Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:10]=[C:9]([O:11][C:12](=[O:14])[CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 57 %

Procedure:
To a solution of 2-fluoro-4-hydroxybenzoic acid (1.87 g, 12 mmol) in 30 mL pyridine was added acetic anhydride (1.84 g, 18 mmol) and catalytic amount of DMAP and the reaction mixture was stirred at rt for 15 h. The pyridine was removed under reduced pressure; the residue was dissolved in EtOAc (100 mL), washed with 1N HCl (20 mL), water (20 mL) and dried over anhydrous Na2SO4. Removal of solvent gave 2-fluoro-4-acetoxybenzoic acid in 57% yield (1.35 g). To a suspension of 2-fluoro-4-acetoxybenzoic acid (1.33 g, 6.71 mmol) in 10 mL anhydrous dichloromethane was added oxalyl chloride (2.56 g, 20.13 mmol). Two drops of DMF was added and the reaction mixture was stirred at rt for 3 h. The solvent and excess oxalyl chloride were removed under reduced pressure to give 1.48 g of 2-fluoro-4-acetoxybenzoyl chloride which was used in next step without purification. To a solution of 2′-hydroxyacetophenone (0.93 g, 6.83 mmol) in 15 mL anhydrous pyridine was added 2-fluoro-4-acetoxybenzoyl chloride (1.48 g, 6.83 mmol) and the reaction mixture was stirred at rt for 15 h under nitrogen atmosphere. Then the reaction mixture was poured into 100 mL 2N HCl, extracted with EtOAc (200 mL). The crude compound was purified by column chromatography (Silica Gel 230-400 mesh; 20% EtOAc in hexanes as eluent) to give 4-acetoxy-2-fluorobenzoic acid 2-acetyl phenyl ester (1.14 g, 53%). The ester compound (0.74 g, 2.34 mmol) was dissolved in 10 mL anhydrous THF. Potassium tert-butoxide (0.53 g, 4.68 mmol) was added in portions and stirred at rt under nitrogen for 1 h. A yellow solid was formed. The reaction mixture was quenched with 15 mL saturated aqueous ammonium chloride. EtOAc (100 mL) was added and the organic phase was separated and dried over anhydrous Na2SO4. Removal of solvent gave crude product (0.725 g) which was used in next step without further purification. This crude compound (0.72 g, 2.62 mmol) was dissolved in 10 mL glacial AcOH, conc. HCl (1 mL) was added and the reaction mixture was stirred at 110° C. for 4 h. The reaction mixture was cooled to rt. The solid was isolated by filtration, washed with AcOH and dried under vacuum to give 126 mg (21%) over 2 steps. MS (ES) m/z: 256.89 (M), 255.86 (M−1); Mp. 287-289° C.
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].[Cl:7][C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=2[C:21]2[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:10][CH:9]=1.OO>CS(C)=O>[Cl:7][C:8]1[CH:30]=[CH:29][C:11]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]([NH2:18])=[O:2])=[CH:15][C:14]=2[C:21]2[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:10][CH:9]=1
Reactant: COc1cccnc1-c1cc(C#N)ccc1Oc1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cccnc1-c1cc(C(N)=O)ccc1Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 145.8 %

Procedure:
Potassium carbonate (0.143 g, 1.0 mmol) was added to a solution of 4-(4-chlorophenoxy)-3-(3-methoxypyridin-2-yl)benzonitrile (Preparation 12, 0.175 g, 0.52 mmol) in DMSO, followed by dropwise addition of 30% hydrogen peroxide aqueous solution (3.1 mL, 3.1 mmol). The mixture was stirred at room temperature for 1.5 hours. The reaction was quenched with aqueous potassium hydrogen sulfate (30 mL) and extracted with DCM (3×30 mL). The organic layer was washed with water (2×30 mL), dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a white solid (0.269 g). This was taken to the next step without further purification.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]2[C:16]([N:17](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]2[CH:36]=1)[CH:2]([CH3:4])[CH3:3]>FC(F)(F)C(O)=O>[CH2:1]([C:5]1[N:6]=[C:7]2[C:16]([NH2:17])=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]2[CH:36]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc3ccccc3n3cc(CC(C)C)nc23)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1cn2c(n1)c(N)nc1ccccc12
Yield: 79.4 %

