Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=C(CN)C=1.[CH3:9][N:10]1[CH:14]=[C:13]([CH2:15][NH2:16])[CH:12]=[N:11]1.FC1C=CC(CN2[C@@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1.[F:41][C:42]1[CH:64]=[CH:63][C:45]([CH2:46][N:47]2[CH2:51][C@H:50]([CH3:52])[N:49]([C:53]3[S:54][C:55]([C:59](O)=[O:60])=[C:56]([CH3:58])[N:57]=3)[C:48]2=[O:62])=[CH:44][CH:43]=1>>[F:41][C:42]1[CH:64]=[CH:63][C:45]([CH2:46][N:47]2[CH2:51][C@H:50]([CH3:52])[N:49]([C:53]3[S:54][C:55]([C:59]([NH:16][CH2:15][C:13]4[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=4)=[O:60])=[C:56]([CH3:58])[N:57]=3)[C:48]2=[O:62])=[CH:44][CH:43]=1
Reactant: Cn1cc(CN)cn1
Reactant: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@@H]2C)sc1C(=O)O
Agent: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@@H]2C)sc1C(=O)NCc1cnn(C)c1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with (1-methyl-1H-pyrazol-4-yl)methanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (S)-2-(3-(4-fluorobenzyl)-5-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white solid (70%): mp 176-177° C. (N,N-dimethylformamide/water); 1H NMR (300 MHz, DMSO-d6) δ 8.28 (t, J=5.7 Hz, 1H), 7.56 (s, 1H), 7.36-7.32 (m, 3H), 7.23-7.17 (m, 2H), 4.57-4.50 (m, 1H), 4.42 (d, J=4.4 Hz, 2H), 4.19 (d, J=5.7 Hz, 2H), 3.78 (s, 3H), 3.63-3.57 (m, 1H), 3.03 (dd, J=9.0, 3.4 Hz, 1H), 2.46 (s, 3H), 1.38 (d, J=6.0 Hz, 3H); MS (ES+) m/z 443.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][C:9]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:10]=1[C:11](O)=[O:12]>>[NH2:8][C:9]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:10]=1[C:11]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:12]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: Brc1ccccn1
Product: Nc1ccc(Br)cc1C(=O)c1ccccn1

Procedure:
The anion of 2-bromo-pyridine 121 and 2-amino-5-bromobenzoic acid 122 were condensed to provide the 2′-pyridylketone 123.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1.C(N(CC)CC)C>CS(C)=O>[F:20][C:19]([F:22])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]2)=[N:14][CH:15]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2ccc(C(F)(F)F)cn2)CC1

Procedure:
0.500 g (3.18 mmol) of ethyl piperidine-4-carboxylate, 0.866 g (4.77 mmol) of 2-chloro-5-trifluoromethylpyridine and 0.483 g (4.77 mmol) of triethylamine were reacted in dimethyl sulfoxide at 60° C. overnight. The reaction mixture was partitioned between ethyl acetate and water, the organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to dryness to yield crude ethyl 1-[5-(trifluoromethyl)pyridin-2-yl]piperidine-4-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH:16]=[CH:15][C:3]=1[C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9])=[O:5].[CH2:24]([N:26]([CH2:38][CH3:39])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH:28]=1)[CH3:25].C(OC(=O)C)(=O)C>O>[CH2:36]([N:33]([CH2:34][CH3:35])[C:29]1[CH:28]=[C:27]([N:26]([CH2:38][CH3:39])[CH2:24][CH3:25])[CH:32]=[CH:31][C:30]=1[C:4]1([C:3]2[CH:15]=[CH:16][C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:18][C:2]=2[CH3:1])[C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8](=[O:9])[O:5]1)[CH3:37]
Reactant: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCN(CC)c1ccc(C2(c3ccc(N(CC)CC)cc3N(CC)CC)OC(=O)c3ccccc32)c(C)c1
Temperature: 40 °C

