Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][NH2:19].[Cl:20][CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][NH:19][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([CH2:21][Cl:20])=[CH:23][CH:24]=1
Reactant: NCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
Triethylamine (0.152 mL; 1.08 mmol) was added at 0° C. to a mixture of (5-chloro-1H-indol-3-yl)methanamine (0.150 g; 0.830 mmol) and 4-(chloromethyl)benzoyl chloride (0.170 g; 0.872 mmol) in dichloromethane (12 mL). The mixture was stirred for 15 minutes at room temperature and was evaporated to dryness. The residue was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) to furnish 0.262 g (95%) of N-((5-chloro-1H-indol-3-yl)methyl)-4-(chloromethyl)benzamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:35])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][N:9]2[C:28]([NH:30][CH2:31][C:32](O)=[O:33])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:36][NH2:37]>>[CH3:36][NH:37][C:32]([CH2:31][NH:30][C:28]([N:9]1[CH2:10][CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:35])=[O:29])=[O:33]
Reactant: CC(C)(C)C[C@@H]1CN(C(=O)NCC(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CN
Product: CNC(=O)CNC(=O)N1CC(CC(C)(C)C)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Yield: 77.1 %

Procedure:
In a manner similar to the method described in Example 60, a mixture of rac-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-acetic acid (22.6 mg, 0.0432 mmole, example 64) was reacted with a solution of methylamine (0.04 mL, 2M in THF, 0.080 mmol, Aldrich) to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid methylcarbamoylmethyl-amide (17.9 mg, 77%) as a white solid. HRMS (ES+) m/z Calcd for C26H28Cl2F2N4O2+H [(M+H)+]: 537.1630; Found: 537.1630.
Reaction SMILES: Cl.[C:2]12([CH2:12][CH2:13][NH2:14])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:25])=[C:20]([CH:24]=1)[C:21](O)=[O:22]>>[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:25])=[C:20]([CH:24]=1)[C:21]([NH:14][CH2:13][CH2:12][C:2]12[CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]3)[CH2:3]1)[CH2:11]2)=[O:22]
Reactant: NCCC12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Agent: Cl
Product: Nc1ccc(Cl)c(C(=O)NCCC23CC4CC(CC(C4)C2)C3)c1
Yield: 58 %

Procedure:
Prepared according to the method of Example 14 from 1-adamantaneethylamine hydrochloride (0.105 g) and 5-amino-2-chlorobenzoic acid (0.132 g) and purified by supercritical fluid chromatography eluting with CO2 in ethanol to give the title compound as a white foam (0.094 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])C.Br[O-:19].[Na+]>O1CCOCC1>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:19])=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(-c2ccc(C(C)=O)cc2)cc1
Reactant: [O-]Br
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
A solution of 18 g of 4-acetyl-4'-methoxybiphenyl in 285 ml of dioxane was oxidized with a dilute sodium hypobromite. Recrystallization from ethanol and acetic acid gave 4'-methoxybiphenyl-4-carboxylic acid melting at 285° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30](OCC)=[O:31])[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:36]1([NH2:39])[CH2:38][CH2:37]1>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30]([NH:39][CH:36]3[CH2:38][CH2:37]3)=[O:31])[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)=[N:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O
Product: CS(=O)(=O)c1ccc(Cn2c(=O)c(C(=O)NC3CC3)c(O)c3ncc(Cc4ccccc4)cc32)cc1

