Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH2:18]Cl)[CH:17]=1)[C:5]2([CH3:21])[CH3:20].[CH3:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH2:18][C:26]3[CH:25]=[N:24][N:23]([CH3:22])[CH:27]=3)[CH:17]=1)[C:5]2([CH3:21])[CH3:20]
Reactant: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc(CCl)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: Cn1cc(Cc2cncc(N3C(=O)c4ccc(Cl)cc4C3(C)C)c2)cn1

Procedure:
In analogy to the procedure described for the preparation of example 204, 5-chloro-2-(5-chloromethyl-pyridin-3-yl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one (intermediate A-12-1) and 1-methylpyrazole-4-boronic acid pinacol ester were used to yield the title compound as a light yellowish solid (yield 15%). MS: 367.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6][CH2:5]2
Reactant: Fc1cccc(CBr)c1
Reactant: O=C1NCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCCc2cc(OCc3cccc(F)c3)ccc21
Temperature: 90 °C
Yield: 87.6 %

Procedure:
A mixture of 6-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (0.400 g, 2.44 mmol), 3-fluorobenzyl bromide (0.509 g, 2.69 mmol), potassium carbonate (0.372 g, 2.69 mmol) and N,N-dimethylformamide (5 ml) was heated to 90° C. for 8 h. Water was added and the resulting precipitate was washed with diethylether and then dried under high vacuum to afford the title compound (0.580 g, 87%). MS: m/e=272.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][CH:10]([NH:15]C(=O)OC(C)(C)C)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]2[O:23][CH2:24][C:25]3[C:30]([C:4]=2[CH:3]=1)=[CH:29][CH:28]=[N:27][CH:26]=3.Cl.C(OCC)C>ClCCl>[Br:1][C:2]1[C:7]([O:8][CH2:9][CH:10]([NH2:15])[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]2[O:23][CH2:24][C:25]3[C:30]([C:4]=2[CH:3]=1)=[CH:29][CH:28]=[N:27][CH:26]=3
Reactant: CC(C)CC(COc1cc2c(cc1Br)-c1ccncc1CO2)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)CC(N)COc1cc2c(cc1Br)-c1ccncc1CO2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 44.7 %

Procedure:
To a solution of tert-butyl (1-((9-bromo-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (0.045 g, 0.094 mmol) in dichloromethane (4 mL) cooled to 0° C. was added hydrogen chloride, 2M in diethyl ether (6 mL, 0.094 mmol) slowly over a period of 5 min. The reaction mixture was stirred at 0° C. for 5 min, then at room temperature for 2 h. The solvents were removed by concentration under reduced pressure. The crude product was taken up in water (10 mL) and washed with diethyl ether (3×10 mL). The aqueous layer was concentrated and purified by reverse phase HPLC (0.1% TFA in water and acetonitrile) to yield 1-((9-bromo-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-amine (0.016 g, 0.042 mmol, 45% yield) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.68 (bs, 2H), 8.35 (s, 1H), 8.26 (s, 1H), 6.90 (s, 1H), 5.39 (s, 2H), 4.41 (m, 1H), 4.27 (m, 1H), 3.76 (m, 1H), 1.82 (m, 2H), 1.69 (m, 1H), 1.05 (m, 6H). LCMS (ESI) m/e 377.0 [(M+H)+, calcd for C18H22BrN2O2 377.1]; LC/MS retention time (Method D): tR=1.25 min; HPLC retention time (method A): tR=8.59 min; HPLC retention time (method B): tR=10.33 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][C:14]2([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[N:18]=3)[O:16][CH2:15]2)[CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:24].[C:25]([O-:28])(=[O:27])[CH3:26].[Na+]>C(O)(=O)C>[C:25]([O:28][CH2:15][C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[N:18]=1)([OH:16])[CH2:13][N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:24])[CH:4]=1)(=[O:9])=[O:10])[CH3:12])(=[O:27])[CH3:26]
Reactant: CC(=O)[O-]
Reactant: Cc1cc(S(=O)(=O)N(C)CC2(c3cccc(Cl)n3)CO2)ccc1Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCC(O)(CN(C)S(=O)(=O)c1ccc(Cl)c(C)c1)c1cccc(Cl)n1
Temperature: 100 °C
Reaction time: 12 h
Yield: 72.6 %

