Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:14][OH:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]1>C(Cl)Cl>[C:1]1([CH2:14][O:15][C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)O1
Reactant: OCc1cccc2c1Cc1ccccc1-2
Solvent: ClCCl
Product: O=C(O)CCC(=O)OCc1cccc2c1Cc1ccccc1-2
Reaction time: 6 h

Procedure:
Fluorenemethanol (10.0 g, 51.0 mmol) was dissolved in 150 ml CH2Cl2, and succinic anhydride (5.6 g, 56 mmol) was added. The solution was stirred for 6 h, and a further portion of succinic anhydride (2.5 g, 25 mmol) was added, and stirring continued overnight. The reaction appeared complete by TLC. The solvent was then removed, and the residue extracted with ethyl acetate, washed with 1% HCl, water, brine, dried (MgSO4) and evaporated to an oil which crystallized on standing. A quantitative yield of crude product was obtained which was used without further purification.
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:5])[NH2:4].C([O:8][CH:9]=[C:10]([C:16]#[N:17])[C:11](OCC)=O)C.C([O-])([O-])=O.[K+].[K+]>CCO>[OH:8][C:9]1[C:10]([C:16]#[N:17])=[CH:11][N:4]=[C:3]([S:2][CH3:1])[N:5]=1
Reactant: CSC(=N)N
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CSc1ncc(C#N)c(O)n1
Temperature: 25 °C
Yield: 65 %

Procedure:
2-Methyl-2-thiopseudourea (5 mmol) and ethyl ethoxymethylenecyanoacetate (5 mmol) were dissolved in 20 ml EtOH. To this was added K2CO3 (10 mmol). After the mixture was refluxed for 48 h, it was cooled to room temperature and filtered. The solvent was concentrated in vacuo and purified by column chromatography to give 4-hydroxy-2-(methylthio)pyrimidine-5-carbonitrile in a yield of 65%.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1[C:16]([CH3:17])=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26](O)[CH2:27][OH:28].C1(C)C=CC(S(O)(=O)=O)=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1.CCOC(C)=O>[CH2:19]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:10]=[C:11]([CH3:18])[C:12]([CH:13]2[O:28][CH2:27][CH2:26][O:14]2)=[CH:15][C:16]=1[CH3:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(C)cc1C=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(N(Cc2ccccc2)Cc2ccccc2)c(C)cc1C1OCCO1
Temperature: 80 °C
Reaction time: 6 h
Yield: 78.4 %

Procedure:
To a stirred solution of 4-dibenzylamino-2,5-dimethylbenzaldehyde (3.60 g, 10.9 mmol) in toluene (35.0 mL) under nitrogen was added 1,2-ethanediol (1.83 mL, 32.8 mmol) and p-toluenesulfonic acid (451 mg, 2.62 mmol). The reaction mixture was heated at 80° C. overnight. TLC (3:1 hexanes:EtOAc) showed a ˜50:50 mixture of product and starting material. Magnesium sulfate (1.32 g, 10.9 mmol) was added and stirring was continued for 6 h. The reaction mixture was then filtered and concentrated under reduced pressure to give title compound (3.19 g, 78% yield) as an oil.
Reaction SMILES: O[CH: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.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:39]I>C1COCC1.C(OCC)(=O)C.[Cl-].[Na+].O.O>[I:39][CH: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
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(I)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.8 %

Procedure:
A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (246 g, 1.224 mol), imidazole (100 g, 1.469 mol, 1.2 eq.) and triphenylphosphine (385 g, 1.469 mol, 1.2 eq.) in THF (750 mL) was cooled using an ice bath. Then a solution of iodine (373 g, 1.469 mol, 1.2 eq.) in THF (750 mL) was added slowly over a period of 1 hour while keeping the internal temperature below 18° C. The resulting mixture was allowed to stir at room temperature for 5 hours and the mixture was diluted with ethyl acetate (2 L), brine (1 L) and water (500 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (1 L×2). The organic layers were combined, washed with 15% aqueous sodium sulfite (1 L), brine (1 L), dried and concentrated. The resulting residue was stirred with hexanes (2 L) and the solid was removed by filtration. The solid was stirred with hexanes (2 L×2) and filtered. The filtrate was concentrated to give 363 g of crude oil which was purified by column chromatography (eluting with hexanes/ethyl acetate=50:1 to 20:1) to afford 319 g of tert-butyl 4-iodopiperidine-1-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])([F:14])[F:13])[N:8]=[C:7]([C:23](O)=[O:24])[CH:6]=[CH:5]2.CCN=C=NCCCN(C)C.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:38]1([NH:37][C:23]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][C:11]([C:12]([P:15](=[O:16])([O:17][CH2:18][CH3:19])[O:20][CH2:21][CH3:22])([F:14])[F:13])=[C:2]([Br:1])[CH:3]=3)[N:8]=2)=[O:24])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CCOP(=O)(OCC)C(F)(F)c1cc2nc(C(=O)O)ccc2cc1Br
Reactant: Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(OCC)C(F)(F)c1cc2nc(C(=O)Nc3ccccc3)ccc2cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the product of step 5 (109 mg) in 5 mL CH2Cl2 was added EDCI (96 mg), aniline (0.1 mL) and Hunig's base (0.1 mL). The solution was stirred at ambient temperature for 3 hours and after concentration and flash chromatography on silica with a gradient of 10-25% EtOAc/toluene the amide was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:16])=O>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:16])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl

