Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([C:28](O)=[O:29])=[CH:25][CH:26]=3)[C:21]([CH3:31])=[C:20]2[CH3:32])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[C:33]1([CH:39]([NH2:42])[CH2:40][CH3:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:32][C:20]1[N:19]([CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:9]2[CH:8]=[CH:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=2)[C:27]2[C:22]([C:21]=1[CH3:31])=[CH:23][C:24]([C:28](=[O:29])[NH:42][CH:39]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:40][CH3:41])=[CH:25][CH:26]=2
Reactant: CCC(N)c1ccccc1
Reactant: CCOC(=O)c1ccc(-c2ccccc2Cn2c(C)c(C)c3cc(C(=O)O)ccc32)cc1
Product: CCOC(=O)c1ccc(-c2ccccc2Cn2c(C)c(C)c3cc(C(=O)NC(CC)c4ccccc4)ccc32)cc1

Procedure:
The title compound was prepared following the same protocol as described in Step 8, Example 1, using the 1-((4′-(ethoxycarbonyl)-[1,1′-biphenyl]-2-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid and the 1-phenylpropan-1-amine instead of the (S)-1-(4-bromophenyl)ethanamine.
Reaction SMILES: C1(C[O:8][C:9](=[O:59])[CH2:10][N:11]([CH2:48][C:49](=[O:58])[O:50]CC2C=CC=CC=2)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:14]([O: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][CH2:46][CH3:47])[CH:13]=2)C=CC=CC=1.[H][H]>[Pd].C1COCC1.C(OCC)(=O)C>[C:9]([CH2:10][N:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:14]([O: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][CH2:46][CH3:47])[CH:13]=1)[CH2:48][C:49]([OH:58])=[O:50])([OH:59])=[O:8]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCOc1ccc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)cc1OCCCCCCCCCCCCCC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(N(CC(=O)O)CC(=O)O)cc1OCCCCCCCCCCCCCC
Yield: 56 %

Procedure:
A mixture of N-[2-oxo-2-(phenylmethoxy)ethyl]-N-[3,4-bis(tetradecyloxy)phenyl]glycine phenylmethyl ester and 0.5 g of 10% palladium on carbon in 40 ml of THF and 20 ml of ethyl acetate was stirred in a hydrogen atmosphere at room temperature for 2.5 hours when uptake ceased. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to a solid which was triturated with hexane and filtered to give 1.4 g (56% yield, mp 89°-93°) of pure N-(carboxymethyl)-N-[3,4-bis(tetradecyloxy)phenyl]glycine.
Reaction SMILES: [Br:1]Br.[S:3]1[C:11]2[C:6](=[N:7][C:8]([C:16]([O:18][CH3:19])=[O:17])=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[CH:5]=[CH:4]1.C([O-])(=O)C.[Na+].S(=O)(O)[O-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:5]1[C:6]2=[N:7][C:8]([C:16]([O:18][CH3:19])=[O:17])=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=[C:11]2[S:3][CH:4]=1
Reactant: COC(=O)c1cc2sccc2nc1C(=O)OC
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc2scc(Br)c2nc1C(=O)OC
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A solution of bromine (20 g, 0.125 mol) in acetic acid (50 mL) is added dropwise over three hours to a solution of dimethyl thieno[3,2-b]pyridine-5,6-dicarboxylate, (26.3 g, 0.104 mol), containing sodium acetate (17.2 g, 0.2 mol) in acetic acid (300 mL) at 85° C. Additional sodium acetate (18 g) and bromine (20 g) in acetic acid (50 mL) is added over an hour and the mixture stirred at 85° C. overnight. Bromine (10 g) is added in one portion then left at 85° C. for four hours. The mixture is cooled and treated with aqueous sodium bisulfite, diluted with ethyl acetate and concentrated. The reaction product is partitioned between water and methylene chloride and the organic layer washed with aqueous sodium chloride and the solvent removed. The residue is washed with ether to give 25 g of crude product, mp 165°-168° C. Recrystallization from methanol gave needles of dimethyl 3-bromothieno[ 3,2-b]pyridine-5,6-dicarboxylate, mp 168°-169° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[N:6][CH:7]=1.[CH2:12](O)[CH3:13].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:12]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH3:13]
Reactant: CCO
Reactant: O=C(O)Cc1cncc(Br)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cncc(Br)c1

