Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[F:8][C:9]([F:21])([F:20])[O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[S:19])=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:3]1[CH2:4][C:5](=[O:7])[N:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][C:9]([F:8])([F:20])[F:21])=[CH:12][CH:13]=2)[C:18]1=[S:19])[CH3:2]
Reactant: CCNCC(=O)O
Reactant: FC(F)(F)Oc1ccc(N=C=S)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CC(=O)N(c2ccc(OC(F)(F)F)cc2)C1=S
Yield: 30.4 %

Procedure:
The title compound was prepared by the procedure described in Example 19 using 9.2 g of N-ethyl glycine, 10.9 g of 4-trifluoromethoxyphenyl-isothiocyanate, 10.1 g of triethylamine, and 150 mL of methylene chloride. Purification was achieved by flash chromatography on silica gel (methylene chloride). Title compound (4.6 g) was obtained as a creamy solid, m.p. 116°-119° C. Anal. Calcd. for. C12H11F3N2O2S: C, 47.37; H, 3.64; N, 9.21. Found: C, 47.20; H, 3.50; N, 9.13. Mass spectrum (EI, M.+) m/z 304.
Reaction SMILES: [CH:1]1([N:4]2[C:8](=[O:9])[N:7]([CH2:10][C:11]3[C:12]([Cl:21])=[C:13]([CH:17]=[CH:18][C:19]=3[Cl:20])[C:14](Cl)=[O:15])[N:6]=[N:5]2)[CH2:3][CH2:2]1.[CH2:22]([N:24]1[C:28]([OH:29])=[CH:27][CH:26]=[N:25]1)[CH3:23].C(N(CC)CC)C>ClCCCl>[CH:1]1([N:4]2[C:8](=[O:9])[N:7]([CH2:10][C:11]3[C:12]([Cl:21])=[C:13]([CH:17]=[CH:18][C:19]=3[Cl:20])[C:14]([C:27]3[CH:26]=[N:25][N:24]([CH2:22][CH3:23])[C:28]=3[OH:29])=[O:15])[N:6]=[N:5]2)[CH2:3][CH2:2]1
Reactant: CCn1nccc1O
Reactant: O=C(Cl)c1ccc(Cl)c(Cn2nnn(C3CC3)c2=O)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCn1ncc(C(=O)c2ccc(Cl)c(Cn3nnn(C4CC4)c3=O)c2Cl)c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.6 %

Procedure:
A 1,2-dichloroethane solution of 3-[(4-cyclopropyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)methyl]-2,4-dichloroberizoyl chloride (0.70 g) was added drop by drop to the solution of 1-ethyl-5-hydroxypyrazole (0.24 g) and triethylamine (0.24 g) in 1,2-dichloroethane (4 ml) at 5° C. and the mixture was stirred at room temperature for 6 hours. After reaction it was extracted with dicbloromethane (100 ml), washed with diluted hydrochloric acid and aqueous solution of sodium hydrogen carbonate and then dried with anhydrous magnesium sulfate. The residue, obtained by distilling off the solvent, was dissolved in 1,4-dioxane (8 ml), added with potassium carbonate (0.38 g) and refluxed by heating for 3 hours. After the solvent was distilled off, the residue was teated with an aqueous solution of potassium carbonate and washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate (150 ml). The organic layer was washed with saturated salt water and dried with anhydrous magnesium sulfate. By distilling off the ethyl acetate, the objective 4-{3-[(4-cyclopropyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)methyl]-2,4-dichlorobenzoyl}-5-hydroxy-1-ethylpyrazole (0.73 g, 88% yield from 3-[(4-cyclopropyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)methyl]-2,4-dichlorobenzoic acid) was obtained. nD20: 1.5510.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([OH:16])=O)[NH:9]2.Cl.Cl.Cl.[N:22]1([CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([CH2:29][CH2:30][N:31]2[CH2:32][CH2:33][CH:34]([NH:37][C:14]([C:8]3[NH:9][C:10]4[C:6]([CH:7]=3)=[C:5]([O:4][CH2:3][C:2]([CH3:1])([CH3:18])[CH3:17])[CH:13]=[CH:12][CH:11]=4)=[O:16])[CH2:35][CH2:36]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)COc1cccc2[nH]c(C(=O)O)cc12
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Agent: Cl
Product: CC(C)(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-(2,2-Dimethyl-propoxy)-1H-indole-2-carboxylic acid 85 (preparation see below) and amine 5.