Procedure:
A mixture of 2-(2-methyl-4-(diethylamino)benzoyl)-benzoic acid (12.48 g.), N,N,N',N'-tetraethyl-m-phenylenediamine (10.56 g.) and acetic anhydride (12 ml.) was warmed (at 40±8° C.) during one hour, diluted with water (50 ml., then 100 ml.), adjusted to pH 4.6 and filtered. The filtrate was clarified with water and adjusted to pH 5.5. Recrystallization of the resulting product (m.p. 134°-140° C.) from methanol afforded 3-(2,4-bis(diethylamino)phenyl)-3-(2-methyl-4-(diethylamino)phenyl)phthalide (I: X= Y4 = (CH3CH2)2N, Y2 = CH3, Z4 = Z5 = Z6 = Z7 = H) (m.p. 149°- 151° C.).
Reaction SMILES: Br[C:2]1[C:3]([C:21]([O:23][CH3:24])=[O:22])=[C:4]([NH:7][C:8](=[O:20])[CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][N:14]=[CH:15]3)[S:5][CH:6]=1.[C:25]([Cu])#[N:26].[NH4+].[OH-].C(OCC)C>CN(C=O)C>[C:25]([C:2]1[C:3]([C:21]([O:23][CH3:24])=[O:22])=[C:4]([NH:7][C:8](=[O:20])[CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][N:14]=[CH:15]3)[S:5][CH:6]=1)#[N:26]
Reactant: COC(=O)c1c(Br)csc1NC(=O)Cc1cccc2cnccc12
Reactant: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1c(C#N)csc1NC(=O)Cc1cccc2cnccc12
Temperature: 100 °C

Procedure:
To a stirring mixture of methyl 4-bromo-2-(2-(isoquinolin-5-yl)acetamido)thiophene-3-carboxylate (100 mg) in DMF (0.5 mL) was added CuCN (150 mg). The resulting mixture was heated to 100° C. overnight. The reaction mixture was cooled to room temperature. To this mixture was added a 10% NH4OH solution and ethyl ether. The crude mixture was stirred at rt for 1 h. A normal aqueous workup with ethyl ether was followed. The organic layers were dried over MgSO4, filtered and concentrated under reduce pressure. The crude product mixture was purified by silica gel column chromatography to give methyl 4-cyano-2-(2-(isoquinolin-5-yl)acetamido)thiophene-3-carboxylate. Method[1], MS (ESI) 352.0 [M+H], Retention time=1.343 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][CH2:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][C:12]=2[NH:22][C:23](=[O:38])[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:36][CH2:35][CH2:34][N:33]([CH3:37])[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[NH2:40][OH:41].C(N(CC)CC)C>C(O)C>[OH:41][NH:40][C:1]([C:3]1[CH:4]=[C:5]([NH:9][CH2:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][C:12]=2[NH:22][C:23](=[O:38])[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:36][CH2:35][CH2:34][N:33]([CH3:37])[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)[CH:6]=[CH:7][CH:8]=1)=[NH:2]
Reactant: NO
Reactant: CCOC(=O)c1ccc(CNc2cccc(C#N)c2)c(NC(=O)c2ccc(N3CCCN(C)CC3)cc2)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(CNc2cccc(C(=N)NO)c2)c(NC(=O)c2ccc(N3CCCN(C)CC3)cc2)c1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Ethyl 4-[(3-cyanophenylamino)methyl]-3-[4-(4-methyl-1,4-diazepan-1-yl)benzoylamino]benzoate (1.42 g) was dissolved in 30 ml of ethanol, then 291 mg of hydroxylamine hydrochloride and 0.78 ml of triethylamine were added and the mixture was stirred at 60° C. for 24 hours. The reaction solution was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography using chloroform-methanol-aqueous ammonia (100:0:0 to 92:8:0.8) to give a crudely purified product, ethyl 4-({[3-(N-hydroxycarbamimidoyl)phenyl]amino}methyl)-3-[4-(4-methyl-1,4-diazepan-1-yl)benzoylamino]benzoate. The crudely purified product was further purified by ODS column chromatography using 0.002N aqueous solution of hydrochloric acid-methanol (100:0 to 88:12) as an eluting solvent and freeze-dried to give 1.03 g of ethyl 4-({[3-(N-hydroxycarbamimidoyl)phenyl]amino}methyl)-3-[4-(4-methyl-1,4-diazepan-1-yl)benzoylamino]benzoate hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:29])[C:9]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][N:16]([C@H:23]([CH3:28])[C:24]([O:26]C)=[O:25])[C:17]3=[O:22])=[O:10])=[CH:4][CH:3]=1.[OH-].[Li+].C(O)(C)(C)C.O.Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:29])[C:9]([NH:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]=2[CH:14]=[CH:15][N:16]([C@H:23]([CH3:28])[C:24]([OH:26])=[O:25])[C:17]3=[O:22])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](C)n1ccc2c(NC(=O)[C@@H](C)c3ccc(Cl)cc3)cccc2c1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: C[C@H](C(=O)Nc1cccc2c(=O)n([C@H](C)C(=O)O)ccc12)c1ccc(Cl)cc1