Procedure:
This compound was prepared from ethyl 7-benzyl-4-hydroxy-1-[4-(methylsulfonyl)benzyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and cyclopropylamine employing methods similar to those described in Example 2. The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.04 (1H, br d, J=3.4 Hz), 8.61 (1H, s), 7.81 (2H, d, J=8.4 Hz), 7.29 (3H, m), 7.17 (2H, d, J=8.4 Hz), 7.05 (1H, s), 7.03 (2H, m), 5.39 (2H, br), 4.05 (2H, s), 3.01 (3H, s), 2.97 (1H, m), 0.90 (2H, m), 0.70 (2H, m); HRMS calcd for C27H25N3O5S+H+: 504.1593. Found: 504.1581.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][C:5]([CH2:17][N:18]1[CH:22]=[C:21]([I:23])[CH:20]=[N:19]1)([O:12][Si](C)(C)C)[CH2:6][C:7](OCC)=[O:8]>CO.O>[OH:12][C:5]1([CH2:17][N:18]2[CH:22]=[C:21]([I:23])[CH:20]=[N:19]2)[CH2:4][NH:3][C:7](=[O:8])[CH2:6]1
Reactant: CCOC(=O)CC(CN)(Cn1cc(I)cn1)O[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1CC(O)(Cn2cc(I)cn2)CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydroxide (113 mg, 2.8 mmol) was added to a mixture of ethyl 4-amino-3-((4-iodo-1H-pyrazol-1-yl)methyl)-3-((trimethylsilyl)oxy)butanoate (1.2 g, 2.8 mmol) in methanol (10 mL) and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether/EtOAc) to afford 4-hydroxy-4-((4-iodo-1H-pyrazol-1-yl)methyl)pyrrolidin-2-one. MS ESI calc'd. for C8H11IN3O2 [M+H]+ 308. found 308. 1H NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.51 (s, 1H), 4.28 (s, 2H), 3.34 (s, 2H), 2.29-2.05 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]#[N:8].[CH:9](=O)[CH2:10][CH2:11][CH2:12][CH3:13].C([BH3-])#N.[Na+]>CO>[CH2:9]([NH:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]#[N:8])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCC=O
Reactant: N#Cc1[nH]cnc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCCCNc1nc[nH]c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
4-amino-1H-imidazole-5-carbonitrile (10.0 g, 0.0925 mol) and pentanal (11 mL, 0.10 mol) were mixed in methanol (100 mL). After stirring at room temperature for 2 hours, Sodium cyanoborohydride (7.0 g, 0.11 mol) was added to the mixture. The mixture was continued to stir overnight. The reaction mixture was concentrated, diluted with EtOAc (IL) and washed with sat. NaHCO3 (30 ml) and then brine (50 ml) solutions respectively. The organic layers were dried over Na2SO4, concentrated and purified with combi-flash silica gel chromatography (20%-80% EtOAc in hexane) to yield the desired product (11.5 g, 70%). LCMS calculated for C9H15N4(M+H): 179; found: 179.1.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[K+]>O.CO>[F:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(NS(C)(=O)=O)ccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1
Yield: 92.8 %

Procedure:
Methyl 2-fluoro-5-methanesulfonylaminobenzoate (72 g) and 49 g of potassium hydroxide were dissolved in 400 ml of a 1:1 mixture of water and methanol and the solution was heated to reflux for 2 hours. Methanol was evaporated and the residue was acidified with hydrochloric acid. The crystals separated out therefrom were filtered followed by washing with water and drying to give 63 g of 2-fluoro-5-methanesulfonylaminobenzoic acid, m.p. 203°-205 ° C.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[S:17](Cl)(=[O:19])=[O:18]>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[S:17]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:19])=[O:18].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[S:17]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2cc(Cl)ccc2Cl)c1Br
Yield: 53 %

