Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([C@H:12]([NH:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=3)[CH2:16]2)[CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:29](Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C)C=O>[C:24]([C:23]1[CH:27]=[CH:28][C:20]([N:17]2[CH2:18][CH2:19][C@H:15]([NH:14][C@@H:12]([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=[CH:4][CH:3]=3)[CH3:13])[CH2:16]2)=[CH:21][CH:22]=1)(=[O:26])[CH3:29]
Reactant: C[C@@H](N[C@H]1CCN(c2ccc(C(=O)O)cc2)C1)c1cccc2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(N2CC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 50 mg of 4-[(S)-3-[(R)-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzoic acid hydrochloride (the compound obtained in Example 3.001) in 5 ml of methylene chloride (MeOH free) was added dropwise 43 μl of oxalyl chloride, and then, several drops of dimethylformamide were added to the mixture, and the resulting mixture was stirred under room temperature for 16 hours. The solvent was removed from the reaction mixture to obtain the residue. (2) To the compound obtained as mentioned above were added dimethylamine (82 μl of 2M THF solution) and 10 ml of methylene chloride to dissolve them, 70.2 μl of triethylamine was added to the mixture, and the mixture was stirred under room temperature for 16 hours. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate 7:1→0:1) to obtain 22.4 mg of N,N-dimethyl-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzamide. (3) To a solution of 22.4 mg of N,N-dimethyl-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]-benzamide dissolved in 1 ml of methylene chloride was added dropwise 3 ml of a solution of 4M hydrochloric acid in dioxane, and the mixture was stirred for a while. The reaction mixture was concentrated, t-butanol was added to the residue to dissolve the same, and freeze-dried to obtain 22.9 mg of N,N-dimethyl-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzamide hydrochloride (Example 3.012 in the following Table A3).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH2:11])[CH:5]=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].O>C(O)(=O)C>[CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1cccc(C)c1C(=O)O
Temperature: 25 °C
Yield: 85 %

Procedure:
A suspension of 15.2 g (100 mmoles) of 6-methyl-2-aminobenzoic acid (obtained from the Aldrich Chemical Company, Inc., Milwaukee Wis.) in 150 mL of glacial acetic acid was heated in a water bath to promote homogeneity. Acetic anhydride, 15 mL (159 mmole), was added and the resultant solution kept in the hot water bath for 40 minutes. Upon cooling to near room temperature, the dark solution was poured over crushed ice. When all ice had melted, the pale beige solid which had separated was collected and air-dried. 16.4 g (85% yield) 6-methyl-2-acetylaminobenzoic acid was obtained. NMR(DMSO-d6): 2.00(s,3H), 2.33(s,3H), 7.05(d,1H,J=7.5 Hz), 7.29(t,1H,J=7.8 Hz), 7.41(d,1H,J=7.8 Hz), 9.60(bs,1H). MS(m/z): 193(M+).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:16])[CH:7](O)[C:8]1[C:9](=O)[CH2:10][CH:11]([CH3:13])[CH:12]=1)[CH2:2][CH2:3][CH3:4].O.C1(C)C=CC(S(O)(=O)=[O:25])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6](=[O:16])[CH:7]=[C:8]1[CH2:12][CH:11]([CH3:13])[C:10](=[O:25])[CH2:9]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C(O)C1=CC(C)CC1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOC(=O)C=C1CC(=O)C(C)C1
Temperature: 15 °C
Reaction time: 2 h
Yield: 1072.9 %