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[NH:3]1.C([Li])CCC.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][C:28](O)=[O:29].[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH3:1][C@@H:2]1[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:28](=[O:29])[CH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[O:20][CH3:19]
Reactant: C[C@H]1NC(=O)O[C@@H]1c1ccccc1
Reactant: COc1ccccc1CC(=O)O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccccc1CC(=O)N1C(=O)O[C@H](c2ccccc2)[C@H]1C
Reaction time: 0.5 h

Procedure:
To a solution of 27.4 g of (4R,5R)-4-methyl-5-phenyl-2-oxazolidinone in 200 cm3 of dry tetrahydrofuran are added, at -78° C., 100 cm3 of a 1.6M butyllithium solution in hexane, followed by addition of 33.12 g of a solution of 2-methoxyphenylacetic acid in 30 cm3 of tetrahydrofuran. The mixture is stirred for 30 minutes at this temperature and then allowed to return to room temperature. 200 cm3 of saturated aqueous ammonium chloride solution are subsequently poured in, followed by 200 cm3 of ethyl acetate. The organic phase is washed three times with 300 cm3 of water, and then with 300 cm3 of saturated aqueous sodium chloride solution, and dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 100 cm3 of diethyl ether. 35.5 g of (4R,5R)-4-methyl-5-phenyl-3-[(2-methoxyphenyl)acetyl]-2-oxazolidinone are obtained, in the form of white crystals melting at 126° C.
Reaction SMILES: C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[NH:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:19]([C:21]([OH:23])=O)[CH3:20].CCN(C(C)C)C(C)C.Cl.[NH2:41][C@H:42]([C:48]([NH:50][C@H:51]([C:61]([NH:63][CH2:64][C:65]([NH:67][C@H:68]([C:73]([NH:75][CH2:76][C:77]([O:79][CH3:80])=[O:78])=[O:74])[CH2:69][CH:70]([CH3:72])[CH3:71])=[O:66])=[O:62])[CH2:52][O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:49])[CH2:43][CH2:44][C:45](=[O:47])[NH2:46]>>[NH:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:19]([C:21]([NH:41][C@H:42]([C:48]([NH:50][C@H:51]([C:61]([NH:63][CH2:64][C:65]([NH:67][C@H:68]([C:73]([NH:75][CH2:76][C:77]([O:79][CH3:80])=[O:78])=[O:74])[CH2:69][CH:70]([CH3:71])[CH3:72])=[O:66])=[O:62])[CH2:52][O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:49])[CH2:43][CH2:44][C:45](=[O:47])[NH2:46])=[O:23])[CH3:20]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](COCc1ccccc1)NC(=O)[C@@H](N)CCC(N)=O
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.1 %

Procedure:
The title compound of this example: DPPA (12.38 g, 45 mmol) was added to a cooled solution (0° C.) of Boc-Ala-OH (3.2 g, 45 mmol) and DIEA (7.8 mL, 45 mmol). The mixture was stirred at 0° C. for 15 min. The pentapeptide from paragraph (d), HCl.H-Gln-Ser(Bzl)-Gly-Leu-Gly-OCH3 (9.0 g, 15 mmol), was added to the mixture. The mixture was stirred for 18 h while the temperature of the mixture gradually came to room temperature. The mixture was concentrated to dryness. The resultant solid was triturated with EtOAc, collected on a filter, and washed with Et2O and then with hexane. The collected solid was suspended in Et2O and the suspension stirred vigorously for 1 h. The solid was collected on a filter and dried to give Boc-Ala-Gln-Ser(Bzl)-Gly-Leu-Gly-OCH3 (10.94 g). The latter compound (6.0 g, 8.15 mmol) was suspended in dioxane (150 mL) and H2 0 (200 mL). The suspension was stirred and cooled to 0° C. A solution of NaOH (425 mg, 10.6 mmol) was added dropwise to the cooled suspension. The mixture was stirred at room temperature until it became clear (2 h). The mixture was rendered acidic (pH=4) by the addition of acetic acid and then concentrated under reduced pressure (after addition of isopropanol to prevent foaming). The residue was dissolved in the minimum amount of butanol/H2O/acetic acid (4:5:1). The solution was passed through a column of Sephadex (tradename for a brand of cross linked chains of organic compounds derived from dextran). The pure fractions were combined to give the desired hexapeptide i.e. the title compound of this example, as the HCl addition salt (4.90 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([F:32])[CH:31]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:10]=[CH:9][C:8]=1C(O)=O.Cl.C(N=C=NCCCN(C)C)C.O.O[N:47]1[C:51]2[CH:52]=CC=CC=2N=N1.C(N)C.C1C[O:62][CH2:61][CH2:60]1>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([F:32])[CH:31]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[CH:16][CH:15]=2)[N:10]=[CH:9][C:8]=1[CH2:60][C:61]([NH:47][CH2:51][CH3:52])=[O:62]
Reactant: C1CCOC1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cnc(Nc2ccc(N3CCOCC3)cc2)cc1NCc1cc(F)cc(F)c1
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: CCNC(=O)Cc1cnc(Nc2ccc(N3CCOCC3)cc2)cc1NCc1cc(F)cc(F)c1
Reaction time: 2 h
Yield: 13 %

Procedure:
100 mg of 4-[(3,5-difluorobenzyl)amino]-6-[(4-morpholinophenyl)amino]pyridine-3-carboxylic acid was dissolved in 15 mL of dimethyl sulfoxide, to which 65.3 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 52.2 mg of 1-hydroxybenzotriazole monohydrate were added at room temperature, and stirred at the same temperature for 2 hours. After the reaction was over, 2 mL of 2 mol/L ethylamine-THF solution was added, stirred overnight at room temperature. Then water was added, extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=10:1) to obtain 13.9 mg (13%) of the title compound as a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14](B2OC(C)(C)C(C)(C)O2)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].Br[C:25]1[N:29]([CH3:30])[CH:28]=[N:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:14]([C:25]2[N:29]([CH3:30])[CH:28]=[N:27][CH:26]=2)=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2ccccc2cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cn1cncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc2ccccc2cc1-c1cncn1C
Temperature: 25 °C
Yield: 72.4 %

Procedure:
To a mixture of methyl-3-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthoate (Preparation 13) (15.37 g, 49.3 mmol) and 5-bromo-1-methyl-1H-imidazole (9.06 g, 49.3 mmol) in toluene/EtOH (350 mL/36 mL) were added Pd(PPh3)4 (11.37 g, 9.84 mmol), Na2CO3 (20.9 g, 197.2 mmol) and water (106 mL). The mixture was degassed, purged with N2, and heated to reflux for 20 hours. It was then cooled to RT, neutralized with HCl (1.0 N, 100 mL), and concentrated in vacuo. The residue was partitioned between water (300 mL) and EtOAc (1 L). The organic layer was washed with water (2 L) and brine, dried over MgSO4, filtered and evaporated in vacuo. The resulting crude material was submitted to flash chromatography (1.5% MeOH/CHCl3), furnishing the title compound as a light-yellow solid (9.5 g, 72%). 1H NMR (CDCl3): 8.53 (s, 1H), 7.99 (d, J=8.1, 1H), 7.80 (d, J=8.1, 1H), 7.77 (s, 1H), 7.56 (m, 1H), 7.54 (m, 1H), 7.54 (s, 1H), 6.94 (s, 1H), 3.73 (s, 3H), 3.29 (s, 3H). (ESI) m/z (M+H)+=267.11.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.Cl[C:13]1[NH:22][C:21](=[O:23])[C:20]2[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=2)[N:14]=1>COC(O)C>[NH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][N:2]([C:13]1[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=3)[N:14]=1)[CH2:1]2
