Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]([CH:19]([CH3:21])[CH3:20])[C:3]([C:5]1[C:6]([CH3:18])=[C:7]([CH3:17])[C:8]2[O:12][CH:11]([C:13]([OH:15])=[O:14])[CH2:10][C:9]=2[CH:16]=1)=[O:4].S(=O)(=O)(O)O>>[CH3:17][C:7]1[C:8]2[O:12][CH:11]([C:13]([OH:15])=[O:14])[CH2:10][C:9]=2[C:16]2[CH2:1][CH:2]([CH:19]([CH3:21])[CH3:20])[C:3](=[O:4])[C:5]=2[C:6]=1[CH3:18]
Reactant: C=C(C(=O)c1cc2c(c(C)c1C)OC(C(=O)O)C2)C(C)C
Agent: O=S(=O)(O)O
Product: Cc1c(C)c2c(c3c1OC(C(=O)O)C3)CC(C(C)C)C2=O
Temperature: 57 °C

Procedure:
A mixture of 2,3-dihydro-5-(2-methyleneisovaleryl)-6,7-dimethylbenzofuran-2-carboxylic acid (5.0 g.) and concentrated sulfuric acid (25.0 ml.) is heated at 57°C. for 6 hours then poured into ice water (300 ml.). The 4,5-dimethyl-6-oxo-7-isopropyl-1,2,7,8-tetrahydro-6H-indeno[5,4-b]furan-2-carboxylic acid which separates is filtered and dried.
Reaction SMILES: N(C1C=C(C=CC=1C)C(O)=O)=[N+]=[N-].NC1C(OC)=C(NS(C)(=O)=O)C=C(C2(C)CC2)C=1.[N:32]([C:35]1[CH:36]=[C:37]([CH:58]=[CH:59][C:60]=1[CH3:61])[C:38]([NH:40][C:41]1[CH:46]=[C:45]([C:47]([CH3:50])([CH3:49])[CH3:48])[CH:44]=[C:43]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])[C:42]=1[O:56][CH3:57])=[O:39])=[N+:33]=[N-:34]>>[N:32]([C:35]1[CH:36]=[C:37]([CH:58]=[CH:59][C:60]=1[CH3:61])[C:38]([NH:40][C:41]1[CH:46]=[C:45]([C:47]2([CH3:49])[CH2:50][CH2:48]2)[CH:44]=[C:43]([NH:51][S:52]([CH3:55])(=[O:53])=[O:54])[C:42]=1[O:56][CH3:57])=[O:39])=[N+:33]=[N-:34]
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: COc1c(N)cc(C2(C)CC2)cc1NS(C)(=O)=O
Agent: Cc1ccc(C(=O)O)cc1N=[N+]=[N-]
Product: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C2(C)CC2)cc1NS(C)(=O)=O

Procedure:
3-Azido-N-[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-4-methyl-benzamide was prepared from 3-azido-4-methyl benzoic acid and N-[3-amino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-methanesulfonamide in the same manner as 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide (Example 15).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+].IC.Cl>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([O:9][CH3:11])=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(O)c(F)cc1Br
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(C)c(Br)cc1F
Temperature: 25 °C
Yield: 93.4 %

Procedure:
To a mixture of 4-bromo-2-fluoro-5-methylphenol (29.6 g, 144.2 mmol) and potassium carbonate (30.0 g, 218 mmol) in acetone (500 mL) was added iodomethane (69.0 g, 486 mmol). The resulting suspension was stirred at reflux for 4 hours. The reaction mixture was cooled to RT, poured into HCl (250 mL of 1 N solution) and extracted with ethyl acetate (3×250 mL). The combined organic layers were washed with sodium bicarbonate solution, dried over sodium sulfate and filtered. Evaporation of the solvent and purification on a silica column (5% ethyl acetate—hexanes) yielded 29.50 g (93%) of the title compound as a clear, colorless oil: 1H NMR (CDCl3): δ 2.33 (3H, s), 3.85 (3H, s), 6.82 (1H, d, J=8.79 Hz), 7.23 (1H, d, J=10.25 Hz); MS m/z,
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[H-].[Na+].I[CH3:13]>CN(C)C=O>[CH3:13][N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: CI
Reactant: c1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cccnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Pyrrolo[2,3-b]pyridine (2.00 g, 16.93 mmol) is dissolved in dimethylformamide (15.0 ml) under an argon atmosphere. Sodium hydride (60% in oil) (0.96 g, 40.0 mmol, 1.5 equiv.) is added at 0° C. over a period of 30 minutes. After 30 minutes' stirring at 0° C., iodomethane (1.49 ml, 24.02 mmol, 1.5 equiv.) is added dropwise. After returning to room temperature, the reaction mixture is stirred for 1 hour. The dimethylformamide is evaporated off under reduced pressure, and the product is taken up in water and extracted with dichloromethane. Purification on a silica column (petroleum ether/ethyl acetate 7/3) allows isolation of the title compound in the form of an oil in a yield of 99%. ##STR31##
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]#[N:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:4]1[CH:3]=[C:2]([NH:22][C:23]([CH3:28])([CH3:27])[C:24]([OH:26])=[O:25])[CH:7]=[CH:6][CH:5]=1)[CH2:17][C:16]2([CH3:19])[CH3:18])#[N:21]
Reactant: CC(C)(N)C(=O)O
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(C#N)cc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(Nc1cccc(C2CC(C)(C)c3cc(C#N)ccc3N2)c1)C(=O)O
Temperature: 25 °C
Yield: 33 %

