Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:8]=2)=[CH:4][CH:3]=1.[OH2:23]>C(O)(=O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:7]2[N:11]([CH3:12])[N:10]=[C:9]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:8]=2)=[O:23])=[CH:4][CH:3]=1
Reactant: O
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1Cc1ccc(Cl)cc1
Solvent: CC(=O)O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.0 g of 5-(4-chlorobenzyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole in 20 ml of acetic acid at 10° C., was added 1.2 g of chromic anhydride. After stirring at room temperature overnight, the reaction mixture was poured into iced water and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturatedaqueous sodium hydrogen carbonate solution and then with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 1.7 g of 5-(4-chlorobenzoyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole.
Reaction SMILES: [N:1]1([C:7]([C:9]2[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][C:12]([C:13](OCC3C=CC=CC=3)=[O:14])=[C:11]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Li+].Cl.C(N(C(C)C)CC)(C)C.[NH2:49][C:50]1[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>O1CCCC1.O.C(OCC)(=O)C>[N:1]1([C:7]([C:9]2[C:24]([C:25]([F:27])([F:26])[F:28])=[CH:23][C:12]([C:13]([NH:49][C:50]3[CH:51]=[N:52][CH:53]=[CH:54][CH:55]=3)=[O:14])=[C:11]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:10]=2)=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1cccnc1
Reactant: O=C(OCc1ccccc1)c1cc(C(F)(F)F)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Agent: Cl
Agent: On1nnc2cccnc21
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cccnc1)c1cc(C(F)(F)F)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Temperature: 45 °C
Reaction time: 18 h

Procedure:
To a solution of phenylmethyl 4-(4-morpholinylcarbonyl)-2-[(phenylmethyl)oxy]-5-(trifluoromethyl)benzoate (may be prepared as described in Description 56; 64 mg, 0.13 mmol) in tetrahydrofuran (3 ml) was added lithium hydroxide (9.21 mg, 0.38 mmol) and water (0.75 ml). The solution was heated at 45° C. for one hour, cooled and 2M hydrochloric acid (0.19 ml, 0.38 mmol) was added. The solvent was removed in vacuo and the residue redissolved in N,N-dimethylformamide (4 ml). Diisopropylethylamine (0.06 ml, 0.32 mmol), 3-aminopyridine (18.09 mg, 0.19 mmol), 1-hydroxy-7-azabenzotriazole (22.67 mg, 0.17 mmol) and EDC (44.2 mg, 0.23 mmol) were added and the mixture was stirred for 18 hours. Ethyl acetate (20 ml) and water (10 ml) were added and the organic layer washed further with water (2×5 ml), dried (MgSO4) and the solvent removed in vacuo to give a gum. Purification by MDAP gave the title compound as a white solid. 38 mg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][C:10]([CH:12]=[O:13])=[CH:9][CH:8]=2)[CH:2]=1.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][C:10]([CH2:12][OH:13])=[CH:9][CH:8]=2)[CH:2]=1
Reactant: O=Cc1ccc(-c2cccnc2)o1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(-c2cccnc2)o1
Yield: 92.1 %