Reactant: Nc1cccc2c1CCNC2
Reactant: COc1cc2nc(Cl)[nH]c(=O)c2cc1OC
Agent: COC(C)O
Product: COc1cc2nc(N3CCc4c(N)cccc4C3)[nH]c(=O)c2cc1OC
Temperature: 60 °C
Reaction time: 48 h
Yield: 49.7 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-isoquinolin-5-ylamine 24a (3.83 g, 25.84 mmol) and 2-chloro-6,7-dimethoxy-3H-quinazolin-4-one 1b (5.9 g, 24.54 mmol) in methoxyethanol (60 mL) was heated to 60° C. with stirring for 48 h. The volatiles were evaporated and the residue was purified by flash column chromatography eluting with 3% methanol in dichloromethane containing 0.3% of ammonium hydroxide to yield 4.3 g of 2-(5-amino-3,4-dihydro-1H-isoquinolin-2-yl)-6,7-dimethoxy-3H-quinazolin-4-one 110.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([N:20]=[C:21]=[O:22])[CH:17]=[CH:18][CH:19]=1>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=1)=[O:22]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: COc1cccc(N=C=O)c1
Product: COc1cccc(NC(=O)Nc2ccc([N+](=O)[O-])cc2O)c1
Yield: 46.2 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 3-methoxy phenyl isocyanate(1.0 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (140 mg, 46%). EI-MS m/z 302(M-H)-
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24].O>C1COCC1>[CH3:1][O:2][C:3](=[O:4])[CH:5]=[CH:19][C:18]1[CH:21]=[CH:22][C:15]([Cl:14])=[C:16]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C=Cc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Trimethyl phosphonoacetate (245 mg, 1.35 mmol) in THF (2.5 mL) was added dropwise (caution—vigorous reaction!) to sodium hydride (60% in oil) (83 mg, 2.02 mmol) under an atmosphere of nitrogen at 0° C. The reaction mixture was stirred for 15 minutes at 0° C. and then 4-chloro-3-nitrobenzaldehyde (46) (250 mg, 1.35 mmol) in THF was added dropwise. After 2 hours, water was added and the solvent concentrated in vacuo. The solid was filtered and dried to provide the crude title compound. Yield: 190 mg
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[C:14]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:15][C:16]3[C:21]([N:22]=1)=[CH:20][C:19]([C:23]([O:25]C)=[O:24])=[CH:18][CH:17]=3)[CH2:8][CH2:7][CH2:6]2)#[N:2].[OH:34]O.[OH-].[Na+]>CS(C)=O.CCO>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[C:14]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:15][C:16]3[C:21]([N:22]=1)=[CH:20][C:19]([C:23]([OH:25])=[O:24])=[CH:18][CH:17]=3)[CH2:8][CH2:7][CH2:6]2)(=[O:34])[NH2:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(C#N)ccc43)nc2c1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: NC(=O)c1ccc2c(c1)CCCN2c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of methyl 3-(6-cyano-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (150 mg, 0.34 mmol) in DMSO (1.6 mL) and EtOH (6.4 mL) was added H2O2 (1.2 mL, 40%), NaOH (0.4 mL, 1M) with stirring overnight at room temperature. The resulting mixture was concentrated under vacuum, diluted with water (15 mL), adjusted pH to 7 with AcOH. The solids were collected by filtration to give 3-(6-carbamoyl-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a solid (131 mg, 87%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH2:7][CH2:6][N:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4]1.[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.C1(S(OCC2C(C3SC=CC=3)CCN(C)C2)(=O)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[C:19]1([S:25]([O:1][CH2:2][CH:3]2[CH:8]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)[CH2:7][CH2:6][N:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:4]2)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCCCN1CCC(c2cccs2)C(CO)C1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN1CCC(c2cccs2)C(COS(=O)(=O)c2ccccc2)C1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCN1CCC(c2cccs2)C(COS(=O)(=O)c2ccccc2)C1