Procedure:
A solution of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (341 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 2-amino-2-methyl-propionic acid (235 mg, 4.0 mmol) and potassium carbonate (420 mg, 3.0 mmol) in dimethyl sulfoxide (4.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (120.1 mg, 33.1%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 364.1.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:13][N:14]=[N+:15]=[N-:16])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:14]([CH2:13][C@@H:8]([NH2:7])[CH2:9][CH:10]([CH3:12])[CH3:11])=[N+:15]=[N-:16]
Reactant: CC(C)C[C@@H](CN=[N+]=[N-])NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N)CN=[N+]=[N-]

Procedure:
((1S)-1-Azidomethyl-3-methyl-butyl)-carbamic acid tert-butyl ester (9.64 g, 39.78 mmol) was treated with TFA (30 mL) in DCM (150 mL) for 3 hrs, the mixture was evaporated under reduced pressure and the residue was dissolved in ethyl acetate and washed with aqueous 1 M K2CO3, dried with Na2SO4 and concentrated to a yellow liquid (4.55 g, 80%).
Reaction SMILES: C1C=CC(C[O:8][C:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([OH:18])=[O:17])[O:11][CH:10]=2)=CC=1.O>Cl>[CH:13]1[C:14](=[O:15])[C:9]([OH:8])=[CH:10][O:11][C:12]=1[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1cc(=O)c(OCc2ccccc2)co1
Agent: Cl
Solvent: O
Product: O=C(O)c1cc(=O)c(O)co1

Procedure:
34.5 q of 5-benzyloxy-4-pyrone-2-carboxylic acid was suspended in 500 ml of concentrated hydrochloric acid and 250 ml of water and reacted for 1 hour at 80° C. The reaction solution was cooled with ice, and the formed crystal was taken out by filtration, washed with water and then dried, to obtain 16.6 g of 5-hydroxy-4-pyrone-2-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:45])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][C@@H:30]([CH2:33][O:34][Si](C(C)C)(C(C)C)C(C)C)[CH2:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][Si](C(C)C)(C(C)C)C(C)C)[CH:11]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1>[OH:34][CH2:33][C@@H:30]1[O:29][C:28]([C:26]2[NH:27][C:23]([C:8]3[CH:9]=[C:10]([OH:12])[CH:11]=[C:6]([O:5][C@@H:4]([CH3:45])[CH2:3][O:2][CH3:1])[CH:7]=3)=[CH:24][CH:25]=2)=[N:32][CH2:31]1
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C3=NC[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)O3)[nH]2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 127.7 %

Procedure:
(5R)-2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrol-2-yl)-5{[(triisopropylsilyl)oxy]methyl}-4,5-dihydro-1,3-oxazole (9.69 g, 14.7 mmol) synthesized in Example (1250 was dissolved in tetrahydrofuran (150 mL), and tetrabutylammonium fluoride (1 mol/L tetrahydrofuran solution, 30.0 mL, 30 mmol) was added dropwise at 0° C., followed by stirring at 0° C. for 30 minutes. A saturated aqueous ammonium chloride solution (200 mL) was added, and extraction was carried out with ethyl acetate (200 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=3%-7%) to afford the desired compound (6.50 g, yield ˜100%) as a pale yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[S:5][C:4]=1[C:18](OCC)=[O:19].[C:23]1([OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[O:29]([CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:16])([F:15])[F:17])=[CH:12][CH:13]=2)[S:5][C:4]=1[CH2:18][OH:19])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1CBr
Reactant: Oc1ccccc1
Product: OCc1sc(-c2ccc(C(F)(F)F)cc2)cc1COc1ccccc1