Procedure:
Step 3 Dehydration (n-Butyl Ester): Into a 5-L, 3-necked, round-bottomed flask equipped with a condenser, thermometer and nitrogen inlet were added 154.8 g (0.68 M) alpha-hydroxy-4-methyl-3-oxo-cyclopentene acetic acid butyl ester (as prepared by Example 4), 2.3 L of toluene, and 12.9 g (0.068 M) of p-toluenesulfonic acid monohydrate. The resulting reaction mixture was stirred at 75°-78° C. for 61/2 hours under nitrogen. When the reaction was complete, the mixture was cooled to 15° C., poured into a separatory funnel, washed with three 1-L portions of a total of 3 L of water, dried (MgSO4) and evaporated to give 153 g of the homogeneous 4-methyl-3-oxo-cyclopentylidene acetic acid butyl ester bp 82°-84° C./0.05 mm Hg, as a red oil for use in Example 8.
Reaction SMILES: [BH4-].[Na+].[C:3]1([S:9]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21](=O)[CH3:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[CH2:21]([C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([S:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:11])=[O:10])[CH2:13][CH2:14]2)[CH3:22]
Reactant: CC(=O)c1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To TFA (1600 mL) at 0° C. was added sodium borohydride (64.0 g, 1.69 mol) over 1 h. To this mixture was added dropwise a solution of 1-(1-(phenylsulfonyl)indolin-5-yl)ethanone (40.0 g, 0.133 mol) in TFA (700 mL) over 1 h. The mixture was then stirred overnight at 25° C. After dilution with H2O (1600 mL), the mixture was made basic by the addition of sodium hydroxide pellets at 0° C. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica column to give 5-ethyl-1-(phenylsulfonyl)indoline (16.2 g, 47% over two steps).
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5]([NH2:6])=[C:4]([F:11])[CH:3]=1.[N:12]([O-])=O.[Na+]>Cl.O>[Cl:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5]([NH:6][NH2:12])=[C:4]([F:11])[CH:3]=1
Reactant: O=N[O-]
Reactant: COc1cc(N)c(F)cc1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(NN)c(F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 43.5 %

Procedure:
A stirred solution of 48.0 g (0.27 mole) of 4-chloro-2-fluoro-5-methoxyaniline in 500 mL of concentrated hydrochloric acid was cooled to -5° C. and 23.5 g (0.34 mole) of sodium nitrite in 100 mL of water was added dropwise. After complete addition the reaction mixture was stirred at 0° C. for one hour. A second solution of 154.0 g (0.68 mole) of stannous chloride in 225 mL of concentrated hydrochloric acid was cooled to 0° C., and the cold diazonium solution prepared above was added to it slowly. After complete addition the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was filtered to collect a solid. This solid was dissolved in an aqueous 50% sodium hydroxide solution and the solution extracted with toluene. The toluene extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield 22.4 g of 4-chloro-2-fluoro-5-methoxyphenylhydrazine as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([O:25]C)=O)=[CH:14][C:12]=2[N:13]=1.[F:28][C:29]1[C:35]([F:36])=[C:34]([F:37])[CH:33]=[CH:32][C:30]=1[NH2:31].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:21])([CH3:22])[O:20][C:16]=3[C:15]([C:23]([NH:31][C:30]3[CH:32]=[CH:33][C:34]([F:37])=[C:35]([F:36])[C:29]=3[F:28])=[O:25])=[CH:14][C:12]=2[N:13]=1
Reactant: Nc1ccc(F)c(F)c1F
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)[nH]c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(F)c(F)c3F)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 58.6 %

Procedure:
The title compound was prepared following the procedure described for Example-137 by using methyl 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylate (Step-1 of Intermediate-3, 0.100 g, 0.245 mmol), 2,3,4-trifluoroaniline (0.078 g, 0.530 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) at room temperature to afford 0.075 g of the desired product. 1HNMR (DMSO-d6): δ 1.57 (s, 6H), 3.09 (s, 2H), 7.28-7.39 (m, 2H), 8.15 (m, 1H), 8.45 (s, 2H), 9.92 (s, 1H), 11.02 (br s, 1H), 11.58 (br s, 1H); MS [M+H]+: 521.93.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=C(C)[S:10][C:6]=2[C:5]([F:12])=[CH:4][C:3]=1[F:13].[ClH:14].O1CCOCC1>C(O)CO.[OH-].[Na+]>[ClH:14].[NH2:8][C:7]1[C:2]([F:1])=[C:3]([F:13])[CH:4]=[C:5]([F:12])[C:6]=1[SH:10]
Reactant: Cc1nc2c(F)c(F)cc(F)c2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: OCCO
Product: Nc1c(F)c(F)cc(F)c1S
Temperature: 125 °C
Yield: 73 %

