Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[S:32][C:31]([C:33](O)=[O:34])=[CH:30][CH:29]=1>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:33]([C:31]4[S:32][C:28]([C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=5)=[CH:29][CH:30]=4)=[O:34])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: O=C(O)c1ccc(-c2ccccn2)s1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)c2ccc(-c3ccccn3)s2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-5-(pyrid-2-yl)thiophene-2- carboxamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide and 5-(pyrid-2-yl)thiophene-2-carboxylic acid using method D. The product was further purified by preparative HPLC. NMR; δH [2H6]—DMSO 10.29,(1H, s), 8.63,(1H, t), 8.58,(1H, d), 8.02-7.99,(2H, m), 7.94,(2H, d), 7.90-7.86,(2H, m), 7.70,(1H, dd), 7.65,(1H, d), 7.46,(2H, d), 7.35,(1H, m), 7.30,(1H, d), 3.17,(2H, t), 2.21,(3H, s), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.60 min, MH+468.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12](F)[N:11]=[CH:10][C:9]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.Cl.[O:30]1CCCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]3)=[CH:10][NH:11][C:12](=[O:30])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cnc(F)cc2-c2ccc(Cl)cc2)CC1
Reactant: C1CCOC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCN(Cc2c[nH]c(=O)cc2-c2ccc(Cl)cc2)CC1
Reaction time: 8 h

Procedure:
A mixture of EXAMPLE 307C (1.6 g) and 5% HCl (20 mL) in tetrahydrofuran (20 mL) was heated at 80° C. overnight. The solvent was removed to dryness. This solid was re-dissolved and added to tetrahydrofuran (50 mL). To this mixture were added BOC2O (di-t-butyl-dicarbonate) (1.118 g), triethylamine (0.72 mL), and 4-dimethylamionpyridine (1.4 g). The solvent was removed, and the residue was partitioned between water and ethyl acetate. The reaction mixture was stirred overnight. The organic layers were dried (MgSO4), filtered, and concentrated. The residue was purified by Prep HPLC eluting with 20-100% acetonitrile/water with 0.1% trifluoroacetic acid to give the title compound.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH2:11]([CH:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1)[C:12]#[CH:13]>>[CH2:11]([CH:14]1[CH2:19][CH2:18][N:17]([C:2]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:3])[CH2:16][CH2:15]1)[C:12]#[CH:13]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Product: C#CCC1CCN(C(=O)Oc2ccccc2)CC1

Procedure:
Phenyl chloroformate (6.2 g, 40.2 mmol) was added to a solution of tert-butyl 4-(prop-2-ynyl)piperidine-1-carboxylate (1.65 g, 13.4 mmol) according to general procedure 1. Yield=0.600 g, 34%. m/z MH+=244.08. HPLC rt=10.3 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([OH:28])[CH:25]=[C:24]([Br:29])[CH:23]=2)[C:10]=1[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:2].[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([Br:29])[CH:25]=[C:26]([O:28][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:27]=2)[C:10]=1[CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(O)cc(Br)c2)c1CCC(=O)OCC
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(OCc3ccccc3)c2)c1CCC(=O)OCC
Yield: 98.9 %

Procedure:
A similar procedure as described in Example 43, step 3 was used, starting from 4-[3-[6-(3-bromo-5-hydroxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (930 mg, 1.6 mmol), benzyl bromide (343 mg, 2.0 mmol), and potassium carbonate (553 mg, 4.0 mmol) to afford 4-[3-[6-(3-benzyloxy-5-bromo-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.06 g, 98%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C36H45BrO7 (M+Na)+ 691.2241. found 691.2238.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(=O)C)(=O)C.[N+:19]([O-])([OH:21])=[O:20]>>[N+:19]([C:10]1[CH:9]=[N:8][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: c1ccc(-n2cccn2)cc1
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1cnn(-c2ccccc2)c1
Reaction time: 4 h
Yield: 36.58 %