Procedure:
1.00 g (4.63 mmol) (5-bromopyridin-3-yl)acetic acid are initially introduced into 20 ml ethanol, 2 ml conc. sulfuric acid are added and the mixture is stirred under reflux overnight. The reaction solution is introduced on to a mixture of 100 ml saturated sodium bicarbonate solution and 100 ml ethyl acetate, while stirring, and the aqueous phase is extracted with ethyl acetate (three times with 50 ml each time). The combined organic phases are dried over sodium sulfate, filtered and concentrated and the residue is freed from solvent residues overnight in vacuo.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[N:12][OH:13])[CH2:10][CH3:11].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:13][N:12]=[C:9]([C:3]1[C:4]([OH:8])=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])[CH2:10][CH3:11])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(=NO)c1c(O)cccc1O
Product: CCC(=NOC(C)=O)c1c(O)cccc1O
Yield: 30.5 %

Procedure:
1-(2,6-dihydroxyphenyl)-1-propanone oxime (Intermediate 29, 716 mg) was stirred in acetic anhydride (2.24 ml, 23.7 mmol) at room temperature for 1 hour. After removal of the volatiles, the residue was washed with water, filtered and dried. The crude compound was charged on a silica gel column (Biotage SP1 system) and eluted with Cyclohexane/EtOAc (from 100/0 to all 0/100) to afford the title compound (269 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.[N+:12]([CH:15]=[C:16](SC)[S:17][CH3:18])([O-:14])=[O:13]>C(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:10][CH3:11])[C:16]([S:17][CH3:18])=[CH:15][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CCNCc1ccc(Cl)nc1
Solvent: CCO
Product: CCN(Cc1ccc(Cl)nc1)C(=C[N+](=O)[O-])SC
Temperature: 25 °C
Yield: 20.5 %

Procedure:
To a 100 ml three necked round bottom flask was added N-((6-chloropyridin-3-yl)methyl)ethanamine (17.0 g, 0.1 mol), (2-nitroethene-1,1-diyl)bis(methylsulfane) (15.0 g, 0.09 mol), dry ethanol (50 mL). The mixture was refluxed. After completion, the reaction mixture was cooled to r.t. and concentrated under reduced pressure to obtain crude product as oil, which was purified by column chromatography to afford 5.3 g N-((6-chloropyridin-3-yl)methyl)-N-ethyl-1-(methylthio)-2-nitroethenamine in 18.5% yield.
Reaction SMILES: [NH2:1][CH2:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12].[O-:15][C:16]#[N:17].[K+]>O>[N+:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][C:3]1[NH:17][C:16](=[O:15])[NH:1][CH:2]=1)([O-:13])=[O:12]
Reactant: NCC(=O)Cc1ccccc1[N+](=O)[O-]
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Product: O=c1[nH]cc(Cc2ccccc2[N+](=O)[O-])[nH]1
Temperature: 60 °C
Yield: 52.6 %

Procedure:
A solution of 1-amino-3-(2-nitrophenyl)-propan-2-one 3a (138 mg, 0.6; Alazard et al. Tetrahedron 1994, 50, 6287–6298) in water was reacted potassium cyanate (97 mg, 1.2 mmol) and heated in a 60° C. oil bath for 4 h. The reaction was purified by reverse-phase HPLC to give 82 mg (62% yield) of 4-(2-nitrobenzyl)-1,3-dihydroimidazol-2-one 3b. MS found: (M+MeCN)+=261.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][C:4]=1[Cl:14].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:15])[CH3:1])=[C:4]([Cl:14])[CH:5]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CN(C)c1ccc(C2CCCN2)cc1Cl
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: CN(C)c1ccc(C2CCCN2S(=O)(=O)c2ccc(Cl)cc2)cc1Cl

