Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[F:35][C:36]1([F:43])[CH2:41][CH2:40][CH:39](O)[CH2:38][CH2:37]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.O1CCCC1>[F:35][C:36]1([F:43])[CH2:41][CH2:40][CH:39]([O:34][C:31]2[CH:32]=[CH:33][C:28]([N:4]3[C:5](=[O:27])[C:6]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]5[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=5)=[CH:15][CH:14]=4)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=[C:3]3[CH2:1][CH3:2])=[CH:29][CH:30]=2)[CH2:38][CH2:37]1
Reactant: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OC1CCC(F)(F)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OC3CCC(F)(F)CC3)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
A mixture of 4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (600 mg), 4,4-difluorocyclohexanol (362 mg,), diisopropyl azodicarboxylate (1.9 M in toluene, 1.4 mL), triphenylphosphine (698 mg) and tetrahydrofuran (10 ml) was stirred at 60° C. for 3 hr. The reaction mixture was diluted with ethyl acetate, and successively washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give the title compound as a pale yellow oil (635 mg, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([N+:17]([O-])=O)[CH:3]=1.[H][H]>C(OCC)(=O)C.[Pt]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1NCCN1CCOCC1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1cc(Br)ccc1NCCN1CCOCC1
Yield: 96.9 %

Procedure:
Dissolve (4-bromo-2-nitro-phenyl)-(2-morpholin-4-yl-ethyl)-amine (15.3 g, 46.4 mmol) in ethyl acetate (1 L) and add 5% Pt/C (sulfided) (382 mg). Place the slurry under 60 psi hydrogen gas at room temperature of 8 h. Filter and concentrate to give 23 g crude product as a dark red oil. Purify using a short plug of silica gel and 10% 2N NH3 in MeOH/dichloromethane to give 13.5 g of a brown oil. HPLC (ISO60-10M) t=1.46 (94%), MS (ES) 301 (M+1).
Reaction SMILES: [OH-:1].[Na+].S([C:7]1[CH:8]=[C:9]([C:16]([OH:18])=[O:17])[C:10](=[CH:14][CH:15]=1)[C:11]([OH:13])=[O:12])(O)(=O)=O.Cl>O>[OH:1][C:7]1[CH:8]=[C:9]([C:16]([OH:18])=[O:17])[C:10](=[CH:14][CH:15]=1)[C:11]([OH:13])=[O:12]
Reactant: [OH-]
Reactant: O=C(O)c1ccc(S(=O)(=O)O)cc1C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(O)cc1C(=O)O
Temperature: 180 °C
Yield: 72 %

Procedure:
Sodium hydroxide (251.9 g, 6.30 mol) was added in portions to 4-sulphophthalic acid (50% in water, 258.4 g, 0.525 mol) in a steel vessel accompanied by stirring. After the addition of approx. one third NaOH the increasingly more viscous mixture was heated to 180° C. Once the addition had ended the mixture was stirred for a further 2 h at 200° C. During cooling, the residue was dissolved in water (1000 ml). Conc. hydrochloric acid (620 ml, pH=1) was added accompanied by ice cooling. The solution was extracted with ethyl acetate (5×400 ml). The combined organic phases were dried over Na2SO4, filtered and concentrated on the rotary evaporator. The slightly yellow solid was recrystallized from ethyl acetate. 68.64 g (0.377 mol; 72% yield) of a white solid was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:15])[S:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22]>>[CH3:30][O:29][C:25]1[CH:24]=[C:20]([CH:19]=[C:18]([O:17][CH3:16])[C:26]=1[O:27][CH3:28])[C:21]([NH:15][C:11]1[S:12][C:13]([CH3:14])=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:10]=1)=[O:22]
Reactant: COc1ccc(-c2nc(N)sc2C)cc1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Product: COc1ccc(-c2nc(NC(=O)c3cc(OC)c(OC)c(OC)c3)sc2C)cc1
Yield: 63 %

