Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][NH2:25])[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][NH:25][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Product: CC(C)(C)OC(=O)N1CCC(CNS(=O)(=O)c2ccccc2)CC1

Procedure:
According to Reference Example 1, benzenesulfonylchloride and 1-Boc-4-(aminomethyl)piperidine were condensed to give the title compound.
Reaction SMILES: C([O:5][C:6](=[O:27])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:26])[CH:13]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:14][S:15][C:16](=[O:18])[CH3:17])(C)(C)C.C(OC(=O)[C@@H]1C(SC(=O)C)CCN1C(=O)C(C)C)(C)(C)C>>[C:16]([S:15][CH2:14][CH:13]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:27])=[O:5])=[O:26])(=[O:18])[CH3:17]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: CC(=O)SC1CCN(C(=O)C(C)C)[C@@H]1C(=O)OC(C)(C)C
Product: CC(=O)SCC(Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
The product of Example 38 is substituted for the 1-(3-acetylthio-2-methylpropanoyl-L-proline tert-butyl ester in Procedure A of Example 29 to obtain 1-(3-acetylthio-2-benzylpropanoyl)-L-proline.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:7][CH:8]=2)[O:3]1.Cl.C1C(=O)N([Cl:25])C(=O)C1.S([O-])([O-])(=O)=S.[Na+].[Na+].[OH-].[Na+]>ClCCl.CO.O>[Cl:25][C:7]1[CH:8]=[C:9]2[C:4](=[C:5]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=1)[O:3][C:2]([CH3:16])([CH3:1])[CH2:11][CH2:10]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cccc2c1OC(C)(C)CC2
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(Cl)cc2c1OC(C)(C)CC2
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2,2-dimethyl-3,4-dihydro-2H-chromene-8-carboxylate (330 mg, 1.50 mmol) in dichloromethane (3.74 mL) and methanol (3.74 mL) was added concentrated HCl (61.5 μL, 0.75 mmol) at 10° C. NCS (206 mg, 1.54 mmol) as added portion-wise. The solution was stirred for 1 hour at 8-12° C. The solution was then poured into a mixture of water (5.00 mL), saturated aqueous sodium thiosulfate (5.00 mL), 1 N aqueous NaOH (5.00 mL) and dichloromethane (30.0 mL). The mixture was stirred for 15 minutes at room temperature and the two phases were separated. The organic phase was acidified to pH<2 with 1 N aqueous HCl. The mixture was then extracted with dichloromethane (10.0 mL, 2×). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with 0-15% EtOAc/hexanes to give the desired product as a colorless oil.
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([O:8][CH2:9][CH2:10][NH2:11])([O-:7])=[O:6].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[S:23][C:22](=[O:24])[NH:21][CH:20]2[C:25](O)=[O:26])=[CH:15][CH:14]=1>>[N+:5]([O:8][CH2:9][CH2:10][NH:11][C:25]([CH:20]1[CH:19]([C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=2)[S:23][C:22](=[O:24])[NH:21]1)=[O:26])([O-:7])=[O:6]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C1NC(C(=O)O)C(c2ccc(Cl)cc2)S1
Solvent: O=[N+]([O-])O
Product: O=C1NC(C(=O)NCCO[N+](=O)[O-])C(c2ccc(Cl)cc2)S1

Procedure:
A procedure similar to that described in Example 1 was repeated, but using 394 mg of N-(2-nitrooxyethyl)amine nitrate and 500 mg of 5-(4-chlorophenyl)-2-oxothiazolidine-4-carboxylic acid, to obtain 350 mg of the title compound as colorless needles, melting at 125°-127° C. (after recrystallization from methylene chloride).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[OH:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][C:27](O)=[CH:28][CH:29]=2)[CH:24]=1>CC#N>[Br:20][C:27]1[CH:26]=[C:25]2[C:30]([CH:31]=[CH:32][C:23]([OH:22])=[CH:24]2)=[CH:29][CH:28]=1
Reactant: BrBr
Reactant: Oc1ccc2ccc(O)cc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Oc1ccc2ccc(Br)cc2c1
Temperature: 10 °C
Yield: 43 %