Procedure:
A solution of 4,5,7-trifluoro-2-methylbenzothiazole (25.0 g, 123 mmol) in ethylene glycol (310 mL, 0.4 M) and 30% aq. NaOH (310 mL, 0.4 M) was degassed using a nitrogen stream then heated to a gentle reflux (125° C.) for 3 h. The solution was cooled to 0° C. and acidified to pH 3-4 using conc. HCl (approx. 200 mL). The solution was extracted with ether (750 mL) and washed with water (200 mL). The organic layer was dried over Na2SO4, filtered and treated with 2,2-di-tert-butyl-4-methylphenol (0.135 g, 0.5 mol %). After concentrating to dryness, the crude product was dissolved in anhydrous methanol (200 mL) and treated with an HCl solution in 1,4-dioxane (37 mL, 4 N, 148 mmol). The resulting mixture was concentrated to dryness, triturated with isopropylether (100 mL) and filtered to give 2-amino-3,4,6-trifluorothiophenol hydrochloride (19.3 g, 73%) as a light brown solid that was used without further purification. mp. 121-124 C; Rf 0.43 (30% ethyl acetate in heptane); Anal. Calcd for C6H5ClF3NS: C, 33.42; H, 2.34; N, 6.50; S, 14.87. Found C, 33.45; H, 2.27; N, 6.48; S, 14.96.
Reaction SMILES: [Br:1]Br.[C:3]([C:11]1[C:12](=[O:21])[N:13]([CH3:20])[C:14](=[O:19])[N:15]([CH3:18])[C:16]=1[CH3:17])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl.CCOC(C)=O>[C:3]([C:11]1[C:12](=[O:21])[N:13]([CH3:20])[C:14](=[O:19])[N:15]([CH3:18])[C:16]=1[CH2:17][Br:1])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrBr
Reactant: Cc1c(C(=O)c2ccccc2)c(=O)n(C)c(=O)n1C
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
Bromine (0.497 mL, 9.68 mmol) was added to a solution of 5-benzoyl-1,3,6-trimethyl pyrimidine-2,4(1H,3H)-dione (step 2) (2.5 g, 9.68 mmol) in chloroform (50 mL) with stirring under nitrogen. The mixture was heated to 55° C. for 2 h. A further portion of bromine (0.25 mL, 0.5 equiv) was added and heating continued at 55° C. for a further 30 min. The mixture was cooled to RT, diluted with CHCl3 (50 mL) and poured into saturated sodium thiosulfate solution (150 mL). The layers were separated and the aqueous phase was extracted with CHCl3 (50 mL). The combined organics were washed with water (50 mL), brine (50 mL), dried (Na2SO4) and filtered under reduced pressure. The solvent was evaporated under reduced pressure to afford a pale yellow solid. This solid was dissolved in hot EtOAc (50 mL) and slowly evaporated until crystallisation was observed. The resulting white solid was collected by reduced pressure filtration and washed with cold EtOAc (10 mL) and dried in air. The compound was further dried under vacuum at 50° C. for 2 h. The title product was isolated as white micro needles.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH:10]=[CH:9]2.[NH2:17][CH2:18][CH2:19][CH2:20][OH:21]>CO>[OH:21][CH2:20][CH2:19][CH2:18][NH:17][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH:10]=[CH:9]2
Reactant: NCCCO
Reactant: O=c1ccc2cc(OCCCCl)ccc2[nH]1
Solvent: CO
Product: O=c1ccc2cc(OCCCNCCCO)ccc2[nH]1

