-(3-hydroxyphenyl)-2-cyclopropyl cyclopropane as a pale yellow liquid at a 68% yield.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:13])[C:11]#[CH:12])=[CH:9][C:4]=2[O:3][CH2:2]1.C([Mg]Cl)#C.C1C(C=O)=CC2OCOC=2C=1.Br[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1/[C:32](=[CH:40]/[C:41]1[NH:42][CH:43]=[CH:44][C:45]=1[O:46][CH3:47])/[C:33](=[O:39])[NH:34]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:13])[C:11]#[C:12][C:30]3[CH:38]=[CH:37][CH:36]=[C:35]4[C:31]=3/[C:32](=[CH:40]/[C:41]3[NH:42][CH:43]=[CH:44][C:45]=3[O:46][CH3:47])/[C:33](=[O:39])[NH:34]4)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: C#CC(O)c1ccc2c(c1)OCO2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Mg]Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccc4c(c3)OCO4)c21

Procedure:
Using Method D above, 3-(1,3-benzodioxol-5-yl)-3-hydroxy-1-propyne (110 mg, 0.62 mmol) (prepared by the addition of ethynylmagnesium chloride (Aldrich) to piperonal (Aldrich) according to Method A above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.34 mmol) (Starting Material 1) using (Ph3P)2PdCl2 (30 mg) (Aldrich) and CuI (16 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 16 h, yielding rac-(Z)-4-[3-(1,3-benzodioxol-5-yl)-3-hydroxy-1-propynyl]-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 46 mg, 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]([N:18]([CH3:20])[CH3:19])[CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:21](OCC)(=[O:23])[CH3:22].C(OC(=O)C)(=O)C>O>[C:21]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10][CH2:11]1)[N:18]([CH3:20])[CH3:19])(=[O:23])[CH3:22]
Reactant: CCOC(C)=O
Reactant: CN(C)C(CCCCO)C1(c2ccc(Cl)cc2)CCC1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)OCCCCC(N(C)C)C1(c2ccc(Cl)cc2)CCC1

Procedure:
A mixture of the product of Example 144 (1.55 g), ethyl acetate (100 ml) and acetic anhydride (20 ml) was heated under reflux for 16 hours, cooled and poured into water. The resulting mixture was basified and extracted with ether. The extract was washed, dried and evaporated to give an oil which was purified by flash chromatography on a silica column using a 9:1 mixture of petroleum ether (b.p. 60°-80° C.) and acetone and then acetone as eluant to give 5-[1-(4-chlorophenyl)cyclobutyl]-5-dimethylaminopentyl acetate as an oil the boiling point of which was not determined.
Reaction SMILES: [C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Na+]>O>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
In a 1 L flask, 83.4 g of ferrous sulfate (heptahydrate) and 10.4 g of sodium nitrite were thoroughly mixed with 500 ml of distilled water, followed by 20 minutes of stirring at 40° C. Thereafter, 125 ml of concentrated ammonia was added thereto and insoluble matter was collected and washed twice with distilled water to obtain magnetite. The resulting magnetite was added to 500 ml of distilled water in a 1 L flask and the temperature of the solution was raised to 80° C. Then, 7.5 g of sodium oleate was added thereto, followed by 20 minutes of stirring at the same temperature. Thereafter, pH of the solution was adjusted to 5.5 and the resulting insoluble matter was collected by filtration and washed twice with distilled water to obtain magnetite having an oleic acid layer. The magnetite was again added into a 1 L flask, 500 ml of distilled water was added, and the temperature of the solution was raised to 70° C. Then, 7.5 g of sodium dodecylbenzenesulfonate was added thereto and the whole was stirred overnight to obtain magnetic fine particles.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:31][C:9]2[C:10]3[S:15][CH:14]=[C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:11]=3[S:12][C:8]=2[C:7]=1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:5])C.[OH-].[Na+].O.Cl>CCO>[CH2:32]([C:7]1[C:8]2[S:12][C:11]3[C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:14][S:15][C:10]=3[C:9]=2[S:31][C:6]=1[C:4]([OH:5])=[O:3])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCCCCCCCCc1csc2c1sc1c(CCCCCCCCCCCCCCC)c(C(=O)OCC)sc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCc1csc2c1sc1c(CCCCCCCCCCCCCCC)c(C(=O)O)sc12
Yield: 98 %