Procedure:
A mixture of 7.0 g of 1-[N-(4-chloro-3-methylbenzenesulfonyl)-N-methylamino]-2-(6-chloropyridin-2-yl)-2,3-epoxypropane, 3.70 g of anhydrous sodium acetate and 60 ml of acetic acid was stirred at 100° C. for 12 hours. The reaction mixture was concentrated under a reduced pressure and 100 ml of water was added thereto. The mixture was extracted with ethyl acetate, subsequently washed with water, saturated aqueous solution of sodium bicarbonate and saturated saline solution in that order, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with ethyl acetate - n-hexane 1:3 ) to obtain 5.87 g of the objective compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:25])[NH:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=1)=[O:12])[CH2:5]2.[NH:26]1[CH:30]=[CH:29][C:28](B(O)O)=[N:27]1.C(=O)(O)[O-].[Na+].O>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:22]([NH:21][C:20]([C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11]([N:6]2[CH2:5][C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:30]4[CH:29]=[CH:28][NH:27][N:26]=4)[CH:3]=3)[CH2:7]2)=[O:12])=[CH:15][CH:16]=1)=[O:25])[CH2:23][CH3:24]
Reactant: OB(O)c1cc[nH]n1
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(Br)cc3C2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(-c4cc[nH]n4)cc3C2)cc1
Temperature: 85 °C
Reaction time: 0.08 h

Procedure:
In a 4 mL vial, a solution of 5-bromo-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide (50 mg, 0.12 mmol) and 1H-pyrazol-3-ylboronic acid (17 mg, 0.15 mmol) in dimethylformamide was treated with saturated aqueous sodium bicarbonate followed by bis(triphenylphosphine)palladium(II) chloride (7 mg). The vial was capped under nitrogen and the reaction heated at 85° C. for 6 hours. The reaction was cooled to ambient temperature and water was added. The resulting suspension was stirred for 5 minutes and filtered. The solid collected was washed with water and dried under vacuum; the solid was purified by reverse-phase HPLC to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.39-13.18 (bs, 1H), 8.59 (s, 1H), 8.24-8.28 (m, 1H), 7.75-7.79 (m, 2H), 7.70-7.80 (m, 3H), 7.62-7.69 (m, 2H), 7.40 (d, J=7.9 Hz, 1H), 6.73 (d, J=2.2 Hz, 1H), 4.79-4.83 (m, 4H), 3.15-3.25 (m, 2H), 1.46-1.57 (m, 2H), 0.89 (t, J=7.4 Hz, 3H); MS (ESI(+)) m/e 390 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].C(=O)([O-])[O-].[K+].[K+].[OH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][CH:30]=2)=[CH:25][C:24]=1[C:40]1[CH:49]=[CH:48][C:47]2[C:46]([CH3:51])([CH3:50])[CH2:45][CH2:44][C:43]([CH3:53])([CH3:52])[C:42]=2[CH:41]=1.O>CC(C)=O>[O:15]=[C:6]1[C:7]2[C:8](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:10])[N:5]1[CH2:4][CH2:3][CH2:2][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:33][CH:34]=2)=[CH:25][C:24]=1[C:40]1[CH:49]=[CH:48][C:47]2[C:46]([CH3:51])([CH3:50])[CH2:45][CH2:44][C:43]([CH3:52])([CH3:53])[C:42]=2[CH:41]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCN3C(=O)c4ccccc4C3=O)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Reaction time: 8 h
Yield: 61.1 %

Procedure:
600 mg (2.24 mmol) of N-(3-bromopropyl)phthalimide and 310 mg (2.24 mmol) of potassium carbonate are added to a solution of 800 mg (1.86 mmol) of ethyl 4′-hydroxy-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate in 50 ml of acetone. The reaction mixture is stirred overnight at reflux. The reaction is stopped by adding water, and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off. The residue is precipitated from a small amount of ethyl acetate. It is filtered off and 700 mg of ethyl 4′-[3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)propoxy]-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a white solid (yield=61%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:15][C:16]2[CH:32]=[CH:31][C:19]([C:20]([N:22]3[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28]([OH:30])=[O:29])[CH2:23]3)=[O:21])=[CH:18][CH:17]=2)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:4]([CH3:33])[CH:3]=1.[C:34]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)#[N:35].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[C:34]([C:36]1[CH:41]=[CH:40][C:39]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:22]4[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28]([OH:30])=[O:29])[CH2:23]4)=[O:21])=[CH:31][CH:32]=3)[CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:4]([CH3:33])[CH:3]=2)=[CH:38][CH:37]=1)#[N:35]
Reactant: Cc1cc(Br)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)N2CCC[C@@H](C(=O)O)C2)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2ccc(C#N)cc2)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)N2CCC[C@@H](C(=O)O)C2)cc1
Yield: 17.8 %