Procedure:
Prepared from intermediate 43 and phenol
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[CH2:9])[CH:5]=[C:4]([CH2:13][O:14][CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])[N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[N:30]1[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]1)[NH2:26].C(=O)([O-])[O-].[Cs+].[Cs+].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:11]([O:10][C:8]([C:6]1[CH:5]=[C:4]([CH2:13][O:14][CH2:15][CH2:16][C:17]([F:20])([F:19])[F:18])[N:3]=[C:2]([NH:26][C:25]2[CH:27]=[CH:28][C:29]([N:30]3[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]3)=[C:23]([O:22][CH3:21])[CH:24]=2)[N:7]=1)=[CH2:9])[CH3:12]
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: C=C(OCC)c1cc(COCCC(F)(F)F)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C=C(OCC)c1cc(COCCC(F)(F)F)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 120 °C

Procedure:
A mixture of 2-chloro-4-(1-ethoxyvinyl)-6-((3,3,3-trifluoropropoxy)methyl)pyrimidine (89 mg, 0.29 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (58 mg, 0.29 mmol), cesium carbonate (187 mg, 0.57 mmol), palladium (II) acetate (10 mg, 0.04 mmol) and (2-biphenylyl)dicyclohexylphosphine (15 mg, 0.04 mmol) in dioxane (3 mL) was heated at 120° C. under argon for 90 minutes in microwave reactor. The mixture was passed through a short silica plug which was eluted with EtOAc. The residue was purified by preparative HPLC to give the title compound as a dry film 93 mg (68%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C:4]([C:8]#[C:9][Si](C(C)C)(C(C)C)C(C)C)([OH:7])[CH2:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:8]([C:4]1([OH:7])[CH2:5][CH2:6][N:2]([CH3:1])[CH2:3]1)#[CH:9]
Reactant: CC(C)[Si](C#CC1(O)CCN(C)C1)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CC1(O)CCN(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure B. Into a solution of Ethynyl-triisopropyl-silane (1.1 g, 6 mmol) in tetrahydrofuran (10 mL) was dropped in n-BuLi (2.4 mL, 6 mmol) at −78° C. The solution was stirred for 0.5 h. Then 1-Methyl-pyrrolidin-3-one (0.5 g, 5 mmol) was added. The solution was allowed to warm up to room temperature and stirred for 3 h. Then the reaction mixture was added in 50 mL EtOAc and washed with water three times. The solvent was removed under vacuum to afford 1-Methyl-3-[(triisopropylsilanyl)-ethynyl]-pyrrolidin-3-ol (0.55 g, 39%). 1H NMR (DMSO-d6, 400 MHz): δ 5.53 (s, 1H), 2.74-2.63 (m, 2H), 2.46-2.44 (m, 1H), 2.23 (s, 3H), 2.13-1.96 (m, 2H), 1.07-0.97 (m, 21H). A solution of 1-Methyl-3-[(triisopropylsilanyl)-ethynyl]-pyrrolidin-3-ol (1.0 g, 3.6 mmol) in tetrahydrofuran (10 mL) was treated with Tetrabutyl-ammonium fluoride (0.94 g, 3.6 mmol). The solution was stirred overnight at room temperature. Then the reaction mixture was purified by column (eluent: CH2Cl2: MeOH=10:1) to afford 3-Ethynyl-1-methyl-pyrrolidin-3-ol (0.26 g, 58%). 1H NMR (DMSO-d6, 400 MHz): δ 5.55 (s, 1H), 3.31 (s, 1H), 2.74-2.56 (m, 3H), 2.49-2.46 (m, 1H), 2.22 (s, 3H), 2.11-1.91 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12](F)[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[CH:21]([NH:24][CH3:25])([CH3:23])[CH3:22]>CS(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([N:24]([CH:21]([CH3:23])[CH3:22])[CH3:25])[C:11]([C:15]#[N:16])=[CH:10][C:9]=1[N+:17]([O-:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(C)C
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C#N)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C#N