Procedure:
The title compound, white solid, m.p. 103° C. and MS: m/e=398 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-dimethylamino-3-chloro-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[CH2:21][CH3:22])/[C:16]([O:18]CC)=[O:17])[CH:11]=[CH:10][C:9]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:40])[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:31])[CH:24]=1)[CH2:4][CH2:5][CH3:6]>C(O)C.O1CCCC1>[CH2:3]([O:7][C:8]1[CH:13]=[C:12](/[CH:14]=[C:15](\[CH2:21][CH3:22])/[C:16]([OH:18])=[O:17])[CH:11]=[CH:10][C:9]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]([CH3:40])[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:31])[CH:24]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\CC)C(=O)OCC)cc2OCCCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\CC)C(=O)O)cc2OCCCC)c1
Temperature: 50 °C
Yield: 64.1 %

Procedure:
40 mg (1 mmol) of sodium hydroxide are added to a solution of 531 mg (1 mmol) of ethyl 2-[1-[2-butoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]meth-(E)-ylidene]butyrate in 1 mL of ethanol and 10 mL of tetrahydrofuran. The reaction mixture is heated at 50° C. for 48 hours. The reaction medium is evaporated to dryness, taken up in water, acidified with aqueous 2 N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. After filtration, the solvent is evaporated off and the oil obtained is purified by chromatography on a column of silica eluted with a 60/40 heptane/ethyl acetate mixture and then precipitated from heptane. 317 mg (76%) of 2-[1-[2-butoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]meth-(E)-ylidene]butyric acid are obtained in the form of a white powder with a melting point of 62-64° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH:11]([CH2:13][OH:14])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH:11]([CH2:13][O:14][S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:10][O:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1COC(c2ccc(F)cc2)C1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2COC(c3ccc(F)cc3)C2)cc1
Temperature: 4 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
2-(4-Fluorophenyl)-4-(hydroxymethyl)tetrahydrofuran (21 g) is dissolved in 170 ml of pyridine whereupon 24.4 g of tosyl chloride is added below 4° C., and the resulting mixture is stirred at 4° C. for 1 hour and then at room temperature for 4 hours. The pyridine is then distilled off at room temperature under reduced pressure. Water is added to the residue and extracted with ethyl acetate. The extract is washed twice with dilute hydrochloric acid and once with water and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. To the residue are added n-hexane and isopropyl ether to give 32.7 g of 2-(4-fluorophenyl)-4-(tosyloxymethyl)tetrahydrofuran. This tosyl compound is recrystallized repeatedly from isopropanol to give cis-2-(4-fluorophenyl)-4-tosyloxymethyl)tetrahydrofuran as colorless needles, melting at 75°-76.5° C., and recrystallized from ethanol to give the trans-isomer as colorless needles, melting at 55°-57° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:32]([O:33][CH3:34])=[CH:31][C:12]2[C:13](=[O:30])[N:14]3[CH2:29][CH2:28][CH2:27][C@H:15]3[C@H:16](O)[N:17](C(OCC(Cl)(Cl)Cl)=O)[C:11]=2[C:10]=1[O:35][CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[C:32]([O:33][CH3:34])=[CH:31][C:12]2[C:13](=[O:30])[N:14]3[CH2:29][CH2:28][CH2:27][CH:15]3[CH:16]=[N:17][C:11]=2[C:10]=1[O:35][CH3:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(c(OC)c1OCc1ccccc1)N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](O)[C@@H]1CCCN1C2=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2c(c(OC)c1OCc1ccccc1)N=CC1CCCN1C2=O
Reaction time: 3.5 h
Yield: 68.4 %