Procedure:
A solution of 6-(3-chloropropoxy)carbostyril (5.0 g) and 3-amino-1-propanol (24 ml) in methanol (25 ml) is heated at 100° C. for 4 hours in an autoclave. The mixture is concentrated under reduced pressure to remove the solvent, and the residue is purified by silica gel column chromatography (solvent; methylene chloride:methanol:aqueous ammonia=70:10:1), and recrystallized from methanol-diethyl ether to give 6-[3-(3-hydroxypropyl)aminopropoxy]carbostyril(4.4 g) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][CH:22](C(OC(C)(C)C)=O)[CH2:23][CH3:24])=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH:21][CH2:22][CH2:23][CH3:24])=[CH:17][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCC(NCCc1ccc(N)cc1)C(=O)OC(C)(C)C
Product: CCCNCCc1ccc(NS(=O)(=O)c2ccc(Br)cc2)cc1

Procedure:
Using procedure 4, 4-bromobenzenesulfonyl chloride was added to 2-(4-aminophenyl)ethyl-1-(tert-butoxycarbonyl)propylamine to give the title compound as a solid, m.p. 141-143° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:35][C:36]([OH:38])=[O:37])[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:6]=1CC1C=CC=CC=1S(C1C=CC=CC=1)(=O)=O.[N:39]1([S:44]([C:47]2[CH:54]=[CH:53][CH:52]=[CH:51][C:48]=2[CH:49]=O)(=[O:46])=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH3:1][C:2]1[N:3]([CH2:35][C:36]([OH:38])=[O:37])[C:4]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:5]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:6]=1[CH2:49][C:48]1[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=1[S:44]([N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1)(=[O:46])=[O:45]
Reactant: O=Cc1ccccc1S(=O)(=O)N1CCCC1
Reactant: Cc1c(Cc2ccccc2S(=O)(=O)c2ccccc2)c(-c2ccccc2)c(-c2ccccc2)n1CC(=O)O
Product: Cc1c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(-c2ccccc2)c(-c2ccccc2)n1CC(=O)O

Procedure:
2-(2-methyl-4,5-diphenyl-3-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetic acid was synthesized according to 2-(2-methyl-4,5-diphenyl-3-(2-(phenylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetic acid using 2-(pyrrolidin-1-ylsulfonyl)benzaldehyde in the general procedure I (step 1). 1H NMR (CDCl3/400 MHz) δ (ppm) 8.00 (d, 1H), 7.50-7.45 (m, 1H), 7.34-7.24 (m, 5H), 7.19-7.16 (m, 2H), 7.05-7.00 (m, 3H), 6.92-6.88 (m, 2H), 4.65 (s, 2H), 4.21 (s, 2H), 3.15 (t, 4H), 2.10 (s, 3H), 1.69-1.65 (m, 4H). MS m/z: 515.34 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([CH2:17][C:18](O)=[O:19])=[CH:10][C:11]2[O:15][CH2:14][O:13][C:12]=2[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([C:8]1[C:9]([CH2:17][CH2:18][OH:19])=[CH:10][C:11]2[O:15][CH2:14][O:13][C:12]=2[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cc2c(cc1Cc1ccccc1)OCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1cc2c(cc1Cc1ccccc1)OCO2
Temperature: 25 °C
Yield: 82.3 %

