Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]([OH:16])=[CH:4][CH:3]=1.I[CH3:18].CN([CH:22]=[O:23])C.Cl>O>[CH3:18][O:16][C:5]1[C:6]2[C:15](=[CH:14][C:13]3[C:8]([CH:7]=2)=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:2]([O:23][CH3:22])=[CH:3][CH:4]=1
Reactant: Oc1ccc(O)c2cc3ccccc3cc12
Reactant: CI
Reactant: CN(C)C=O
Agent: Cl
Solvent: O
Product: COc1ccc(OC)c2cc3ccccc3cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94 %

Procedure:
To a 0.275 g (11.0 mmol) of pre-washed (with distilled diethyl ether) sodium hydride under argon were added 1.00 g (4.80 mmol) of 1,4-dihydroxyanthracene, 0.75 mL (12.0 mmol) of iodomethane, and 10 mL of DMF (distilled over CaH2). The solution was stirred at 25° C. for 1.5 h, diluted with 20 mL of water, and acidified with 6 N HCl (pH ˜2). The mixture was extracted three times with ethyl acetate, and the combined extract was washed twice with water, and brine, dried (MgSO4), concentrated to give 1.07 g (94% yield) of compound 2. Recrystallization from ether:hexane (1:1) gave 0.89 g (78% yield) of yellow solids: mp 132-133° C. (Lit.6 134-136° C.); MS, FAB, m/z 239 (M+1), 238 (M+); 1H NMR d 8.70 (s, 2H, C9,10H), 7,97 (dd, J=6.1, 3.6 Hz, 2H, C5,8H), 7.40 (dd, J=6.6, 3.2 Hz, 2H, C6,7H ), 6.55 (s, 2H, C2,3H), 3.97 (s, 6H, OCH3); 13C NMR d 149.5 (s, C8a,10a), 131.5 (s, C4a,9a), 128.5 (d, C9,10), 125.5 (d, C5,8), 120.7 (d, C6,7), 100.9 (d, C2,3), 55.6 (s, OCH3).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9](=[O:49])[CH2:10][C:11]1[C:12]([CH2:17][CH2:18][C:19]2[C:24]([C:25]([F:28])([F:27])[F:26])=[CH:23][N:22]=[C:21]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([CH:36]4[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]4)=[CH:32][CH:31]=3)[N:20]=2)=[N:13][CH:14]=[CH:15][CH:16]=1>C(Cl)Cl.C1CCCCC1>[NH:39]1[CH2:40][CH2:41][CH:36]([C:33]2[CH:34]=[CH:35][C:30]([NH:29][C:21]3[N:20]=[C:19]([CH2:18][CH2:17][C:12]4[C:11]([CH2:10][C:9]([NH2:8])=[O:49])=[CH:16][CH:15]=[CH:14][N:13]=4)[C:24]([C:25]([F:28])([F:26])[F:27])=[CH:23][N:22]=3)=[CH:31][CH:32]=2)[CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncccc4CC(N)=O)n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: NC(=O)Cc1cccnc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 23 h
Yield: 66.6 %

Procedure:
Trifluoroacetic acid (0.337 mL, 4.40 mmol) was added to a solution tert-butyl 4-(4-((4-(2-(3-(2-amino-2-oxoethyl)pyridin-2-yl)ethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I124) (64.3 mg, 0.110 mmol) in dry DCM (15 mL) under an atmosphere of nitrogen and the reaction was stirred at room temperature for 23 hours. The volatiles were removed in vacuo and the residue partitioned between EtOAc (40 mL) and 2 M NaOH (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were washed with water (40 mL), brine (40 mL) and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a yellow solid which was suspended in DCM (5 mL) and cyclohexane (15 mL). The precipitate was filtered to afford the title compound (32) (35.5 mg, 53%) as yellow solid; 1H NMR (400 MHz, d6-DMSO) δ 10.05 (s, 1H), 8.64 (s, 1H), 8.36 (dd, J=4.8, 1.7 Hz, 1H), 7.62-7.55 (m, 3H), 7.53 (s, 1H), 7.18 (dd, J=7.6, 4.8 Hz, 1H), 7.15 (d, J=8.6 Hz, 2H), 7.00 (s, 1H), 3.53 (s, 2H), 3.24 (s, 4H), 3.02 (d, J=11.9 Hz, 2H), 2.61-2.52 (m, peaks obscured by solvent), 1.67 (d, J=11.3 Hz, 2H), 1.49 (qd, J=12.2, 3.8 Hz, 2H). LCMS Method C: rt 1.50, 1.59 min; m/z 485 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:17]([O:21][C:22]([N:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>COCCOC.C(O)C>[C:17]([O:21][C:22]([N:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1cccc1-c1cccc([N+](=O)[O-])c1
Yield: 51 %