Procedure:
A mixture of 5 (4.2 g, 6.1 mmol) and NaOH (0.49 g, 12.2 mmol) in EtOH (80 mL) was refluxed for 6 h. The mixture was poured into water (400 mL). The pH was adjusted to 1 with aqueous 10 M HCl solution. The precipitated solid was collected by filtration and dried under vacuum. The crude product was used for the next step without any purification (3.9 g, 98% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:19][OH:20])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[C:12]([F:18])[CH:11]=2)=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[C:41](N1C=CN=C1)(=[O:43])[CH3:42].Cl>O1CCCC1.CCCCCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[C:12]([F:18])[CH:11]=3)[C:41]([CH3:42])([OH:43])[O:20][N:19]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)n1ccnc1
Reactant: CSc1ccc(CC(=NO)c2ccc(Br)cc2)cc1F
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CSc1ccc(C2C(c3ccc(Br)cc3)=NOC2(C)O)cc1F
Reaction time: 1 h
Yield: 36.1 %

Procedure:
To a solution of 1-(4-bromophenyl)-2-(3-fluoro-4-methylthiophenyl)ethanone oxime (1.56 g, 4.42 mmol) in tetrahydrofuran (10 ml) was added dropwise 9.7 ml (9.70 mmol) of 1 M lithium N,N-diisopropylamide in tetrahydrofuran and hexane, which was prepared from N,N-diisopropylamine and 1.6 M n-butyl lithium in hexane, over 0.5 h at −78˜−50° C. After 1 h, a solution of N-acetyl imidazole (584 mg, 5.31 mmol) in tetrahydrofuran (10 ml) was added to the mixture at the same temperature. The resulting mixture was allowed to warn up to room temperature and stirred for further 1 h. Then, the mixture was acidified with 2M hydrochloric acid (˜30 ml) and extracted with diethyl ether (150 ml). The separated organic layer was washed with saturated sodium bicarbonate (50 ml×2) and water (50 ml), dried over magnesium sulfate, and evaporated. The obtained oily residue was chromatographed on a column of silica gel (80 g) as eluting with ethyl acetate/hexane (1/4) to afford 632 mg (36%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][C:4]=1[C:11]1[C:20]([CH3:21])=[CH:19][C:18]2[C:17]([CH3:23])([CH3:22])[CH2:16][CH:15]([CH3:24])[CH:14]([CH3:25])[C:13]=2[CH:12]=1.[BrH:26]>C(O)(=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Br:26])=[CH:5][C:4]=1[C:11]1[C:20]([CH3:21])=[CH:19][C:18]2[C:17]([CH3:23])([CH3:22])[CH2:16][CH:15]([CH3:24])[CH:14]([CH3:25])[C:13]=2[CH:12]=1
Reactant: COc1ccc(CO)cc1-c1cc2c(cc1C)C(C)(C)CC(C)C2C
Reactant: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(CBr)cc1-c1cc2c(cc1C)C(C)(C)CC(C)C2C
Temperature: 25 °C

