Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:23][S:24]([OH:27])(=O)=[O:25]>C(Cl)Cl>[C:1]([N:4]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:24]([Cl:23])(=[O:27])=[O:25])=[CH:13][CH:12]=2)[C:8]2[CH:17]=[C:18]([O:21][CH3:22])[C:19]([S:24]([Cl:23])(=[O:27])=[O:25])=[CH:20][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)C(c1ccccc1)CN(C(C)=O)CC2
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1cc2c(cc1S(=O)(=O)Cl)CCN(C(C)=O)CC2c1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 3-acetyl-8-methoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (13 g, 0.01 m) in methylene chloride (50 ml) stirred at 5° was treated with chlorosulfonic acid (11.6 g, 0.1 m). The mixture was stirred at 25° for 2 hours, poured into ice water and extracted with chloroform. The chloroform extract was washed, dried with sodium sulfate and concentrated in vacuo to give 3-acetyl-7-chlorosulfonyl-1-[4-(chlorosulfonyl)phenyl]-8-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[Cl-].[Al+3].[Cl-].[Cl-].[S:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1.O>[N+](C1C=CC=CC=1)([O-])=O>[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: c1ccsc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: O=C(O)c1ccccc1C(=O)c1cccs1
Reaction time: 2 h
Yield: 26.8 %

Procedure:
A solution of 74.1 g (0.5 mole) of phthalic anhydride in 300 mL of nitrobenzene was treated with 147 g (1.1 mole) of aluminum chloride. The solution was stirred for two hours and 42.1 g (0.5 mole) of thiophene was added dropwise over 80 minutes at 40°-45°. The reaction was stirred at 50°-55° for two hours and then let sit at room temperature overnight. The reaction was poured into 2.8 L of cold water, stirred, separated, and the nitrobenzene was removed from the nitrobenzene layer by steam distillation. The residue was recrystallized from toluene to provide 31.1 g (27%) of 2-thienoylbenzoic acid, mp 141-143. The thienoylbenzoic acid was treated with methylhydrazine as described in Example 185 to provide 24.4 g (75%) of the phthalazinone product, mp 143-144, after recrystallization from ethyl acetate.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])C.[CH2:33]([CH2:35][NH2:36])[OH:34]>>[OH:34][CH2:33][CH2:35][NH:36][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5]
Reactant: NCCO
Reactant: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccccc4F)c3)csc12
Product: O=C(Nc1cccc(OCc2csc3c(C(=O)NCCO)cncc23)c1)c1ccccc1F

Procedure:
3-[3-(2-Fluoro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide was prepared from 3-[3-(2-fluoro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 12 supra) and ethanolamine (Aldrich) following the procedure described in Example 16 as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][CH2:11][CH:12]([CH3:16])[C:13](O)=[S:14])=[CH:5][CH:4]=1.S(Cl)([Cl:19])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][CH2:11][CH:12]([CH3:16])[C:13]([Cl:19])=[S:14])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CSCC(C)C(O)=S)cc1
Product: COc1ccc(CSCC(C)C(=S)Cl)cc1

Procedure:
3-[[(4-Methoxy)phenylmethyl]thio]-2-methylthiopropanoic acid prepared according to the procedure of Example 10 in U.S. Pat. No. 4,116,962 is treated with thionyl chloride to yield 3-[[(4-methoxy)phenylmethyl]-thio]-2-methylthiopropionyl chloride.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([P:16]([OH:18])[OH:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19](Cl)[CH2:20]Cl>C(O)C.C(Cl)Cl>[CH2:19]([O:18][P:16]([CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH:13]([CH3:15])[CH3:14])[OH:17])[CH3:20]
Reactant: ClCCCl
Reactant: CC(C)C(NC(=O)OCc1ccccc1)P(O)O