Procedure:
A mixture of 2-chloro-4-nitrobenzoic acid (20 g), thionyl chloride (40 ml) and DMF (5 drops) was stirred and heated to reflux for 1 hour. The mixture was evaporated to give 2-chloro-4-nitrobenzoyl chloride which was used without further purification.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]#[N:12])=[N:8][CH:9]=1.Br[CH2:14][CH2:15][O:16][CH2:17][CH2:18]Br.O>CN(C)C=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:11]#[N:12])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:8][CH:9]=1
Reactant: BrCCOCCBr
Reactant: N#CCc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(Br)cn2)CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
NaH (55% in mineral oil, 0.23 g) was added to a solution of (5-bromo-pyridin-2-yl)-acetonitrile (0.50 g) in N,N-dimethylformamide (5 mL) chilled in an ice bath. The resulting mixture was stirred for 10 min in the cooling bath prior to the dropwise addition of bis(2-bromoethyl)ether (0.35 mL) dissolved in N,N-dimethylformamide (2 mL). The mixture was stirred with cooling for 2 h and at room temperature for 1 h. Water was added and the resulting mixture was extracted with ethyl acetate. The combined extracts were washed with brine and dried (MgSO4). The solvent was evaporated and the residue was chromatographed on silica gel (cyclohexane/ethyl acetate 4:1→1:1) to give the title compound as a colorless oil. Yield: 0.62 g (91% of theory); LC (method 1): tR=1.70 min; Mass spectrum (ESI+): m/z=267/269 (Br) [M+H]+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C(N(CC)CC)C.O[CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH2:22][CH2:23][CH2:24][NH:25][C:26]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:35])=[O:8])(=[O:3])[CH3:2]
Reactant: O=C(NCCCO)OCc1ccccc1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccccc1C(=O)OCCCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
To a solution of 2-acetoxybenzoic acid (2.0 g, 11.1 mmol) and triethylamine (1.8 mL, 11.1 mmol) in CH2Cl2 (40 mL) at 0° C. was slowly added CICO2Et (1.1 mL, 167 mmol). The reaction mixture was stirred (0° C., 2 h) and filtered. The filtrate was added to a solution of benzyl 3-hydroxypropylcarbamate (2.1 g, 10.0 mmol) and triethylamine (15 mL) in CH2Cl2 (40 mL). The reaction mixture was stirred (RT, 4 h) and quenched with H2O (50 mL). The organic layer was washed with 1 M HCl, saturated Na2CO3 (30 mL) and H2O (50 mL). The organic solution was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica chromatography, (PE-EtOAc, 5:1) to afford 3-(benzyloxycarbonylamino)propyl 2-acetoxybenzoate (2.0 g, 54%) as a colorless oil. Mass calculated for C20H21NO64=371.38. found: [M+H]+=372.3.
Reaction SMILES: C(O[C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1Cl)N=C(C)C=C2)CO)(C)(C)C.C([O:34][CH2:35][C@H:36]([C:42]1[C:43]([Br:54])=[C:44]2[C:49](=[CH:50][C:51]=1[CH3:52])[N:48]=[C:47]([CH3:53])[CH:46]=[CH:45]2)[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])(=O)C(C)(C)C>>[Br:54][C:43]1[C:42]([C@H:36]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])[CH2:35][OH:34])=[C:51]([CH3:52])[CH:50]=[C:49]2[C:44]=1[CH:45]=[CH:46][C:47]([CH3:53])=[N:48]2
Reactant: Cc1ccc2c(Br)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(C)cc2n1
Agent: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](CO)OC(C)(C)C)c(Cl)cc2n1
Product: Cc1ccc2c(Br)c([C@@H](CO)OC(C)(C)C)c(C)cc2n1