Procedure:
3-benzenesulphonyloxymethyl-1-pentyl-4-(2-thienyl)-piperidine (14) was prepared from 3-hydroxymethyl-1-pentyl-4-(2-thienyl)piperidine (13 g), benzenesulphonyl chloride (13 ml) and triethylamine (12.5 ml) in dry toluene (100 ml) as described for (2). Yield: 20.4 g, mass spectrum (M+ 407) in accordance with proposed structure
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:18]([O:22][C:23](=[O:26])[CH2:24]Br)([CH3:21])([CH3:20])[CH3:19]>CC#N.C(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH2:10][OH:11])[CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCNCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 66 h
Yield: 90.1 %

Procedure:
To a solution of Compound 2 (1.86 g, 12.3 mmol) and potassium carbonate (1.70 g, 12.3 mmol) in CH3CN anhydrous (50 mL) at 0° C. was dropwise added t-Butyl-bromoacetate (2.41 g, 12.4 mmol) over 45 minute. The reaction mixture was gradually warmed to room temperature and stirred for 66 h. The resulting reaction mixture was filtered, and the filtrate was concentrated to give a white oily compound. The residue was then dissolved in CH2Cl2 (50 mL), and the resulting solution was filtered, and the filtrate was concentrated to afford white Compound 4 (2.94 g, 90%), 1H NMR (CDCl3) δ 1.45 (s, 9H), 2.86 (t, 2H), 3.23 (s, 2H), 3.54 to 3.62 (m, 2H), 3.82 (s, 2H), 7.23 to 7.34 (m, 5H); 13C NMR (CDCl3) δ 28.00, 55.27, 26.52, 58.47, 58.84, 81.29, 127.28, 128.36, 128.81, 138.27, 171.02. HRMS (Positive ion FAB) Calcd for C15H24NO3 [M+H]+ m/z 266.3605. Found: [M+H]+ m/z 266.1756.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O>[C:9]12([NH:8][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[NH:7]1)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2
Reactant: Nc1ccccc1N
Reactant: O=C1CCCCC1
Solvent: O
Product: c1ccc2c(c1)NC1(CCCCC1)N2
Yield: 59.5 %

Procedure:
In a procedure similar to that described by H. Suschitszky in Croatica Chemica Acta, 59, 57-77 (1986), o-phenylenediamine (108 g, 1.0 mol) was dissolved in 1 liter hot water on a steam bath. With vigorous stirring and heating, cyclohexanone (98 g, 1.0 mol) was added in a rapid stream. After 5 minutes a brown gum formed; after 15 minutes a solid resulted. Stirring was continued for a total of 35 minutes. The slurry was cooled in an ice bath and then filtered to yield 112 g (59.5%) 1,3-dihydrobenzimidazole-2-spirocyclohexane. To a stirred solution of this compound (50 g, 0.266 mol) in 1 liter dichloromethane chloride was added, in several portions, 100 g MnO2. The resulting slurry was stirred vigorously for 30 minutes and filtered. The solids were washed with dichloromethane and the filtrate evaporated to obtain an oil. The oil was dissolved in 200 ml, ligroin, and the solution cooled to -10° C. The resulting solid was filtered to yield 46 g (93%) 2H-benzimidazole-2-spirocyclohexane. A solution of 2-chloroethyl methyl sulfide (19.8 g, 0.20 mol) and thiourea (15.2 g, 0.20 mol) in 50 ml absolute alcohol was refluxed for 6 hours. To this was added a solution of KOH (22.4 g, 0.40 mol) in 100 ml methanol, and the resulting slurry refluxed for 45 minutes. After cooling to 30°, 37.2 g (0.20 mol) of freshly prepared 2H-benzimidazole-2-spirocyclohexane was added in