Procedure:
(R)-Methyl 2-(5-((S)-2-(4-chlorophenyl)propanamido)-1-oxoisoquinolin-2(1H)-yl)propanoate (0.23 g, 0.00050 mol) was stirred with lithium hydroxide (0.03 g, 0.001 mol) in tert-butyl alcohol (4 mL, 0.04 mol) and water (2 mL, 0.1 mol) at 0° C. for 1 hour. 1 N HCl was added until pH<7 and the reaction mixture was extracted with CH2Cl2 (40 mL×3). The organic layers were dried over MgSO4, filtered, purified via flash chromatography (12 g of silica gel, 0-50% EtOAc/Hexane) and gave a light yellow solid. 1H NMR δ (CDCl3) δ: 8.05-8.01 (m, 1H), 7.89-7.62 (m, 2H), 7.38-7.29 (m, 5H), 6.89-6.80 (m, 1H), 6.04-5.94 (m, 1H), 5348-5.39 (m, 1H), 3.86 (d, J=6.6 Hz, 1H), 3.03-2.88 (m, 6H). MS m/z 399.0 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([O:21]C)=[CH:4][C:5]([O:19]C)=[C:6]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17]C)=[CH:16][C:11]=3[O:10][N:9]=2)[CH:7]=1.[Li][CH2:24]CCC.IC.B(Br)(Br)Br>C1COCC1>[OH:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]([C:6]3[CH:7]=[C:2]([CH3:24])[C:3]([OH:21])=[CH:4][C:5]=3[OH:19])=[N:9][O:10][C:11]=2[CH:16]=1
Reactant: COc1ccc2c(-c3cc(Br)c(OC)cc3OC)noc2c1
Reactant: [Li]CCCC
Agent: BrB(Br)Br
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(-c2noc3cc(O)ccc23)c(O)cc1O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
To a solution of 3-(5-bromo-2,4-dimethoxyphenyl)-6-methoxy-1,2-benzisoxazole (200 mg, 0.55 mmol) in THF (6 mL) at −78° C. was added n-BuLi (0.24 mL, 0.60 mmol, 2.5 M in hexanes) dropwise. The solution was stirred at −78° C. for 30 min and then iodomethane (60 μL, 0.96 mmol) was added dropwise. The cooling bath was switched to an ice bath and the solution was stirred at 0° C. for 2 h. The reaction was quenched with water, most of the solvent was removed in vacuo, and extraction was conducted in EtOAc (2×30 mL) with water (20 mL). Flash chromatography with silica gel (gradient to 25% EtOAc/hexanes) provided a mixture of the desired methylated product and the protonated side product (both compounds have the same Rf). The above mixture of compounds was treated with BBr3 according to Example 2, Step i, to produce the title compound as a light orange solid (114 mg, 81% yield for two steps): mp 195° C. (dec.); 1H NMR (300 MHz, acetone-d6) δ 2.25 (s, 3H), 6.59 (s, 1H), 7.04 (dd, 1H, J=8.5, 2.1 Hz), 7.09 (d, 1H, J=1.8 Hz), 7.80 (s, 1H), 8.12 (d, 1H, J=8.8 Hz), 8.88 (broad s, 1H), 9.42 (broad s, 1H), 9.52 (s, 1H); MS m/e 258 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17](O)=[O:18])=[C:12]([N+:20]([O-])=O)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]>C(O)(=O)C.[Fe]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]3[C:13]([CH2:16][C:17](=[O:18])[NH:20]3)=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(-c2ccc(CC(=O)O)c([N+](=O)[O-])c2)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Yield: 90.5 %

