Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:23])=[CH:6][C:7]([CH3:22])([CH3:21])[NH:8]2.[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[C:3]([CH2:2][S:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:22])([CH3:21])[CH:6]=[C:5]2[CH3:23]
Reactant: COc1ccccc1-c1ccc2c(c1CCl)C(C)=CC(C)(C)N2
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1ccc2c(c1CSc1ccccc1)C(C)=CC(C)(C)N2
Temperature: 50 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
A mixture of 5-chloromethyl-6-(2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 5-1, 80 mg, 0.24 mmol), thiophenol (148 μL, 1.44 mmol) and potassium carbonate (266 mg, 1.92 mmol) was suspended in anhydrous N,N-dimethylformamide (2 mL), and the reaction mixture was stirred at 50° C. overnight. After cooling down, it was diluted with ethyl acetate (50 mL). The whole was washed with water (50 mL) and saturated brine (30 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (53 mg) as a colorless solid. (Yield 55%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[C:10](=O)([O-])[O-].[K+].[K+].IC.C(OCC)C>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: Oc1c(F)cccc1F
Agent: [K+]
Solvent: CCOCC
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(F)cccc1F
Yield: 81.4 %

Procedure:
In 254 ml of N,N-dimethylformamide was dissolved 25.4 g of 2,6-difluorophenol, followed by adding thereto 29.7 g of potassium carbonate and 83.1 g of iodomethane, and the resulting mixture was stirred at 50° C. for 2 hours. The reaction mixture was added to a mixed solvent of 200 ml of diethyl ether and 600 ml of water and the organic layer was separated. The organic layer obtained was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The resulting residue was purified by vacuum distillation (43-45° C./20 mmHg) to obtain 22.9 g of 2,6-difluoroanisole as a colorless oil.
Reaction SMILES: [CH2:1](O)[CH3:2].[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[OH:15])[O:11][CH2:10][CH2:9][CH:8]2[C:16]([OH:18])=[O:17].S(=O)(=O)(O)O>C(OCC)(=O)C>[Cl:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[OH:15])[O:11][CH2:10][CH2:9][CH:8]2[C:16]([O:18][CH2:1][CH3:2])=[O:17]
Reactant: CCO
Reactant: O=C(O)C1CCOc2cc(O)c(Cl)cc21
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2cc(O)c(Cl)cc21
Temperature: 25 °C
Yield: 43 %

Procedure:
A 20-liter 4-neck round-bottom flask was charged with ethanol (8.6 L) and crude 6-chloro-7-hydroxychroman-4-carboxylic acid (1.70 kg, 7.44 mol) and the resulting mixture was stirred at ambient temperature. Concentrated sulfuric acid (397 mL) was added over 10 minutes. The resulting mixture was stirred and heated to reflux for 16 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (9.0 mL). The resulting mixture was washed with brine (2×12 L). The brine washes were combined and extracted with ethyl acetate (4 L). The ethyl acetate layer was washed with brine (2 L). The organic layers were combined and dried over sodium sulfate, then concentrated under reduced pressure at a temperature below 50° C. The residue was purified by chromatography on silica gel (18 kg), eluting with 85:15 hexanes:ethyl acetate (235 L), to afford ethyl 6-chloro-7-hydroxychroman-4-carboxylate as a white powder (822 g, 43% yield). MS (apci) m/z=255.1 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH:11]1([C:14]2[CH:15]=[C:16]([CH3:26])[C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[N:18][CH:19]=2)[CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:23]2[CH2:24][CH2:25][N:20]([C:17]3[C:16]([CH3:26])=[CH:15][C:14]([CH:11]4[CH2:12][CH2:13]4)=[CH:19][N:18]=3)[CH2:21][CH2:22]2)=[O:10])=[N:6][CH:7]=1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: O=C(O)c1ccc(Br)cn1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cn2)CC1
Yield: 47 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 5-bromo-2-picolinic acid (1.5 g) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (1.8 g) described in Preparation Example 96, the title compound (1.4 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][NH:5][N:4]=1.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20](O)C1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]([CH:21]2[CH2:22][N:18]([C:16]([O:15][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:17])[CH2:20]2)[N:4]=1
Reactant: COc1n[nH]cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1nn(C2CN(C(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.9 %