Procedure:
1-Phenyl-1H-pyrazole (500 mg, 3.4 mmol) was added to a cold mixture (−10° C.) of acetic anhydride (2.6 mL) and conc. HNO3 (0.3 mL) and stirring was continued at ambient temperature for 4 hrs. The reaction mixture quenched with cold water and filtered. Isolation of the filter cake afforded 240 mg (36.58% Yield) of 4-nitro-1-phenyl-1H-pyrazole.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22](O)=[O:23]>>[CH3:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22]([NH:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18])=[O:23]
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: CC(C)(C)CC(=O)O
Product: CC(C)(C)CC(=O)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 3,3-dimethylbutanoic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.2 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.97-8.00 (m, 1H), 7.89-7.93 (m, 1H), 3.79-3.84 (m, 4H), 3.08-3.13 (m, 4H), 2.16 (s, 2H), 1.07 (s, 9H); MS (ESI−) M/Z 343 (M−H)−.
Reaction SMILES: [H-].[Na+].[CH3:3][OH:4].C(OC1C=CC(O[C:18]2[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][C:19]=2[N+:26]([O-:28])=[O:27])=CC=1)C1C=CC=CC=1>O>[CH3:3][O:4][CH2:22][C:21]1[CH:24]=[CH:25][CH:18]=[C:19]([N+:26]([O-:28])=[O:27])[CH:20]=1
Reactant: O=[N+]([O-])c1cc(CCl)ccc1Oc1ccc(OCc2ccccc2)cc1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% Oily sodium hydride (0.22 g, 5.5 mmol) was added to methanol (50 ml) under ice-cooling, and after stirring at room temperature for 30 minutes, 4-[4-(benzyloxy)phenoxy]-3-nitrobenzyl chloride (1.00 g, 2.7 mmol) was added thereto, followed by stirring for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate. After drying, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography [eluent; hexane - chloroform (1:1)] to give 1-[4-benzyloxy)phenoxy]-4-(methoxymethyl)-2-nitrobenzene (0.92 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([OH:18])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:52][CH2:53][C:54]1[C:55](=[O:70])[NH:56][C:57]([CH3:69])=[CH:58][C:59]=1[CH2:60][O:61][Si](C(C)(C)C)(C)C.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([NH:52][CH2:53][C:54]2[C:55](=[O:70])[NH:56][C:57]([CH3:69])=[CH:58][C:59]=2[CH2:60][OH:61])=[O:18])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)[C:9]=2[CH:10]=1
Reactant: O=C(O)c1cc(Br)cc2c1cnn2C1CCCC1
Reactant: Cc1cc(CO[Si](C)(C)C(C)(C)C)c(CN)c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(CO)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.6 %

Procedure:
To a solution of 6-bromo-1-cyclopentyl-1H-indazole-4-carboxylic acid (2.3 g, 7.5 mmol) in DMSO (30 mL), PyBOP (5.82 g, 11.20 mmol) was added and reaction stirred at room temperature for 15 min. 3-(Aminomethyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-2(1H)-one (2.52 g, 8.96 mmol) was then added and reaction mixture stirred overnight. On completion, water was added and the resulting precipitate filtered and washed with water. This solid was then stirred with acetonitrile for 10 min and filtered again to obtain 6-bromo-1-cyclopentyl-N-((4-(hydroxymethyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (1.4 g, 40.9%).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13].[BH4-].[Li+].C(O)(=O)C>O1CCCC1>[N+:12]([C:6]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:5]=1[CH:4]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[CH2:3][OH:2])([O-:14])=[O:13]
Reactant: COC(=O)C(c1ccccc1Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(Cl)cc1C(CO)c1ccccc1Cl
Yield: 45.6 %