Procedure:
A solution of 1.82 g of (6-benzyl-1,3-benzodioxol-5-yl)acetic acid in 22 ml of anhydrous tetrahydrofuran was dropwise added at 0° C. to a suspension of 0.38 g of lithium aluminum hydride in anhydrous tetrahydrofuran. The obtained mixture was warmed to a room temperature to carry out the reaction for 4 hours, followed by the addition of water. The mixture was filtered to remove the precipitate. The filtrate was concentrated in a vacuum to obtain a yellow oil residue. This residue was purified by silica gel column chromatography (ethyl acetate/hexane=2:8) to obtain 1.42 g of the title compound as a colorless crystal.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9]([OH:11])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:46]([N+:50]1[N:54]=[C:53]([CH3:55])[S:52][C:51]=1[CH3:56])[CH2:47][CH2:48][CH3:49]>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9](/[CH:56]=[C:51]1\[S:52][C:53]([CH3:55])=[N:54][N:50]\1[CH2:46][CH2:47][CH2:48][CH3:49])=[O:11]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: O=C(O)CC1CC2CCC1C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)CC1CC2CCC1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2-(bicyclo[2.2.1]heptan-2-yl)acetic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (77 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (53 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (50 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.90 (t, 3H) 0.98-1.18 (m, 4 H) 1.23-1.49 (m, 6 H) 1.62-1.73 (m, 2 H) 1.80-1.88 (m, 1 H) 1.89-1.95 (m, 1 H) 2.11-2.19 (m, 2 H) 2.23-2.31 (m, 1 H) 2.38-2.43 (m, 3 H) 4.02 (t, 2 H) 5.86-5.92 (m, 1 H); MS (ESI) m/z 307 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1([N:14]2[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]2)[CH2:11][CH2:10][C:9]([F:13])([F:12])[CH2:8][CH2:7]1)=O)C.[NH3:20]>CO>[F:12][C:9]1([F:13])[CH2:10][CH2:11][C:6]([N:14]2[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]2)([C:4]([NH2:20])=[O:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1(n2cnc(C)c2)CCC(F)(F)CC1
Reactant: N
Solvent: CO
Product: Cc1cn(C2(C(N)=O)CCC(F)(F)CC2)cn1
Reaction time: 72 h
Yield: 45 %

Procedure:
4,4-Difluoro-1-(4-methyl-imidazol-1-yl)-cyclohexanecarboxylic acid ethyl ester (199 mg, 0.731 mmol was dissolved in 7 M ammonia in methanol (5 mL) and stirred for 72 hours. The sample was concentrated and the residue was purified by flash column chromatography on silica gel (eluding w a gradient elution from heptane to AcOEt to 5% Et3N/10% MeOH185% AcOEt) to give the title compound (84 mg, 45%) 1H NMR (CDCl3 500 MHz): 6 ppm 7.64 (s, 1H), 6.82 (s, 1H), 5.17 (m, 2H), 2.68 (m, 2H), 2.41 (m, 2H), 2.30 (s, 3H), 2.23 (m, 2H), 1.85 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:8][C:7]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)([C:9]([NH:11][NH2:12])=O)[CH2:6]1.CO[C:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:8][C:7]([C:9]2[N:27]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]3=[N:12][N:11]=2)([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:6]1
Reactant: COCOC1CC(C(=O)NN)(c2cccs2)C1
Reactant: COC1=NCCCCCC1
Solvent: Cc1ccccc1
Product: COCOC1CC(c2cccs2)(c2nnc3n2CCCCCC3)C1
Yield: 83.1 %

Procedure:
3-(Methoxymethoxy)-1-(2-thienyl)cyclobutanecarbohydrazide (5.45 g) and 8-methoxy-2,3,4,5,6,7-hexahydroazocine (4.51 g) were heated in toluene (60 ml) at 110° C. for 19 hours. After concentration, the concentrate was purified by silica gel column chromatography (methanol:chloroform=2:98) to obtain 3-[3-(methoxymethoxy)-1-(2-thienyl)cyclobutyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (6.14 g).
Reaction SMILES: O=[C:2]1[CH2:6][S:5][C:4]([NH:7][C:8](=[O:10])[CH3:9])=[N:3]1.O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:2]1[N:3]=[C:4]([NH:7][C:8](=[O:10])[CH3:9])[S:5][CH:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)NC1=NC(=O)CS1
Product: CC(=O)Nc1nc(Cl)cs1
Temperature: 105 °C
Reaction time: 0.25 h

Procedure:
A mixture of N-(4-oxo-4,5-dihydro-thiazol-2-yl)-acetamide (Step 37.3) (14.8 g, 94 mmol) and POCl3 (175 mL, 20 eq) is heated to 105° C., stirred for 15 min, allowed to cool and concentrated. The residue is poured onto ice-H2O and extracted with EtOAc (2×100 mL). The organic phase is washed with a saturated solution of NaHCO3 (2×100 mL), dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH, 99:1) to afford 13.9 g of the title compound as a white solid: ESI-MS: 177.0 [M+H]+; tR=2.74 min (System 1); TLC: Rf=0.66 (DCM/MeOH, 9:1).
Reaction SMILES: [C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[NH4+:9].[NH4+].C(O)(=O)/C=C\C(O)=O>>[NH2:9][C@H:2]([C:1]([O-:8])=[O:7])[CH2:3][C:4]([O-:6])=[O:5].[NH4+:9].[NH4+:9]
Reactant: O=C([O-])/C=C\C(=O)[O-]
Agent: O=C(O)/C=C\C(=O)O
Agent: [NH4+]
Product: N[C@@H](CC(=O)[O-])C(=O)[O-]
Temperature: 30 °C
Reaction time: 24 h
Yield: 99.3 %