Procedure:
A procedure similar to that in Example 4 was used. 4-(4-methoxy-phenyl)-5-methyl-thiazol-2-ylamine prepared in Example 52 and 3,4,5-trimethoxy-benzoyl chloride prepared in the step 1 of Example 37 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to give a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (15:1) to obtain a product as a white solid in a yield of 63.0%, mp: 105-106 └. 1H-NMR (CDCl3, 400 MHz) δ: 2.51 (3H, s, ArCH3), 3.78 (3H, s, OCH3), 3.79 (3H, s, OCH3), 3.80 (3H, s, OCH3), 3.89 (3H, s, OCH3), 6.78 (2H, d, J=8.44 Hz, ArH), 6.98 (2H, s, ArH), 7.35 (2H, d, J=8.44 Hz, ArH); EI-MS m/e (%): 414.1 (M+, 70), 195.1 (100); HREI-MS Calcd. for C21H22N2O5S: 414.1249. found: 414.1258.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][N:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[C:4]=1C(O)=O>N1C2C(=CC=CC=2)C=CC=1.CCOCC>[CH3:1][S:2][C:3]1[S:7][N:6]=[C:5]([C:8]([F:11])([F:9])[F:10])[CH:4]=1
Reactant: CSc1snc(C(F)(F)F)c1C(=O)O
Solvent: c1ccc2ncccc2c1
Solvent: CCOCC
Product: CSc1cc(C(F)(F)F)ns1
Temperature: 170 °C

Procedure:
5-Methylthio-3-(trifluoromethyl)isothiazole-4-carboxylic acid (9.4 g, 39 mmol) was dissolved in 15 mL of quinoline and 0.6 g (4.2 mmol) of cuprous oxide was added. The mixture was heated at 170° C. for about 30 min and then allowed to cool. It was then diluted with ether and the resulting solution was washed with 100 mL of 2N hydrochloric acid, dried over sodium bicarbonate, filtered, and distilled to obtain 6.55 g (85 percent of theory) of the title compound as a colorless liquid boiling at 126°-127° C. at 84 mm Hg (11 kPa (kiloPascals)) pressure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[C:11]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:29])=O.C(N(C(C)C)CC)(C)C>ClCCCl>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:29])=[N:14][CH:15]=[N:16]2)=[C:11]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2cc(OCc3ccccc3)cc(OC3CCOCC3)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncnc2cc(OCc3ccccc3)cc(OC3CCOCC3)c12
Temperature: 80 °C

Procedure:
A mixture of 7-benzyloxy-5-tetrahydropyran-4-yloxy-3,4-dihydroquinazolin-4-one (9 g), phosphoryl chloride (2.8 ml), di-isopropylethylamine (11.4 ml) and 1,2-dichloroethane (130 ml) was stirred and heated to 80° C. for 3 hours. The mixture was evaporated to give 7-benzyloxy-4-chloro-5-tetrahydropyran-4-yloxyquinazoline which was used without further purification.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[I:13].[CH3:15]C([O-])(C)C.[K+].CI>C1COCC1>[F:14][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:15])[N:8]=[C:7]2[I:13]
Reactant: FC(F)Oc1ccc2[nH]nc(I)c2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(I)c2cc(OC(F)F)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of 5-(difluoromethoxy)-3-iodo-1H-indazole (562 mg, 1.81 mmol) in THF (10.00 mL) at 0° C. was added KOtBu (1M in THF, 2.54 mL, 2.54 mmol) and the mixture stirred at 0° C. for 30 min then MeI (360 mg, 159 μL, 2.54 mmol) added. The reaction mixture was stirred at 0° C. for 30 min then warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride in water and extracted with dichloromethane (3×30 mL), organics dried over MgSO4 and concentrated to a clear oil. Purification by chromatography (80 g column, 50 μm from Analogix, 0-20% EtOAc in hexanes over 20 min) gave 5-(difluoromethoxy)-3-iodo-1-methyl-1H-indazole (465 mg, 1.43 mmol, 79.2%) as a waxy off-white solid. MS (M+H)+=324.9; 1H NMR (CDCl3) δ: 7.32-7.40 (m, 1H), 7.24-7.30 (m, 1H), 7.21 (d, J=2.3 Hz, 1H), 6.55 (t, J=73.7 Hz, 1H), 4.10 (s, 3H). The regioisomeric product, 5-(difluoromethoxy)-3-iodo-2-methyl-2H-indazole, (108 mg, 333 μmol, 18%) was also obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:9]=1)[C:7]#[N:8].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[Sn](CCCC)(CCCC)CCCC>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: N#Cc1cc(O)ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1cc(O)ccc1-c1ccco1
Temperature: 100 °C