Procedure:
A mixture solution of α-(5-chloro-2-nitrophenyl)-2-chlorophenyl acetic acid methyl ester (26.3 g) and lithium borohydride (2 g) in tetrahydrofuran (200 ml) was stirred for 4 hours at room temperature. This mixture solution was added to a 20% aqueous solution of acetic acid (50 ml), which was extracted with acetic acid ethyl ester. The extract solution was washed with water, dried over anhydrous sodium sulfate and, then, the solvent was distilled off. The residual oily compound was purified by means of a silica-gel column chromatography to give 11.0 g of an oily compound.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5C(=[CH:16][CH:17]=[CH:18][CH:19]=5)C=4C[CH2:12][N:11]3[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:4][C:3]=2[O:2]1.C[C:31]([CH3:34])([O-:33])[CH3:32].[K+].O=O>CN(C=O)C>[CH2:23]([N:11]1[CH2:12][C:34]2[C:31](=[O:33])[C:32]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[NH:21][C:22]=2[CH:10]1[C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)[O-]
Reactant: c1ccc(CN2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Agent: O=O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)N(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3,4-Methylenedioxyphenyl)-2-benzyl-2,3,4,9-tetrahydro-1H-β-carboline (0.79 g, 2.0 mmol) (prepared as in Example 1) was dissolved in dry DMF (15 mL). Potassium t-butoxide (0.56 g, 5.0 mmol) was added, followed by oxygen, bubbled in via syringe needle. The mixture was maintained at room temperature for one hour and then poured onto a mixture of 1N HCl (5 mL), water (35 mL) and ethyl acetate (35 mL). A fluffy yellow precipitate was collected, the organic layer removed, and the aqueous solution extracted with ethyl acetate (15 mL). The extracted layer was agitated and set aside overnight. The following day an additional quantity of product (as a precipitate) was collected. Drying of the combined solids yielded the product as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[OH:11].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)c1cc(C)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)ccc1OCc1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A mixture of 2-hydroxy-5-methylbenzoic acid methyl ester (4.98 g, 30 mmol), 4-methoxybenzyl chloride (4.69 g, 30 mmol) and K2CO3 (4.55 g, 33 mmol) in DMF (50 mL) is stirred at 60° C. for 48 h. The mixture is diluted with EtOAc and washed with 1N HCl and brine then the organic phase is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by column chromatography using a gradient of 0-100% EtOAc/hexane as eluent to give the title compound as a colorless oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[S:13][CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[NH:10]2)=[C:4]([CH2:18][CH2:19][CH3:20])[CH:3]=1.[C:21]([Cu])#[N:22]>CN(C=O)C>[C:21]([C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[S:13][CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[NH:10]2)=[C:4]([CH2:18][CH2:19][CH3:20])[CH:3]=1)#[N:22]
Reactant: N#C[Cu]
Reactant: CCCc1cc(I)ccc1N=C1NC2(CCCC2)CS1
Solvent: CN(C)C=O
Product: CCCc1cc(C#N)ccc1N=C1NC2(CCCC2)CS1
Temperature: 25 °C
Yield: 64.3 %

Procedure:
4-Iodo-2-n-propylaniline was converted into 4-iodo-2-n-propylphenyl isothiocyanate in a manner analogous to Method A2b. Concurrently, 1-amino-1-(hydroxymethyl)cyclopentane was converted to the chloromethyl analogue, then reacted with the isothiocyanate in a manner analogous to Method C2a to give 2-(4-iodo-2-propylphenylimino)-3-thia-1-azaspiro[4.4]nonane. A slurry of 2-(4-iodo-2-propylphenylimino)-3-thia-1-azaspiro[4.4]nonane (0.54 g, 1.35 mmol) and CuCN (0.24 g, 2.70 mmol) in DMF (4 mL) was heated at 140° C. overnight. The resulting mixture was cooled to room temp, concentrated under reduced pressure and purified by flash chromatography (10% EtOAc/hex) to give 2-(4-cyano-2-propylphenylimino)-3-thia-1-azaspiro[4.4]nonane as a white solid (0.26 g, 65%): TLC (30% EtOAc/hex) Rf0.37.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:17])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[C:7]2O.P(Br)(Br)([Br:20])=O>C1(C)C=CC=CC=1.CC#N>[Br:20][C:7]1[C:6]2[C:11](=[C:2]([F:1])[C:3]([CH3:17])=[CH:4][CH:5]=2)[N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=1
Reactant: COC(=O)c1cc(O)c2ccc(C)c(F)c2n1
Reactant: O=P(Br)(Br)Br
Solvent: Cc1ccccc1
Solvent: CC#N
Product: COC(=O)c1cc(Br)c2ccc(C)c(F)c2n1
Temperature: 75 °C
Yield: 66.5 %