Procedure:
To a slurry of 23 (54 mg, 0.31 mmol) in CH3OH (5 mL) was added sodium borohydride (12 mg, 0.31 mmol) in one portion and the resultant solution was stirred at room temperature for 10 min. The reaction was stopped by the addition of aqueous sodium bicarbonate (50:50 satd. soln./water, v:v) and the CH3OH was removed in vacuo. The residue was partitioned between water (20 mL) and ether (20 mL), the organic layer was collected and the aqueous fraction was re-extracted with ether (2×20 mL). The combined organic portions were washed with water (20 mL), dried (MgSO4), filtered and concentrated in vacuo to afford the title compound 45 (50 mg, 92% yield) as an off white solid: mp=119-120° C.; 1H NMR (CDCl3, 500 MHz) δ 8.88 (s, 1H), 8.42 (m, 1H), 7.88 (m, 1H), 7.27, (m, 1H), 6.65 (d, J=3.1 Hz, 1H), 6.38 (d, J=3.1 Hz, 1H), 4.66 (s, 2H); LRMS (ESI) m/z calcd for C10H10NO2 [M+H]+ 176. found 176; HRMS (ESI) m/z calcd for C10H10NO2[M+H]+ 176.0712. found 176.0694; HPLC>98% (tR=4.60 min, 55 (A):45 (B): 0.032 (C); tR=3.64 min, 55 (A):45 (B): 0.1 (C)).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:38])[C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)=[O:20])[CH2:15]1>>[C:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:38])[C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:35])([F:37])[F:36])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CNC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(c2ccccc2)CC1
Product: O=C(CNC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccccc3)CC2)C1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-phenyl-cyclohexanone (Aldrich) and N-(azetidin-3-ylcarbamoylmethyl)-3,5-bistrifluoromethyl-benzamide (as prepared in the previous step) using the procedure described in Step C of Example 4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C@@H:5]([NH:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[C@@H:5]([NH:16][C:17](=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
(S)-Ethyl-2-benzoylamino-3-(4-nitrophenyl)propionate (0.542 g, 1.58 mmol) was dissolved with warming in EtOH (20 mL) and to the cooled solution was added 10% Pd/C (0.108 g, 20% w/w). The mixture was stirred overnight at room temperature under a balloon of H2. The mixture was filtered through a pad of celite and the filtrate was concentrated to an off-white solid and flash chromatographed (silica gel, 1:1 hexanes:EtOAc) to afford the title compound as a white solid (0.323 g, 66%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][C:8]3[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:9]=3[N:10]=2)[CH2:3]1.[Cl:20][C:21]1[N:22]=[C:23]([C:28](O)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:20][C:21]1[N:22]=[C:23]([C:28]([NH:1][CH:2]2[CH2:5][N:4]([C:6]3[S:7][C:8]4[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[CH:11][C:9]=4[N:10]=3)[CH2:3]2)=[O:29])[NH:24][C:25]=1[CH2:26][CH3:27]
Reactant: CCOC(=O)c1ccc2nc(N3CC(N)C3)sc2c1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCOC(=O)c1ccc2nc(N3CC(NC(=O)c4nc(Cl)c(CC)[nH]4)C3)sc2c1
Yield: 42.1 %

Procedure:
The same operation as in Example (221c) was performed using ethyl 2-(3-aminoazetidin-1-yl)-1,3-benzothiazole-6-carboxylate obtained in Example (225c) (190 mg, 0.69 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (132 mg, 0.75 mmol), WSC hydrochloride (394 mg, 2.06 mmol), 1-hydroxybenzotriazole (102 mg, 0.75 mmol) and N-methylmorpholine (0.15 mL, 1.37 mmol), to obtain 126 mg of the title compound as a milk white solid (42%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]([O:19]CC)=O)[N:8]=2)=[N:2]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([Mg]Br)=[CH:25][CH:24]=1>C1COCC1>[NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:17]([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)([C:26]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)[OH:19])[N:8]=2)=[N:2]1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)c1nc(Nc2cc[nH]n2)c2ccccc2n1
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)c1nc(Nc2cc[nH]n2)c2ccccc2n1
Temperature: -40 °C
Reaction time: 2 h
Yield: 8 %

Procedure:
To a stirred solution of ethyl 4-(1H-pyrazol-3-ylamino)quinazoline-2-carboxylate (595 mg, 2.1 mmol) in THF (15 mL) at −40° C., was added dropwise a 2 M solution of 4-fluorophenylmagnesium bromide in THF (4.2 mL, 8.4 mmol). The mixture was stirred at −40° C. for 2 h and then stored at −30° C. for 18 h. The reaction was quenched by adding 0.5 N HCl at 0° C. and the mixture was extracted with EtOAc (2×20 mL). The solid precipitate from the combined organic layers was removed by filtration and the resulting filtrate was washed with brine. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with 0-5% MeOH/DCM to afford (4-(1H-pyrazol-3-ylamino)quinazolin-2-yl)bis(4-fluorophenyl)methanol as a solid (75 mg, 8%). 1H NMR (300 MHz, DMSO-d6) δ 12.50 (s, 1H), 10.66 (s, 1H), 8.67 (d, J=8.1, 1H), 7.81-7.87 (m, 2H), 7.60-7.62 (m, 2H), 7.42-7.47 (m, 4H), 7.07-7.13 (m, 4H), 6.66 (s, 1H), 6.26 (s, 1H); LC-MS (ESI) m/z 430 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[C:6]([Cl:13])[C:3]=1[C:4]#[N:5].[OH-].[Na+]>CN(C=O)C.O>[NH2:10][C:9]1[C:2]([Cl:1])=[C:3]([C:6]([Cl:13])=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: N#Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(Cl)ccc(N)c1Cl