Procedure:
5-Hydroxy-2-iodo-benzonitrile (200 mg, 0.82 mmol) and PdCl2(PPh3)2 (20 mg, 0.028 mmol) and 2-furyltributyltin (400 g, 1.12 mmol) in N,N-dimethylformamide (5 mL) is degassed and heated at 100° C. for 15 min. After the mixture cooled to room temperature, an aqueous work up is performed and the product is isolated from chromatography (100 mg, 66%). MS (ESI): 184 (M−1)−1.
Reaction SMILES: [F:1][CH2:2][C:3]([N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])([CH2:6][CH2:7][CH2:8]I)[C:4]#[N:5].[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K]>CN(C)C=O>[F:1][CH2:2][C:3]([N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])([CH2:6][CH2:7][CH2:8][N:25]1[C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]2[C:21]1=[O:31])[C:4]#[N:5]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#CC(CF)(CCCI)N1C(=O)c2ccccc2C1=O
Agent: [K]
Solvent: CN(C)C=O
Product: N#CC(CF)(CCCN1C(=O)c2ccccc2C1=O)N1C(=O)c2ccccc2C1=O
Reaction time: 8 h

Procedure:
2-Fluoromethyl-2-phthalimido-5-iodo-valeronitrile (1.20 g, 3.11 mmol) and potassium phthalimide (0.75 g, 4 mmol) are heated in dimethylformamide (25 ml) to 80° C. for 2 hours. After standing overnight at room temperature, the DMF is removed by vacuum distillation and the residue is dissolved in chloroform and washed with 1 N KOH and water. After drying (Na2SO4), evaporation gives 2-fluoromethyl-2,5-diphthalimidovaleronitrile as a solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18]1>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][O:1][C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:5][CH2:6]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(CCOC(=O)CCC(=O)O)CC1
Reaction time: 18 h

Procedure:
Compound 57 (5.3 g, 23.0 mmol), succinic anhydride (2.30 g, 23.0 mmol) and 4-dimethylaminopyridine (281 mg, 2.30 mmol) were dissolved in CHCl3 (14 mL) and stirred for 18 h. The solution was concentrated in vacuo and used without further purification. 1H NMR (400 MHz, CDCl3) δ 1.42 (s, 9H), 2.54-2.60 (m, 8H), 2.72 (t, J=5.6, 2H), 3.43-3.46 (m, 4H), 4.23 (t, J=5.5, 2H).
Reaction SMILES: C(OC([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH2:11][CH2:10][C@H:9]1[C:23](=[O:34])[NH:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([O:32][CH3:33])[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:23]([C@@H:9]2[CH2:10][CH2:11][C@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[NH:8]2)=[O:34])=[CH:26][C:27]=1[O:32][CH3:33]
Reactant: COc1cc(NC(=O)[C@@H]2CC[C@H](c3ccc(OC)c(OC)c3)N2C(=O)OC(C)(C)C)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(NC(=O)[C@@H]2CC[C@H](c3ccc(OC)c(OC)c3)N2)ccc1Cl
Temperature: 0 °C
Yield: 100 %

Procedure:
(2S,5R)2-(4-Chloro-3-methoxy-phenylcarbamoyl)-5-(3,4-dimethoxy-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.48 g, 7.09 mmol) was dissolved in dichloromethane (100 ml) and cooled to 0° C. in an ice bath. TFA (30 ml) was then added slowly to the stirring solution. The reaction was allowed to stir and warm to room temperature overnight. The reaction mixture was concentrated in vacuo. The pH of the resulting residue was adjusted to 8 with 1N NaOH and the product extracted into ethyl acetate. The extract was then washed with brine solution (2×100 ml), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude oil was chromatographed to afford (2S,5R)5-(3,4-dimethoxy-phenyl)-pyrrolidine-2-carboxylic acid (4-chloro-3-methoxy-phenyl)-amide (2.77 g, 7.09 mmol, 100% yield). Analysis H1 NMR (400 MHz, CDCl3): 10.02 (1H, broad s), 7.59 (1H, broad s), 7.21 (1H, d), 7.03-6.82 (4H, m) 4.52-4.30 (2H, m), 3.90 (9H, m), 2.70-1.88 (5H, m). MS (LC-MS): Calculated for C20H23ClN2O4 390.13, found 391.16 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH2:13]O)[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:15]>>[C:1]1([C:7]2[CH:8]=[C:9]([CH2:13][Br:15])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br
Reactant: OCc1cccc(-c2ccccc2)c1
Product: BrCc1cccc(-c2ccccc2)c1
Temperature: 0 °C

