Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22](Cl)=[O:23]>ClCCl>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:16][C:22]([C:18]1[S:17][CH:21]=[CH:20][CH:19]=1)=[O:23]
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Reactant: O=C(Cl)c1cccs1
Solvent: ClCCl
Product: O=C(Nc1ccc2oc3c(c2c1)CCCCCC3)c1cccs1
Yield: 43 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.15 g, 0.70 mmol), 2-thiophenecarbonyl chloride (0.082 mL, 0.77 mmol), and poly(vinylpyridine) (0.5 g) in dichloromethane (17 mL) provided N-(6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl)thiophene-2-carboxamide (0.098 g). MS (ESI) m/z 326 ([M+H]+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH:15]=[N:14][N:13]=[N:12]1.C(N(CC)CC)C.O>CN(C=O)C>[N+:8]([C:5]1[CH:4]=[N:3][C:2]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[N:7][CH:6]=1)([O-:10])=[O:9]
Reactant: c1nnn[nH]1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cnc(-n2cnnn2)nc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2-chloro-5-nitropyrimidine (1.6 g, 10 mmol), 1H-tetrazole (24.44 mL, 11 mmol, 0.45M in MeCN) were added in DMF (20 mL), cooled to 0° C., then triethylamine (1.67 mL, 12 mmol) was added drop-wise. After 15 minutes, water (100 mL) was added, extracted with ethyl acetate (100 mL×1, 50 mL×6). The organic phase were combined and dried by magnesium sulfate, filtered, concentrated and purified by column chromatography through a 100 gram Biotage SNAP KP-Sil™silica gel cartridge eluting with 30% ethyl acetate/hexanes to give the title compound as a pale yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2ccccc2[N+](=O)[O-])c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1-c1cccc(O)c1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
2-(3-Methoxyphenyl)nitrobenzene, as described above in Step A, (8.6 g, 37.52 mmol) was dissolved in CH2Cl2 (500 mL) and cooled to −78° C. BBr3 (1.0M sol. in CH2Cl2, 43 mL, 43 mmol) was slowly added and the reaction was warmed to ambient temperature and stirred for 18 hours. The reaction was partitioned between saturated aqueous NaHCO3 and CH2Cl2 and extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo, to yield the above-titled compound.
Reaction SMILES: [C:1]1([N:7]2[N:14]([C:15]3C=C[CH:18]=[CH:17][CH:16]=3)[C:13](=[O:21])[CH2:12][S:11][S:10][CH2:9][C:8]2=[O:22])C=CC=C[CH:2]=1.C(N(C(=O)CS)N(CC)C(=O)CS)CCC.C1(N(C(=O)CS)N(C2C=CC=CC=2)C(=O)CS)C=CC=CC=1>>[CH2:15]([N:14]1[N:7]([CH2:1][CH3:2])[C:8](=[O:22])[CH2:9][S:10][S:11][CH2:12][C:13]1=[O:21])[CH2:16][CH2:17][CH3:18]
Reactant: O=C1CSSCC(=O)N(c2ccccc2)N1c1ccccc1
Agent: CCCCN(C(=O)CS)N(CC)C(=O)CS
Agent: O=C(CS)N(c1ccccc1)N(C(=O)CS)c1ccccc1
Product: CCCCN1C(=O)CSSCC(=O)N1CC

Procedure:
Following the procedure for the preparation of Compound 4, the title compound is prepared by substituting N-butyl,N'-ethyl-N,N'-bis(mercaptoacetyl) hydrazine (Intermediate 3) for N,N'-diphenyl-N,N'-bis(mercaptoacetyl) hydrazine.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10]2[C:15](=[O:16])[CH2:14][NH:13][C:12]3[N:17]=[CH:18][C:19]([C:21]4[C:22]([CH3:29])=[CH:23][C:24]([C:27]#[N:28])=[N:25][CH:26]=4)=[N:20][C:11]2=3)[CH2:5][CH2:4]1.FC(F)(F)C(O)=[O:33].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10]2[C:15](=[O:16])[CH2:14][NH:13][C:12]3[N:17]=[CH:18][C:19]([C:21]4[C:22]([CH3:29])=[CH:23][C:24]([C:27]([NH2:28])=[O:33])=[N:25][CH:26]=4)=[N:20][C:11]2=3)[CH2:5][CH2:4]1
Reactant: O=C(O)C(F)(F)F
Reactant: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(C#N)cc4C)nc32)CC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(C(N)=O)cc4C)nc32)CC1
Temperature: 65 °C