Procedure:
A solution of 2,6-dichloro-3-nitrobenzonitrile (1.38 mmol) and SnCl2 dihydrate (4.15 mmol) in 3 mL DMF was heated to 100° C. for 10 min under microwave conditions. The reaction mixture was diluted with water, basified with 1M NaOH solution to pH 11-12 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to give the desired product as brown solid;
Reaction SMILES: [C:1]([Si:5]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11]O)([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:26].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:26][CH2:11][CH2:10][C:9]#[C:8][CH2:7][O:6][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)[Si](OCC#CCCO)(c1ccccc1)c1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC#CCCBr)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
A solution of compound 5 (1.09 g, 3.22 mmol) and CBr4 (1.28 g, 3.86 mmol) in CH2Cl2 (70 mL) was treated with a solution of Ph3P (1.27 g, 4.84 mmol) in CH2Cl2 (30 mL) dropwise at −78° C. After 30 min, the reaction mixture was slowly warmed up to room temperature for 2 h and then stirred for overnight. The reaction mixture was poured to the silica gel pad. The filtrate was concentrated to dryness. After concentration, the residue was purified with 0˜2% EtOAc in hexanes by silica gel column chromatography to give 1.28 g of product 6 (3.19 mmol, 99% yield); 1H NMR (CDCl3) δ 7.80˜7.65 (m, 4H), 7.50˜7.32 (m, 6H), 4.34 (t, J=1.9 Hz, 1H), 3.35 (t, J=5.8 Hz, 2H), 2.73 (tt, J=2.1, 6.0 Hz, 2H) 1.08 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Br:9])[CH:8]=1)N.BrC1C=C([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)C=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[C:7]([Br:9])[CH:8]=1
Reactant: Nc1cc(Br)cc(Br)c1
Reactant: Brc1cccc(-c2cccs2)c1
Product: Brc1cc(Br)cc(-c2cccs2)c1
Yield: 55 %

Procedure:
3,5-dibromoaniline was treated as described in the procedure for 2-(3'-bromophenyl)thiophene to give 2-(3',5'-dibromophenyl)thiophene in 55% yield as a yellow oil, which solidified as a glassy solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[NH2:19].FC1C=CC(NC2CCN(C(OC(C)(C)C)=O)CC2)=CC=1OC>>[F:15][C:16]1[CH:17]=[C:18]([NH:19][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1ccc(N)cc1F
Agent: COc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1F
Product: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1F