Procedure:
Compound 5F was prepared following the procedure used to prepare compound 1K of Example 1, except that (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyethyl pivalate (5E) was used instead of compound 1J. LCMS-ESI+ (m/z): 352.2, 354.2 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[CH:13][C:12]([NH:15]C(=O)OC(C)(C)C)=[C:11]([I:23])[CH:10]=1>ClCCl>[Cl:8][C:9]1[N:14]=[CH:13][C:12]([NH2:15])=[C:11]([I:23])[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cnc(Cl)cc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.4 %

Procedure:
Trifluoroacetic acid (2.4 mL) was added to a solution of 1,1-dimethylethyl (6-chloro-4-iodo-3-pyridinyl)carbamate (Description 7, 2.2 g, 6.2 mmol) in dichloromethane (50 mL) and the mixture was stirred at room temperature for 24 h. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate. The mixture was washed with aqueous sodium hydroxide (1M), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (70:30), to give the title compound as a yellow solid (1.3 g, 82%). 1H NMR (360 MHz, CDCl3) δ 7.80 (1H, s), 7.60 (1H, s), and 4.13 (2H, br s). m/z (ES+) 255, 257 (M+1).
Reaction SMILES: [O:1]1[CH2:5][CH:4]=[CH:3][C@H:2]1[C@H:6]([OH:19])[CH2:7][NH:8]C(=O)OCC1C=CC=CC=1.[Cl-].[NH4+].CC1C=CC(S(O[C@H]2CO[C@@H]3[C@@H](Br)CO[C@H]23)(=O)=O)=CC=1.N>O.O1CCCC1.CC(O)C.[OH-].[NH4+].[Zn].CO>[NH2:8][CH2:7][C@H:6]([C@@H:2]1[CH:3]=[CH:4][CH2:5][O:1]1)[OH:19]
Reactant: O=C(NC[C@@H](O)[C@@H]1C=CCO1)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O[C@H]2CO[C@H]3[C@@H]2OC[C@@H]3Br)cc1
Agent: N
Agent: [Cl-]
Solvent: CO
Solvent: CC(C)O
Solvent: C1CCOC1
Product: NC[C@@H](O)[C@@H]1C=CCO1
Temperature: 75 °C
Reaction time: 6 h

Procedure:
Alternative preparation of Benzyl (R)-2-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethylcarbamate (18); Zinc and ‘One-Pot’ Procedure 2. A solution of ammonium chloride (4 g, 74.8 mmol) in water (50 mL) then zinc dust (4 g, 61.6 mmol) were added to a solution of bromotosylate (47) (20 g, 55 mmol) in tetrahydrofuran (200 mL) and propan-2-ol (100 mL). The mixture was stirred for 6 hours then zinc dust (4 g, 61.6 mmol) was added. The mixture was stirred for an additional 16 hours before filtering the suspension through celite in vacuo. The filter cake was washed with diethyl ether (400 mL). Hydrochloric acid (1M, 400 mL) was added to the filtrate then the organic phase separated. The aqueous layer was extracted with diethyl ether (400 mL) then the combined organic phase was washed with brine (400 mL), then dried (MgSO4), filtered and reduced in vacuo to leave a residue. The residue was partially dissolved in ammonium hydroxide (92 mL) and a solution of ammonia in 2-propanol (60 mL, 2.0M, 120 mmol) then divided into 6 equal portions and heated in sealed tubes at 75° C. for 16 hours. The mixtures were combined using methanol, then the solvents were removed in vacuo. The residue was azeotroped with diethyl ether (3×50 mL) to obtain (R)-2-amino-1-((S)-2,5-dihydrofuran-2-yl)ethanol which was used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([F:18])=[C:12]([F:17])[CH:13]=2)[N:8]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[F:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[F:18])[N:8]([C:19]([CH3:21])([CH3:22])[CH3:20])[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15]2=[O:16]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2cc(F)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reaction time: 8 h