Procedure:
10% Cd/Pb couple (1.2 g; 10 mmol Cd) was added to a rapidly stirring solution of 142 (1.08 g; 1.9 mmol) in a mixture of THF (15 mL) and 1N NH4OAc (15 mL). After 3.5 h, TLC revealed that reaction was still incomplete and more 10% Cd/Pb couple (500 mg) was added. After a further 1 hour the reaction mixture was diluted with EtOAc (150 mL). The solution was dried over anhydrous MgSO4 and the solids were filtered and rinsed with EtOAc (50 mL). Removal of excess solvent yielded the product as a yellow glass (0.48 g, 1.3 mmol, 68%). H1NMR (270 MHz, CDCl3) δ 7.73 (d, 1H, J=4.4 Hz), 7.36 (s, 2H), 7.31 (s, 2H), 7.11 (s, 1H), 7.08 (s, 1H), 5.12 (br s, 2H), 3.98-3.42 (m, 9H), 2.38-2.29 (m, 2H), 2.23-1.83 (m, 2H).
Reaction SMILES: OS(O)(=O)=O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1.[CH3:17][C:18](=[CH2:20])[CH3:19].C([O-])(O)=O.[Na+]>O1CCOCC1>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]([O:16][C:18]([CH3:20])([CH3:19])[CH3:17])=[O:15])=[CH:11][CH:12]=1
Reactant: C=C(C)C
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Cc1ccc(O)cc1
Reaction time: 24 h

Procedure:
A solution of H2SO4 (5 ml) in dioxane (80 ml) was added to 4-hydroxyphenylacetic acid (20 gm, 0.13 mol) in a pressure bottle. Isobutylene (250 ml) was added and the bottle was sealed and the mixture was stirred for 24 hr. The reaction mixture was poured into saturated NaHCO3 solution and extracted with EtOAc. The combined organic extracts were washed successively with saturated NaHCO3, H2O (twice) and brine before being dried over Na2SO4 and evaporated to dryness. Crystals formed after standing overnight and they were filtered, washed with cold hexane and dried to give 20.99 gm of the title compound. M.pt. 95°-96° C.
Reaction SMILES: [OH:1][C@@H:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1O>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[O:1][C@H:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: Cc1ccc(Cl)c(O)c1
Reactant: CC[C@H](O)C(=O)OC
Product: CC[C@@H](Oc1cc(C)ccc1Cl)C(=O)OC

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 42, using the (S)-methyl 2-hydroxybutanoate instead of the (S)-methyl 2-hydroxypropanoate and the 2-chloro-5-methylphenol instead of the m-cresol.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]([CH3:4])[CH3:3].[F:7][C:8]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].[Cl-].[NH4+].Cl>C1COCC1.CCOCC>[F:7][C:8]1[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:9]=1[CH:10]([OH:11])[CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C[Mg]Br
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)CC(O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 23 %

Procedure:
To mixed solution of 2M isobutylmagnesium bromide in THF (6.25 mL) and ether (50 mL), was added dropwise a solution of 2-fluoro-4-(trifluoromethyl)benzaldehyde (2.0 g, 10 mmol) in ether (18 mL) under N2 atmosphere. The mixture was stirred at room temperature for 45 minutes, to which was added saturated aqueous ammonium chloride solution and 1M hydrochloric acid under ice-cooling. The aqueous layer was extracted with ether. The organic layer was washed with saturated aqueous sodium bicarbonate solution, saturated brine successively. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1), to give the titled compound as a yellow oil (601 mg, yield 23%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2O[C:12](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)=[N:13][N:14]=2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:35]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[NH:35][C:12](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)=[N:13][N:14]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(/C=C/c2nnc(CCc3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1cc(/C=C/c2nnc(CCc3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 24.3 %