Procedure:
5-(8-(((trans)-4-Methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinonitrile (0.607 g, 1.55 mmol), trifluroacetic acid (2.0 mL, 26.0 mmol) and sulfuric acid (0.5 mL, 9.38 mmol) were combined and heated at 65° C. for 1 h. Reaction pH was adjusted to 10 with sodium carbonate and the resulting solution was extracted with ethyl acetate (3×15 mL). Organic layers were collected, dried over magnesium sulfate, concentrated and purified using reverse-phase preparatory HPLC (10-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Clean fractions were combined and condensed under reduced pressure and dried under high vacuum to afford the title compound as a yellow solid (0.425 g, 1.04 mmol, 67% yield). MS (ESI) m/z 411.5 [M+1]+.
Reaction SMILES: [OH:1][C:2]1([C@@H:8]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:9]([N:11]([CH3:13])[CH3:12])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.B.Cl>O1CCCC1>[CH3:13][N:11]([CH3:12])[CH2:9][C@@H:8]([C:2]1([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1
Reactant: COc1ccc([C@@H](C(=O)N(C)C)C2(O)CCCCC2)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc([C@@H](CN(C)C)C2(O)CCCCC2)cc1
Temperature: 75 °C

Procedure:
A solution of (2R)-2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)-N,N-dimethylacetamide (135 mg, 0.46 mmol) in dry tetrahydrofuran (1 mL) was treated with a solution of borane (1.0 M in tetrahydrofuran, 1.02 mL, 1.02 mmol). The reaction was heated at 75° C. for 1.5 h, and was cooled to 0° C. and treated dropwise with a 2N aqueous solution of hydrochloric acid. The reaction was then heated at 75° C for 20 minutes, the reaction was cooled, and the tetrahydrofuran was removed in vacuo. The resulting residue was diluted with water (3 mL) and was washed with ethyl acetate (6 mL). The aqueous layer was then basified to pH=10 with a 2N aqueous solution of sodium hydroxide, and the product was extracted with methylene chloride (3×15 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to yield (1S)-1-[2-dimethylamino-1-(4-methoxyphenyl)ethyl]cyclohexanol as a colorless oil. The oil was dissolved in methanol (0.5 mL) and was treated with a saturated methanolic solution of hydrochloric acid followed by enough diethyl ether to cause crystallization to yield 127 mg (88%) S-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride as a white solid. MS (ESI) m/z 278; [α]D25=−1.0° (c=0.010 g/mL, EtOH) (Yardley, John P.; Husbands, G. E. Morris; Stack, Gary; Butch, Jacqueline; Bicksler, James; Moyer, John A.; Muth, Eric A.; Andree, Terrance; Fletcher, Horace, III, et. al. J. Med. Chem. 1990, 33(10), 2899-905( [α]D25==−4°, c=0.095 g/mL, EtOH); enantiomeric excess >99%. The enantiomeric purity was determined, compared to the racemate, under the following Supercritical Fluid Chromatography conditions using Analytical Supercritical Fluid Chromatography (Berger Instruments, Inc. Newark, Del. USA):
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[C:8](=O)[O:7][C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[NH3:22].CO>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[C:8](=[O:7])[NH:22][C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: N
Solvent: CO
Product: O=C(O)c1[nH]c(=O)c2ccc(Br)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 6-bromo-4-phenylisocoumarin-3-carboxylic acid (15 g) in methanol (100 ml) was added 12% ammonia-methanol solution (60 ml) and the mixture was stirred at room temperature for 24 hrs. The reaction mixture was concentrated, and 1N hydrochloric acid was added to the obtained residue. The mixture was extracted with ethyl acetate. The organic layer was dried and concentrated and 4N hydrochloric acid ethyl acetate solution (30 ml) was added to the obtained oily substance. The mixture was stirred at room temperature for 2 hrs. and the reaction mixture was concentrated. The obtained crystal was washed with water and dried under reduced pressure to give 6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid as colorless crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2].[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.O>N1C=CC=CC=1>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][S:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)(=[O:11])=[O:10])=[CH:16][CH:15]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: CCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
To a solution of 4-ethylbenzenesulfonyl chloride (90%, 4.25 g (20.8 mmol)) in pyridine (10 ml), 4-chloroaniline (2.55 g (20.0 mmol)) was added with stirring at room temperature. After 18 hours' stirring at room temperature, water (100.0 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid, water and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 5.26 g (89%) of 4′-chloro-4-ethylbenzenesulfonanilide as white crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:19])=[C:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:25][CH2:26]O>>[CH2:25]([O:17][C:16](=[O:18])[CH2:15][C:13]1[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=[CH:11][C:12]=1[Cl:19])[CH3:26]
Reactant: O=C(O)Cc1cc(OCc2ccccc2)ccc1Cl
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (5-benzyloxy-2-chloro-phenyl)-acetic acid (1.5 g, 5.4 mmol) in EtOH (30 mL) was added sulfuric acid (1 mL), and the mixture was stirred overnight at room temperature. Once no starting material was seen by analytical LCMS, the reaction was worked up to give the desired product (1.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].ClCCCl.[CH3:14][O:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:17]=1[C:18]([N:20]=[C:21]=[O:22])=[O:19]>C(OCC)C>[CH3:28][O:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:16]([O:15][CH3:14])[C:17]=1[C:18]([NH:20][C:21]([NH:4][C:3]1[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:9])=[O:22])=[O:19]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: COc1cccc(OC)c1C(=O)N=C=O
Solvent: ClCCCl
Solvent: CCOCC
Product: COc1cccc(OC)c1C(=O)NC(=O)Nc1c(Cl)cccc1Cl