Procedure:
A solution of 1-bromo-3-nitrobenzene (1.5 g 7.42 mmol) in anhydrous 1,2-dimethoxyethane (10 ml) was treated sequentially with 1,1-bistriphenylphosphine palladium II dichloride (260 mg, 0.371 mmol), 2M aqueous sodium carbonate (7.4 ml), and 1-(t-Butoxycarbonyl)pyrrole-2-boronic acid (1.88 g, 8.91 mmol) dissolved in ethanol (10 ml). The reaction was heated under reflux for 5 hours under argon. The solvent was evaporated and the residue dissolved in dichloromethane, washed with water, brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with a mixture of ether/hexane (5:95) to afford the title compound (1.09 g, 51%); MS (ES+) m/e 288 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[N+:9]([C:3]1[C:2]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])([O-:11])=[O:10]
Reactant: C1CCNCC1
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cccc(N2CCCCC2)c1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a solution of 3-chloro-2-nitroaniline (CXXI) (2.00 g, 11.6 mmol, 1 eq) and piperidine (2.95 g, 34.7 mmol, 3 eq) in DMF (60 ml) was added K2CO3 (4.78 g, 34.4 mmol, 3 eq) in one portion and the mixture was stirred at 120° C. under nitrogen overnight. The reaction mixture was diluted with ethyl acetate (60 ml) and washed with saturated NaHCO3 solution (50 mL). The organic phases were dried over Na2SO4 and concentrated in vacuo, the resultant residue was purified by silica gel column chromatography (PE:EtOAc=5:1→1:1) to give 2-nitro-3-(piperidin-1-yl)aniline (CXXII) (1.8 g, 8.14 mmol, 70.3% yield) as a black solid. ESIMS found for C11H15N3O2 m/z 222 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[CH:5]=1)=[O:3].[CH3:11][Mg]Br.[Cl-].[NH4+]>C(OCC)C.O1CCCC1.C(OCCCC)CCC>[Br:10][C:6]1[CH:5]=[C:4]([C:2]([OH:3])([CH3:11])[CH3:1])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCOCCCC
Product: CC(C)(O)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under an argon stream, 6.5 g of 3-bromoacetophenone are placed in a round-bottomed flask and dissolved in 544 ml of diethyl ether and 272 ml of tetrahydrofuran. The mixture is cooled to 0° C. using an ice bath, and 100 ml of a 1M solution of methylmagnesium bromide in dibutyl ether are added thereto, dropwise. The mixture is stirred at 0° C. for 1 h and 400 ml of a saturated aqueous solution of ammonium chloride are added. The organic phase is separated, dried over magnesium sulphate and concentrated under reduced pressure. 10.0 g of compound are obtained. 1H NMR (DMSO-d6, δ in ppm): 1.45 (s, 6H); 5.15 (s, 1H); 7.25 (t, 1H); 7.4 (d, 1H); 7.45 (d, 1H); 7.65 (s, 1H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:43])(=O)=O)=CC=1.Cl>O1CCCC1.CO>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:32])[CH:27]([F:43])[CH2:28][C:29]([OH:31])=[O:30])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CO
Product: O=C(O)CC(F)C(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 9.8 %

Procedure:
To a stirred solution of diisopropylamine (0.295 mL, 0.0021 mol) in anhydrous tetrahydrofuran (10 mL) at room temperature under nitrogen was added in portions a 2.1 M solution of n-butyl lithium in hexanes (1.0 mL, 0.0021 mol), and the mixture cooled to −78° C. To a solution was added a solution of 4-(4′-chloro-biphenyl-4-yl)-4-oxo-butyric acid (0.288 g, 0.000997 mol) in THF (10 mL), and the mixture stirred for 1 hour. To the yellow solution was added dropwise a solution of N-fluorodibenzenesulfonamide (NFSI, 0.346 g, 0.00110 mol) in THF (10 mL), and the mixture stirred for 2 hours at −78° C. The mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction was quenched with 1 M hydrochloric acid (1.1 mL, 0.0011 mol HCl), and the mixture was rotary evaporated to dryness. The residue was passed through a column of silica gel, eluting with dichloromethane-methanol (10:1 then 9:1) to give a gum. The gum was dissolved in methanol and acidified with additional 1 M hydrochloric acid (3.4 mL, 0.0034 mol HCl). The volatiles were rotary evaporated, and the resulting suspension was filtered. The filter cake was purified by chromatography on silica gel, eluting with dichloromethane-methanol (14:1) to give 0.030 g of (±)-4-(4′-chloro-biphenyl-4-yl)-3-fluoro-4-oxo-butyric acid as a white solid: mp 170-173° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:18][C:17]3[C:16]4[CH:15]=[CH:14][N:13]=[CH:12][C:11]=4[O:10][C:9]=3[C:8]([CH3:20])([CH3:19])[C:7]=2[CH:21]=1.Cl([O-])=[O:23].[Na+].ON1C(=O)C2=CC=CC=C2C1=O.C(OCC)(=O)C>C(#N)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:18](=[O:23])[C:17]3[C:16]4[CH:15]=[CH:14][N:13]=[CH:12][C:11]=4[O:10][C:9]=3[C:8]([CH3:19])([CH3:20])[C:7]=2[CH:21]=1
Reactant: COc1ccc2c(c1)C(C)(C)c1oc3cnccc3c1C2
Reactant: [O-][Cl+][O-]
Agent: O=C1c2ccccc2C(=O)N1O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)C(C)(C)c1oc3cnccc3c1C2=O
Temperature: 40 °C
Reaction time: 0.67 h
Yield: 57.1 %