Procedure:
The title compound was prepared from 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate and 3-fluoro-4-methoxyaniline using a method similar to that described for D9 in Description 9.
Reaction SMILES: [F:1][C:2]1[C:7]2[S:8][CH:9]=[C:10]3[C:14](=[O:15])[N:13]([C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=4)[N:12]=[C:11]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:58][N:59]([CH3:64])[CH2:60][CH2:61][CH2:62][NH2:63]>CC(N(C)C)=O>[CH3:58][N:59]([CH3:64])[CH2:60][CH2:61][CH2:62][NH:63][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][C:16]([N:13]2[C:14](=[O:15])[C:10]3=[CH:9][S:8][C:7]4[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=4[C:11]3=[N:12]2)=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccc(-n2nc3c4cccc(F)c4scc-3c2=O)cc1
Reactant: CN(C)CCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCCNC(=O)c1ccc(-n2nc3c4cccc(F)c4scc-3c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(6-Fluoro-3-oxothiochromeno[4,3-c]pyrazol-2(3H)-yl)benzoic acid (41 mg, 0.12 mmol) was dissolved in anhydrous dimethyl-acetamide(1 ml). Diisopropyl-ethyl amine (46 mg, 0.36 mmol, 62 μl) was added followed by [(benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammonium hexafluoro phosphate (65 mg, 0.17 mmol) and 3-dimethylaminopropylamine (12 mg, 0.12 mmol). The mixture was stirred at room temperature overnight and purified by preparative HPLC. The title compound was isolated as a brown solid. LCMS: m/z 425 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])=[O:22]>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH3:32])=[O:22])[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: COc1ccc(C(=O)CBr)c(OC)c1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cn2c(CC(F)(F)F)nc3cc(Cl)c(Cl)cc32)c(OC)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (317 mg) in DMF (5 mL) was added sodium hydride (71 mg of 60% in oil dispersion). The resulting mixture was stirred at room temperature for 5 min. To the dark green solution was added 2-bromo-2′,4′-dimethoxyacetophenone (382 mg) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes) to yield the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:27]([OH:28])=[CH:26][C:8]2[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][CH2:19][C:7]=2[CH:6]=1)=[CH:15][C:14]([Br:20])=[C:13]([C:21]([F:24])([F:23])[F:22])[C:12]=4[F:25])=[O:4].C(O)C.O.[Li+].[OH-]>C(OCC)(=O)C>[Br:20][C:14]1[CH:15]=[C:16]2[C:11](=[C:12]([F:25])[C:13]=1[C:21]([F:22])([F:23])[F:24])[NH:10][C:9]1[C:8]3[CH:26]=[C:27]([OH:28])[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[CH2:19][CH2:18][C:17]2=1
Reactant: COC(=O)c1cc2c(cc1O)-c1[nH]c3c(F)c(C(F)(F)F)c(Br)cc3c1CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc2c(cc1O)-c1[nH]c3c(F)c(C(F)(F)F)c(Br)cc3c1CC2
Temperature: 50 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
A sample of 8-Bromo-10-fluoro-2-hydroxy-9-trifluoromethyl-5,11-dihydro-6H-benzo[a]carbazole-3-carboxylic acid methyl ester (28.9 mg, 63.4 μmol) is treated with ethanol (0.3 mL) and water (0.5 mL) followed by LiOH (4 mg, 190 μmol). The reaction is then stirred at 50° C. overnight. The reaction is then diluted with ethyl acetate and extracted with 1 M HCl. The organics are then dried over MgSO4, filtered and the solvent is removed. The resulting residue is purified using a UV triggered HPLC to afford 22 mg of the title compound as a white solid; 1H NMR (400 MHz, MeOD) δ 7.78 (s, 1H), 7.76 (s, 1H), 7.32 (s, 1H), 3.00 (m, 2H), 2.95 (2, H); LC/MS calculated for [M+H]+ C18H11F4NO3: 445.1, found: 445.9.
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:14])=[C:6]([O:12]C)[CH:7]=[C:8]([CH:11]=1)[CH:9]=[O:10])([O-:3])=[O:2].B(Br)(Br)Br>ClCCl>[N+:1]([C:4]1[CH:11]=[C:8]([CH:7]=[C:6]([OH:12])[C:5]=1[OH:14])[CH:9]=[O:10])([O-:3])=[O:2]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 48 h
Yield: 55.4 %

Procedure:
35 g of 5-nitro vanillin (commercial) and 1200 ml of dichloromethane were mixed together under nitrogen and the mixture was cooled to 0° C. 533 ml of a molar solution of boron tribromide in dichloromethane were added and the mixture stood for 2 days at abmient temperature and then was concentrated. The residue was taken up cold (ice bath+methanol) in 300 ml of 2N hydrochloric acid and the mixture was stirred for two to three hours at this temperature, then left for 16 hours at ambient temperature. Extraction was carried out with ethyl acetate and the organic phase was washed, dried and concentrated to obtain 18 g of the expected product melting at >260° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[S:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[S:15].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[N:1]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[C:19]3/[C:17](=[O:18])[NH:16][C:14](=[S:15])[S:13]/3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc2ncccc2c1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=S)S/C1=C\c1ccc2ncccc2c1
Temperature: 25 °C
Yield: 98.6 %

Procedure:
The suspension of 6-quinolinecarboxaldehyde (6 g, 38 mmol), rhodanine (2-thioxo-4-thiazolidinone) (5.08 g, 38 mmol) and sodium acetate (12.5 g, 152 mmol) in acetic acid (50 mL) was stirred under reflux for 12 h. After cooling to room temperature, water (150 mL) was added. The solid was collected by filtration, washed with water and dried to obtain 5-[1-quinolin-6-yl-meth-(Z)-ylidene]-2-thioxo-thiazolidin-4-one (10.2 g, 98%) as a yellow solid. LC-MS m/e 273 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](OC)[N:3]=1.[F:13][C:14]([F:23])([F:22])[C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N+:8]([C:7]1[C:2]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:13])([F:22])[F:23])[CH:16]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1Oc1cccc(C(F)(F)F)c1
Temperature: 70 °C
Yield: 59.1 %