Procedure:
A mixture of 6.08 g (19.7 mmoles) of 6,7-difluoro-1-(1,1-dimethylethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester and 19.7 mmoles of 2N aqueous sodium hydroxide in 80 mL of ethanol was stirred overnight. The resulting mixture was concentrated in vacuo, taken up with 200 mL of water and extracted with dichloromethane. About 8 mL of 2N HCl was added to the aqueous layer to adjust the pH to 3. The precipitate was collected by filtration, washed with H2O and dried to give 4.47 g, of titled compound. MP >260° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@@H:22]3[C@@H:18]([CH2:19][NH:20][CH2:21]3)[C@@H:17]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C=O.[C:36]([O-])(=O)C.[Na+].[BH4-].[Na+]>CO.O>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:24][CH2:23][C@@H:22]3[C@@H:18]([CH2:19][N:20]([CH3:36])[CH2:21]3)[C@@H:17]2[C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CC[C@H]2CNC[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)[O-]
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@@H](O[C@H]1CC[C@H]2CN(C)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 30 mg (0.063 mmol) of (3aR,4R,5S,7aR)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindole (Example 2) in ˜2 mL methanol was added ˜20 mg (excess) aq. formaldehyde and 40 mg sodium acetate. The resulting mixture was stirred at RT for 10 min then 20 mg of NaBH4 was added. The resulting mixture was stirred at RT for 1 hr then water was added. The methanol was evaporated under vacuum and residue extracted with ether (2×25 mL). The combined extracts were dried over drying agent, filtered and the solvent was evaporated under vacuum. The residue was purified by prep TLC eluting with EtOAc/MeOH (9/1) to give the title compound. 1H-NMR (CDCl3): δ: ppm. 7.68 (1H, s), 7.23 (2H, s), 7.02 (2H, m), 6.87 (2H, m), 4.45 (1H, m), 3.27 (1H, ), 2.78-2.65 (2H, m), 2.57 (2H, m), 2.45-2.30 (3H, m), 2.23-2.12 (2H, m), 1.98 (1H, m), 1.83-1.68 (2H, m), 1.30 (3H, 6.2) MS: (MH)+489.9.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]=[C:9]1[O:13][C:11](=[O:12])[CH2:10]1>C1C=CC=CC=1>[CH:1]1([NH:7][C:11](=[O:12])[CH2:10][C:9](=[O:13])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C1CC(=O)O1
Reactant: NC1CCCCC1
Solvent: c1ccccc1
Product: CC(=O)CC(=O)NC1CCCCC1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A mixture of 500 ml of benzene and 99 g of cyclohexyl amine were introduced over 30 minutes to 84 g of diketene and after stirring for 4 hours at 20° C., the mixture was evaporated to dryness by distillation under reduced pressure. The residue was taken up in isopropyl ether and the solution was cooled and vacuum filtered. The recovered precipitate was dried and crystallized from isopropyl ether to obtain 137 g of N-cyclohexyl-acetylacetamide melting at 74° C.
Reaction SMILES: I[C:2]1[C:3]([CH3:25])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[N:8]=[C:7]2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=1.[CH3:26][NH:27][C:28]1[N:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=2)[N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1>[CH3:12][C:9]1[N:8]=[C:7]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[C:6]2[C:11](=[C:2]([C:33]3[CH:34]=[C:35]4[C:30](=[CH:31][CH:32]=3)[N:29]=[C:28]([NH:27][CH3:26])[N:37]=[CH:36]4)[C:3]([CH3:25])=[CH:4][CH:5]=2)[N:10]=1
Reactant: Cc1nc(Nc2cccc(OC(F)(F)F)c2)c2ccc(C)c(I)c2n1
Reactant: CNc1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CNc1ncc2cc(-c3c(C)ccc4c(Nc5cccc(OC(F)(F)F)c5)nc(C)nc34)ccc2n1
Temperature: 150 °C
Yield: 79.5 %

Procedure:
8-Iodo-2,7-dimethyl-N-(3-(trifluoromethoxy)phenyl)quinazolin-4-amine (0.250 g, 0.544 mmol), N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (0.186 g, 0.653 mmol), tetrakis(triphenylphosphine) palladium(0) (0.0629 g, 0.0544 mmol) and 2 M aqueous sodium carbonate (0.544 mL, 1.09 mmol) were placed in a microwave vial and dioxane (3 mL) was added. The tube was capped and heated in a microwave reactor at 150° C. for 10 min. The mixture was concentrated in vacuo and the residue dissolved in ethyl acetate and washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was dried with sodium sulfate and then purified by column chromatography on silica gel using a gradient of 20 to 80% EtOAc in hexanes. The clean fractions were combined and concentrated under vacuum to give a yellow film. The film was triturated with a 1:1 mixture of ether and hexanes. This resulted in the formation of an off-white solid which was collected by filtration and dried in a vacuum oven to give 6-(2,7-dimethyl-4-(3-(trifluoro-methoxy)phenylamino)quinazolin-8-yl)-N-methylquinazolin-2-amine (0.212 g, 79%). MS (M+H)+ 491.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]12[C:17](=[O:18])O[C:14](=[O:15])[C:12]3=[C:13]1[C:8](=[CH:9][CH:10]=[CH:11]3)[CH:7]=[CH:6][CH:5]=2>N1C=CC=CC=1>[CH:6]1[CH:5]=[C:4]2[C:17]([N:2]([OH:3])[C:14]([C:12]3=[CH:11][CH:10]=[CH:9][C:8](=[C:13]23)[CH:7]=1)=[O:15])=[O:18]
Reactant: NO
Reactant: O=C1OC(=O)c2cccc3cccc1c23
Agent: Cl
Solvent: c1ccncc1
Product: O=C1c2cccc3cccc(c23)C(=O)N1O
Temperature: 40 °C
Yield: 80.9 %