Procedure:
To (3R)-1-(4-((1-(4-bromo-2-methylphenyl)-4,4,4-trifluorobutyl)amino)benzoyl)piperidine-3-carboxylic acid (42 mg) was added a solution of 4-cyanophenylboronic acid (24 mg) in DME (0.5 mL), polymer-supported triphenylphosphinepalladium(0) (0.1 mg), and a solution of potassium carbonate (16 mg) in water (0.2 mL), and the mixture was stirred at 80° C. overnight. The reaction solution was passed through a filter, and washed twice with THF (2 mL). The solvent was evaporated from the obtained solution by an air blowing apparatus. The residue was purified by HPLC (C18, mobile phase: water/acetonitrile (0.1% TFA-containing system)), and the solvent was evaporated from the obtained solution by an air blowing apparatus. The residue was purified by HPLC (C18, mobile phase: water/acetonitrile (10 mM ammonium acetate-containing system)) to give the title compound (7.8 mg).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=1)=O.[Br-].[O:27]([CH2:34][CH2:35][CH2:36][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[H-].[Na+]>O1CCCC1.CS(C)=O>[CH2:19]([O:18][C:6]1[CH:5]=[C:4]([C:2]([CH3:1])=[CH:36][CH2:35][CH2:34][O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: c1ccc(OCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(=CCCOc1ccccc1)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
Under a nitrogen atmosphere a mixture of 3,5-dibenzyloxyacetophenone (50.0 g., 0.15 M) in tetrahydrofuran (175 ml.) and 3-phenoxypropyltriphenylphosphonium bromide (7.18 g., 0.15 M) in dimethylsulfoxide (450 ml.) is added dropwise over 1.75 hours to a suspension of 50% sodium hydride (7.89 g., 0.165 M) (previously washed with pentane) in tetrahydrofuran (75 ml.) maintained at 0°-5° C. After stirring for 4 hours at 0°-5° C. the reaction is allowed to warm to room temperature and is then carefully stirred into ice water (2000 ml.), acidified with concentrated hydrochloric acid, and extracted with ethyl acetate (5×400 ml.). The combined organic phases are washed with saturated sodium chloride solution (3×300 ml.), dried over sodium sulfate and concentrated under vacuum to yield an oil which is triturated with ether to precipitate triphenylphosphine oxide. Filtration, followed by concentration of the filtrate, gives an oily residue which is chromatographed over silica gel (1300 g.) eluting with benzene-hexane consisting of 30% to 100% benzene. From the middle fractions 51 g. (75%) of 4-(3,5-dibenzyloxyphenyl)-1-phenoxypent-3-ene is isolated as an oil; Rf =0.8 (silica gel, 2-benzene:1-hexane); m/e--450 (m+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]([CH3:28])[C:9](=[O:27])[NH:10][C:11]1[N:12]=[C:13]([C:21]#[C:22][Si](C)(C)C)[C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].CO>O>[C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]([CH3:28])[C:9]([NH:10][C:11]1[N:12]=[C:13]([C:21]#[CH:22])[C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cc2ccccc2c(C#C[Si](C)(C)C)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C#Cc1nc(NC(=O)C(C)NC(=O)OC(C)(C)C)cc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl-N-[1-oxo-1-[[1-(2-trimethylsilylethynyl)isoquinolin-3-yl]amino]-propan-2-yl]carbamate C4a (319 mg, 0.78 mmol), aqueous 1 N KOH solution (3 ml) and MeOH (10 ml) is stirred at RT for 2 h. The mixture is diluted with water and extracted with EtOAc. The combined organic layers are dried over Na2SO4 and concentrated in vacuo and the product purified by RP HPLC. Yield: 225 mg (86%). HPLC-MS: M+H=340; tR=1.84 min (*Method—1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][N:17]([C:19]([N:21]3[CH2:26][CH2:25][S:24][CH2:23][CH2:22]3)=[O:20])[CH2:16][CH:15]([C:27](O)=[O:28])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]([F:12])([F:11])[F:10].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.O[N:64]=[C:65]([O:67][CH2:68][CH3:69])[NH2:66]>CN(C)C=O>[CH2:68]([O:67][C:65]1[N:66]=[C:27]([CH:15]2[CH2:14][CH:13]([C:4]3[CH:5]=[CH:6][C:7]([CH2:8][C:9]([F:12])([F:10])[F:11])=[C:2]([F:1])[CH:3]=3)[CH2:18][N:17]([C:19]([N:21]3[CH2:22][CH2:23][S:24][CH2:25][CH2:26]3)=[O:20])[CH2:16]2)[O:28][N:64]=1)[CH3:69]
Reactant: O=C(O)C1CC(c2ccc(CC(F)(F)F)c(F)c2)CN(C(=O)N2CCSCC2)C1
Reactant: CCOC(N)=NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1noc(C2CC(c3ccc(CC(F)(F)F)c(F)c3)CN(C(=O)N3CCSCC3)C2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 400 mg (0.783 mmol, purity 85%) of the carboxylic acid from Example 79A in 10.6 ml of N,N-dimethylformamide were added, at room temperature, 357 mg (0.939 mmol) of HATU and 0.30 ml (1.72 mmol) of N,N-diisopropylethylamine, and the mixture was stirred for 30 min. Subsequently, the mixture was admixed with 118 mg (1.02 mmol, purity 90%) of ethyl N′-hydroxyimidocarbamate [G. Zinner, G. Nebel, Arch. Pharm. 1970, 303, 385-390] and stirred at room temperature overnight. The reaction solution was diluted with 11 ml of N,N-dimethylformamide and then stirred at 140° C. for 3 h. The reaction solution was purified directly by means of preparative HPLC. Yield: 111 mg (28% of theory)
Reaction SMILES: [N+:1]([C:4]([CH2:9][CH3:10])([CH2:7][OH:8])[CH2:5][OH:6])([O-:3])=[O:2].[C:11]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:17])[CH2:12][CH2:13][C:14]([CH3:16])=O.O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:11]([CH2:12][CH2:13][C:14]1([CH3:16])[O:8][CH2:7][C:4]([N+:1]([O-:3])=[O:2])([CH2:9][CH3:10])[CH2:5][O:6]1)([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:17]
Reactant: CCCCOC(=O)CCC(C)=O
Reactant: CCC(CO)(CO)[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOC(=O)CCC1(C)OCC(CC)([N+](=O)[O-])CO1
Yield: 90 %