Procedure:
A 16.2 g. portion of 2,6-dichloroaniline (Aldrich Chemical Co., Milwaukee, Wis.) was dissolved in 200 ml. 1,2-dichloroethane in a flask under a nitrogen atmosphere at about 25° C. To this was added 25 g. of 2,6-dimethoxybenzoylisocyanate in 25 ml. 1,2-dichloroethane and the solution was warmed to 40° C. for two hours after the addition was complete. Thin layer chromatography on silica gel developed in diethyl ether indicated that no 2,6-dichloroaniline remained. The solvent was removed in vacuo and the residue slurried in methanol. The solids were collected and washed with methanol. Yield 26.5 g. (72%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:20][CH:19]([OH:21])[CH2:18]3)[CH:14]=[C:13]([NH:22][C:23]3[CH:28]=[N:27][CH:26]=[CH:25][N:24]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].[NH4+]>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:20][C:19](=[O:21])[CH2:18]3)[CH:14]=[C:13]([NH:22][C:23]3[CH:28]=[N:27][CH:26]=[CH:25][N:24]=3)[N:12]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CC(O)C2)n1)c1ccc(F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(N2CC(=O)C2)n1)c1ccc(F)cc1
Temperature: 15 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
156 mg of (S)-1-{2-[1-(4-fluorophenyl)ethylamino]-6-(pyrazin-2-ylamino)pyrimidin-4-yl}azetidin-3-ol (Example 72) was dissolved in 1 ml of dimethyl sulfoxide, and 571 μl of triethylamine was added thereto and cooled to 15° C. 0.5 ml of dimethyl sulfoxide suspension including 388 mg of pyridine-trisulfur oxide complex was added thereto, and the mixture was stirred at room temperature overnight. Ice and saturated ammonium chloride aqueous solution were added to the reaction solution, and the mixture was stirred for 15 minutes, and diluted with ethyl acetate, and the organic layer was washed with saturated ammonium chloride aqueous solution and water in turn, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 50 mg of the objective compound as a brown amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([CH2:11][CH2:12]O)[N:7]([C:14](=[O:25])[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:6]=2[CH:26]=1.S(Cl)([Cl:29])=O>ClCCl>[Cl:29][CH2:12][CH2:11][CH:8]1[N:7]([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:6]2[CH:26]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][CH2:9]1
Reactant: O=S(Cl)Cl
Reactant: O=C(c1cccc(C(F)(F)F)c1)N1c2cc(F)ccc2OCC1CCO
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1)N1c2cc(F)ccc2OCC1CCCl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 11.27 g (0.031 mol) of (±)-6-fluoro-4-[3-(trifluoromethyl)benzoyl]-3,4-dihydro-2H-1,4-benzoxazine-3-ethanol dissolved in 140 ml of dichloromethane are added 9 ml (0.124 mol) of thionyl chloride and the mixture is stirred at room temperature for 5 h.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([S:11](=[O:30])(=[O:29])[N:12]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=3[O:27][CH3:28])[C:13]3[S:17][N:16]=[CH:15][N:14]=3)=[CH:8][CH:9]=2)[N:4]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:3]=1.[CH3:38][N:39]1[C:43]([C:44]2[CH:49]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:47]=[CH:46][C:45]=2B(O)O)=[CH:42][CH:41]=[N:40]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[CH3:28][O:27][C:20]1[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=1[CH2:18][N:12]([C:13]1[S:17][N:16]=[CH:15][N:14]=1)[S:11]([C:7]1[N:6]=[C:5]2[N:4]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH:3]=[C:2]([C:45]3[CH:46]=[CH:47][C:48]([C:50]([F:53])([F:51])[F:52])=[CH:49][C:44]=3[C:43]3[N:39]([CH3:38])[N:40]=[CH:41][CH:42]=3)[C:10]2=[CH:9][CH:8]=1)(=[O:29])=[O:30]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C(=O)OC(C)(C)C)c3n2)c(OC)c1
Reactant: Cn1nccc1-c1cc(C(F)(F)F)ccc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccnn4C)cn(C(=O)OC(C)(C)C)c3n2)c(OC)c1
Temperature: 90 °C
Yield: 71.3 %