Procedure:
Iron chips (2.4 g) were added in one portion to 4.6 g of 3′-ethoxy-3-nitrobiphenyl-4-acetic acid in glacial acetic acid (40 ml). The mixture was refluxed for 2 hours. The reaction mixture was cooled and concentrated to dryness. The residue was treated repeatedly with ethyl acetate and filtered to remove insolubles. The filtrate was washed twice with 1 N hydrochloric acid and brine, dried over anhydrous sodium sulfate and concentrated to give 3.5 g (91%) of 6-(3-ethoxyphenyl)-2-oxindole as a light brown solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[N:7]2[CH:13]=[N:12][CH:11]=[C:8]2[S:9][CH:10]=1.C(N(CC)CC)C.[S:21](Cl)(=[O:24])(=[O:23])[NH2:22]>CN(C=O)C>[NH2:22][S:21]([N:4]([CH2:5][C:6]1[N:7]2[CH:13]=[N:12][CH:11]=[C:8]2[S:9][CH:10]=1)[CH2:3][CH2:2][OH:1])(=[O:24])=[O:23]
Reactant: NS(=O)(=O)Cl
Reactant: OCCNCc1csc2cncn12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)N(CCO)Cc1csc2cncn12
Temperature: -25 °C
Reaction time: 4 h

Procedure:
A 410 mg potion of 3-[N-(2-hydroxyethyl)amino]methyl imidazo[5,1-b]thiazole was dissolved in 6 ml of DMF, and 1.40 ml of triethylamine and 491 mg of sulfamoyl chloride were added thereto at -30° C., followed by stirring at -30 to -20° C. for 4 hours. The reaction solution was concentrated under reduced pressure, dissolved in water, adjusted to pH 7.5 with an aqueous sodium hydrogencarbonate solution, and then purified by Diaion HP-20 Resin and Cephadex LH-20, whereby 59 mg of 3-[N-aminosulfonyl-N-(2-hydroxyethyl)amino]methylimidazo[5,1-b]thiazole was obtained from the first half of the fraction of Cephadex LH-20.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.C[N:19](C)C=O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([NH2:19])=[O:5]
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(F)ccc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1cc(F)ccc1Br
Reaction time: 4 h
Yield: 96 %