Procedure:
A mixture of (methyl 8-fluoro-4-hydroxy-7-methylquinoline-2-carboxylate (7-15, 842.1 mg, 3.58 mmol) and POBr3 (1129 mg, 3.94 mmol) in Toluene (8.14 mL) and CH3CN (0.81 mL) was heated at 75° C. for 1 h. After cooling to room temperature, the mixture was poured to a mixture of ice-H2O, followed by CH2Cl2 extraction (twice). The combined organic fractions were dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash chromatography (gradient 0-50% EtOAc/Hexanes) to afford methyl 4-bromo-8-fluoro-7-methylquinoline-2-carboxylate (7-16, 710 mg). LRMS m/z (M+H)+ 298.1 found, 298.0 required.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]([CH3:9])=[CH:7][CH:8]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:2][C:1]([C:4]1[O:5][C:6]([CH3:9])=[CH:7][CH:8]=1)=[O:3]
Reactant: CC(=O)c1ccc(C)o1
Reactant: COC(OC)N(C)C
Product: Cc1ccc(C(=O)C=CN(C)C)o1

Procedure:
A mixture of 37.24 g of 2-acetyl-5-methylfuran and 150 ml of N,N-dimethylformamide dimethylacetal was heated on a steam bath under an air condenser for 16.5 hours. The solvent was removed in vacuo and the residue taken up in dichloromethane and passed through a short column of magnesium silicate. The filtrate was evaporated on a steam bath with the addition of n-hexanes to a volume of 100-150 ml. Cooling with scratching gave 28.31 g of the desired compound, mp 123°-125° C.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:15])[CH:5]=1)(=[O:3])[CH3:2].[Cl:16][C:17]1[CH:18]=[C:19]([C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:20]=[C:21]([Cl:23])[CH:22]=1.C(N(CC)CC)C>CCCCCCC>[Cl:16][C:17]1[CH:18]=[C:19]([C:24]([OH:29])([C:25]([F:26])([F:27])[F:28])[CH2:2][C:1]([C:4]2[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:15])[CH:5]=2)=[O:3])[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CCOC(=O)c1ccc(C(C)=O)cc1C
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: CCOC(=O)c1ccc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1C
Temperature: 60 °C
Reaction time: 4 h
Yield: 71.9 %

Procedure:
0.63 g of ethyl 4-acetyl-2-methylbenzoate, 0.73 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 0.73 g of n-heptane and 0.30 g of triethylamine were fed and the mixture was stirred for 4 hours at 60° C. The mixture was left to cool, and further stirred for one night at room temperature. 0.53 g of n-heptane was added to the slurry-state reaction solution, and the mixture was filtered under reduced pressure. The solid was washed with a small amount of n-heptane, and dried under reduced pressure. 0.97 g of ethyl 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoate as a light yellow solid was obtained by drying under reduced pressure.
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=3[N:7]([CH3:19])[C:6]=2[C:5]([C:20]#[N:21])=[CH:4][N:3]=1.[NH4+:22].[OH-]>CCO>[NH2:22][C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:9][C:8]=3[N:7]([CH3:19])[C:6]=2[C:5]([C:20]#[N:21])=[CH:4][N:3]=1
Reactant: Cn1c2cc(C(F)(F)F)ccc2c2c(Cl)ncc(C#N)c21
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c2cc(C(F)(F)F)ccc2c2c(N)ncc(C#N)c21
Temperature: 145 °C