Procedure:
A solution of 2-[2-(4-fluorophenyl)ethyl]-5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazole (33 mg) and ammonium acetate (126 mg) in acetic acid (1 mL) was stirred at 150° C. for 10 hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate→ethyl acetate:methanol=5:1) to obtain 8 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N[C@@H]2CCc3cccc(N4CCN(C)CC4)c3C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (130 mg, 0.53 mmol) and triethylamine (110 μL, 0.80 mmol) in methylene chloride (30 mL) was added dropwise 4-methoxybenzoyl chloride (95 mg, 0.56 mmol) in methylene chloride (5 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and then washed with water. The phases were separated and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 143 mg (71%) of the title compound as white crystals: mp 186-187° C.; [α]21D −52° (c 0.50, CHCL3); EIMS (70 eV) m/z (relative intensity) 379 (23, M+).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[NH:32][CH:33]([CH3:35])[CH3:34])=[O:26])[CH3:23].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:22]([O:24][C:25]([CH:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[N:32]([CH:33]([CH3:34])[CH3:35])[C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)=[O:26])[CH3:23]
Reactant: CCOC(=O)C1CCCC1NC(C)C
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)C1CCCC1N(C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1)C(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.1665 g, 0.5 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL). 2-Isopropylamino-cyclopentanecarboxylic acid ethyl ester (0.0996 g, 0.5 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.1003 g, 0.525 mmol). Then N-methylmorpholine (115 μL, 1.05 mmol) was added. The mixture was stirred at 25° C. for 5 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product, 2-{isopropyl-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid ethyl ester, as a yellow oil. LC-MS (ESI) calcd for C21H30N4O7S2 514.16, found 515.3 [M+H+].
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16].Cl[CH2:20][CH2:21][F:22]>CO>[F:22][CH2:21][CH2:20][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16]
Reactant: FCCCl
Reactant: NS(=O)(=O)c1ccccc1S
Solvent: CO
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccccc1SCCF
Reaction time: 23 h
Yield: 74.5 %

Procedure:
A mixture of 5.8 g of the 2-mercaptophenylsulfonamide triethylamine salt obtained in accordance with Example H6 and 1.7 g of 2-chloro-1-fluoroethane in 40 ml of methanol is stirred in a bomb tube for 23 hours at a temperature of +50° to +55° C. The reaction mixture is then evaporated and water is added to the residue which remains. The mixture is extracted with ethyl acetate, and the organic phase is washed and dried. Evaporation of the solution gives 3.5 g of 2-(2-fluoroethylthio)-phenylsulfonamide (74.5% of theory) having a melting point of +83° to +85° C.
Reaction SMILES: I[C:2]1[N:3]=[C:4]2[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:7][CH2:6][N:5]2[C:20]=1[CH3:21].C([Mg]Br)C.[C:26]([OH:29])(=[O:28])C>C1COCC1>[CH2:13]([O:12][C:10]([N:8]1[CH2:7][CH2:6][N:5]2[C:20]([CH3:21])=[C:2]([C:26]([OH:29])=[O:28])[N:3]=[C:4]2[CH2:9]1)=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1c(I)nc2n1CCN(C(=O)OCc1ccccc1)C2
Reactant: CC(=O)O
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)nc2n1CCN(C(=O)OCc1ccccc1)C2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52.3 %

Procedure:
A solution of benzyl 2-iodo-3-methyl-5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-carboxylate (900mg, 2.266 mmol) in dry THF (25 ml) was cooled to 0 ° C. and ethyl magnesiumbromide (1.888 ml, 5.66 mmol) was added at such a rate as to maintain the reaction temperature below 2.5° C. The reaction was stirred under Nitrogen at 0 ° C. for 15 minutes, then the reaction was quenched with a stream of carbon dioxide. The reaction was concentrated to solids and acetic acid (0.60 ml, 10.48 mmol) ethyl acetate (50 ml) were added and the suspension was stirred vigorously at room temperature for 15 minutes. The resulting solid was filtered and washed with an additional 15 ml ethyl acetate. The residue was dissolved in 10 ml water plus 2N HCl to pH 4, then washed 2 times 10 ml ether then extract with 4×20 ml CH2Cl2. Dry the combined organic extracts over sodium sulfate, filtered and dried under reduced pressure to yield 3-Methy-5,6-dihydro -8H-imidazo[1,2-a] pyrazine-2,7-dicarboxylic acid 7-benzyl ester (374 mg, 52%) as a foam. LCMS (Table 1, Method a) Rt=2.28 min, m/z 316.10 (M+H)+; 1H NMR (400 MHz, DMSO-d6)δ 7.35 (m, 5H), 5.11 (s, 2H), 4.56 (s,broad, 2H), 3.88 (m, 2H), 3.83 (s, broad, 2H), 2.36 (s, 3H).