Procedure:
A vial was charged with tert-butyl 3-bromo-6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (531.8 mg, 0.871 mmol), (2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)boronic acid (306 mg, 1.132 mmol), potassium phosphate (555 mg, 2.61 mmol), and Pd(AmPhos)2Cl2 (30.8 mg, 0.044 mmol). 1,4-Dioxane (2178 μl) and water (726 μl) were added in sequence. The vial was sealed and heated in a microwave reactor for 30 min at 90° C. The organic layer was removed via pipette, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were concentrated in vacuo. The crude product was purified by chromatography on silica gel (0 to 50% EtOAc/Heptane) to give tert-butyl 6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (469 mg, 0.621 mmol, 71.2% yield) as a white solid. m/z (ESI) 756.2 (M+H)+.
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([C:13]2[O:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[CH:14]=2)[CH2:8][C:7]1=[O:22])(=O)[CH2:2][CH2:3][CH3:4].[CH2:23]([O:26][NH2:27])[CH:24]=[CH2:25]>C(O)C>[CH2:23]([O:26][NH:27][C:1](=[C:6]1[C:11](=[O:12])[CH2:10][CH:9]([C:13]2[O:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[CH:14]=2)[CH2:8][C:7]1=[O:22])[CH2:2][CH2:3][CH3:4])[CH:24]=[CH2:25]
Reactant: CCCC(=O)C1C(=O)CC(c2cc3ccccc3o2)CC1=O
Reactant: C=CCON
Solvent: CCO
Product: C=CCONC(CCC)=C1C(=O)CC(c2cc3ccccc3o2)CC1=O
Yield: 92 %

Procedure:
4.6 parts by weight of 2-butyryl-5-(benzo[b]fur-2-yl)-cyclohexane-1,3-dione, 1.2 parts by weight of allyloxyamine and 30 parts by volume of ethanol were stirred for 12 hours at room temperature. The solvent was distilled off under reduced pressure, the residue was taken up in 50 parts of dichloromethane, the solution was washed twice with water and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. 2-(1-Allyloxyaminobutylidene)-5-(benzo[b]fur-2-yl)-cyclohexane-1,3-dione was obtained as a viscous oil in a yield of 92% (compound no. 2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[CH2:13]=[C:14]1[O:18][C:16](=[O:17])[CH2:15]1>F>[C:16]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1])(=[O:17])[CH2:15][C:14]([CH3:13])=[O:18]
Reactant: C=C1CC(=O)O1
Reactant: COc1ccc2ccccc2c1
Agent: F
Product: COc1ccc2ccccc2c1C(=O)CC(C)=O
Yield: 88 %