portions. The mixture was stirred at room temperature for 10 minutes and then at reflux for 2 minutes. After cooling, the mixture was evaporated to a thick slurry; 100 ml dichloromethane was added and the mixture evaporated. This was repeated and the residue treated with 100 ml water and 200 ml dichloromethane. The organic layer was separated, washed with water, dried over MgSO4, filtered and evaporated. The residue was chromatographed through silica gel using an increasingly polar mixture of dichloromethane and acetonitrile. Product fractions were combined and evaporated to give 7.0 g 5'-(2-methylthioethylthio)-1',2'-phenylenediamine. A stirred solution of the phenylenediamine (5.0 g, 0.027 mol) in 50 ml acetic acid was treated with sodium nitrite (2.6 g, 0.037 mol), in 5 ml water, over 30 seconds at room temperature. The mixture was stirred for 15 minutes and then evaporated. The residue was treated with 50 ml water and 50 ml dichloromethane. The organic layer was dried over MgSO4, filtered, and evaporated. Solid was chromatographed through silica gel using an increasingly polar mixture of dichloromethane chloride and acetone. The isolated product was recrystallized from ethyl acetate to yield 3.2 g (62%) 6'-(2-methyl-thioethylthio)benzotriazole, I-139.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([O:14]CC)=[O:13])=[CH:8][NH:9]2)=[CH:4][C:3]=1[O:18][CH3:19].[OH-].[Na+].C(O)C.O>C(O)(=O)C>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([OH:14])=[O:13])=[CH:8][NH:9]2)=[CH:4][C:3]=1[O:18][CH3:19]
Reactant: CCOC(=O)c1c[nH]c2cc(F)c(OC)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc2c(=O)c(C(=O)O)c[nH]c2cc1F
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A mixture of ethyl 7-fluoro-6-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate (2.2 g, 8.30 mmol) and 13.2 mL of 1 N sodium hydroxide and 40 mL of ethanol is heated at reflux for 3 hours then cooled to room temperature. Water is added and the mixture is acidified with acetic acid. The resultant solid is collected by filtration washing with water to provide 1.90 g of 7-fluoro-6-methoxy-4-oxo-1,4,-dihydro-3-quinolinecarboxylic acid as a white solid, mp 265-267° C.
Reaction SMILES: [CH3:1][Si:2]([CH:5]=[N+]=[N-])([CH3:4])[CH3:3].C(OCC)C.[O:13]1[CH2:18][CH2:17][CH2:16][O:15][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[CH:33]=[C:32]([C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH2:35])[CH:31]=[CH:30][C:28]=3[N:29]=2)=[C:21]([F:42])[CH:20]=1>O1CCOCC1>[O:15]1[CH2:16][CH2:17][CH2:18][O:13][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[CH:33]=[C:32]([C:34]4([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[CH2:35][CH:5]4[Si:2]([CH3:1])([CH3:3])[CH3:4])[CH:31]=[CH:30][C:28]=3[N:29]=2)=[C:21]([F:42])[CH:20]=1
Reactant: C=C(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: C[Si](C)(C)C1CC1(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2c1
Temperature: 150 °C

Procedure:
In a reactor bottle (trimethylsilyl)diazomethane, 2.0 M in diethyl ether (2.4 mL, 4.8 mmol) was added to a mixture of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-(1-phenylvinyl)-benzo[d]thiazole (0.650 g, 1.6 mmol), in anhydrous dioxane 15.00 mL. The reaction mixture was heated to 150° C. for 18 h. At which time the crude reaction mixture was concentrate in vacuo and purified by silica gel chromatography to afford as a mixture of isomers 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-(1-phenyl-2 (trimethylsilyl)cyclopropyl)benzo[d]thiazole. MS (ESI) m/z: Calculated: 503.2; Observed: 504.0 (M++1).