Procedure:
Triphenyl phosphine (89.7 g, 0.342 mol) and acetonitrile (350 mL) were combined in a 1-L flask under N2 atmosphere. The mixture was cooled to 10° C. Bromine (17.6 mL, 0.342 mol) was added dropwise over 10 minutes. The cooling bath was removed and 2,7-dihydroxynaphthalene (50.0 g, 0.312 mol) was added along with 350 mL of CH3CN rinse. The resulting yellow tan mixture was heated at reflux for 3 hours. Acetonitrile was distilled off using a water aspirator over 2 hours, resulting in a grayish white solid. The solid was heated to 280° C. over 30 minutes, giving a black liquid. The liquid was heated to 310° C. over 20 minutes and the temperature was maintained at 310° C. for an additional 15 minutes until gas evolution ceased. The black mixture was cooled to room temperature. Chromatography yielded 34.5 g of the intermediate title compound as an off-white solid which was 87% pure by HPLC (43% yield).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]1[CH3:18])(=[O:3])[CH3:2].[N+:19]([O-])([O-:21])=[O:20].[Na+]>S(=O)(=O)(O)O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:19]([O-:21])=[O:20])=[CH:10][CH:11]=2)[CH:6]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]1[CH3:18])(=[O:3])[CH3:2]
Reactant: COC(=O)CC1c2ccccc2N(C(C)=O)C1C
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)CC1c2cc([N+](=O)[O-])ccc2N(C(C)=O)C1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 1-acetyl-2-methylindolin-3-ylacetate (6.83 g.) in concentrated sulphuric acid (45 ml.) was cooled to 0° C. and a solution of sodium nitrate (2.67 g.) in concentrated sulphuric acid (20 ml.) was added dropwise during 0.5 hr. The mixture was stirred at 0° C. for a further 0.5 hr. and then poured onto ice (300 ml.). The resulting precipitate was filtered and washed well with water. Crystallisation from methanol gave methyl 1-acetyl-2-methyl-5-nitroindolin-3-ylacetate, m.p. 106° C.
Reaction SMILES: [CH2:1](OC(ON1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:27]([N:29]([CH2:31][C:32]1[NH:33][C:34]2C(C=1)=CC=C[CH:35]=2)C)=O)C1C=CC=CC=1.CNCC1NC2C(C=1)=CC=CC=2.C(N(CC)CC)C>CN(C=O)C>[CH2:34]([N:33]1[C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:1]=[C:32]1[CH2:31][NH:29][CH3:27])[CH3:35]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CN(Cc1cc2ccccc2[nH]1)C(=O)OCc1ccccc1
Agent: CNCc1cc2ccccc2[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1c(CNC)cc2ccccc21
Reaction time: 8 h
Yield: 114.6 %

Procedure:
2-[N-(Benzyloxycarbonyl)-N-methylaminomethyl]-1H-indole N-(Benzyloxycarbonyloxy)succinimide (17.10 g, 68.6 mmole) was added to a solution of 2-(methylaminomethyl)-1H-indole (10.00 g, 62.4 mmole), from Preparation 33, and triethylamine (9.60 mL, 68.6 mmole) in DMF (100 mL) at RT. The reaction was stirred overnight then was concentrated in vacuo. The residue was diluted with water and the mixture was extracted with ethyl acetate. The combined extracts were dried over K2CO3 and concentrated. Flash chromatography on silica gel (20% ethyl acctate/hexanes) gave the title compound (14.80 g, 80%) as an off-white solid: MS (ES) m/e 295 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:59])[C@H:10]([CH2:49][C:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[NH:52][CH:51]=1)[NH:11][C:12](=[O:48])[CH:13]([C:39]1[CH:44]=[CH:43][C:42]2[O:45][CH2:46][O:47][C:41]=2[CH:40]=1)[CH2:14][C:15]1[N:16]=[CH:17][N:18](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.O.O>[CH2:1]([O:8][C:9](=[O:59])[C@H:10]([CH2:49][C:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[NH:52][CH:51]=1)[NH:11][C:12](=[O:48])[CH:13]([C:39]1[CH:44]=[CH:43][C:42]2[O:45][CH2:46][O:47][C:41]=2[CH:40]=1)[CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc2c(c1)OCO2
Solvent: CC(=O)O
Solvent: O
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1)C(Cc1c[nH]cn1)c1ccc2c(c1)OCO2
Temperature: 50 °C
Reaction time: 5 h
Yield: 90.1 %