Procedure:
The title compound was prepared from (4-cyano-5-fluoro-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example B9) (1.95 g, 6.93 mmol) and N-isopropyl-N-methylamine (3.60 ml, 34.7 mmol) in DMSO (30 mL) at RT according to the general procedure C. Obtained as a yellow solid (1.84 g, 79%).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=3)=[CH:11][C:10]([S:27](O)(=[O:29])=[O:28])=[C:9]2[CH3:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(C([Cl:36])=O)=O>C(Cl)Cl>[CH:1]1([CH2:7][N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:14]=3)=[CH:11][C:10]([S:27]([Cl:36])(=[O:29])=[O:28])=[C:9]2[CH3:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(S(=O)(=O)O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1c(S(=O)(=O)Cl)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n1CC1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
To a solution of compound 5c (1.0 g, 2.2 mmol) in CH2Cl2 (10 mL) was added (COCl)2 (0.8 g, 6.6 mmol) dropwise at 0° C. Then this mixture was stirred at 0° C. for 2 h and concentrated to obtain compound 5d (1.0 g, 100%).
Reaction SMILES: Cl[C:2]1[C:3]([N+:19]([O-])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]2.CCN(CC)CC>CO.N.[Pd]>[NH2:19][C:3]1[CH:2]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCCN(CCC)C1CCc2ccc([N+](=O)[O-])c(Cl)c2C1
Agent: [Pd]
Agent: N
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCN(CCC)C1CCc2ccc(N)cc2C1
Reaction time: 5 h
Yield: 48.2 %

Procedure:
A mixture of 3b (1.65 g), Pd/C (0.8 g) and Et3N (6 ml) in MeOH (70 ml) was hydrogenated at 36 psi in a Parr apparatus for 5 hours. The mixture was filtered through celite and the solvent was evaporated to yield 2.5 g of the raw product, which was suspended in diluted ammonia and extracted three times with Et2O. The combined organic extracts were dried (MgSO4), filtered and evaporated to yield 0.63 g (48%) of pure 7-amino-2-(N,N-di-n-propylamino)tetralin (4b).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N+:11]([O-])=O>CO.C1COCC1.[Ni]>[NH2:11][C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[S:6][C:2]=1[CH3:1]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)s1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(N)c(C)s1
Temperature: 25 °C
Reaction time: 36 h
Yield: 64.3 %

Procedure:
To a solution of methyl 5-methyl-4-nitrothiophene-2-carboxylate (F-3) (14.8 g, 73.6 mmol) in MeOH/THF (1:1, 300 mL) was added Raney Ni. The reaction mixture was degassed and charged with hydrogen 3 times, and then stirred at room temperature for 36 h under 1 atmosphere of hydrogen. Raney Ni was filtered, and the filtrate was concentrated. The residue was treated with aqueous HCl (1 N, 150 mL) and filtered. The filtrate was treated with aqueous NaOH (1 N) to bring pH to about 8 to 9. Then the mixture was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, and the solvent was removed to give the title compound (8.1 g).
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][O-])[CH2:5][CH2:4][O:3]1.[Na+].[Br:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[Br:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:7]=[C:6]2[CH2:5][CH2:4][O:3][C:2]2=[O:1])[CH:12]=1
Reactant: O=C1OCCC1=C[O-]
Reactant: Nc1cc(Br)ccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1OCCC1=CNc1cc(Br)ccn1

Procedure:
A solution of sodium (2-oxodihydrofuran-3(2H)-ylidene)methano-late (134 mg, 1 mmol), 4-bromopyridin-2-amine (173 mg, 1.0 mmol) and 4-methylbenzenesulfonic acid (50 mg, 0.29 mmol) in toluene was stirred at 150° C. for 1 hr. After the suspension was diluted with water, the solution was adjusted to pH 8 and extracted with ethyl acetate. Then, the organic layers were dried over Na2SO4 and concentrated to give crude product, which was used for then next reaction without further purification. MS (ESI): 269, 271 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+].CO>C(Cl)Cl.[N+](CCCC)(CCCC)(CCCC)CCCC.[O-]S(O)(=O)=O>[C:12]1([S:18]([N:8]2[C:5]3=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=[C:4]3[C:10]([I:11])=[CH:9]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Brc1cnc2[nH]cc(I)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1cc(I)c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96.8 %