Procedure:
2,5-Dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide 2,5-Dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,5-dichlorobenzenesulfonyl chloride according to the procedures described in Example 25b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a yellow powder, m.p. 148-150° C., yield 53%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]([OH:19])=O)[CH2:12][CH2:11]1.[NH2:20][C@@H:21]([CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)=[O:23]>>[CH2:41]([O:40][CH2:39][C@H:21]([NH:20][C:17](=[O:19])[CH2:16][N:13]1[CH2:12][CH2:11][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH3:2])[CH2:15][CH2:14]1)[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[CH:27][CH:26]=1)=[O:23])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: COc1ccccc1N1CCN(CC(=O)O)CC1
Agent: Cl
Product: COc1ccccc1N1CCN(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)CC1
Yield: 38.8 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(2-methoxyphenyl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 217, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(2-methoxyphenyl)piperazin-1-yl)acetamido)propanamide (19 mg, 38.8%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.23 (1H), 5.02 (d, 1H), 7.61 (d, 2H), 7.25-4.30 (m, 4H), 7.20-7.23 (m, 3H), 4.00-7.04 (m, 3H), 6.85-6.98 (m, 5H), 4.71 (m, 1H), 4.53 (s. 2H), 3.80 (m, 1H), 3.77 (s, 3H), 3.72 (m, 1H), 3.05 (d, 2H), 2.99 (m, 4H), 2.62 (m, 4H). MS (EI) for C35H37FN4O5. found 613.6 (MH+).
Reaction SMILES: [C:1]12([SH:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[NH2:14][C:15]1[C:20](Br)=[N:19][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][N:16]=1>C(#N)C>[NH2:14][C:15]1[C:20]([S:11][C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]4)[CH2:2]2)[CH2:10]3)=[N:19][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][N:16]=1
Reactant: Nc1ncc(-c2ccccc2)nc1Br
Reactant: SC12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Nc1ncc(-c2ccccc2)nc1SC12CC3CC(CC(C3)C1)C2
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 59.3 %

Procedure:
To a solution of 1-adamantanethiol (0.07 g, 0.4 mmol) in dry acetonitrile (10 mL), sodium hydride (NaH) (9 mg, 0.4 mmol) was added and the resulting mixture was stirred for 15 min. After this time 2-amino-3-bromo-5-phenylpyrazine 17b (0.05 g, 0.2 mmol) was added and the mixture heated at 80° C. for 4 h, cooled and quenched with water. Then EtOAc was added and the organic layer was anidrified over Na2SO4, filtered and the solvent removed under reduced pressure to get a crude that was purified by flash chromatography using petroleum ether-EtOAc (7:3 v/v) as eluent, to obtain 0.04 g of the title compound 18o as a yellow oil (62% yield). 1H-NMR (CDCl3): 1.73 (s, 6H), 2.08 (s, 3H), 2.23 (s, 6H), 5.13 (br s, 2H), 7.32-7.36 (m, 1H), 7.42-7.46 (m, 2H), 7.91-7.93 (m, 2H), 8.29 (s, 1H). MS (ESI): m/z 338 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6](O)[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[ClH:21]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH:6]([Cl:21])[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc(C(O)c2cccc3ccccc23)c1
Reactant: Cl
Solvent: CCOCC
Product: COc1cccc(C(Cl)c2cccc3ccccc23)c1
Temperature: 25 °C
Yield: 72 %

Procedure:
To a solution of 3-methoxy-α-(1-naphthyl)benzyl alcohol (2.5 g, 9.5 mmol) in diethyl ether (5 mL) was added 35% hydrochloric acid (10 mL) at 0° C. The reaction mixture was warmed to r.t. in 1 h, and then extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with aqueous NH4Cl solution and brine, dried over MgSO4. Evaporation of solvents gave 3-methoxy-α-(1-naphthyl)benzyl chloride (1.94 g, 72%). GC-MS (Rt=10.30 min) 282 (M+), 247, 232,215, 202, 189, 163, 151, 139, 123, 101.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][NH:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].O.C(=O)([O-])O.[Na+].Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>O1CCCC1>[CH2:32]([O:31][C:29]([N:8]([CH2:9][C:10]1[N:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[CH:12][CH:11]=1)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)c1cccc(CNCC(=O)OC(C)(C)C)n1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(CN(CC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 6-{[(2-tert-butoxy-2-oxoethyl)amino]methyl}pyridine-2-carboxylate (2.81 g) in tetrahydrofuran (30.0 mL) were added water (30.0 mL) and sodium hydrogen carbonate (962 mg), and then benzyl chloroformate (1.47 mL) was added thereto under ice-cooling. The reaction suspension was stirred at room temperature overnight and extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain ethyl 6-({[(benzyloxy)carbonyl](2-tert-butoxy-2-oxoethyl)amino}methyl)pyridine-2-carboxylate (3.27 g).
Reaction SMILES: C[O:2][C:3]1[N:4]=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([CH2:13][C:14]([OH:16])=[O:15])[CH:7]=2.Br>>[OH:2][C:3]1[N:4]=[CH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([CH2:13][C:14]([OH:16])=[O:15])[CH:7]=2
Reactant: COc1cc2ccc(CC(=O)O)cc2cn1
Agent: Br
Product: O=C(O)Cc1ccc2cc(O)ncc2c1