Solvent: ClCCl
Solvent: CCO
Product: CCOP(O)C(NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a solution of 1-(benzyloxycarbonylamino)-2-methylpropylphosphonous acid (5.8 g, 21.4 mmol) in 15 mL ethanol and 200 mL CH2Cl2 was added EDC (5.0 g, 26 mmol). The resulting reaction mixture was stirred at ambient temperature for 30 minutes. The mixture was concentrated in vacuo, and the residue was taken up into 200 mL ethyl acetate, washed with water and brine. The solvent was evaporated in vacuo to afford 1-(benzyloxycarbonylamino)-2-methylpropylphosphonous acid ethyl ester (6.2 g, 20.7 mmol, 96.8%) as white solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].C(N(C(C)C)CC)(C)C.[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26].CCCCCC>C1COCC1.C(OCC)C>[Cl:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH:4][C:25](=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][Cl:20]
Reactant: Cc1cc(C)c(N)c(Cl)c1
Reactant: O=C(Cl)CCCCCl
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(C)c(NC(=O)CCCCCl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-4,6-dimethylaniline (14.7 g) and diisopropylethylamine (18 mL) in 150 mL of THF, was added a solution of 5-chlorovaleryl chloride (12.2 mL) in 75 mL of THF. After the reaction mixture had been allowed to stir at room temperature overnight, it was filtered and the filtrate concentrated on the rotary evaporator. The residue was dissolved in ethyl acetate and washed with 1 M aqueous HCl, saturated aqueous sodium bicarbonate, and brine. The ethyl acetate solution was then dried with magnesium sulfate and concentrated on the rotary evaporator to give a solid which was combined with a 1:1 mixture of hexane and diethyl ether. After this mixture had been stirred for an hour, it was filtered and the collected solids were dried to provide 12.2 g of 5-chloropentanoic acid (2-chloro-4,6-dimethylphenyl)amide, mp 80.6-82.9° C.
Reaction SMILES: [NH2:1][C@:2]([CH3:53])([C:49]([CH3:52])([CH3:51])[CH3:50])[CH2:3][O:4][C@@H:5]1[C@@:12]2([CH3:37])[C@@H:13]3[CH2:14][CH2:15][C@H:16]4[C:25]([C@@:8]3([CH2:9][O:10][CH2:11]2)[CH2:7][C@H:6]1[N:38]1[C:42]([C:43]2[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=2)=[N:41][CH:40]=[N:39]1)=[CH:24][CH2:23][C@:22]1([CH3:26])[C@:17]4([CH3:36])[CH2:18][CH2:19][C@@:20]([C@H:31]([CH3:35])[CH:32]([CH3:34])[CH3:33])([CH3:30])[C@H:21]1[C:27]([OH:29])=[O:28].C(N(CC)CC)C.ClC(Cl)(Cl)[C:63]([N:65]=C=O)=[O:64]>ClC(Cl)C>[NH2:65][C:63]([NH:1][C@:2]([CH3:53])([C:49]([CH3:50])([CH3:51])[CH3:52])[CH2:3][O:4][C@@H:5]1[C@@:12]2([CH3:37])[C@@H:13]3[CH2:14][CH2:15][C@H:16]4[C:25]([C@@:8]3([CH2:9][O:10][CH2:11]2)[CH2:7][C@H:6]1[N:38]1[C:42]([C:43]2[CH:44]=[CH:45][N:46]=[CH:47][CH:48]=2)=[N:41][CH:40]=[N:39]1)=[CH:24][CH2:23][C@:22]1([CH3:26])[C@:17]4([CH3:36])[CH2:18][CH2:19][C@@:20]([C@H:31]([CH3:35])[CH:32]([CH3:34])[CH3:33])([CH3:30])[C@H:21]1[C:27]([OH:29])=[O:28])=[O:64]
Reactant: CC(C)[C@@H](C)[C@@]1(C)CC[C@]2(C)[C@H]3CC[C@@H]4[C@@]5(COC[C@@]4(C)[C@@H](OC[C@](C)(N)C(C)(C)C)[C@H](n4ncnc4-c4ccncc4)C5)C3=CC[C@@]2(C)[C@@H]1C(=O)O
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(C)[C@@H](C)[C@@]1(C)CC[C@]2(C)[C@H]3CC[C@@H]4[C@@]5(COC[C@@]4(C)[C@@H](OC[C@](C)(NC(N)=O)C(C)(C)C)[C@H](n4ncnc4-c4ccncc4)C5)C3=CC[C@@]2(C)[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