Procedure:
8-Methoxy-10,10-dimethyl-5,10-dihydro-11-oxa-2-aza-benzo[b]fluorene (Compound GT15-10, 20 mg) was dissolved in acetonitrile (0.2 ml) and water (0.15 ml), added with sodium chlorite (16 mg) and N-hydroxyphthalimide (2.3 mg), and the mixture was stirred at 40° C. for 40 min. To the reaction mixture, ethyl acetate was added. The organic layer was washed with saturated aqueous solution of sodium bicarbonate and saturated brine, and then concentrated under reduced pressure. The resulting residues were purified by silica gel column (ethyl acetate/hexane) to obtain the title compound (12 mg, 57%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.CCN(C(C)C)C(C)C.F[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[N+:33]([O-])=O.C(O)(=O)C>CO.[Zn]>[NH2:33][C:27]1[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:26]=1[NH:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CN)C1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: Cc1ccc(NC[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)c(N)c1
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 99.6 %

Procedure:
A mixture of (R)-tert-butyl 2-(aminomethyl)morpholine-4-carboxylate (0.715 g, 3.31 mmol), DIPEA (0.577 mL, 3.31 mmol), and 1-fluoro-4-methyl-2-nitrobenzene (0.513 g, 3.31 mmol) in MeOH (14 mL) was heated at 140° C. in A microwave reactor for 30 min and then cooled to room temperature. Acetic acid (1.9 mL, 33.1 mmol) was added, followed by zinc (2.162 g, 33.1 mmol). The resulting mixture was stirred at room temperature for 90 min to afford the (R)-tert-butyl 2-((2-amino-4-methylphenylamino)methyl)morpholine-4-carboxylate product (1.06 g), which was used without further purification in the next step. The product was analyzed on analytical HPLC MS using the high pH gradient method (mobile phase: 5-95% B; A: H2O with 10 mM NH4CO3 and 0.375% NH4OH v/v; B: CH3CN; 2.25 min run; X-Bridge C18; column size: 2.1×30 mm; and particle size: 5 μm). MS m/z 322.4 [M+H]+ (ESI), Rt 1.80 min.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:22])[C:8]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:22])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(Cl)ccc21
Reactant: CCN(CC)CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Cl)ccc3c1C2=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
3-Chloro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound S2-1, 10 mg, 0.03207 mmol) was dissolved in DMF (0.1 mL), added with (2-chloroethyl)diethylamine (5.5 mg, 0.03207 mmol) and cesium carbonate (20.9 mg, 0.06414 mmol), and stirred at 80° C. for 2 hr. The reaction solution was added to water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The residues obtained after concentration under reduced pressure were purified by NH silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (11.6 mg, 76%).
Reaction SMILES: C([Li])[CH2:2][CH2:3][CH3:4].C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1.C1C[O:24][CH2:23]C1>CCCCCC>[Cl:13][C:14]1[C:19]([CH:23]([OH:24])[CH:3]([CH3:2])[CH3:4])=[C:18]([Cl:20])[CH:17]=[CH:16][N:15]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: [Li]CCCC
Reactant: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CC(C)C(O)c1c(Cl)ccnc1Cl
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
Normal-butyllithium (a 1.6 M solution in hexane, 8.13 mL) was dropwise added to a solution of N,N-diisopropylamine (1.99 mL) in THF (30 mL) at −78° C. under a nitrogen atmosphere, followed by increasing the temperature to 0° C. Then, the solution was cooled to −78° C., and a solution of 2,4-dichloropyridine (1.0 g) in THF (3 mL) wad dropwise added thereto at −78° C., followed by stirring for 1.5 hr. Then, a solution of isobutylaldehyde (1.85 mL) in THF (3 mL) was dropwise added to the reaction solution at −78° C., followed by stirring at the same temperature for 30 min. Then, the reaction solution was poured into ice water and was extracted with ethyl acetate. The organic layer was washed with saturated saline, and the organic layer after the washing was dried over anhydrous sodium sulfate. Then, the solvent was distilled away, and the residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain 1-(2,4-dichloropyridin-3-yl)-2-methylpropan-1-ol (1.48 g, 99%) as a colorless oily substance. A solution of DMSO (0.9 mL) in dichloromethane (5 mL) and a solution of 1-(2,4-dichloropyridin-3-yl)-2-methylpropan-1-ol (1.39 g) in dichloromethane (5 mL) were sequentially added to a solution of oxalyl chloride (0.8 mL) in dichloromethane (30 mL) at −78° C., followed by stirring for 30 min. Then, triethylamine (3.52 mL) was added to the reaction solution at 0° C., followed by stirring for 1 hr. The reaction solution was poured into ice water and was extracted with chloroform. The organic layer was washed with saturated saline. The organic layer after the washing was dried over anhydrous sodium sulfate, and then the solvent was distilled away. The residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain 1-(2,4-dichloropyridin-3-yl)-2-methylpropan-1-one (1.18 g, 86%) as a colorless oily substance. Hydrazine monohydrate (1.3 mL) was added to a solution of 1-(2,4-dichloropyridin-3-yl)-2-methylpropan-1-one (0.93 g) in THF (13 mL), followed by stirring at room temperature for 12 hr and then at 50° C. for 25 hr. The reaction solvent was distilled away under reduced pressure, and the residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain compound (4a) (0.55 g, 66%) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:16]([CH3:23])([O:18][Si](C)(C)C)[CH3:17])[N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([C:16]([OH:18])([CH3:23])[CH3:17])[CH:5]=[C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[N:7]=1
Reactant: CC(C)(O[Si](C)(C)C)c1cc(Cc2ccc(Cl)cc2)nc(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(Cc2ccc(Cl)cc2)nc(Cl)n1
Yield: 76.7 %

Procedure:
A solution of 2-chloro-4-(4-chloro-benzyl)-6-(1-methyl-1-trimethylsilanyloxy-ethyl)-pyrimidine (3.69 g, 10.0 mmol) and toluene-4-sulfonic acid monohydrate (0.19 g, 1.0 mmol) in 90% aqueous tetrahydrofuran (40 mL) was stirred at 20° C. for 2 h. The solution was diluted with ethyl acetate and washed successively with saturated sodium hydrogencarbonate solution and with brine. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residual oil was crystallized from cyclohexane to give the title compound (2.28 g, 77%) as a white solid.
Reaction SMILES: C([N-:4]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[S:21]1[C:29]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[CH:23]=[CH:22]1.N(C(C1C=CC=CC=1)=C)=[N+]=[N-]>C1COCC1.CCCCCC>[NH2:4][C:22]1[S:21][C:29]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[CH:23]=1
Reactant: c1cc2sccc2cn1
Reactant: CC(C)[N-]C(C)C
Agent: C=C(N=[N+]=[N-])c1ccccc1
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Nc1cc2cnccc2s1
Temperature: -15 °C

Procedure:
To a cold (-70° C.) stirred solution of lithium diisopropylamide in THF, prepared in situ by reaction of 3.63 g of freshly distilled diisopropylamine and 22 ml of 1.6M n-butyl lithium in 50 ml of hexane, were added dropwise over twenty minutes 4.05 g (30 mMoles) of thieno[3,2-c]pyridine in 20 ml of THF. The reaction mixture was stirred for twenty minutes following the addition, and then was diluted by the dropwise addition of 5.22 g (36 mMoles) of α-azido styrene in 20 ml of THF. The reaction mixture was stirred for two hours while maintaining the temperature at -70° to -50° C.; and then for an additional hour while allowing the temperature to warm to -15° C. The reaction was then quenched by the addition of 50 ml of 5% aqueous hydrochloric acid. Removal of the reaction solvent by evaporation under reduced pressure afforded 3.0 g of crude product. Purification by chromatography over silica gel, eluting with ethyl acetate, afforded 1.2 g of 2-aminothieno[3,2-c]pyridine. Mass Spec. M+ theory: 150, found: 150.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][OH:13].[OH-:14].[CH2:15]([N+](C)(C)C)[C:16]1[CH:21]=CC=C[CH:17]=1>CO>[CH3:9][CH2:10][CH2:1][CH:2]([CH3:11])[CH3:3].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][O:13][CH2:2][CH2:11][C:12]([O:13][C:16]([CH3:15])([CH3:17])[CH3:21])=[O:14]
Reactant: [OH-]
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: OCCc1ccc2ccccc2c1
Solvent: CO
Product: CC(C)(C)OC(=O)CCOCCc1ccc2ccccc2c1
Product: CCCC(C)C
Temperature: 0 °C
Reaction time: 96 h