Procedure:
To a solution of 4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzyl alcohol (195 mg, 0.57 mmol) in acetic acid (glacial, 3 mL) was added HBr (48%, 1 mL) and the resulting mixture heated at reflux for 2 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to afford 200 mg of crude 4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzyl bromide. To a stirred solution of 2,4-thiazolidinedione (133 mg, 1.14 mmol) in anhydrous THF (6 mL) was added, at −78° C. under argon, n-BuLi (1.6M in hexane, 1.5 mL, 2.4 mmol) dropwise. The mixture was maintained at −78° C. for 15 minutes and then warmed to 0° C. for 30 minutes to complete the dianion formation. Upon recooling to −78° C., 4-methoxy-3-(3,5,5,8,7-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) benzyl bromide was added in THF (3 mL). After 30 minutes the orange solution was allowed to warm to room temperature. After 1.5 hours, the solution was treated with 2N HCl, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (eluent:ethyl acetate/hexane 2:8) to give 61 mg of 5-[4-methoxy-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzyl] thiazolidine-2,4-dione (24% for 3 steps from benzaldehyde). 1H NMR (500 MHz; CDCl3): δ 1.27 (s, 6 H); 1.26 (s, 6 H); 1.69 (s, 4 H); 2.08 (s, 3 H); 3.12 (dd, J1=14.0 Hz, J2=9.5 Hz, 1 H); 3.50 (dd, J1=14.0 Hz, J2=4.0 Hz, 1 H); 3.76(s, 3 H); 4.54 (dd, J1=9.5 Hz, J2=4.0 Hz, 1 H); 6.89 (d, J=8.0 Hz, 1 H); 7.03 (d, J=2 Hz, 1 H); 7.07 (s, 1 H); 7.14 (s, 1 H); 7.17 (dd, J1=8.0 Hz, J2=2.0 Hz, 1 H), 7.95 (br, 1 H).
Reaction SMILES: Cl.[C:2]([C:4]1([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].[O:19]=[C:20]1[C:25]([CH:26]=O)=[CH:24][CH:23]=[CH:22][NH:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C.ClCCl>[O:19]=[C:20]1[C:25]([CH2:26][N:7]2[CH2:8][CH2:9][C:4]([CH2:10][O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])([C:2]#[N:3])[CH2:5][CH2:6]2)=[CH:24][CH:23]=[CH:22][NH:21]1
Reactant: Cc1ccccc1OCC1(C#N)CCNCC1
Reactant: O=Cc1ccc[nH]c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1OCC1(C#N)CCN(Cc2ccc[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.7 %

Procedure:
After then adding 117 mg of the 4-cyano-4-(2-methylphenoxymethyl)piperidine hydrochloride and 70 mg of 2-oxo-1,2-dihydropyridine-3-carboxaldehyde [CAS No. 36404-89-4] to 10 ml of dichloromethane, the mixture was stirred for 20 minutes at room temperature. 139 mg of sodium triacetoxyborohydride was added and the mixture was stirred overnight at room temperature. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extraction was performed with ethyl acetate and chloroform. After drying the organic layer over magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (solvent: chloroform/methanol) to obtain the title compound (7 mg, 5% yield).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:19][CH2:18][CH:17]([N:20]2[C:25]3[N:26]=[C:27]([NH2:31])[N:28]=[C:29]([CH3:30])[C:24]=3[CH:23]=[C:22]([C:32]3[CH:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)[C:21]2=[O:40])[CH2:16]1)=O)(C)(C)C>ClCCl>[NH2:31][C:27]1[N:28]=[C:29]([CH3:30])[C:24]2[CH:23]=[C:22]([C:32]3[CH:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=3)[C:21](=[O:40])[N:20]([CH:17]3[CH2:18][CH2:19][NH:15][CH2:16]3)[C:25]=2[N:26]=1
Reactant: COc1ccc(-c2cc3c(C)nc(N)nc3n(C3CCN(C(=O)OC(C)(C)C)C3)c2=O)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cc3c(C)nc(N)nc3n(C3CCNC3)c2=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
The TFA (0.56 ml, 10 eq.) was added into the solution of 3-[2-Amino-6-(6-methoxy-pyridin-3-yl)-4-methyl-7-oxo-7H-pyrido[2,3-d]pyrimidin-8-yl]pyrrolidine-1-carboxylic acid tert-butyl ester (328 mg, 0.725 mmol) in 2 ml dichloromethane at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction was complete and the solvent was removed. The residue was partitioned in EA/sat. sodium bicarbonate. The EA layer was dried and concentrated to obtain the title compound as a solid (237 mg, 92.8% yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[N-:14]=[N+:15]=[N-:16].[Na+].C1OCCOCCOCCOCCOC1>O1CCOCC1>[N:14]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=[N+:15]=[N-:16]
Reactant: CC(C(=O)O)c1ccc(CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C(=O)O)c1ccc(CN=[N+]=[N-])cc1
Temperature: 80 °C