Procedure:
A mixture of Nα-[3-(1-triphenylmethylimidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophan benzyl ester (290 mg) in 80% acetic acid-water (5 ml) was stirred at 50° C. for 5 hours. The resulting mixture was cooled to ambient temperature and the solution was diluted with water. Carbinol was removed by filtration and the filtrate was neutralized with saturated sodium hydroxide aqueous solution, and then the aqueous layer was extracted with ethyl acetate. Drying, filtering and removal of the solvents afforded Nα-[3-(imidazol-4-yl)-2-(3,4-methylenedioxyphenyl)propionyl]-L-tryptophan benzyl ester (180 mg) as a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I[C:38]1[C:39](=[O:56])[C:40]2[CH:45]=[CH:44][N:43]([CH3:46])[C:42](=[O:47])[C:41]=2[O:48][C:49]=1[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:38]3[C:39](=[O:56])[C:40]4[CH:45]=[CH:44][N:43]([CH3:46])[C:42](=[O:47])[C:41]=4[O:48][C:49]=3[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1ccc2c(=O)c(I)c(-c3ccccc3)oc2c1=O
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: Cn1ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2c1=O
Yield: 41 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-7-methyl-2-phenyl-7H-pyrano[2,3-c]pyridine-4,8-dione was reacted to give the title compound (25.2 mg, 41%) as a colourless gum. LCMS (Method B): RT=4.49 min, [M+Na]+=521.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH:12]=O)[C:3]1=[O:14].[CH2:15]([N:22]1[CH2:26][CH2:25][C:24]([CH3:28])([NH2:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:15]([N:22]1[CH2:26][CH2:25][C:24]([NH:27][CH2:12][C:4]2[C:3](=[O:14])[N:2]([CH3:1])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)([CH3:28])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cn1c(=O)c(C=O)cc2ccccc21
Reactant: CC1(N)CCN(Cc2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cn1c(=O)c(CNC2(C)CCN(Cc3ccccc3)C2)cc2ccccc21
Reaction time: 0.5 h

Procedure:
1-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (956 mg, 5.11 mmol), 1-benzyl-3-methylpyrrolidin-3-amine (972 mg, 5.11 mmol), and acetic acid (0.877 ml, 15.32 mmol) were combined in CH2Cl2 (25 ml) and stirred for 30 min. Sodium triacetoxyborohydride (3248 mg, 15.32 mmol) was added and the reaction stirred for 2.5 hours before being partitioned between CH2Cl2 and satd. bicarb. The aqueous portion was extracted 3×CH2Cl2, and the organic portion dried (Na2SO4) then concentrated in vacuo. The resulting material was carried on crude.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:20])=[C:7]([C:11]([I:19])=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[C:13]=1[I:14])[C:8](Cl)=[O:9])(=[O:3])[CH3:2].Cl.[CH2:22]([O:24][C:25](=[O:32])[C@H:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH2:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:32])[C@H:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH:27][C:8](=[O:9])[C:7]1[C:6]([I:20])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:13]([I:14])=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[C:11]=1[I:19])[CH3:23]
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)Cl)c1I
Agent: Cl
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)c1c(I)c(NC(C)=O)c(I)c(NC(C)=O)c1I