Procedure:
Eiglmeier, in U.S. 4,082,807, teaches the acylation of 2-methoxynaphthalene in anhydrous hydrogen fluoride with diketene to yield 1-acetoacetyl-2-methoxynaphthalene in 88% yield at -25° C. to -35° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([O:7][CH3:8])=[S:6].[C:18](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:18][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([O:7][CH3:8])=[S:6]
Reactant: COC(=S)c1ccc(-c2ccccc2)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=S)c1ccc(-c2ccccc2)c(OC)c1
Reaction time: 6 h

Procedure:
To a mixture of methyl 3-hyroxy-4-phenylthiobenzoate (49.11 g), potassium carbonate (27.33 g) and acetone (627 ml) is added dimethyl sulfate (17.85 ml), and the mixture is refluxed with stirring for 6 hours. The reaction mixture is cooled, and the precipitate is separated by filtration and washed with acetone. The filtrate and washings are combined and concentrated under reduced pressure to give methyl 3-methoxy-4-phenylthiobenzoate.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:24]=[CH:25][C:26]=3[O:27][CH:28]([CH3:30])[CH3:29])[CH2:14][CH2:15][N:16](C)[C:17](=O)C(F)(F)F)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH-].[Na+]>CO>[C:1]12([C:11]3[CH:12]=[C:13]([CH2:14][CH2:15][NH:16][CH3:17])[CH:24]=[CH:25][C:26]=3[O:27][CH:28]([CH3:29])[CH3:30])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: CC(C)Oc1ccc(CCN(C)C(=O)C(F)(F)F)cc1C12CC3CC(CC(C3)C1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNCCc1ccc(OC(C)C)c(C23CC4CC(CC(C4)C2)C3)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a stirred solution of the product of Step E (0.21 g; 0.5 mmol) in MeOH (10 ml) was added NaOH (0.1 g) and this was stirred for 3 h at room temperature. The solvent was evaporated to dryness and the residue was taken in a mixture of solvents (EtOAc:MeOH:AcOH; 10 ml:2 ml:0.5 ml) and passed through Celite bead, which was washed with EtOAc (10 ml). The combined filtrates were evaporated to dryness to give the title compound (0.145 g, 94%) as pale paste. 1H-NMR (CDCl3) 1.36 (d, 6H, J=6 Hz); 1.74 (5, 6H); 2.04 (s, 3H, 2.1 (s, 6H); 2.43 (s, 3H); 2.72-2.81 (m, 4H); 4.55-4.63 (m, 1H); 6.74 (d, 1H, J=8.25 Hz); 6.94 (dd, 1H, J=1.97, 8.18 Hz); 7.01 (d, 1H, J=1.98 Hz).
Reaction SMILES: [Cl:1][C:2]1[N+:11]([O-])=[CH:10][C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:14]([N:16](CC)CC)C.C[Si](C#N)(C)C>C(#N)C>[Cl:1][C:2]1[N:11]=[C:10]([C:14]#[N:16])[C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)c[n+]([O-])c1Cl
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Product: COC(=O)c1cc(Cl)c(C#N)nc1Cl
Temperature: 70 °C
Yield: 84.2 %

Procedure:
Methyl 2,5-dichloronicotinate 1-oxide (16 g, 72 mmol) was dissolved in acetonitrile (200 mL) with triethylamine (15 mL, 110 mmol) and trimethylsilyl cyanide (24 mL, 180 mmol) was added. The mixture was heated to 70° C. for 30 minutes. Evaporation and purification on silica gel using ethyl acetate in hexanes (0-30%) gave the desired compound (14 g, 82%). LCMS calculated for C8H5Cl2N2O2 (M+H)+: m/z=231.0. found: 230.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)[N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([O:37]CC)=[O:36].[OH-].[Na+]>C1COCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=4)[N:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(C)cc5)n4)cc3)c(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(-c2cccc(NC(=O)c3ccc(Oc4cc5c(cc4Cl)C(C(=O)O)CCO5)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.6 %

Procedure:
To a solution of ethyl 6-chloro-7-(4-(6-p-tolylpyridin-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (0.049 g, 0.090 mmol) in 3:1 THF/ethanol (1 ml) was added 1M sodium hydroxide (0.19 ml, 0.19 mmol), and the reaction was stirred at ambient temperature for 16 hours. The reaction was concentrated to dryness and acidified with 1M hydrochloric acid. The reaction was diluted with water and extracted twice with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to yield the desired compound (0.035 g, 0.068 mmol, 75% yield). MS (apci) m/z=515.1 (M+H).