Procedure:
A solution of 2-bromo-5-fluorobenzoic acid (10.0 g, 45.66 mmol) in dichloromethane (100 ml) was treated at 25° C. with oxalyl chloride (8.0 ml, 91.3 mmol) followed by a drop of N,N-dimethylformamide. The resulting mixture was then stirred for 4 h. The solvent and excess reagent were evaporated in vacuo and the residual oil was dissolved in tetrahydrofuran (100 ml) and added to a mixture of tetrahydrofuran (200 ml), water (100 ml) and concentrated ammonium hydroxide (10 ml). The resulting mixture was then stirred at 25° C. for 20 h. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated to give 9.51 g (96% yield) of the title amide as a white solid. 1HNMR 400 MHz (CDCl3) δ (ppm): 5.9-6.3 (2H, broad, NH2), 7.05 (1H, m, aromatic), 7.42 (1H, dd, J=3.2 Hz and J=8.3 Hz, aromatic), 7.61 (1H, dd, J=5.1 Hz and J=9.1 Hz, aromatic).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([OH:15])=O)[O:10][C:11]=2[CH3:12])=[C:5]([CH3:16])[CH:4]=[N:3]1.[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21]3=[O:30])=[O:15])[O:10][C:11]=2[CH3:12])=[C:5]([CH3:16])[CH:4]=[N:3]1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1cnn(C)c1-c1cc(C(=O)O)oc1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnn(C)c1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (53 mg, 0.24 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (93 mg, 0.24 mmol)[prepared according to Preparation 6] and N,N-diisopropylethylamine (0.21 ml, 1.20 mmol) in dichloromethane (2.4 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (124 mg, 0.26 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(1,4-dimethyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide (113 mg, 0.21 mmol, 85% yield) as a white foam: LCMS (ES) m/e 551 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].C(N(CC)CC)C.Cl>C(#N)C.[C-]#N.[Zn+2].[C-]#N>[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15]([CH:8]1[C:9](=[O:10])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:11])[C:6]1=[O:7])=[O:16]
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN1C(=O)C(C(=O)c2ccc(Cl)cc2Cl)C(=O)N(C)C1=O
Yield: 80.2 %

Procedure:
1,3-Dimethylbarbituric acid (15.6 g, 0.1 mole), 2,4-dichlorobenzoyl chloride (20.9 g, 0.1 mole) and zinc cyanide (12.9 g, 0.11 mole) were combined in acetonitrile (175 ml). Triethylamine (10.1 g, 0.12 mole) was slowly added with cooling. The reaction mixture was then heated at reflux for one hour. After cooling, the reaction mixture was poured into 2N hydrochloric acid. The resulting product precipitate was filtered and washed with ether to afford 26.4 grams of the desired product, m.p. 123°-127° C. (80.2% yield). The structure was confirmed by instrumental analysis.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([CH3:9])=[CH:4][N:3]=1.Br[CH:11]([CH3:15])[C:12](=O)[CH3:13].C(N(CC)CC)C>C(O)C>[NH2:8][C:7]1[C:2]2[N:3]([C:11]([CH3:15])=[C:12]([CH3:13])[N:1]=2)[CH:4]=[C:5]([CH3:9])[CH:6]=1
Reactant: CC(=O)C(C)Br
Reactant: Cc1cnc(N)c(N)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(N)c2nc(C)c(C)n2c1
Yield: 37.5 %

Procedure:
To a solution of 2,3-diamino-5-methylpyridine (2.0 g, 16 mmol) in ethanol (100 ml) was added 3-bromo-2-butanon (2.4 g, 16 mmol). The reaction mixture was refluxed for 16 h. An additional amount of 3-bromo-2-butanon (1.0 g 6.7 mmol) and triethylamine (1.0 g, 9.9 mmol) were added and the mixture was refluxed for 2 h. The ethanol was evaporated under reduced pressure and the residue was treated with methylene chloride and a solution of bicarbonate. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The oily residue was purified by column chromatography on silica gel, using methanol:methylene chloride (1:20) as eluent to give the desired product (1.05 g, 37%).
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[N:16]=[N:15][CH:14]=1>O.C(O)C>[Cl:23][C:19]1[CH:18]=[C:17]2[C:22]([C:13]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([S:1]([OH:11])(=[O:10])=[O:2])=[CH:8][CH:7]=3)=[CH:14][N:15]=[N:16]2)=[CH:21][CH:20]=1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Reactant: Clc1ccc2c(Cl)cnnc2c1
Solvent: CCO
Solvent: O
Product: O=S(=O)(O)c1ccc(Nc2cnnc3cc(Cl)ccc23)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Sulphanilic acid (1.95 g) in water (75 ml) and ethanol (10 ml) at 70° C. was treated with 4,7-dichlorocinnoline (2.2 g) and ethanol (10 ml) was added. The resultant green suspension was stirred vigorously overnight at 70° C. The mixture was cooled, and the solid was filtered, washed with water and dried at room temperature to give 3.45 g of the title compound as the monohydrate, melting point greater than 280° C.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:47]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])(=[O:50])[NH:48][NH2:49]>CN(C=O)C>[C:52]([O:51][C:47]([NH:48][NH:49][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:18]([N+:20]([O-:22])=[O:21])=[CH:19][C:11]=1[F:10])=[O:50])([CH3:55])([CH3:54])[CH3:53]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: CC(C)(C)OC(=O)NN
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: CC(C)(C)OC(=O)NNC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57.3 %