Procedure:
Following the procedure of example 13, 48 g (64%) of this product was synthesized from 63.2 g (0.1 Mol) 3,5-diacetamido-2,4,6-triiodobenzoyl chloride and 29.4 g (0.15 Mol) L-leucine ethyl ester hydrochloride.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH3:14])[CH:8]=1.II>C1(C)C=CC=CC=1>[CH3:14][O:13][C:9]1[N:10]=[CH:11][C:12]2[C:7]([CH:8]=1)=[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]1=[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=21
Reactant: COc1cc(-c2ccccc2-c2ccccc2)ccn1
Agent: II
Solvent: Cc1ccccc1
Product: COc1cc2c3ccccc3c3ccccc3c2cn1
Yield: 17.7 %

Procedure:
4-(biphenyl-2-yl)-2-methoxypyridine (2.9 g, 10.9 mmol), iodine (281 mg, 1.1 mmol) and toluene were charged into a double-walled quartz photochemical reactor equipped with magnetic stirring, an air bubbler and an ultraviolet lamp. Gentle air was bubbled through the solvent while it was irradiated for 15 h. The reaction mixture was purified by flash chromatography on silica (hexane:ethyl acetate) and sonicated in MeOH to give 3-methoxydibenzo[f,h]isoquinoline (0.5 g, 17%).
Reaction SMILES: C([O:5][C:6](=[O:36])[C:7]([CH3:35])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][O:17][C:18]2[N:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)=[CH:20][N:19]=2)[N:14]=1)[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:35][C:7]([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][O:17][C:18]2[N:23]=[CH:22][C:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][C:31]([F:34])([F:32])[F:33])=[CH:28][CH:29]=3)=[CH:20][N:19]=2)[N:14]=1)([CH3:8])[C:6]([OH:36])=[O:5]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ncc(-c3ccc(OC(F)(F)F)cc3)cn2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Sc1nc(CCOc2ncc(-c3ccc(OC(F)(F)F)cc3)cn2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.1 %

Procedure:
2-Methyl-2-({4-[2-({5-[4-(trifluoromethoxy)phenyl]pyrimidin-2-yl}oxy)ethyl]-1,3-thiazol-2-yl}thio)propionic acid tert-butyl ester (600 mg) obtained in Example 110-2 was dissolved in dichloromethane (6 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1 to 0:1) to give the title compound (350 mg) as a white solid.
Reaction SMILES: Br.Br.[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(O)C.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>O>[OH:15][C:12]1[CH:11]=[CH:10][C:9]([N:3]2[CH2:4][CH2:5][N:6]([S:26]([C:23]3[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=3)(=[O:28])=[O:27])[CH2:7][CH2:8]2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2CCN(c3ccc(O)cc3)CC2)cc1
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 15.5 parts of 4-(1-piperazinyl)phenol dihydrobromide, 40 parts of ethanol and 75 parts of water are added 15.2 parts of 4-methylbenzenesulfonyl chloride and stirring is continued for 30 minutes at room temperature. Then there are added portionwise 12.6 parts of sodium hydrogen carbonate at 0° C. Upon completion, stirring is continued overnight at room temperature. The precipitated product is filtered off and taken up in alkaline water. The mixture is filtered over hyflo and the filtrate is acidified with acetic acid. The precipitated product is filtered off and taken up in water. The free base is liberated in the conventional manner with a sodium hydroxide solution. The whole is filtered over hyflo and the filtrate is acidified with acetic acid. The precipitated product is filtered off and dried, yielding 4.8 parts of 1-(4-hydroxyphenyl)-4-(4-methylphenylsulfonyl)piperazine; mp. 193.1° C.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[C:1]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: C1CCNCC1
Product: CCCCCCC/C=C/C(=O)N1CCCCC1