Procedure:
According to the same procedure of Example 6, the cells of Pseudomonas maltophilia ATCC 13270 and the cells of Escherichia coli ATCC 11303 were added to 2 L of an ammonium maleate substrate solution containing 400 g of maleic acid, and the substrate solution was gently stirred at 30° C. for 24 hours. After the reaction, ammonium L-aspartate was formed with a molar yield of 99.3% based on maleic acid. To the reaction solution from which the cells had been removed by centrifugation was added 410 g maleic acid at 30° C. After the addition, a temperature of the solution was 34° C., and pH valve thereof was 3.7. L-aspartic acid crystals were separated by filtration so as to recover 1.6 L of mother liquors. The crude crystals were 517 g (excluding water) (88.0 wt % aspartic acid, 10.7 wt % maleic acid, 400 μm average crystal size). The crystals were washed with about 400 ml of water and dried so as to obtain 452 g (excluding water) of L-aspartic acid crystals (98.6 wt % aspartic acid, 1.0 wt % maleic acid, 300 μm average crystal size).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][C@H:9]3[NH:20][CH2:19][CH2:18][C@@:15]4([C:16]=2[CH:17]=1)[C@@:10]3([O:23][CH3:24])[C@H:11]([CH3:22])[CH2:12][C:13](=[O:21])[CH2:14]4.C(=O)(O)[O-].[Na+].[CH2:30](Br)[CH:31]1[O:35][CH2:34][CH2:33][CH2:32]1.Cl>CN(C)C=O>[ClH:1].[CH2:30]([N:20]1[CH2:19][CH2:18][C@@:15]23[C:16]4[CH:17]=[C:4]([O:3][CH3:2])[CH:5]=[CH:6][C:7]=4[CH2:8][C@@H:9]1[C@:10]2([O:23][CH3:24])[C@H:11]([CH3:22])[CH2:12][C:13](=[O:21])[CH2:14]3)[CH:31]1[O:35][CH2:34][CH2:33][CH2:32]1
Reactant: COc1ccc2c(c1)[C@]13CCN[C@H](C2)[C@]1(OC)[C@H](C)CC(=O)C3
Reactant: BrCC1CCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)[C@]13CCN(CC4CCCO4)[C@H](C2)[C@]1(OC)[C@H](C)CC(=O)C3
Temperature: 110 °C

Procedure:
A mixture of 3,14-dimethoxy-8α-methylmorphinan-6-one hydrochloride (26) (0.24 g, 0.68 mmol), sodium bicarbonate (0.6 g, 7.14 mmol), (+) tetrahydrofurfuryl bromide (0.4 g, 2.42 mmol) and dimethylformamide (15 ml) was heated at 110° C. for 16 hours with stirring under a nitrogen atmosphere. The mixture was filtered hot and the residue washed with 10 milliliters of dimethylformamide. Most of the DMF was removed by distillation under high vacuum (bath temperature 35° C.) and the resulting brownish material was treated with CHCl3 (50 ml) and water (25 ml). After separation of the two layers, the aqueous layer was saturated with sodium chloride and re-extracted with ethyl acetate (3×25 ml). The organic extracts were combined, dried (MgSO4) and filtered. The filtrate was concentrated to an oily solid which was chromatographed over silica gel to give a mixture of R and S isomers of the product; yield 0.181 g (66.5% theory). A portion of the free base was converted to the HCl salt by treatment with ethereal HCl to form the title compound as a tan solid.