Procedure:
7.46 g of 2-nitro-2-ethyl-1,3-propanediol, 8.61 g of butyl levulinate, 50 mg of p-toluenesulfonic acid in 50 ml of toluene was refluxed until no more water separated. The reaction mixture was cooled, washed with 2% sodium bicarbonate and water, dried and concentrated to give 13.65 g of 2-carbobutoxyethyl-2-methyl-5-nitro-5-ethyl-1,3-dioxane as a light yellow oil. This was dissolved in 50 ml of ethanol and hydrogenated over 1 g Raney Nickel catalyst at 60 under pressure. Distillation of the crude material at 160° C./3mm gave 11 g of the product.
Reaction SMILES: [C:1]1([C:7]([CH:9]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3]C=1.B(F)(F)F.C[CH2:23][O:24]CC>CCOCC>[O:10]=[C:9]([C:7]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:1]=1)[CH:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:23]=[O:24]
Reactant: O=C(c1ccccc1)C1OC1c1ccccc1
Reactant: CCOCC
Agent: FB(F)F
Product: O=CC(C(=O)c1ccccc1)c1ccccc1
Temperature: 50 °C

Procedure:
Phenyl(3-phenyloxiran-2-yl)methanone (5.0 g, 22.3 mmol) was suspended in dry Et2O (40 mL) under an argon balloon. Boron trifluoride diethyl etherate (3.00 mL, 23.7 mmol) was added slowly via syringe. The reaction was refluxed at 50° C. for an hour, then cooled and extracted with 60 mL each of H2O and Et2O/EtOAc. The aqueous layer was extracted again with EtOAc (60 mL). The combined organic layer was dried and concentrated to give 3-oxo-2,3-diphenylpropanal.
Reaction SMILES: CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:30]([N:37]([S:42]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=1)(=[O:44])=[O:43])[CH2:38][C:39](O)=[O:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[NH2:53][C:54]1[S:55][S:56][C:57](=[S:59])[N:58]=1.Cl>CN(C)C=O>[CH2:30]([N:37]([S:42]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=1)(=[O:44])=[O:43])[CH2:38][C:39]([NH:53][C:54]1[S:55][S:56][C:57](=[S:59])[N:58]=1)=[O:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1nc(=S)ss1
Reactant: COc1ccc(S(=O)(=O)N(CC(=O)O)Cc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(CC(=O)Nc2nc(=S)ss2)Cc2ccccc2)cc1
Reaction time: 1 h
Yield: 31.7 %