Procedure:
The product of Step 2 was dissolved in a 2:3 (v/v) mixture of EtOH and conc. NH4OH (0.027 M) in a stainless steel Parr pressure vessel. The vessel was sealed and the reaction was heated for 16 h at 145° C. After cooling to 0° C., the mixture was concentrated to dryness under vacuum and the resulting solid was stirred with 1:10 EtOAc:hexanes containing 10% MeOH to give the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[C:16]([F:21])[C:17]([NH:19][CH3:20])=[CH:18][C:11]=3[O:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:24][C:25](=O)[NH:26][S:27]([C:30]1[S:31][C:32]([Cl:35])=[CH:33][CH:34]=1)(=[O:29])=[O:28])C>O1CCOCC1>[Cl:35][C:32]1[S:31][C:30]([S:27]([NH:26][C:25]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:13](=[O:14])[C:12]4[CH:15]=[C:16]([F:21])[C:17]([NH:19][CH3:20])=[CH:18][C:11]=4[O:10][CH2:9]3)=[CH:6][CH:7]=2)=[O:24])(=[O:29])=[O:28])=[CH:34][CH:33]=1
Reactant: CCOC(=O)NS(=O)(=O)c1ccc(Cl)s1
Reactant: CNc1cc2c(cc1F)C(=O)N(c1ccc(N)cc1)CO2
Solvent: C1COCCO1
Product: CNc1cc2c(cc1F)C(=O)N(c1ccc(NC(=O)NS(=O)(=O)c3ccc(Cl)s3)cc1)CO2
Temperature: 110 °C
Yield: 37.4 %

Procedure:
A mixture of 3-(4-aminophenyl)-6-fluoro-7-(methylamino)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (Ex. 4) (130 mg, 0.45 mmol) and (5-Chloro-thiophene-2-sulfonyl)-carbamic acid ethyl ester (150 mg, 0.53 mmol, 1.2 eq) in dry 1,4-dioxan (3 mL) was heated at 110° C. for 2 hr. Upon cooling, the reaction was concentrated in vacuo and the crude residue was purified by HPLC (C-18) to give 86 mg (37%) of pure 1-(5-chlorothiophen-2-ylsulfonyl)-3-(4-(6-fluoro-7-(methylamino)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)phenyl)urea. RP-HPLC: 2.49 min; ES-MS (M+H)+=511.0; 1H-NMR (MeOH-d4) δ (ppm): 2.8 (s, 3 H), 5.4 (s, 2 H), 6.2 (d, 1 H), 6.9 (d, 2 H), 7.1 (d, 2 H), 7.3 (d, 1 H), 7.4 (d, 1 H), 7.5 (d, 2 H).
Reaction SMILES: F[C:2]([C:4]1[O:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]=1[C:15]([O:17][CH3:18])=[O:16])=[O:3].O/[N:20]=[C:21](/[C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)=[CH:25][CH:24]=1)\[NH2:22].C(N(C(C)C)CC)(C)C>C(#N)C>[C:35]([O:34][C:32]([CH:30]1[CH2:31][N:28]([CH2:27][C:26]2[CH:39]=[CH:40][C:23]([C:21]3[N:22]=[C:2]([C:4]4[O:8][N:7]=[C:6]([C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=5)[C:5]=4[C:15]([O:17][CH3:18])=[O:16])[O:3][N:20]=3)=[CH:24][CH:25]=2)[CH2:29]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Reactant: COC(=O)c1c(-c2ccccc2)noc1C(=O)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(-c2ccccc2)noc1-c1nc(-c2ccc(CN3CC(C(=O)OC(C)(C)C)C3)cc2)no1
Temperature: 25 °C
Yield: 62.5 %