Procedure:
To a solution of 2-(4-bromomethylphenyl)-proprionic acid (1.5 g) in 1,4-dioxane was added NaN3 (5 g) and 15-crown-5 (100 mg). The mixture was heated to 80° C. for 16 h, then cooled. The solvent was removed under reduced pressure, and the residue chromatographed on silica to yield 2-(4-azidomethylphenyl)-proprionic acid as an off white solid.
Reaction SMILES: O1[CH2:3][CH:2]1[CH:4]([CH3:27])[CH2:5][S:6]([C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7].NC(N)=[S:30]>CO.C(Cl)Cl>[S:30]1[CH2:3][CH:2]1[CH:4]([CH3:27])[CH2:5][S:6]([C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7]
Reactant: NC(N)=S
Reactant: COC(=O)Cc1ccc(Oc2ccc(S(=O)(=O)CC(C)C3CO3)cc2)cc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Cc1ccc(Oc2ccc(S(=O)(=O)CC(C)C3CS3)cc2)cc1
Reaction time: 8 h
Yield: 71.3 %

Procedure:
To a stirred solution of 1.9 (500 mg, 1.38 mmol) in MeOH—CH2Cl2 (10:1, 11 mL) was added thiourea (262 mg, 3.45 mmol) at room temperature, and the mixture was stirred overnight. After concentration under reduced pressure, the residue was dissolved in ethyl ether. The ethyl ether solution was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/5) to give 1.3 (400 mg, 77%) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 2.15 (dd, 1H, J=5.5, 2.0 Hz), 2.53 (dd, 1H, J=6.5, 2.0 Hz), 3.05 (m, 1H), 3.17 (dd, 1H, J=14.5, 7.0 Hz), 3.51 (dd, 1H, J=14.5, 5.5 Hz), 3.65 (s, 2H), 3.72 (s, 3H), 7.03-7.05 (m, 2H), 7.08-7.10 (m, 2H), 7.33-7.34 (m, 2H), 7.85-7.86 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 24.2, 26.0, 40.3, 52.1, 62.6, 117.7, 120.5, 130.7, 130.9, 131.1, 131.9, 153.8, 162.8, 171.8; HRMS (FAB) calcd for C18H19O5S2 (M+H+) 379.0674. found 379.0645.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5](/[CH:6]=[C:7]2/[C:8](=[O:24])[C:9]3[C:14]([CH2:15]/2)=[CH:13][C:12]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:11]([O:22][CH3:23])[CH:10]=3)=[C:4]([F:27])[CH:3]=1>CO.[Pd]>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH:7]2[CH2:15][C:14]3[C:9](=[CH:10][C:11]([O:22][CH3:23])=[C:12]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[CH:13]=3)[C:8]2=[O:24])=[C:4]([F:27])[CH:3]=1
Reactant: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1ccc(Cl)cc1F)C2=O
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N1CCOCC1)CC(Cc1ccc(Cl)cc1F)C2=O