Procedure:
N-methylmorpholine (0.79 ml, 7.15 mmol), N-hydroxybenzotriazole (1.10 g, 7.15 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (1.37 g, 7.15 mmol) are added to a solution of 2-{benzyl[(4-methoxyphenyl)sulfonyl]amino}acetic acid (2.00 g, 5.96 mmol) in N,N-dimethylformamide (20 ml) while being cooled with ice, and stirred for 1 hour. Then, the mixture, with 3-amino-1,2,4-dithiazole-5-thione (1.08 g, 7.15 mmol) added thereto, was stirred for 5 hours at room temperature. The reaction, with 1N hydrochloric acid added thereto, was extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate water and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (3% methanol/chloroform), to give aimed 2-{benzyl[(4-methoxyphenyl)sulfonyl]amino}-N-(3-thioxo-3H-1,2,4-dithiazol-5-yl)acetoamide (Compound 1) (0.883 g, 32%).
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:6]([C:12](=O)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[N:7][CH:8]=[C:9]([Cl:11])[CH:10]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[Cl:11][C:9]1[CH:10]=[C:5]2[NH:3][N:2]=[C:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]2=[N:7][CH:8]=1
Reactant: NN
Reactant: O=C(Cc1ccccc1F)c1ncc(Cl)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: Fc1ccccc1Cc1n[nH]c2cc(Cl)cnc12
Temperature: 160 °C

Procedure:
A little DMAP and 238 mg (4.75 mmol) of hydrazine hydrate are added to a solution of 1.35 g (4.75 mmol) of 1-(3,5-dichloropyridin-2-yl)-2-(2-fluorophenyl)ethanone from example 2A in 12 ml of pyridine. The mixture is heated in a closed vessel in a microwave at 160° C. for 20 min and then concentrated in vacuo, and the residue is purified by chromatography on silica gel (eluent: dichloromethane/methanol 100:3). 507 mg (41% of theory) of the title compound and 388 mg of the uncyclized hydrazone are obtained. The latter is heated anew in 5 ml of DMF in the microwave at 200° C. for 1.5 h. The solution is concentrated and the residue is purified by preparative HPLC. A further 176 mg (12% of theory) of the title compound are obtained in this way.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[CH:19][N:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:28][C:29]=3[CH3:30])=[CH:19][N:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cn2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cn2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridylmethyl]-1H-pyrazol-4-yl]propionate (730 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridylmethyl]-1H-pyrazol-4-yl]propionic acid (650 mg, yield: 95%). This was recrystallized from acetone-hexane. Melting point: 133–134° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)([O-])[O-].[K+].[K+].F[C:23]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1>C1(C)C=CC=CC=1>[CH3:5][C:4]([O:3][C:1]([NH:8][CH:9]1[CH2:10][CH2:11][CH:12]([NH:15][C:23]2[N:24]=[CH:25][CH:26]=[CH:27][C:28]=2[N+:29]([O-:31])=[O:30])[CH2:13][CH2:14]1)=[O:2])([CH3:7])[CH3:6]
Reactant: O=[N+]([O-])c1cccnc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncccc2[N+](=O)[O-])CC1
Temperature: 120 °C

Procedure:
To a flask charged with toluene (37.3 mL) were added trans-N-boc-1,4-cyclohexanediamine (2.00 g, 9.33 mmol), potassium carbonate (1.290 g, 9.33 mmol) and 2-fluoro-3-nitropyridine (commercially available from Matrix Scientific, Columbia, S.C.) (1.326 mL, 9.33 mmol). The resulting bright yellow solution was heated overnight at 120° C. leading to conversion to the desired product as the primary species along with a more polar impurity according to LC-MS. The mixture was diluted with water, transferred to a separatory funnel and extracted with EtOAc (2×). The combined organic layers were dried with Na2SO4, filtered, and dried under reduced pressure providing a bright yellow solid which was triturated with DCM providing tert-butyl ((1r,4r)-4-((3-nitropyridin-2-yl)amino)cyclohexyl)carbamate (1.51 g, 4.49 mmol, 48.1% yield) as a bright yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.49 (dd, J=1.8, 4.5 Hz, 1H), 8.41 (dd, J=1.8, 8.4 Hz, 1H), 8.06 (d, J=7.7 Hz, 1H), 6.79-6.69 (m, 2H), 4.13-4.00 (m, J=3.9, 7.4, 7.4, 11.3 Hz, 1H), 3.29-3.20 (m, 1H), 2.01-1.92 (m, 2H), 1.82 (d, J=10.6 Hz, 2H), 1.55-1.41 (m, 2H), 1.38 (s, 9H), 1.35-1.21 (m, 2H). m/z (ESI) 281.2 (M+H)+.