Procedure:
The solution of 2-isobutyl-N,N-bis(4-methoxybenzyl)imidazo[1,2-a]quinoxalin-4-amine (16 mg, 0.033 mmol) in 1 mL of trifluoroacetic acid was stirred at 70° C. for 6 hours. The solvent was removed under reduced pressure. And then 10 mL of saturated aqueous sodium bicarbonate was added. The resulting mixture was extracted with 75 mL of ethyl acetate. The organic layer was separated and then washed with water (15 mL), brine (15 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by preparative TLC sheet (ethyl acetate and hexanes) to give the titled compound (6.3 mg, 79%). MS: MH+=241. 1H NMR (300 MHz, CDCl3): δ 7.74 (s, 1H), 7.68 (m, 2H), 7.30-7.40 (m, 4H), 5.70 (brs, 2H), 2.67 (d, 2H), 2.08 (m, 1H), 1.00 (d, 6H).
Reaction SMILES: C([O:3][C:4](=[O:44])[CH:5]([C:10]1[CH:11]=[C:12]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=3)[CH2:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[Na+]>CO>[F:33][C:25]1[CH:24]=[C:23]([CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=1)[CH2:22][N:19]1[CH2:18][CH2:17][CH:16]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:44])=[O:3])[CH:11]=[C:12]([C:34]3[CH:35]=[CH:36][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:39]=3)[CH:13]=2)[CH2:21][CH2:20]1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCN(Cc3cc(F)cc(C(F)(F)F)c3)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCN(Cc3cc(F)cc(C(F)(F)F)c3)CC2)c1
Temperature: 60 °C

Procedure:
To a solution of a mixture of 2-{5-[1-(3-fluoro-5-trifluoromethyl-benzyl)-piperidin-4-yl]-4′-trifluoromethyl-biphenyl-3-yl}-4-methyl-pentanoic acid ethyl ester and methyl ester (38 mg, 0.06 mmol) in MeOH (1 mL) was added 3N NaOH (0.750 mL) and heated to 60° C. for 2 h. The reaction was concentrated in vacuo to remove MeOH. The thick liquid was acidified to pH=2 by 2N HCl. The resulting acidic solution was extracted with EtOAc. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by Gilson reverse phase column chromatography to obtain 2-{5-[1-(3-fluoro-5-trifluoromethyl-benzyl)-piperidin-4-yl]-4′-trifluoromethyl-biphenyl-3-yl}-4-methyl-pentanoic acid. 1H-NMR (MeOD-d4): δ 0.84 (d, 6H), 1.41 (m, 1H), 1.57 (m, 1H), 1.88-1.93 (m, 3H), 2.09 (m, 2H), 2.92 (t, 1H), 3.14 (t, 1H), 3.52 (m, 2H), 3.65 (t, 1H), 4.40 (s, 2H), 7.21 (s, 1H), 7.36 (s, 1H), 7.42 (s, 1H), 7.56-7.69 (m, 7H); Calcd for C32H32F7NO2 (M+H) 596.59, Found 596.40
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:14][O:15][C:16](=[O:36])[C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][C:18]=1[O:32]COC.C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C.O>[CH3:14][O:15][C:16](=[O:36])[C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:11]=[C:10]([C:12]#[N:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:19][C:18]=1[OH:32]
Reactant: COCOc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C(=O)OC
Reactant: N#Cc1cc(Cl)nc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc(C#N)c3ccccc3n2)cc1O
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
2-Chloroquinoline-4-carbonitrile (0.15 g), 2-methoxymethoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane-2-yl)benzoic acid methyl ester (0.26 g), tetrakis(triphenylphosphine)palladium (0.045 g) and sodium carbonate (0.16 g) were suspended in a mixed solvent of dimethoxyethane (2 mL) and water (0.5 mL), and the resulting mixture was stirred at 150° C. for 30 minutes using microwave reactor (Biotage). To the reaction mixture was added ethyl acetate, and the mixture was filtered through a Celite pad. The filtrate was poured into water. The organic layer was washed with water and brine, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=100/0-66/34) to give 4-(4-cyanoquinoline-2-yl)-2-hydroxy-benzoic acid methyl ester (0.1 g). To a mixed solution of this compound (0.1 g) in tetrahydrofuran (4 mL), ethanol (1 mL) and water (1 mL) was added lithium hydroxide monohydrate (0.060 g), and the mixture was stirred at room temperature overnight. To this reaction mixture was added 2 mol/L hydrochloric acid (2.8 mL), and the mixture was stirred at 50° C. for 10 hours. After the reaction mixture was cooled to room temperature, the precipitated solid was collected by filtration, and dried under reduced pressure to give the title compound (0.068 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20](=[O:21])[C:11]2=[CH:12][NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1.Br[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]2[NH:31][C:32]3[C:33](F)=CC=C(F)[C:37]=3[C:38]3C=2C(=O)N(C2C=CC=CC=2F)N=3)=[C:25](F)[CH:24]=1.C1(B(O)O)C=CC=CC=1.C(N1C=C(B2OC(C)(C)C(C)(C)O2)C=N1)C(C)C>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20](=[O:21])[C:11]2=[CH:12][N:13]([CH2:33][C:32]3[CH:37]=[CH:38][C:29]([C:26]4[CH:25]=[CH:24][CH:23]=[CH:28][CH:27]=4)=[CH:30][N:31]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1
Reactant: Cc1ccccc1-n1nc2c3ccccc3[nH]cc-2c1=O
Reactant: O=c1c2c(Cc3ccc(Br)cc3F)[nH]c3c(F)ccc(F)c3c-2nn1-c1ccccc1F
Agent: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: OB(O)c1ccccc1
Product: Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-c4ccccc4)cn3)cc-2c1=O