Procedure:
To a cooled (0° C.) suspension of 3-methoxy-4-nitro-1H-pyrazole (1.00 g, 6.99 mmol, 1.00 eq), tert-butyl-3-hydroxypyrrolidine-1-carboxylate (2.12 g, 12.2 mmol, 1.75 eq), and polystyrene bound triphenylphosphine (4.06 g, 12.2 mmol, 1.75 eq, 3 mmol/gram) in THF (45 mL) was added diethyl azodicarboxylate (2.42 mL, 13.0 mmol, 1.90 eq) in a drop-wise manner over 3 min. The reaction mixture was allowed to warm to ambient temperature and stirred for 15 hr. The reaction mixture was then diluted with EtOAc (60 mL), filtered and the filtrate concentrated. The crude reaction mixture was purified via flash chromatography on silica gel eluting with a gradient of 0-60% EtOAc in heptane to give the title compound (1.52 g, 72.9% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.12 (s, 1H) 4.87 (tt, J=5.6, 7.5 Hz, 1H) 4.40-4.28 (m, 4H) 4.09 (s, 3H) 1.48 (s, 9H). m/z (APCI+) for C7H11N4O3 198.9 (M−Boc+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-:18].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.C(OCC)C>[CH3:17][S:14]([N:11]1[CH2:12][CH:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:18])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)N1CC=C(c2ccc(Br)cc2)CC1
Reactant: [OH-]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Product: CS(=O)(=O)N1CC=C(c2ccc(O)cc2)CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A mixture of 4-(4-bromo-phenyl)-1-methanesulfonyl-1,2,3,6-tetrahydro-pyridine (23.50 g, 74.32 mmol), potassium hydroxide (14.72 g, 222.95 mmol), 2-di-tert-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (2.52 g, 5.95 mmol) and tris(dibenzylideneacetone)dipalladium (0) (1.36 g, 1.49 mmol) is purged with nitrogen, and then deoxygenated 1,4-dioxane (150 mL) and deoxygenated water (150 mL) are added. The mixture is stirred at 100° C. for 1 h. The mixture is cooled to 23° C. and 1 M aq hydrochloric acid is added until pH 2-3. The aqueous layer is extracted with ethyl acetate. The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and the solvent is removed to obtain a red solid. Diethyl ether is added and the solid is filtered to obtain 16 g of the title compound as an off-white solid. MS (m/z) 254 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[CH2:10][N:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCOCC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][N:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(=O)CN1C(=O)OCc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)CN1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 93 %

Procedure:
4-Oxo-pyrazolidine-1,2-dicarboxylic acid 1-benzyl ester 2-tert-butyl ester, 27, (5.0 g, 15.6 mmol) is dissolved in tetrahydrofuran (150 mL) and the solution cooled to −78° C. A 5.0 M solution of borane-dimethyl sulfide complex in ether (6.24 mL, 31.2 mmol) is added dropwise via syringe. After 40 minutes at −78° C., the reaction is quenched by slow addition of a saturated aqueous solution of ammonium chloride (20 mL). The cooling bath is removed, and the mixture allowed to warm to ambient temperature with vigorous stirring. The solvent is removed in vacuo and the residue diluted with dichloromethane (200 mL). The mixture is washed with water (150 mL) and saturated aqueous sodium bicarbonate solution (150 mL), water and brine. The combined aqueous layers are extracted with dichloromethane (200 mL), water (150 mL), NaCl (sat.) (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 4.66 g (93% yield) of the desired product as a clear, viscous oil.
Reaction SMILES: C1(=O)CCCCC1.NC1C=CC=CC=1.[N+](C1C=CC=CC=1)([O-])=O.[C:24]1([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(N(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH:31]1([NH:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O=C1CCCCC1
Solvent: Nc1ccccc1
Product: c1ccc(NC2CCCCC2)cc1
Yield: 2.9 %