Procedure:
Under a nitrogen atmosphere a stirred solution of 12.9 grams of 3-phenylphenylmethanol in 50 mL of 47-49% hydrobromic acid was heated at reflux for two hours. Thin layer chromatographic analysis of the reaction mixture indicated that the reaction was incomplete. An additional 50 mL of 47-49% hydrobromic acid was added, and the stirred reaction mixture was heated at reflux for an additional two hours. After this time the reaction mixture was poured into ice-water, and the mixture was extracted with 100 mL of diethyl ether. The extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 16.2 grams of 3-phenylphenylmethyl bromide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[CH2:2][CH:3]1[O:19][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[C:9]([CH3:18])([CH3:17])[CH2:8]3.[N-:20]=[N+:21]=[N-:22].[Na+]>>[N:20]([CH2:2][CH:3]1[O:19][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[C:9]([CH3:18])([CH3:17])[CH2:8]3)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc2c(c3c1NC(=O)C(C)(C)C3)OC(CBr)C2
Agent: [Na+]
Product: Cc1cc2c(c3c1NC(=O)C(C)(C)C3)OC(CN=[N+]=[N-])C2
Yield: 86.1 %

Procedure:
Using the compound obtained in Example 299 (1.93 g 5.96 mmol) and sodium azide (2.8 g, 43.1 mmol), the procedure of Example 278 was followed (reaction, post-treatment, and recrystallization from chloroform-ether). 1.47 g of the title compound was obtained as colorless crystals (86.2%).
Reaction SMILES: Cl.Cl.[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35]>C(Cl)Cl>[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[CH2:6][CH2:5][N:4]1[C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[C:31]([C:30]([F:29])([F:40])[F:41])[CH:32]=2)=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(N2CCc3ccncc3C2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCc3ccncc3C2)cc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.2 %

Procedure:
To a mixture of 4-(3,4-dihydro-2,7-naphthyridin-2(1H)-yl)aniline dihydrochloride (75.0 mg, 0.251 mmol) and N,N-diisopropylethylamine (0.153 mL, 0.88 mmol) in 3.0 mL CH2Cl2 at rt was added 3-(trifluoromethyl)benzoyl chloride (0.041 mL, 0.277 mmol) and the reaction stirred for 15 min at rt. The reaction was evaporated, then partitioned between EtOAc and H2O/brine mixture, the EtOAc layer washed with aqueous Na2CO3 solution, brine, and dried with anhydrous Na2SO4. The EtOAc solution was filtered past a silica gel plug, rinsed with EtOAc, and evaporated to a yellow solid. The solid was recrystallized from EtOAc/hexane to give the title compound as a light tan solid (83 mg, 83%). 1H NMR (DMSO-d6) δ: 10.28 (s, 1H), 8.44 (s, 1H), 8.32 (d, J=5.0 Hz, 1H), 8.23-8.30 (m, 2H), 7.95 (d, J=7.9 Hz, 1H), 7.74-7.80 (m, 1H), 7.61-7.68 (m, 2H), 7.19 (dd, J=5.0, 0.6 Hz, 1H), 7.03-7.09 (m, 2H), 4.40 (s, 2H), 3.54 (t, J=5.9 Hz, 2H), 2.93 (t, J=5.9 Hz, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:13]=2)=[O:10])=[CH:5][CH:4]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CS(C)=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9]([C:6]2[CH:7]=[N:8][C:3]([CH2:2][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:4][CH:5]=2)=[O:10])=[CH:13][C:14]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)nc1
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CN2CCOCC2)nc1