Procedure:
A solution of 2-chloro-6-methoxy-3-nitropyridine (20 g, 125 mmol) in DMF (120 mL) was treated with 3-trifluoromethylphenol (21 g, 129 mmol) and cesium carbonate (50 g, 154 mmol). The mixture was heated at 70° C. for 14 h. The reaction was concentrated. The residue was dissolved in ethyl acetate and washed with brine, 5% lithium chloride, and aqueous HCl and brine. After concentration, purification was achieved by column chromatography on silica gel using a continuous gradient from 0% to 40% ethyl acetate in hexanes as eluant afforded 21 g (60% yield) of 3a as a white crystals. [M+H]+=285.17.
Reaction SMILES: CS([C:4]1[NH:5][CH:6]=[C:7]([CH2:12][CH2:13][CH2:14][CH3:15])[C:8]=1[N+:9]([O-:11])=[O:10])=O.[CH3:16][C:17]1[NH:21][CH:20]=[N:19][C:18]=1[CH2:22][S:23][CH2:24][CH2:25][NH2:26].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31]>C(O)C.C(O)(C)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]\[C:30]([OH:32])=[O:31].[CH3:16][C:17]1[NH:21][CH:20]=[N:19][C:18]=1[CH2:22][S:23][CH2:24][CH2:25][NH:26][C:4]1[NH:5][CH:6]=[C:7]([CH2:12][CH2:13][CH2:14][CH3:15])[C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CCCCc1c[nH]c(S(C)=O)c1[N+](=O)[O-]
Agent: O=C(O)/C=C\C(=O)O
Solvent: CC(C)O
Solvent: CCO
Product: CCCCc1c[nH]c(NCCSCc2nc[nH]c2C)c1[N+](=O)[O-]
Yield: 9.7 %

Procedure:
2-Methylsulphinyl-3-nitro-4-n-butylpyrrole (2.78 g) was dissolved in ethanol and added to a solution of 2-(5-methyl-4-imidazolylmethylthio)ethylamine (2.08 g) in ethanol (total 100 ml). The mixture was heated under reflux for nine days. The solution was evaporated to dryness, and the residue was chromatographed on a silica gel column using chloroform and ethyl acetate to give 0.65 g of crude product as a brown oil. The crude product was dissolved in isopropanol (30 ml) and reacted with a solution of maleic acid (0.5 g) in 2-propanol. The mixture was warmed on a steam bath for a few minutes and then allowed to cool, yielding bright yellow crystals of 2-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amino-3-nitro-4-n-butylpyrrole maleate (0.19 g), m.p. 94°-95°.
Reaction SMILES: [CH:1]1([C:4]2[C:13]3[O:12][CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][C:7]=3[S:6][CH:5]=2)[CH2:3][CH2:2]1.[Br:21]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[Br:21][C:5]1[S:6][C:7]2[CH2:8][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:11][O:12][C:13]=2[C:4]=1[CH:1]1[CH2:2][CH2:3]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCOc2c(C3CC3)csc2C1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCOc2c(sc(Br)c2C2CC2)C1
Yield: 75.6 %

Procedure:
A solution of tert-butyl 8-cyclopropyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (375 mg) obtained in Example 3, step 1, N-bromosuccinimide (237 mg) and acetonitrile (3 ml) was stirred at room temperature for 2 hr, 10% aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 2→10% ethyl acetate/hexane) to give the title compound (359 mg, 75%) as an oil.
Reaction SMILES: [NH:1]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[NH2:2].C1(C)C=CC=CC=1.[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12>O>[O:21]=[C:20]1[C:19]2[C:18](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17](=[O:22])[N:2]1[NH:1][C:3](=[O:4])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NN
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)NN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 104.1 %

Procedure:
250 g of tert-butyl hydrazinecarboxylate was added to toluene (3 L) solution of 280 g of phthalic anhydride. Using a Dean-Stark water separator, the reaction mixture was heated under reflux for 3 hours. This was cooled to room temperature, the formed solid was taken out through filtration to obtain 516 g of crude tert-butyl (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)carbamate.