Procedure:
Refluxing 1 part of 3-methoxy-2-azanaphthalene-7-acetic acid in 25 parts by volume of 16% hydrobromic acid followed by extraction with methylene chloride and isolation provides 3-hydroxy-2-azanaphthalene-7-acetic acid, having the following formula ##SPC21##
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[O:23][C:16]3=[C:17]([NH2:22])[N:18]=[CH:19][C:20](Br)=[C:15]3[CH:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][N:37]([CH:39]3[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]3)[CH:38]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[NH2:22][C:17]1[N:18]=[CH:19][C:20]([C:34]2[CH:35]=[N:36][N:37]([CH:39]3[CH2:40][CH2:41][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:43][CH2:44]3)[CH:38]=2)=[C:15]2[CH:14]=[C:13]([C:5]3[CH:4]=[C:3]([C:2]([F:25])([F:24])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=3)[O:23][C:16]=12
Reactant: Nc1ncc(Br)c2cc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)oc12
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5cc(C(F)(F)F)cc(C(F)(F)F)c5)cc34)cn2)CC1
Temperature: 95 °C
Reaction time: 4 h
Yield: 36.3 %

Procedure:
A solution of 2-(3,5-bis-trifluoromethyl-phenyl)-4-bromo-furo[2,3-c]pyridin-7-ylamine (0.449 g, 1.06 mmol) and tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (0.419 g, 1.11 mmol) in 1,4-dioxane (60 mL) and water (12 mL) was stirred for 10 min and degassed with nitrogen for 15 min. To this stirred mixture was added Pd(PPh3)2Cl2 (100 mg, 0.14 mmol) and the solution was degassed with nitrogen for an additional 5 min. Na2CO3 (168 mg, 1.59 mmol) was added and resulting mixture was stirred at 95° C. for 4 h. The reaction mixture was cooled to RT and the solvent was removed on a rotary evaporator to give the crude compound, which was purified by flash chromatography (2% MeOH:DCM) to afford 229 mg (36%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.45 (s, 9H), 2.10 (m, 2H), 2.22 (m, 2H), 2.97 (t, J=13.2 Hz, 2H), 4.35 (m, 3H), 5.59 (br, 2H), 7.34 (s, 1H), 7.71 (s, 1H), 7.81 (s, 1H), 7.92 (d, J=5.1 Hz, 2H), 8.32 (s, 2H). MS (ESI): 596 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:11]([C:13]2[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=2)=[O:12])=[C:7]([OH:10])[C:8]=1[OH:9]>CO>[CH3:1][O:2][CH2:3][O:10][C:7]1[C:8]([O:9][CH2:17][O:19][CH3:20])=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[C:11](=[O:12])[C:13]1[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=1
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)c(OC)c2)c(O)c1O
Solvent: CO
Product: COCOc1c(OC)ccc(C(=O)c2cc(OC)c(OC)c(OC)c2)c1OCOC