Procedure:
N, N-Diisopropylethylamine (14.1 ml, 0.081 mol) is added to 2-fluoro-4-nitrobenzoic acid (5 g, 0.027 mol) and O-(7-azabenzotriazol-1-yl)-N, N, N′, N′-tetramethyluronium hexafluorophosphate (10.8 g, 0.0284 mol) in DMF (100 ml) and the mixture stirred at room temperature for 20 minutes. tert-Butyl carbazate (3.57 g, 0.0270 mol) is added in one portion and the reaction stirred overnight at room temperature. The mixture is concentrated and diluted with water (100 ml). The resulting precipitate is filtered, washed well with water, and dried under vacuum to give the title compound as a white solid (4.63 g, 57%), [M+H]+=300.
Reaction SMILES: [C:1]([O:4][C:5](=[O:17])[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[OH:7])(=[O:3])[CH3:2].[C:18]([O:21][CH2:22]Br)(=[O:20])[CH3:19].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:18]([O:21][CH2:22][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])([OH:7])[C:5]([O:4][C:1](=[O:3])[CH3:2])=[O:17])(=[O:20])[CH3:19]
Reactant: CC(=O)OCBr
Reactant: CC(=O)OC(=O)C(O)c1ccccc1[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(O)(C(=O)OC(C)=O)c1ccccc1[N+](=O)[O-]
Yield: 87.1 %

Procedure:
A pale brown solution of O-Acetyl-2-nitromandelic acid (23) (14 mg, 0.059 mmol), bromomethyl acetate (10 μL, 0.10 mmol), and triethylamine (10 μL, 0.072 mmol) in chloroform (1 mL) is incubated overnight. The volatiles are removed in vacuo, and the residue is purified by flash chromatography (chloroform) to give 16 mg of the title compound (24) as a clear colorless oil, Rf 0.65 (5% MeOH/chloroform.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1.OC1C=CC(O)=CC=1C(=O)C.[F:31][C:32]([F:42])([F:41])C1C=CC(C=O)=CC=1>>[OH:19][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[O:9][CH:8]([C:4]1[CH:5]=[CH:6][C:7]([C:32]([F:42])([F:41])[F:31])=[CH:2][CH:3]=1)[CH2:17][C:16]2=[O:18]
Reactant: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CC(=O)c1cc(O)ccc1O
Product: O=C1CC(c2ccc(C(F)(F)F)cc2)Oc2ccc(O)cc21

Procedure:
6-Hydroxy-2-(4-trifluoromethylphenyl)chroman-4-one was prepared as described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 2.0 g of 2′,5′-dihydroxyacetophenone and 2.1 ml of 4-trifluoromethylbenzaldehyde. The product was purified by column chromatography using heptane-ethyl acetate (2:1) as an eluant. Further purification was carried out by column chromatography using toluene-ethyl acetate (4:1) as an eluant. Finally the product was crystallised from ethanol. 1H NMR (400 MHz, d6-DMSO) δ: 9.47 (s, 1H), 7.82-7.76 (m, 4H), 7.13 (d, 1H, J 3.0 Hz), 7.06 (dd, 1H, J 8.8, 3.0 Hz), 6.99 (d, 1H, J 8.8 Hz), 5.70 (dd, 1H, J 12.9, 2.9 Hz), 3.16 (dd, 1H, J −16.9, 12.9 Hz), 2.86 (dd, 1H, J −16.9, 2.9 Hz).