Procedure:
2-Naphthalene ethanol (3 g) was treated with benzyltrimethylammonium hydroxide (Triton B®; 198 uL of a 40% solution in methanol). The methanol was removed by evaporation and residue azeotroped with toluene (×2). THF (5 ml) was added. The mixture was cooled to 0° C. and tert Butyl acrylate (2.45 g) added slowly. The mixture was stirred for 4 days. The majority of the THF was removed by evaporation, and the residue purified using silica column chromatography, eluting with isohexane, then 2:1 isohexane:ethyl acetate to give the sub-titled compound (4.96 g).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:11]=1[C:12]([O:14][CH3:15])=[O:13].[C:24](=[O:26])=[O:25]>O1CCCC1>[F:9][C:10]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:18][C:19]=1[C:24]([OH:26])=[O:25]
Reactant: COC(=O)c1c(F)cccc1C(F)(F)F
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1c(C(F)(F)F)ccc(C(=O)O)c1F
Temperature: -78 °C
Reaction time: 3 h

Procedure:
A solution of lithium diisopropyl amide in dry tetrahydrofuran (prepared from diisopropylamine (17.0 ml) and n-butylithium (48.4 ml) in dry tetrahydrofuran)was added to a solution of methyl 2-fluoro-6-trifluoromethylbenzoate (22.39 g) in dry tetrahydrofuran while maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 3 hours. The solution was poured onto solid carbon dioxide pellets and stirred until it had warmed to room temperature. The mixture was evaporated and treated with hydrochloric acid (2M). It was extracted with ether, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 2-fluoro-3-methoxycarbonyl-4-trifluoromethylbenzoic acid (24.43 g) as an off-white solid, NMR (CDCl3) 3.95(s,3H), 7.55(d,1H), 8.15(t,1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18](Cl)[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[C:26]1([OH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O.[Cu]>[CH3:1][O:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[C:21]4[CH2:22][CH2:23][CH2:24][C:20]=4[N:19]=[C:18]([O:32][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:17]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(Nc3nc(Cl)nc4c3CCC4)cc2)CCC1
Reactant: Oc1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccc(Nc3nc(Oc4ccccc4)nc4c3CCC4)cc2)CCC1
Temperature: 27.5 °C
Reaction time: 13 h

Procedure:
The title compound was prepared following a published procedure in the literature (D'Angelo, N. D. et al. Tetrahedron Letters, 2006, 47, 5045-5048). A mixture of 1-[4-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-phenyl]cyclobutane carboxylic acid methyl ester (0.45 g, 1.26 mmol), phenol (0.23 g, 2.5 mmol), copper powder (0.010 g) and cesium carbonate (1.25 g, 3.8 mmol) in anhydrous dimethylformamide (3 mL) was stirred at a temperature in the range of 10° C. to 100° C. for 6 to 20 hours. The mixture was cooled to about 20 to 35° C. and diluted with water. The organics were extracted with EtOAc and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by column chromatography (silica gel) to afford white solid (43% yield).
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].CN(CCN(C)C)C.CN([CH:30]=[O:31])C>C1COCC1>[OH:18][CH:11]1[C:12]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:30](=[O:31])[N:10]1[C:2]([CH3:1])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(C)(NC(=O)c1ccccc1)c1ccccc1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)N1C(=O)c2ccccc2C1O
Yield: 96.7 %

Procedure:
In a similar manner to Step 2 of Example 16. N-(1-methyl-1-phenylethyl)benzamide (5.00 g, 20.9 mmol) was dissolved in THF (200 mL), and the solution was treated with TMEDA (10.0 mL, 66.9 mmol), sec-butyl lithium-hexane solution (1.01 mol/L, 66.0 mL, 66.9 mmol) and DMF (3.60 mL, 46.0 mmol), followed by purification by slurry using diisopropylether to obtain 3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (5.40 g, yield 97%).