To a solution of (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[(2R)-2-amino-2,3,3-trimethylbutyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-14-[5-(4-pyridinyl)-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid (Example 173, 20 mg, 0.027 mmol) and triethylamine (0.015 mL, 0.11 mmol) in dichloroethane (0.27 mL) was added trichloroacetyl isocyanate (0.004 mL, 0.032 mmoL). The solution was stirred at room temperature for 70 min and then evaporated to dryness. Methanol (0.5 mL) was added to the residue followed by solid potassium carbonate (14.6 mg, 0.11 mmol and the mixture was stirred at room temperature. After 55 min, water (0.1 mL) was added giving a clear solution. The solution was stirred at room temperature for 1 hour and then stored at 5° C. for 64 hours. The solution was evaporated and the residue purified by reverse phase HPLC using a 19×150 mm Sunfire Preparative C18 OBD column (elution with MeCN/water+0.05% TFA). Fractions containing the product were evaporated and freeze-dried from a mixture of ethanol and benzene to give the title compound (not a salt form) as a white solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([S:11]([O-:14])(=O)=[O:12])[CH2:7][CH2:8][CH:9]=[CH2:10].[Na+]>>[CH2:6]([S:11]([Cl:3])(=[O:14])=[O:12])[CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCS(=O)(=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Product: C=CCCCS(=O)(=O)Cl
Temperature: 0 °C
Yield: 54.5 %

Procedure:
Phosphorus oxychloride (570.02 g) was added to sodium 4-pentene-1-sulfonate (199.18 g) at room temperature. After reflux for 3 hours, the solution was cooled in an ice bath. The reaction solution was added gradually to a large amount of ice water. After extraction with diethyl ether, the organic layer was washed with brine, dried with magnesium sulfate, and concentrated under reduced pressure to obtain 4-pentene-1-sulfonyl chloride (106.31 g) as dark brown oil.
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][N:13]([C:25](=[O:32])[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1>CO>[CH3:12][N:13]([C:25](=[O:32])[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:1])=[O:30])[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CN(CCc1c[nH]c2ccccc12)C(=O)CCCC(=O)O
Solvent: CO
Product: COC(=O)CCCC(=O)N(C)CCc1c[nH]c2ccccc12
Yield: 16231 %

Procedure:
30 ml of methanol and 10 mg of p-toluenesulfonic acid were added to 2.88 g of N-methyl-N-(4-carboxybutyryl)-tryptamine (i.e., 3-[2-(N-methyl-4-carboxybutanamido)ethyl]-indole). The mixture was refluxed for 5 hours. After the reaction was completed, the mixture was concentrated to about 10 ml. The concentrated mixture was diluted with an aqueous saturated sodium bicarbonate solution under cooling and then extracted with ethyl acetate. The extract was washed with water, dried and then concentrated to dryness. The residue thus obtained was recrystallized from a mixture of ethyl acetate and n-hexane. 2.85 g of N-methyl-N-(4-methoxycarbonylbutyryl)-tryptamine (i.e., 3-[2-(N-methyl-4-methoxycarbonylbutanamido)ethyl]-indole) were thereby obtained. M.p. 101°-102° C. Yield: 95%
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1>C1COCC1>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:20]2([OH:23])[CH2:21][CH2:22][O:17][CH2:18][CH2:19]2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CCOCC1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2ccc(OCc3ccccc3)cc2)CCOCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