Procedure:
Using the procedure described in Example 95, substituting 5-[5-bromopyridin-2-yl)methyl]-2-(2-methylphenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one for 5-[(4-bromo-2-fluorophenyl)methyl-6,9-difluoro-2-(2-fluorophenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one, and, substituting phenylboronic acid for 1-iso-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, the titled compound was obtained: 1H-NMR (400 MHz, CD3OD) δ 9.03 (1H, s), 8.77 (1H, s), 8.36-8.33 (1H, m), 8.10-8.07 (1H, m), 7.85 (1H, d, J=8.8 Hz), 7.68-7.37 (12H, m), 5.93 (2H, s), 2.29 (3H, s), ppm; low resolution mass spectrometry (ES+) m/z 442.9 [(M+H)+; calculated for C29H22N4O: 443.2].
Reaction SMILES: [Br-].[CH3:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N+:6]([CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[CH:5][CH:4]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.C(=O)(O)[O-].[Na+].[C:36](#[N:39])[CH:37]=[CH2:38]>CN(C)C=O>[C:14]([C:13]1[N:6]2[C:7]3[C:12]([C:3]([CH3:2])=[CH:4][C:5]2=[C:37]([C:36]#[N:39])[CH:38]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)(=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc[n+](CC(=O)c2ccccc2)c2ccccc12
Reactant: C=CC#N
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CN(C)C=O
Product: Cc1cc2c(C#N)cc(C(=O)c3ccccc3)n2c2ccccc12