Procedure:
To a cooled solution of 45 (15.00 g, 46.6 mmol) in CH2Cl2 (210 mL) was added benzenesulfonyl chloride (9.18 mL, 71.8 mmol), 50% aq NaOH (13.04 mL) and Bu4NHSO4 (2.35 g, 6.94 mmol). The mixture was allowed to warm to ambient temperature and stirred for 2 h 45 min. The mixture was diluted with CH2Cl2 (200 mL) and washed with saturated brine solution (200 mL). The aqueous layer was extracted with CH2Cl2 (2×200 mL), the combined organics were dried (MgSO4) and concentrated to afford a pale yellow solid. The solid was stirred vigorously with cold methanol for 1 h and the resulting precipitate was filtered off and dried under vacuum to afford 46 as a white solid (20.90 g, 97%); 1H NMR (400 MHz, CDCl3) δ7.49 (t, J=15.5, 7.4 Hz, 2H), 7.60-7.64 (m, 1H), 7.81 (d, J=2.2 Hz, 1H), 7.87 (s, 1H), 8.17-8.19 (m, 2H), 8.45 (d, J=2.1 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:9][CH2:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][C:20]=2[F:21])[N:17]=[CH:16][CH:15]=[CH:14]3)[C:5]([NH2:8])=[N:6][CH:7]=1.[N:22]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[N:3]=[C:4]2[N:9]([CH2:10][C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][C:20]=3[F:21])[N:17]=[CH:16][CH:15]=[CH:14]4)[N:22]=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)nc1NCc1cc2cccnc2cc1F
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Fc1cc2ncccc2cc1Cn1nnc2ncc(Br)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of 5-bromo-N*3*-(7-fluoro-quinolin-6-ylmethyl)-pyrazine-2,3-diamine (90 mg, 0.26 mmol) in acetic acid (4 mL) was added a solution of sodium nitrite (11.4 mg, 0.26 mmol) in water (1 mL). After stirring at rt for 3 h, the solvent was removed in vacuo. The residue was diluted with NaHCO3 (aq.), extracted with DCM. The organic layer was separated and washed with water, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography with DCM:MeOH=50:1 to give the title compound as a yellow solid (57.0 mg, 61%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.03 (s, 1H), 8.94 (d, 1H), 8.40 (d, 1H), 8.08 (d, 1H), 7.84 (d, 1H), 7.55 (dd, 1H), 7.53 (dd, 1H), 6.21 (s, 2H). LCMS (method A): [MH]+=359/361, tR=2.23 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2>C1COCC1.O>[CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccccn2)=CCC3(C)C)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC=C(c2ccccn2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
A solution of 80.0 mg (0.196 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(2-pyridyl)-2-naphthalenyl)ethynyl]benzoate (Compound 10) and 20.6 mg (0.491 mmol) of LiOH--H2O in 3 ml of THF/water (3:1, v/v), was stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound as a colorless solid. 1H NMR (d6-DMSO): δ 8.64 (1H, m), 7.94 (2H, d, J=8.3 Hz), 7.87 (1H, dt, J=1.7, 7.8 Hz), 7.58 (2H, d, J=8.3 Hz), 7.50 (1H, d, J=8.2 Hz), 7.47 (2H, s), 7.37 (1H, m), 7.25 (1H, s), 6.30 (1H, t, J=4.6 Hz), 2.39 (2H, d, J=4.6 Hz), 1.31 (6H, s).
Reaction SMILES: [NH:1]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:2]([C:8]([NH:10][C@H:11]([C:23]([NH:25][C@H:26]([C:31]([O:33]CC1C=CC=CC=1)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:24])[CH2:12][CH2:13][C:14](=[O:22])[O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].C(OCC)C.CCCCCC>C1COCC1.[C].[Pd]>[NH:1]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[C@H:2]([C:8]([NH:10][C@H:11]([C:23]([NH:25][C@H:26]([C:31]([OH:33])=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:24])[CH2:12][CH2:13][C:14](=[O:22])[O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CCC(=O)OC1CCCCC1)NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)C[C@H](NC(=O)[C@H](CCC(=O)OC1CCCCC1)NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)C(=O)O
Yield: 98.5 %

Procedure:
21.0 Grams of Boc-Gln-Glu(OcHex)-Leu-OBzl was dissolved in 200 ml of THF, and the solution was subjected to catalytic reduction in the presence of 2.00 g of 5%-palladium-carbon as the catalyst. After the reduction was finished, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue thus obtained was added diethyl ether-n-hexane to crystallize to obtaine 17.86 g (yield: 98.5%) of the above-mentioned objective product.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][CH:15]=2)=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH2:28]([Mg]Br)[CH3:29].O>O1CCCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][CH:15]=2)=[C:9]([CH:10]([OH:11])[CH2:28][CH3:29])[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2nccc(Oc3ccc(C(C)(C)C)cc3C=O)c2cc1OC
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)c1cc(C(C)(C)C)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-(Tert-butyl)-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzaldehyde was dissolved in anhydrous tetrahydrofuran (1 ml) to prepare a solution. A 1 M tetrahydrofuran solution (0.5 ml) of ethylmagnesium bromide was added to the solution at 0° C., and the mixture was stirred at 0° C. for one hr. Water (1 ml) was added dropwise to the reaction solution to stop the solution. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure to give 1-{5-(tert-butyl)-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-1-propanol.