In a 100 ml round-bottomed flask was placed magnesium turnings (1.85 g, 76.1 mmol), which was stirred under vacuum without solvent overnight. To it were slowly added anhydrous THF 40 ml and 4-benzyloxy bromobenzene (10 g, 38 mmol) over 15 min with occasional heating by a heat gun to keep the Grignard reagent formation going. After the addition was complete, the resulting gray slurry was stirred for 1 hr at 60° C. To it was added tetrahydro-4H-pyran-4-one (3.5 ml, 38 mmol) upon cooling in an ice-water bath. After stirring for 30 min, the solvent was removed under reduced pressure and diluted with AcOEt and sat. NH4Cl aq. The organic phase was separated, concentrated, and chromatographed on silica gel eluting with 40% AcOEt/hexanes to give 4-(4-benzyloxyphenyl)tetrahydro-2H-pyran-4-ol 5.95 g (55%).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].C1(C2(C3C=CC=CC=3)OB(C)N3CCC[C@@H]23)C=CC=CC=1.[OH-].[Na+]>O1CCCC1>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]2[CH2:2][O:4]2)=[CH:6][CH:7]=1
Reactant: O=C(CCl)c1ccc(F)cc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Fc1ccc(C2CO2)cc1
Reaction time: 0.17 h
Yield: 106.2 %

Procedure:
1.0 g of 2-Chloro-4′-fluoroacetophenone was dissolved in 5 ml of tetrahydrofuran, and 0.16 g of (S)-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine and 1M borane-tetrahydrofuran complex 7.0 ml of tetrahydrofuran solution were added with ice-cooling, followed by stirring for 10 minutes. Then, to the reaction solution was added 2 ml of 4M aqueous sodium hydroxide solution, followed by stirring at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ether and washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (Wako-gel C200, hexane:ethyl acetate=10:1) to give an optically active 2-(4-fluorophenyl)oxirane (0.85 g) as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][O-:11].[Na+]>CN(C=O)C>[CH3:10][O:11][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: C[O-]
Reactant: Cc1cc(C)nc(Cl)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C)cc(C)n1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
2-chloro-4,6-dimethylpyridine (CAS number: 30838-93-8) (400 mg) was added to DMF (3.3 mL). Sodium methoxide (28% solution in methanol, 2.6 mL) was added to the solution, and the mixture was stirred at 100° C. for 12 hours. The reaction mixture was partitioned by adding ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (380 mg) as a 50% solution in DMF.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:15][N:16]=[N+]=[N-])[CH2:9][CH2:8]1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:15][NH2:16])[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC[C@H]1CC[C@H](C(CCN=[N+]=[N-])NC(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: CC(=O)OCC[C@H]1CC[C@H](C(CCN)NC(=O)OC(C)(C)C)CC1
Reaction time: 18 h

Procedure:
A mixture of the azide from Step 15 (0.72 g, 1.95 mmol) and 10% Pd/C (0.1 g) in MeOH (20 mL) was hydrogenated via a H2 balloon at rt for 18 h. Filtration and evaporation to dryness afforded the amine in a quantitative yield. LC/MS: 343.1 (MH)+.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:10]2=[O:38])=[N:5][CH:4]=1)[CH3:2].[ClH:39]>O1CCOCC1>[ClH:39].[CH2:1]([C:3]1[O:7][C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]2=[O:38])=[N:5][CH:4]=1)[CH3:2]
Reactant: CCc1cnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)o1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1cnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tert-butyl 4-{1-[(5-ethyl-1,3-oxazol-2-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (530 mg; compound B1) is dissolved in a solution of hydrogen chloride in 1,4-dioxane (10 ml, 6.8 M). The solution is stirred for 0.5 h at RT. The resulting precipitate is filtered off, washed with diethyl ether and dried in vacuo to give the title compound as a solid.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9](=[O:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(OCC)(OCC)O[CH2:14][CH3:15].[Cl-].[NH4+]>C(O)C>[CH2:14]([O:11][C:9]([CH3:10])=[CH:8][C:2](=[O:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:15]