Procedure:
The title compound was prepared from 4-methyl-1-phenacyl-quinolinium bromide (86.5 mg, 0.253 mmol), tetrapyridinecobalt(II) dichromate (163 mg, 0.263 mmol), sodium bicarbonate (53.6 mg, 0.638 mmol), acrylonitrile (100 μL, 1.52 mmol), and N,N-dimethylformamide (2.0 mL), similar to Example 1b, and yielded 30.0 mg (38%) as a yellow solid. 1H NMR (CDCl3): 8.12 (m, 1H), 8.06 (m, 2H), 7.98 (m, 1H), 7.69 (tt, J=7.37, 1.56 Hz, 1H), 7.53–7.64 (m, 5H) 7.38 (s, 1H), 2.72 (d, J=1.10 Hz, 3H).
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[F-].[K+].[CH2:12]([O:19][C:20](=[O:31])[CH2:21][CH:22]1[NH:25][C:24](=[O:26])[CH:23]1[C:27](O)([CH3:29])[CH3:28])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>ClCCl>[CH2:12]([O:19][C:20](=[O:31])[CH2:21][CH:22]1[NH:25][C:24](=[O:26])[CH:23]1[C:27]([F:7])([CH3:29])[CH3:28])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(O)C1C(=O)NC1CC(=O)OCc1ccccc1
Reactant: CCN(CC)S(F)(F)F
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(F)C1C(=O)NC1CC(=O)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a -78° cold solution of 3 ml of diethylaminosulphurtrifluoride and 1.7 g of potassium fluoride in 80 ml of dichloromethane is added a solution of 3.2 g of (3SR,4RS)-3-(1-hydroxy-1-methyethyl)-2-oxoazetidine-4-yl acetic acid benzylester in 170 ml of dichloromethane. This mixture is stirred for 15 minutes at -78° and then mixed with water. After addition of further dichloromethane the phases are separated and the organic phase washed with saturated NaCl, dried over MgSO4 and evaporated to dryness. Chromatography of the residue over silica gel (ethylacetate/cyclohexane=1/1) yields the title compound m.p. 112°-116°.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[NH:3][C:2]1=[O:16].Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24]([C:26]2[CH:36]=[C:35]([CH3:37])[C:29]3[N:30]([CH3:34])[C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)=[O:25])[CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[CH3:34][N:30]1[C:29]2[C:35]([CH3:37])=[CH:36][C:26]([C:24]([C:20]3[CH:19]=[C:18]([N:13]4[CH2:12][CH2:11][C:4]5([C:5]6[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=6)[NH:1][C:2](=[O:16])[NH:3]5)[CH2:15][CH2:14]4)[N:23]=[CH:22][N:21]=3)=[O:25])=[CH:27][C:28]=2[O:32][C:31]1=[O:33]
Reactant: O=C1Nc2ccccc2C2(CCNCC2)N1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)c2cc(N3CCC4(CC3)NC(=O)Nc3ccccc34)ncn2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
87.0 mg (0.400 mmol) 1′H-spiro[piperidin-4,4′-quinazolin]-2′(3′H)-one, 122 mg (0.400 mmol) 6-(6-chloropyrimidin-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.140 mL (0.800 mmol) DIPEA were combined in 3.0 mL DMF and stirred for 48 h at RT. The reaction mixture was diluted with MeOH, the precipitate was suction filtered, washed with diethyl ether and dried.
Reaction SMILES: CC1C=CC(C2C=NN(C)C=2)=C(C=1)C(O)=O.[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([C:28]2[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[N:29]=2)=[C:22]([CH:27]=1)[C:23]([O:25]C)=[O:24]>>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([C:28]2[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[N:29]=2)=[C:22]([CH:27]=1)[C:23]([OH:25])=[O:24]
Reactant: COC(=O)c1cc(C)ccc1-c1ccnc(C)n1
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)O)c1
Product: Cc1ccc(-c2ccnc(C)n2)c(C(=O)O)c1

Procedure:
The title compound was synthesized following the same general protocol as described for 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid in Example A1, using methyl 5-methyl-2-(2-methylpyrimidin-4-yl)benzoate. ESI-MS (m/z): 229 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14](F)[CH:13]=1.O>CN(C)C=O>[F:11][C:12]1[CH:13]=[C:14]([CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1)[O:8][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(Oc2cc(F)cc([N+](=O)[O-])c2)CC1
Temperature: 65 °C
Reaction time: 0.67 h
Yield: 34.5 %