Procedure:
The same procedures as in Example 1 were carried out using (E)-2-decenoic acid and piperidine as starting raw materials, to produce an intended compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[N:14][N:15]=[CH:16][C:17]1[NH:21][C:20]([CH3:22])=[C:19]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=O)=[O:24])[C:18]=1[CH3:34])([O-:3])=[O:2].Cl.C(N=C=NCCCN(C)C)C.O[C:48]1[C:56]2[N:55]=N[NH:53][C:52]=2[CH:51]=[CH:50][CH:49]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[N:14][N:15]=[CH:16][C:17]1[NH:21][C:20]([CH3:22])=[C:19]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([NH:53][C:52]2[CH:51]=[CH:50][CH:49]=[CH:48][C:56]=2[NH2:55])=[O:33])=[O:24])[C:18]=1[CH3:34])([O-:3])=[O:2]
Reactant: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc([N+](=O)[O-])cc32)c(C)c1C(=O)NCCCCCC(=O)O
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc([N+](=O)[O-])cc32)c(C)c1C(=O)NCCCCCC(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
6-(5-(((5-nitro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-hexanoic acid (468 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (402 mg, 72% yield) as a red solid. LC-MS (m/z) 559 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:9]2[S:10][CH:11]=[C:12]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:13]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[F:22][C:23]([F:39])([F:38])[C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](O)=[O:33])[N:25]=1>>[C:18]([C:17]1[CH:16]=[CH:15][C:14]([C:12]2[N:13]=[C:9]([C:3]3([CH2:2][NH:1][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([C:26]5[N:25]=[C:24]([C:23]([F:39])([F:38])[F:22])[O:28][N:27]=5)[CH:30]=4)[CH2:4][CH2:5][O:6][CH2:7][CH2:8]3)[S:10][CH:11]=2)=[CH:21][CH:20]=1)#[N:19]
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: N#Cc1ccc(-c2csc(C3(CN)CCOCC3)n2)cc1
Product: N#Cc1ccc(-c2csc(C3(CNC(=O)c4cccc(-c5noc(C(F)(F)F)n5)c4)CCOCC3)n2)cc1
Yield: 7 %

Procedure:
This compound was synthesized from 4-(2-(4-(aminomethyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)benzonitrile and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (3 mg, 7% yield). 1H NMR (300 MHz, CD3OD) δ 8.40 (d, J=1.8 Hz, 1H), 8.23 (d, J=7.2 Hz, 1H), 8.10-8.07 (m, 2H), 7.94 (m, 1H), 7.81 (m, 1H), 7.69-7.53 (m, 3H)) 3.94 (m, 2H), 3.87 (s, 2H), 3.55 (m, 2H), 2.45 (m, 2H), 2.08 (m, 2H). MS (ESI) m/z: Calculated for C26H20F3N5O3S: 539.12. found: 540.1 (M+H).
Reaction SMILES: [CH2:1](Cl)[O:2][CH3:3].C(N(CC)C(C)C)(C)C.[CH2:14]([O:16][C:17]([C@H:19]1[CH2:23][C@@H:22]([OH:24])[CH2:21][N:20]1[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:18])[CH3:15]>ClCCl>[CH2:14]([O:16][C:17]([C@H:19]1[CH2:23][C@@H:22]([O:24][CH2:1][O:2][CH3:3])[CH2:21][N:20]1[CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)=[O:18])[CH3:15]
Reactant: COCCl
Reactant: CCOC(=O)[C@H]1C[C@@H](O)CN1CCc1ccc(OC)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1C[C@@H](OCOC)CN1CCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.6 %