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)C(=O)CC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=O)C=C(C)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.5 %

Procedure:
To a stirred solution of ethyl 2,4-dioxopentanoate (36.5 g, 231 mmol) and triethyl orthoformate (41 mL, 246 mmol) in ethanol (60 mL) was added ammonium chloride (3.7 g, 69 mmol). The suspension was stirred at RT overnight. LCMS showed that the reaction was mostly complete. (Hydrolyzes on LCMS to some degree?) The reaction was concentrated under vacuum. The remaining oil was taken up in Et2O (300 mL), filtered to remove insolubles, rinsed with Et2O, and concentrated under vacuum. The product was obtained by short path distillation under vacuum (bp 70 to 77° C. at 0.09 mmHg) to give the product ethyl 4-ethoxy-2-oxopent-3-enoate (36.5 g, 47.3 mmol, 79% yield) as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:12]=[C:11]2[N:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[C:4](=[O:5])[C:3]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:22]3[CH:23]=[CH:24][C:25]([F:30])=[CH:26][C:27]=3[O:28][N:29]=2)[CH2:17][CH2:16]1.[C:31]([OH:42])(=[O:41])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>C(O)C>[CH3:1][C:2]1[N:12]=[C:11]2[N:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[C:4](=[O:5])[C:3]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:22]3[CH:23]=[CH:24][C:25]([F:30])=[CH:26][C:27]=3[O:28][N:29]=2)[CH2:17][CH2:16]1.[C:31]([O-:42])(=[O:41])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCCC(=O)O
Agent: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2
Solvent: CCO
Product: CCCCCCCCCC(=O)[O-]
Temperature: 52.5 °C
Reaction time: 0.17 h

Procedure:
150 ml of ethanol and 5 gm Risperidone were charged in the flask. The reaction mixture was heated at 50-55° C. and stirred for 10 minutes to get clear solution. 2.1 gm decanoic acid solution in 30 ml ethanol was added to the reaction mixture at 40-45° C. The reaction mixture was further cooled to 25-30° C., stirred for 18-20 hours and distilled out completely under vacuum at 50-55° C. The solid was dried under vacuum at 40-45° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:9]3[CH:11]=[CH:12][C:13]([S:15]([O-:18])(=[O:17])=[O:16])=[CH:14][C:8]=3[CH:7]=[CH:6][C:5]=2[N:4]=[C:3]1[CH3:19].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28]>CC(C)C(=O)C>[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][N+:4]1[C:5]2[CH:6]=[CH:7][C:8]3[CH:14]=[C:13]([S:15]([O-:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:9]=3[C:10]=2[C:2]([CH3:20])([CH3:1])[C:3]=1[CH3:19])([OH:29])=[O:28]
Reactant: CC1=Nc2ccc3cc(S(=O)(=O)[O-])ccc3c2C1(C)C
Reactant: O=C(O)CCCCBr
Agent: [K+]
Solvent: CC(=O)C(C)C
Product: CC1=[N+](CCCCC(=O)O)c2ccc3cc(S(=O)(=O)[O-])ccc3c2C1(C)C
Temperature: 140 °C
Yield: 7.2 %

Procedure:
To a solution of 1,1,2-trimethyl-1H-benzo[e]indole-7-sulfonic acid (723 mg, 2.5 mmol) in methanol (5 mL) was added a saturated solution of potassium hydroxide in isopropanol (3.134%, 4.913 g, 1.1 eq.) and the resulting suspension was heated at reflux for 2 h. Then the mixture was concentrated and the corresponding potassium salt was obtained. Under nitrogen atmosphere, a mixture of potassium 1,1,2-trimethyl-1H-benzo[e]indole-7-sulfonate and 5-bromovaleric acid (585 mg, 3 mmol) in 3-methyl-2-butanone (5 mL) was heated at 140° C. for 20 h. Removal of the solvent and purification by chromatography (dichloromethane/methanol) afforded 3-(4-carboxybutyl)-1,1,2-trimethyl-1H-benzo[e]indolium-7-sulfonate (70 mg, isolated yield 7.2%). LC-MS: 390.18 [M+].