Procedure:
Dissolve 1-methyl-piperidin-4-ol (3.62 g, 31.43 mmol) in N,N-dimethylformamide (20 mL) and add 95% sodium hydride (0.83 g, 33.0 mmol) at ambient temperature. After 40 min., add 1,3-difluoro-5-nitro-benzene (5.0 g, 31.43 mmol), stir and heat at 65° C. After 2 hr., cool to ambient temperature and pour slowly into water (100 mL). Extract the reaction mixture with ethyl acetate (3×150 mL), wash the combined organic layers with aqueous NaCl solution (100 mL), dry over sodium sulfate, filter and concentrate. Purify the residue by silica gel flash chromatography eluting with 10% (2M NH3/methanol)/methylene dichloride to obtain of the title compound (2.76 g, 35%). 1H NMR (CDCl3): 7.6 (s, 1H), 7.5 (d, 1H), 7.0 (d, 1H), 4.4 (m, 1H), 2.7 (m, 2H), 2.4 (m, 5H), 2.0 (m, 2H), 1.9 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]2[C:5]([N:6]=[C:7]3[C:12](=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8]3)=[C:4]2[CH:21]=[CH:22][CH:23]=[CH:24][C:3]=12.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.O>[C:25]([O:1][C:2]1[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:14]2[C:5]([N:6]=[C:7]3[C:12](=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8]3)=[C:4]2[CH:21]=[CH:22][CH:23]=[CH:24][C:3]=12)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1c(O)c2ccccc2c2nc3ccccc3nc12
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1c(OC(C)=O)c2ccccc2c2nc3ccccc3nc12
Reaction time: 8 h
Yield: 91.1 %

Procedure:
A mixture of 640 mg ethyl 5-hydroxybenzo[a]phenazine-6-carboxylate, 6 ml of acetic anhydride and two drops of pyridine was stirred overnight and poured into water. The precipitated solid was collected by filtration and recrystallized from ethanol to give 600 mg (91.1% yield) of ethyl 5-acetoxybenzo[a]phenazine-6-carboxylate as orange needles, m.p. 195°-196° C., Anal. Calcd. (%) for C21H16N2O4 : C, 69.99; H, 4.48; N, 7.77; Found: C, 70.12; H, 4.45; N, 7.63
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11]([N:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:14](=[O:25])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:12])=[CH:2]1>CN(C=O)C.[C].[Pd]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH:15]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[C:14](=[O:25])[N:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]2=[O:12])=[CH:2]1
Reactant: O=C1C(c2c[nH]c3ccccc23)=C(c2c[nH]c3ccccc23)C(=O)N1c1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C1C(c2c[nH]c3ccccc23)C(c2c[nH]c3ccccc23)C(=O)N1c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.4 %

Procedure:
A small amount of 10% palladium-carbon was added to a solution of 2,3-bis(1H-indol-3-yl)N-phenylmaleimide (55 mg, 0.14 mmol) dissolved in DMF (2 mL), and the whole was stirred at room temperature for 1 day under hydrogen atmosphere. The palladium-carbon was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane=2:1) to obtain 3,4-bis(1H-indol-3-yl)-1-phenyl-2,5-dioxopyrrolidine (36 mg, 56.1%) as pale red solids.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].C([O:15][CH:16]=[C:17]([C:23](OCC)=O)[C:18]([O:20]CC)=[O:19])C.C1(C)C=CC=CC=1>CCCCCC>[O:15]=[C:16]1[C:5]2[C:3](=[CH:2][CH:8]=[CH:7][C:6]=2[C:9]([F:12])([F:11])[F:10])[NH:4][CH:23]=[C:17]1[C:18]([OH:20])=[O:19]
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C(O)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Temperature: 140 °C
Yield: 133 %