Procedure:
Compound 15 (45 mg, 0.121 mmol) was dissolved in methanol and was added Pd/C 20 mg and stirred the reaction under hydrogen balloon for 6 h. The reaction was filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude compound 16. The crude 16 was purified by flash chromatography using 100-200 mesh silica gel. Compound 16 was eluted at 23% ethyl acetate in hexane as half white coloured solid 2-(4-chloro-2-fluorobenzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 16. 1HNMR (400 MHz, CDCl3) δ ppm 7.18 (m, 2H), 6.82 (m, 3H), 3.88 (m, 3H), 3.86 (m, 4H), 3.31 (m, 1H), 3.16 (m, 4H), 3.06 (m, 1H), 2.95 (m, 1H), 2.73 (m, 2H); MS (ESI) m/z 389.8 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][C@@H:15]([NH:19][C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([CH:25]=O)[CH:11]=2.Cl.[NH2:31][OH:32].[OH-].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:18]2[CH2:17][CH2:16][C@@H:15]([NH:19][C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([CH:25]=[N:31][OH:32])[CH:11]=2
Reactant: NO
Reactant: O=Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CC[C@@H](NC(=O)C2CC2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(N[C@@H]1CCc2c(c3cc(C=NO)ccc3n2Cc2cccc(F)c2)C1)C1CC1
Yield: 82 %

Procedure:
Combine (R)-cyclopropanecarboxylic acid[9-(3-fluorobenzyl)-6-formyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amide (Preparation 71) (1.50 g, 3.82 mmol), hydroxylamine hydrochloride (0.801 g, 11.5 mmol), and sodium hydroxide (0.23 g, 5.76 mmol) and stir under nitrogen for 1.5 h. Dilute with water and extract with EtOAc. Pass the dark residue through a pad of silica eluting with 50% EtOAc/hexanes to give 1.27 g (82%) of the title compound. MS (ES): m/z 406 (M+1).
Reaction SMILES: Cl[CH:2]([S:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:8][S:7][CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: c1ccccc1
Reactant: COC(=O)C(Cl)SC
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)C(SC)c1ccccc1

Procedure:
In a round-bottom glass flask equipped with a magnetic stir bar methyl 2-chloro-2-(methylthio)acetate (1.3 g, 1 equiv) was dissolved in benzene (20 mL) and aluminum chloride (3.36 g, 2.8 equiv) added in one portion and heated to reflux for 3 hours. The mixture was then cooled and washed with H2O, brine, and dried over MgSO4. The organic layer was concentrated under reduced pressure to yield a yellow oil that was used without further purification (0.56 g, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([CH2:22][N:11]([C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18](=[O:19])[NH2:20])[S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: NC(=O)[C@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1ccc(CN([C@@H]2CCCC[C@@H]2C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.6 %

Procedure:
A mixture of (1S,2R)-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide (670 mg, 2.12 mmol), methyl 4-(bromomethyl)benzoate (534 mg, 2.33 mmol), cesium carbonate (1.04 g, 3.18 mmol) and acetonitrile (20 mL) was stirred vigorously at room temperature for 18 h. The crude mixture was filtered through celite and concentrated in vacuo. The product was purified by silica gel column chromatography (methanol/chloroform, 0.25%) to afford 213 mg (22% yield) of 4-[[(1R,2S)-(2-carbamoyl-cyclohexyl)-(4-chlorobenzenesulfonyl)-amino]-methyl]-benzoic acid methyl ester. An analytical sample was obtained after recrystallization from ethyl acetate/hexanes: 1H NMR (400 Mz, DMSO) δ 7.85 (d, 2 H, J=8.3), 7.82 (d, 2 H, J=8.5), 7.63 (d, 2 H, J=8.5), 7.42 (d, 2 H, J=8.3), 7.28 (br s, 1 H), 6.60 (br, s, 1 H), 4.64 (ABq, 2 H, Δv=69.4, Jab=17.4), 3.88 (m, 1 H), 3.85 (s, 3 H), 2.79 (m, 1 H), 2.42 (m, 1 H), 1.78 (m, 1 H), 1.64 (m, 2 H), 1.38–1.21 (m, 3 H), 0.90 (m, 1 H); MS m/e 465.1 (M+H)+.