Procedure:
9.32 ml (123 mmol) of MOMCl was added to a solution of 25 ml (144 mmol) of N,N-diisopropylethylamine and 6.00 g (20.5mmol) of (2R, 4R)-(+)-2-(ethoxycarbonyl)-4-hydroxy-1-(4-methoxyphenethyl) pyrrolidine in dichloromethane (100 ml) and the mixture was stirred for 14 hours at room temperature. The mixture was washed with saturated aqueous sodium carbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography (ethyl acetate:n-hexane=1:1) to give 6.20 g of (2R, 4R)-(+)-2-(ethoxycarbonyl)-4-(methoxymethoxy)-1-(4-methoxyphenethyl)pyrrolidine in 89.8% yield.
Reaction SMILES: CN([CH:4]=[O:5])C.[CH3:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10]>O>[CH3:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([O:5][CH3:4])=[O:10]
Reactant: CN(C)C=O
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Solvent: O
Product: COC(=O)c1cccc([N+](=O)[O-])c1C
Temperature: 40 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
With reference to FIG. 4, DMF (130 mL) was added to a well mixed 2-methyl-3-nitrobenzoic acid 2 (50 g, 0.28 mol) and KHCO3 (84 g, 0.84 mol) solution. Since the mixture became highly viscous, it was heated to 40° C. with manual shaking. lodomethane (79 g, 0.56 mol) was added via syringe after the gas evolution had ceased. The resulting orange colored solution was stirred for 12 hours at room temperature. The reaction mixture was poured into water (800 mL), and the resulting precipitate collected by filtration and dried over P2O5 to give pure methyl 2-methyl-3-nitrobenzoate 3 (56 g, 100%) as a white solid: mp. 64.2-65.5° C.; 1H-NMR (CDCl3) δ 8.00 (d, J=7.8 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H), 3.95 (s, 3H), 2.63 (s, 3H); IR (KBr, cm−1) 1724, 1548, 1279; MS (EI): 195 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:9])([CH3:8])[S:6](=[O:11])(=[O:10])[C@@H:5]2[CH2:12][C@H:13]([CH3:34])[O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:33])[C:23]4[C:28]([CH2:29][O:30]C)=[CH:27][C:26]([Cl:32])=[CH:25][N:24]=4)=[CH:17][C:16]=3[C@@:4]2([CH3:35])[N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:1][C:2]1[C:7]([CH3:9])([CH3:8])[S:6](=[O:10])(=[O:11])[C@@H:5]2[CH2:12][C@H:13]([CH3:34])[O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:33])[C:23]4[C:28]([CH2:29][OH:30])=[CH:27][C:26]([Cl:32])=[CH:25][N:24]=4)=[CH:17][C:16]=3[C@@:4]2([CH3:35])[N:3]=1
Reactant: COCc1cc(Cl)cnc1C(=O)Nc1ccc2c(c1)[C@@]1(C)N=C(N)C(C)(C)S(=O)(=O)[C@@H]1C[C@H](C)O2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@H]1C[C@@H]2[C@](C)(N=C(N)C(C)(C)S2(=O)=O)c2cc(NC(=O)c3ncc(Cl)cc3CO)ccc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 24.6 %

Procedure:
A round bottom flask was charged with N-((4aR,6S,11bR)-2-amino-3,3,6,11b-tetramethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-10-yl)-5-chloro-3-(methoxymethyl)picolinamide (125 mg, 0.240 mmol) and DCM (2.4 ml), and the solution was cooled to 0° C. under nitrogen. BBr3 (47.6 μl, 0.504 mmol) was added dropwise, and the mixture was allowed to warm to RT. After stirring at RT for 1 h, the reaction was quenched with water and neutralized with saturated aqueous sodium bicarbonate. EtOAc was added, and the layers were separated. The aqueous portion was extracted with additional EtOAc, and the combined organic portions were dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography using a gradient of 0-75% 75/25/2 EtOAc/EtOH/NH4OH in heptane to provide N-((4aR,6S,11bR)-2-amino-3,3,6,11b-tetramethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-10-yl)-5-chloro-3-(hydroxymethyl)picolinamide (30 mg, 0.059 mmol, 24.66% yield) as a tan solid. LC/MS (ESI+) m/z=507.0 (M+H).