Procedure:
X-Ray Crystal Structure Determination of Hydroxyphenstatin (6a). A thick, plate-shaped X-ray sample (˜0.38×0.36×0.08 mm), grown from methanol solution, was mounted on the tip of a glass fiber with Super-Glue. Data collection was performed at 301±1° K. Accurate cell dimensions were determined by least-squares fitting of 25 carefully centered reflections in the range of 35°<è<40° using Cu Ká radiation.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=1)\[CH2:4][C@H:5]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].[NH2:29][CH2:30][C@@H:31]([OH:33])[CH3:32].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[OH:1]/[N:2]=[C:3](/[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=1)\[CH2:4][C@H:5]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:29][CH2:30][C@@H:31]([OH:33])[CH3:32])=[O:18])=[CH:20][CH:21]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12]
Reactant: Cc1cc(/C(C[C@H](c2ccc(C(=O)O)cc2)c2ccccc2C)=N/O)ccn1
Reactant: C[C@H](O)CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(/C(C[C@H](c2ccc(C(=O)NC[C@H](C)O)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 207, step 2, 4-[(R)-3-[(E)-hydroxyimino]-3-(2-methyl-pyridin-4-yl)-1-o-tolyl-propyl]-benzoic acid (example 272) was coupled with (S)-1-aminopropan-2-ol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as a yellow solid, MS (ESI+): m/z=432.4 [M+H]+.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13].[CH3:15][C:16]1[O:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[CH:17]=1.Cl>C(=S)=S>[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([C:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[O:20][C:16]=1[CH3:15])=[O:13]
Reactant: Cc1cc2ccccc2o1
Reactant: O=C(Cl)CCCCCBr
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: S=C=S
Product: Cc1oc2ccccc2c1C(=O)CCCCCBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
Tin tetrachloride (1.15 ml) was added to a solution of 6-bromohexanoyl chloride (2 g) and 2-methylbenzo[b]furan (1.24 g) in carbon disulfide (30 ml) under ice-cooling, the mixture was stirred at room temperature for 3 hr. Ice water and conc. hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 2.2 g of 6-bromo-1-(2-methyl-3-benzo[b]furyl)-1-hexanone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C@H:16]([C:24]([NH2:26])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO>[CH2:17]([CH:16]1[NH:15][C:11]2([CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[NH:26][C:24]1=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)C(Cc1ccccc1)N2

Procedure:
N-tert-Butyloxycarbonylpiperidone (6.0 g, 29.8 mmol) was added to a solution of phenylalaninamide (4.9 g, 29.8 mmol) in dry EtOH (20 ml) and the mixture was heated under reflux for 2.5 h. The solvent was removed by distillation, and the tert-butyl 3-benzyl-2-oxo-1,4,8-triazaspiro[4,5]decane-8-carboxylate (10.8 g) was used in the following reaction without further workup.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[CH:5][S:4][CH:3]=1.[CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O)=[O:9].C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>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(OCC)(=O)C>[CH3:7][C:6]1[C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:8]=[O:9])=[CH:3][S:4][CH:5]=1
Reactant: Cc1cscc1Br
Reactant: O=Cc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cscc1-c1ccccc1C=O
Temperature: 150 °C
Yield: 78 %

Procedure:
In a microwave vial, 3-bromo-4-methyl-thiophene (653 mg, 3.69 mmol), 2-formyl phenylboronic acid (500 mg, 3.36 mmol) and 7 ml of actonitrile were mixed together. 6.7 ml of 1N aqueous sodium carbonate was added to above solution, followed by 5 mole percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated at 150° C. for 5 minutes with microwave irradiation. After cooling, 50 ml of ethyl acetate was added, the organic layer was separated, washed with water, dried with sodium sulfate. The organic solvent was evaporated to give crude product, which was purified by ISCO CombiFlash column to give 530 mg of 2-(4-methyl-thiophen-3-yl)benzaldehyde, yield: 78%.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:24][CH3:25])[CH:21]=2)[NH:16]1.CCN(CC)CC>C(Cl)Cl>[CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:24][CH3:25])[CH:21]=2)[NH:16]1)=[O:4]
Reactant: COc1ccc2c(c1)CC(c1ccccc1N)N2
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)CC(c1ccccc1NC(=O)C(C)(C)C)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trimethylacetyl chloride (2.40 ml) was added dropwise to a solution of 4.68 g 2-(2-aminophenyl)-5-methoxy-2,3-dihydro-1H-indole and 3.00 ml Et3N in 150 ml CH2Cl2 at 0° C. The resulting mixture was stirred at room temperature for two hours and then quenched with water. The organic extract was washed with 7.5% NaHCO3 and sat. NaCl solution, dried (MgSO4), and concentrated to yield 5.59 g crystalline solid. Recrystallization from MeOH/water yielded 2.38 g solid, m.p. 117°-119° C.