Procedure:
A 3-L flask equipped with a stirrer, cooling tube and thermometer was purged by nitrogen gas. 55.2 g (770 mmol) of hydroxylamine-hydrochloride (purity of 97%) and 1.2 L of pyridine were added to the flask and were stirred to dissolve at room temperature under nitrogen atmosphere. To the stirred mixture, 138.7 g (700 mmol) of 1,8-naphthalenedicarboxylic anhydride was added. The stirred mixture was heated at 40° C. for 1 hour and subsequently was heated at 70° C. for 1 hour. After stirring at 90° C. for 1 hour, the reaction mixture was cooled to room temperature with stirring. The resulting crystalline solid was filtered off and washed with 5% by weight of acetic acid aqueous solution and dried at 80° C. for 20 hours under a reduced pressure to yield 120.7 g (81%) of N-hydroxynaphthalimide with yellow color.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>CN(C)C=O>[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.5 g) (45-55% dispersion in oil was added to a solution of 1-(4-pyridyl)piperazine (0.9 g) in dry dimethylformamide (10 ml) at ambient temperature and stirred for 30 minutes. After this time, 4-fluoronitrobenzene (0.65 ml) was added slowly and the temperature raised to 70° C. The mixture was maintained at this temperature for 2 hours. The reaction mixture was then quenched by pouring into water and acidifying with aq 2N HCl solution to pH 1. The acidic layer was washed with diethyl ether and then basified with aq 2N.NaOH solution. The resulting precipitate was filtered, washed with water, dissolved in methanol, filtered through phase separator paper and evaporated to dryness. The resulting crude material was recrystallised from methanol/ether to give 1-(4-pyridyl)-4-(4nitrophenyl)piperazine (0.64 g) as an oil, NMR: (CDCl3) 3.61(q,8H), 6.58(d,2H), 6.81(d,2H), 8.16(d,2H), 8.33(bs,2H); MS: m/z 285 (MH)+.
Reaction SMILES: [C:1]1([C:7](=NN)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl([O-])=O.[Na+].C1(C(C2C=CC=CC=2)=[N+]=[N-])C=CC=CC=1.CCCCCC.[C:43]([O:47][CH2:48][CH3:49])(=[O:46])[CH:44]=[CH2:45]>C(Cl)Cl.O.[Cl-].C([N+](C)(C)CCCCCCCC)C1C=CC=CC=1>[CH2:48]([O:47][C:43]([CH:44]1[CH2:45][C:7]1([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:46])[CH3:49]
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: C=CC(=O)OCC
Agent: CCCCCCCC[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCCCCC
Product: CCOC(=O)C1CC1(c1ccccc1)c1ccccc1
Yield: 56 %

Procedure:
Diphenylketone hydrazone (8.9 g, 45.4 mmol) in DCM (19 mL) was mixed with KI (0.45 g) in water (0.6 mL) and benzyldimethyloctylammonium chloride (10 mg). To the mixture was added the aqueous solution composing of 25% NaOH (27 mL), water (18 mL), and sodium chlorite (12-14%, 28 mL) at 5° C. with vigorous stirring. Twenty minutes later after addition, the stirring was turned off to let the reaction mixture separate. The red DCM solution was separated and dried over anhydrous Na2SO4. After removing the desiccant, the solvent was removed under reduced pressure; the residue was re-dissolved in hexane, and the unreacted hydrazone and side product was insoluble in hexane and removed by filtration. The red hexane diphenyl diazomethane solution was added to ethyl acrylate (13.6 g, 136 mmol) at 50° C. within 30 mints. When the red colour fade off the solvent and excess of ethyl acrylate was removed under reduced pressure to give crude product with 94% purity in 56-94% yield.