Procedure:
To a mixture of methyl 5-(fluorocarbonyl)-3-phenylisoxazole-4-carboxylate (99 mg, 0.397 mmol) and (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (121 mg, 0.397 mmol) in acetonitrile (2 mL) at rt was added diisopropylethylamine (0.083 mL, 0.477 mmol) and the reaction mixture was allowed to stir at rt over the weekend. The reaction mixture was partitioned between EtOAc (30 mL) and water (30 mL). The organic layer was washed with brine (20 mL), dried (MgSO4) and concentrated to afford a white solid that was chromatographed on a 12 gm Isco silica gel cartridge, eluting with a 0-100% EtOAc/Hex gradient. The essentially pure fractions containing product were concentrated to afford methyl 5-(3-(4-((3-(tert-butoxycarbonyl)azetidin-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-phenylisoxazole-4-carboxylate (128 mg, 0.248 mmol, 62.4% yield) as a white solid. HPLC retention time=1.78 minutes (YMC Combi 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1 TFA a 2 minute gradient. MS: (M+H)=517.22. 1H NMR (400 MHz, chloroform-d) d ppm 1.45 (s, 9H) 3.23-3.32 (m, 3H) 3.51-3.58 (m, 2H) 3.68 (s, 2H) 3.95 (s, 3H) 7.44 (d, J=8.0 Hz, 2H) 7.48-7.56 (m, 3H) 7.75 (dd, J=7.91, 1.63 Hz, 2H) 8.11 (d, J=8.3 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@H:7]([CH3:12])[CH2:6][C:5]2=[O:13].Cl.NO.C([O-])([O-])=[O:18].[K+].[K+]>O>[F:1][C:2]1[CH:11]=[CH:10][C:9]([O:8][C@H:7]([CH3:12])[CH2:6][C:5]([OH:13])=[O:18])=[CH:4][CH:3]=1
Reactant: C[C@@H]1CC(=O)c2cc(F)ccc2O1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: O
Product: C[C@H](CC(=O)O)Oc1ccc(F)cc1
Temperature: 25 °C
Yield: 184.5 %

Procedure:
6-fluoro-2,3-dihydro-2-methylchromen-4-oxime (13). To a suspension of the ketone 12 (2.79 g, 15.5 mmol) was added a solution of hydroxylamine hydrochloride (2.09 g, 30 mmol) and K2CO3 (1.2 g, 8.75 mmol) in 18 mL of H2O. The reaction mixture was refluxed for four hours. After cooling to room temperature, the solution was removed under vacuum, and the residual solid was triturated with ice water. The crude product was recrystallized from EtOH to give 3.2 g (84%) of the white solid oxime 13, m.p. 102-105° C., 1H NMR (CDCl3) δ 7.58 (br s, 1H), 7.48 (dd, J=3.0, 9.5 Hz, 1H), 6.97 (ddd, J=3.0, 9.0, 8.0 Hz, 1H), 6.85 (dd, J=4.5, 9.0 Hz, 1H), 4.21-4.15 (m, 1H), 3.28 (dd, J=3.0, 17.0 Hz, 1H), 2.37 (dd, J=12.0, 17.0 Hz, 1H), 1.47 (d, J=6.5 Hz, 3H). EI-MS (m/z) 195 (M+). The reaction is shown as follows:
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1)[CH:23]=O.O>CO>[CH3:29][O:28][C:26]1[CH:25]=[C:22]([CH:21]=[C:20]([O:19][CH3:18])[CH:27]=1)[CH2:23][NH:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4]
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Solvent: CO
Solvent: O
Product: COc1cc(CN[C@@H](C)[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
To a solution of the amine (4) (363 mg, 1.39 mmol) and 3,5-dimethoxybenzaldehyde (301 mg, 1.81 mmol) in methanol (10 mL) was added borane-pyridine complex (445 μL, 4.18 mmol) at 40° C. and the resulting mixture was stirred for 2 hours. The reaction mixture was cooled to room temperature and water was added thereto, followed by extraction with a mixed solvent (ethyl acetate:methanol=10:1) and subsequent washing of the organic layer with saturated brine. The organic layer was dried and concentrated and the obtained crude product was purified by amine silica gel column chromatography (eluent; chloroform:methanol=7:1) to obtain the desired amine (5) as a pale yellow solid (329 mg, Yield: 57%).