Procedure:
2-Chloro-5-(trifluoromethyl)aniline 2 (200 g, 1.023 mol), diethyl 2-(ethoxymethylene)malonate 3 (276 g, 1.3 mol) and toluene (100 mL) were combined under a nitrogen atmosphere in a three-neck, 1-L round bottom flask equipped with Dean-Stark condenser. The solution was heated with stirring to 140° C. and the temperature was maintained for 4 h. The reaction mixture was cooled to 70° C. and hexane (600 mL) was slowly added. The resulting slurry was stirred and allowed to warm to room temperature. The solid was collected by filtration, washed with 10% ethyl acetate in hexane (2×400 mL) and then dried under vacuum to provide a white solid (350 g, 94% yield) as the desired condensation product diethyl 2-((2-chloro-5-(trifluoromethyl)phenylamino) methylene) malonate 4. 1H NMR (400 MHz, DMSO-d6) δ 11.28 (d, J=13.0 Hz, 1H), 8.63 (d, J=13.0 Hz, 1H), 8.10 (s, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.50 (dd, J=1.5, 8.4 Hz, 1H), 4.24 (q, J=7.1 Hz, 2H), 4.17 (q, J=7.1 Hz,2H),1.27 (m, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:18])[CH:10]([O:17][N:20]1[C:24](=[O:25])[C:23]2[C:22](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]1=[O:30])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)C(O)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C(ON1C(=O)c2ccccc2C1=O)c1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a solution of benzyl-2-hydroxy-2-phenylacetate (2.42 g, 10 mmol), N-hydroxyphthalimide (1.96 g, 12 mmol) and PPh3 (3.4 g, 13 mmol) in CH2Cl2 (30 mL) was added DIAD (2.63 g, 13 mmol) at −20° C. The resulting mixture was stirred at −20° C. for 1 hour. The reaction mixture was concentrated and purified by flash chromatography (silica gel, Hexanes/CH2Cl2=1/3) giving 3.8 g (98%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@H:3]([NH:33][C:34](=[O:37])[O:35][CH3:36])[C:4](=[O:32])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:14][C:13]2[C:15]3[C:20]([CH:21]=[CH:22][C:12]=2[N:11]=1)=[CH:19][C:18](B1OC(C)(C)C(C)(C)O1)=[CH:17][CH:16]=3.[Br:39][C:40]1[CH:41]=[CH:42][C:43]2[CH:47]=[C:46](I)[S:45][C:44]=2[CH:49]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:39][C:40]1[CH:41]=[CH:42][C:43]2[CH:47]=[C:46]([C:18]3[CH:19]=[C:20]4[C:15](=[CH:16][CH:17]=3)[C:13]3[NH:14][C:10]([C@@H:6]5[CH2:7][CH2:8][CH2:9][N:5]5[C:4](=[O:32])[C@@H:3]([NH:33][C:34](=[O:37])[O:35][CH3:36])[CH:2]([CH3:38])[CH3:1])=[N:11][C:12]=3[CH:22]=[CH:21]4)[S:45][C:44]=2[CH:49]=1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2[nH]1)C(C)C
Reactant: Brc1ccc2cc(I)sc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4cc5ccc(Br)cc5s4)ccc3c2[nH]1)C(C)C
Temperature: 85 °C
Yield: 152.1 %

Procedure:
To a solution of methyl (S)-3-methyl-1-oxo-1-((S)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (251 mg, 0.48 mmol) in DME (5 mL) was added 6-bromo-2-iodobenzo[b]thiophene (82 mg, 0.24 mmol), Pd(PPh3)4 (28 mg, 0.024 mmol), and K2CO3 (2M in H2O, 0.8 mL, 1.58 mmol). The solution was degassed with N2 for 10 min, then heated to 85° C. for 24 h. The mixture was cooled to rt, diluted with EtOAc, and washed with sat. NaHCO3, brine, dried with MgSO4, and concentrated. The residue was purified by silica gel chromatography to yield product (221 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:19])[C:5]([CH:8](C(OCC)=O)C(OCC)=O)=[N:6][CH:7]=1.Cl>>[Br:1][C:2]1[CH:3]=[C:4]([Cl:19])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc(Br)cc1Cl
Agent: Cl
Product: Cc1ncc(Br)cc1Cl
Yield: 48.4 %

Procedure:
A solution of impure diethyl 2-(5-bromo-3-chloropyridin-2-yl)malonate (Intermediate 42, 0.41 g, 1.2 mmol) and cone. aq. HCl (3 mL) was heated at reflux for 3 h. The volatiles were removed in vacuo, and the residue was co-evaporated with acetonitrile. The residual solid (mono-decarboxylated acid) was dissolved in dioxane (4.5 mL) and heated at reflux overnight. The volatiles were removed in vacuo. The residue was purified by flash chromatography (4 g SiO2, heptane/EtOAc gradient) affording the title compound (0.12 g, 51% yield): 1H NMR (500 MHz, CDCl3) δ ppm 2.60 (s, 3 H), 7.82 (d, 1 H), 8.46 (d, 1 H); MS (CI) m/z 206 [M+H]+.