Procedure:
6-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamide was dissolved in DMSO (1 mL) treated with morpholine (33 uL) for 1 h. The reaction was concentrated, and the crude residue was purified by reverse phase HPLC to produce N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(morpholinomethyl)pyridine-3-carboxamide. MS (Q1) 409.3 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:3]=1[N:4]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][CH:6]([CH3:8])[CH3:7].C(Cl)Cl>[Pd].CO>[F:1][C:2]1[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:3]=1[N:4]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: CC(C)CN(CC(C)C)c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(C)CN(CC(C)C)c1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
To a solution of 2-fluoro-N,N-diisobutyl-4-nitroaniline (0.8 g, 3 mmol) in mixed solvents of CH2Cl2 (15 mL) and MeOH (15 mL) was added catalyst Pd/C (80 mg). The reaction mixture was stirred at rt under H2 overnight, and filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=8:1) to give the title compound as pale yellow oil (0.40 g, 56%).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16](Cl)[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([N:31]1[C:39](=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32]1)[CH3:30]>>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([N:32]2[C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:39](=[O:40])[N:31]2[CH2:29][CH3:30])[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CCn1[nH]c2ccccc2c1=O
Product: CCn1c(=O)c2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)C)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 4-(8-((4-tert-butylpiperazin-1-yl)methyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine and 2-ethyl-1H-indazol-3(2 H)-one were reacted to give 472. LCMS m/z: 534.3 (MH+)
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([NH2:7])=O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:19]2)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](=[S:19])[NH2:7]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)CCC(F)(F)F
Solvent: Cc1ccccc1
Product: NC(=S)CCC(F)(F)F
Temperature: 80 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
A mixture of 4,4,4-trifluorobutanamide (17.9 g), 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (51.3 g) and toluene (400 mL) was stirred at 80° C. for 3 hr. The reaction mixture was purified by aminopropylsilane-bonded silica gel column chromatography (ethyl acetate), and again purified by aminopropylsilane-bonded silica gel column chromatography (ethyl acetate/hexane) to give the title compound (14.6 g) as a solid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23])(=O)C.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH3:41])[CH:34]=[C:35]([O:39]C)[C:36]=1[O:37][CH3:38]>ClCCCl>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:34]1[C:35]([OH:39])=[C:36]([O:37][CH3:38])[C:31]([O:30][CH3:29])=[CH:32][C:33]=1[CH3:41])=[O:23]
Reactant: COc1cc(C)cc(OC)c1OC
Reactant: CC(=O)OCCCCCCCCCCCCCCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1cc(C)c(C(=O)CCCCCCCCCCCCCCCCCO)c(O)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.6 %

Procedure:
To a solution of 18-acetoxy-n-octadecanoyl chloride (11 g) in 1,2-dichloroethane (50 ml) is added aluminum chloride (7 g) and the mixture is stirred at room temperature for 2 hours. This reaction mixture is cooled to 5° C. and a solution of 3,4,5-trimethoxytoluene (6.2 g) in 1,2-dichloroethane (20 ml) is added. The mixture is stirred at room temperature for 72 hours. Then, this reaction mixture is heated to 50° C.-60° C. and stirred for 30 minutes. After cooling, ice-water is added to the reaction mixture and the product is extracted with dichloromethane. The dichloromethane layer is washed with water and the solvent is distilled off to recover an oil (12.1 g). This oil is dissolved in methanol (150 ml) followed by addition of sodium hydroxide (5.2 g). The mixture is stirred at room temperature for 2 hours, at the end of which time it is neutralized with 5N--HCl and the solvent is distilled off. The resultant crude crystals are rinsed with water and recrystallized from dichloromethane-ether (1:1). The above procedure yields 6-(18-hydroxy-1-oxooctadecyl)-2,3-dimethoxy-5-methylphenol (6.4 g) as colorless needles, m.p. 101° C.
Reaction SMILES: CC([CH:5]1[CH2:10][N:9]([CH2:11][CH:12]([C:15]2[CH:24]=[CH:23][C:18]3[C:19](=[O:22])[O:20][CH2:21][C:17]=3[C:16]=2[CH3:25])[O:13][CH3:14])[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.[ClH:29]>O1CCOCC1>[ClH:29].[CH3:25][C:16]1[C:17]2[CH2:21][O:20][C:19](=[O:22])[C:18]=2[CH:23]=[CH:24][C:15]=1[CH:12]([O:13][CH3:14])[CH2:11][N:9]1[CH2:10][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: COC(CN1CCN(C(=O)[O-])C(C(C)(C)C)C1)c1ccc2c(c1C)COC2=O
Agent: Cl
Solvent: C1COCCO1
Product: COC(CN1CCNCC1)c1ccc2c(c1C)COC2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl-4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)-2-(methyloxy) ethyl]-piperazine-1-carboxylate was treated with 4M HCl in dioxane (4 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness. Analysis by LC indicated complete removal of the Bac group and formation of compound 4-methyl-5-[1-(methyloxy)-2-piperazin-1-ylethyl]-2-benzofuran-1(3H)-one hydrochloride. 1H-NMR (DMSO, 500 MHz), δ 7.747 (d, J=7.5 Hz, 1H), 7.577 (d, J=7.5 Hz, 1H), 5.402-5.388 (m, 2H), 5.113 (d, J=9 Hz, 1H), 3.850 (s, 3H), 3.496-3.327 (m, 8H), 3.228-3.140 (m, 3H), 2.500 (s, 3H).