Procedure:
Reaction was carried out by the same procedure as in Example I1 except that 32.39 g (0.39 mol) of cyclohexanone, 9.31 g (0.1 mol) of aniline and 24.62 g (0.2 mol) nitrobenzene were used. As a result, the yield of diphenylamine was 89.5%, and 1.8% of triphenylamine and 2.9% of N-cyclohexylaniline were produced.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16]([NH:18][C:19](=[O:21])[O-:20])[CH3:17].[OH:22][C:23]1[C:24]([Cl:36])=[CH:25][C:26]2[CH:27]([CH3:35])[CH:28]3[CH2:32][NH:31][CH2:30][CH:29]3[C:33]=2[CH:34]=1>C(#N)C>[CH2:16]([NH:18][C:19](=[O:20])[O-:21])[CH3:17].[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:22][C:23]2[C:24]([Cl:36])=[CH:25][C:26]3[CH:27]([CH3:35])[CH:28]4[CH2:32][NH:31][CH2:30][CH:29]4[C:33]=3[CH:34]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CC1c2cc(Cl)c(O)cc2C2CNCC12
Agent: CCNC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1c2cc(Cl)c(OCc3ccc(F)cc3)cc2C2CNCC12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-Fluorobenzyl bromide (23 μL, 0.19 mmol) and potassium carbonate (100 mg, 0.78 mmol) were added to a solution of N-ethylcarbamate-5-hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 5, Step A) (46 mg, 0.16 mmol) in acetonitrile (3 mL), and stirred overnight at 80° C. The reaction was cooled to room temperature, concentrated by rotary evaporation and taken up in H2O (5 mL). The product was extracted with EtOAc (3×10 mL). The combined organic extracts were dried over MgSO4 and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C22H23ClFNO3+H: 404, observed: 404.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:20]#[C:21][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:33][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:20]#[C:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:31][CH:32]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)cc2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1ccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-ethylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 5) 47.0 mg (0.108 mmol) in 3 ml of EtOH and 2 ml of THF was added 28.0 mg (0.70 mmol, 0.7 ml) of NaOH (1.0 M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ 7.90 (2H, d, J=8.3 Hz), 7.59 (2H, d, J=8.3 Hz), 7.46 (2H, s), 7.29-7.21 (4H, m), 7.02 (1H, s), 6.01 (1H, t, J=4.5 Hz), 2.64 (2H, q, J=7.5 Hz), 2.33 (2H, d, J=4.5 Hz), 1.29 (6H, s), 1.22 (3H, t, J=7.5 Hz).
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[O:11][C:12](=[O:27])[C@H:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[NH:14][CH3:15].[C:28]([NH:35][C@H:36]([C:46](O)=[O:47])[CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12](=[O:27])[C@H:13]([CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[N:14]([C:46](=[O:47])[C@H:36]([CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH:35][C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: CN[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)Oc1ccc2ccccc2c1
Product: CN(C(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)Oc1ccc2ccccc2c1
Yield: 96.1 %

Procedure:
Using Procedure D, crude Nδ-Boc-Nα-methylornithinyl 2-naphthyl ether (37 mg) and Boc-O-benzylserine (62 mg) was coupled to afford product (62 mg) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ1.49 (broad s, 21H), 1.77 (m, 1H), 3.08 (s, 3H), 3.17 (s, 2H), 3.64 (m, 2H), 4.05 (dd, J=13.0; 3.8 Hz, 1H), 4.14 (dd, J=13.0; 7.3 Hz, 1H), 4.52 (m, 3H), 4.91 (m, 1H), 7.05 (m, 2H), 7.20 (m, 3H), 7.32 (m, 3H), 7.41 (m, 1H), and 7.69 (m, 3H); mass spectrum (ES+) m/e 636 (M+1).
Reaction SMILES: C(OC([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])=[CH:21][CH:20]=3)=[CH:18][C:13]=2[CH:12]=[C:11]([C:32]([O:34][CH3:35])=[O:33])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[OH-].[Na+]>C(OCC)(=O)C>[CH2:30]([O:29][CH2:28][CH2:27][CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[CH:16]=[CH:15][C:14]3[NH:8][CH2:9][CH2:10][C:11]([C:32]([O:34][CH3:35])=[O:33])=[CH:12][C:13]=3[CH:18]=2)=[CH:20][CH:21]=1)[CH3:31]
Reactant: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
In ethyl acetate (50 ml) was dissolved methyl 1-(t-butoxycarbonyl)-7-[4-(3-ethoxypropoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.2 g). To the solution was added 6N hydrochloric acid (10 ml), and the mixture was stirred at 80° C. for 30 minutes, neutralized with 1N sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give methyl 7-[4-(3-ethoxypropoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.8 g) as yellow crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:4]([C:10]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]([F:14])[C:12]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(C(C)C)CC)(C)C.[CH3:38][O:39][CH2:40]Cl.O>ClCCl>[F:1][C:2]1[C:3]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:4]([C:10]([NH:15][C:16](=[O:21])[C:17]([CH3:18])([CH3:19])[CH3:20])=[C:11]([F:14])[C:12]=1[O:13][CH2:38][O:39][CH3:40])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: COCCl
Reactant: CCOC(=O)c1c(NC(=O)C(C)(C)C)c(F)c(O)c(F)c1OC1CCCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1c(NC(=O)C(C)(C)C)c(F)c(OCOC)c(F)c1OC1CCCCO1
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
4.23 g (10.5 mmol) of the above ethyl 3,5-difluoro-4-hydroxy-6-pivaloylamino-2-(2-tetrahydropyranyloxy)benzoate was dissolved in 50 mL of dichloromethane, 2.4 mL (13.7 mmol) of diisopropylethylamine and 0.96 mL (12.6 mmol) of chloromethyl methyl ether were added under ice-cooling and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction solution and the mixture was extracted once with chloroform. The organic layer was washed once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was triturated with n-hexane to give 4.33 g of ethyl 3,5-difluoro-4-methoxymethoxy-6-pivaloylamino-2-(2-tetrahydropyranyloxy)benzoate (yield: 93%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[NH2:19][C:20]1[N:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[N:21]=1>C(OCC)(=O)C>[Cl:27][C:22]1[CH:23]=[C:24]([Cl:26])[N:25]=[C:20]([N:19]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:21]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: BrCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1cc(Cl)nc(N2CCOCC2)n1
Yield: 28.1 %