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[I:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[I:19][C:20]1[CH:21]=[C:22]([CH2:23][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:25]=[CH:26][CH:27]=1
Reactant: BrCc1cccc(I)c1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(I)c2)CCCC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.5 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (680 mg, 3.5 mM), 3-iodobenzyl bromide (1.2 g, 4.7 mM), and potassium carbonate (500 mg, 3.61 mM) in 20 mL DMF was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate, washed with H2O and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated. The residue was purified trituration with methylene chloride-diethyl ether) to afford 0.70 g (55%) of the 9-[(3-iodophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a white solid. 1H NMR (DMSO-d6) δ 7.7-7.6 (m, 3H), 7.2 (m, 2H), 7.1 (t, 1H, J=8 Hz), 6.95 (d, 1H, J=8 Hz), 5.6 (s, 2H), 3.8 (s, 3H), 3.0 (t, 2H, J=6 Hz), 2.5 (t, 2H, J=6 Hz), and 2.2 (m, 2H). IR (KBr, cm−1) 1732, 1639, 1441, 1421, 1273, 1117, and 763. MS (ES) m/e 458, 460.
Reaction SMILES: [O:1]=[C:2]1[O:6][CH2:5][C@@H:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.CC(C)=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>O>[OH:20][CH2:5][C@@H:4]([NH:7][C:8]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:17])[CH2:3][C:2]([OH:6])=[O:1]
Reactant: O=C1C[C@H](NC(=O)OCc2ccccc2)CO1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: O=C(O)C[C@@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a 500 ml round-bottomed flask phenylmethyl [(3S)-5-oxotetrahydro-3-furanyl]carbamate (4.3 g, 18.28 mmol, available from Sigma-Aldrich # 419249) was dissolved in water (100 ml) and acetone (100 ml) and to this solution Cs2CO3 (10.72 g, 32.9 mmol) was added and the reaction left under stirring at room temperature for 5 hours. The solution was then transferred into a separatory funnel and washed with EtOAc (2×50 ml). The aqueous phase was then acidified to pH=2 by the addition of a 2 M HCl aqueous solution and then extracted with EtOAc (5×100 mls). The organic phase was dried (Na2SO4) and solvent removed under reduced pressure to give the title compound D1 (3.78 g) as a white solid. MS: (ES/+) m/z: 254 (M+1). C12H15NO5 requires 253. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.11 (bs, 1 H), 7.41-7.07 (m, 5 H), 5.17-4.92 (m, 2 H), 3.95-3.62 (m, 1 H), 3.42-3.22 (m, 2H), 2.55-2.40 (m, 1 H), 2.34-2.23 (m, 1 H).
Reaction SMILES: NC(N)=O.[CH3:5][O:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([NH2:20])[C:14]=1[OH:21])(=[O:12])=[O:11].[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31]>>[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30]([NH:20][C:15]1[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([S:10]([NH:9][CH2:8][CH2:7][O:6][CH3:5])(=[O:12])=[O:11])[C:14]=1[OH:21])=[O:31]
Reactant: COCCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Reactant: O=C=Nc1ccccc1Br
Agent: NC(N)=O
Product: COCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Br)c1O
Yield: 72.7 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-(2-methoxyethyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (140 mg, 0.50 mmol) and 2-bromophenylisocyanate (119 mg, 0.60 mmol) were coupled to form the desired urea (174 mg, 72%). EI-MS (m/z) 476.0, 478.0, 479.9 (M−).