Procedure:
2-bromoethylether (3.65 g), potassium carbonate (8.29 g), and N,N-dimethylformamide (75 mL) were added to 2-amino-4,6-dichloropyrimidine (2.46 g), and the mixture was refluxed for 3 hours while heated. Subsequently, the reaction mixture was diluted with ethyl acetate, was washed with water, and was dried over anhydrous sodium sulfate. The solvent was removed and the resulting residue was purified on a silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain 4,6-dichloro-2-(morpholine-4-yl)pyrimidine (985 mg, 28%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])[C:16]=1[CH3:28].Cl.C(N=C=NCCCN(C)C)C.O[C:42]1[C:50]2[N:49]=N[NH:47][C:46]=2[CH:45]=[CH:44][CH:43]=1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][C:25]([NH:47][C:46]2[CH:45]=[CH:44][CH:43]=[CH:42][C:50]=2[NH2:49])=[O:26])=[O:22])[C:16]=1[CH3:28]
Reactant: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCC(=O)O
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1ccccc1N
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCC(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
2-(5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-acetic acid (385 mg, 1 mmol), and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxy-benzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (342 mg, 72% yield) as a red solid. LC-MS (m/z) 476 (M+1).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:20]=[CH:21][CH:22]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14](I)[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].[CH2:23]([O:25]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:24].Cl>C1(C)C=CC=CC=1.O1CCOCC1.C(OCC)(=O)C.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>[C:23]([C:14]1[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]2[CH:20]=[CH:21][CH:22]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=2)[CH:17]=[CH:16][C:15]=1[CH3:18])(=[O:25])[CH3:24]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1I
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(NC(=O)c2cccc(C(C)(C)C#N)c2)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
A solution of 3-(2-cyanopropan-2-yl)-N-(3-iodo-4-methylphenyl)benzamide 111 (1.546 mmol, 625 mg), 1-ethoxyvinyltri-n-butyltin (4.64 mmol, 1.567 mL) and bis(triphenylphosphine)palladium(II) chloride (0.155 mmol, 109 mg) in toluene (5 mL) was stirred at 100° C. for 2 h. Cooled down to room temperature, 4N HCl in dioxane (1 mL) was added and stirred for 1 h. Diluted with ethyl acetate, filtrated and evaporated. Purification by chromatography (0-5% ethyl acetate in CH2Cl2) gave N-(3-acetyl-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide 112 (364 mg, 73.5%). NMR (400 MHz, CDCl3) 1.79 (s, 6H), 2.52 (s, 3H), 2.62 (s, 3H), 7.26 (d, J=8.2 Hz, 1H), 7.55 (m, 2H), 7.72 (d, J=7.8 Hz, 1H), 7.81 (d, J=7.4 Hz, 1H), 7.91 (br s, 1H), 8.00 (t, J=1.9 Hz, 1H), 8.15 (d, J=2.3 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH:10]1([CH2:13]O)[CH2:12][CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:13][CH:10]1[CH2:12][CH2:11]1
Reactant: Oc1ccc(F)cc1Br
Reactant: OCC1CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(OCC2CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.8 %

Procedure:
To a solution of 2-bromo-4-fluorophenol (0.50 g, 2.6 mmol) in tetrahydrofuran (13 mL) were added cyclopropanemethanol (0.209 mL, 2.62 mmol), triphenylphosphine (0.687 g, 2.62 mmol), and DIAD (0.509 mL, 2.62 mmol). The reaction mixture was stirred for 16 hours at ambient temperature. The solvent was removed under reduced pressure. The residue was triturated with hexanes. The mixture was filtered, and the filtrate containing the product was concentrated by under reduced pressure. The residue was purified by flash chromatography (silica gel, hexanes) to provide the title compound (400 mg, 62% yield).