Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[O:3][C:4]([CH3:12])=[CH:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1cc(C)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C(=O)O)c(C)o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.1 %

Procedure:
A mixture of 3.2 g of ethyl 2,5-dimethylfuran-3-carboxylate, 35 ml of ethanol and 20 ml of 2 N sodium hydroxide was stirred at room temperature for 1.5 hours followed by heating under ref lux for an hour. After the reaction mixture was allowed to cool to room temperature, it was concentrated under reduced pressure. The residue was dissolved in water and acidified with diluted sulfuric acid. Precipitated crystals were collected by filtration, washed with water and dried to give 2.27 g of 2,5-dimethylfuran-3-carboxylic acid in a 85% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C@@H:11]([CH:19]([NH:21]C(=O)OC(C)(C)C)[CH3:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C@@H:11]([CH:19]([NH2:21])[CH3:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(NC(=O)OC(C)(C)C)[C@@H]1Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(N)[C@@H]1Cc2ccccc2[C@H](c2ccc(Cl)c(Cl)c2)C1
Reaction time: 1 h
Yield: 88.5 %

Procedure:
To a solution of the above tert-butyl 1-((2S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-2-yl)ethylcarbamate 50b (50 mg, 0.12 mmol) in CH2Cl2 (3 mL) was added TFA (2 mL). The reaction mixture was stirred for 1 h before being concentrated. The residue was subjected to reverse phase column chromatography (CH3CN/H2O/0.1% formic acid=5% to 100%) to give 51 (34 mg, 90%). 1HNMR (400 MHz, CDCl3) δ 7.36 (d, J=8.0 Hz, 1 H), 7.26 (d, J=2.0 Hz, 1 H), 7.12 (m, 2 H), 7.03 (m, 1 H), 7.00 (dd, J=1.6, 8.0 Hz, 1 H), 6.71 (d, J=8.0 Hz, 1 H), 4.04 (dd, J=5.2, 12.0 Hz, 1 H), 2.92 (m, 2 H), 2.72 (dd, J=12.4, 16.0 Hz, 1 H), 2.22 (m, 2 H), 1.85 (m, 1 H), 1.48 (q, J=12.0 Hz, 1H), 1.20 (d, J=6.0 Hz, 3 H); 13CNMR (100 MHz, CDCl3) δ 147.45, 138.65, 136.88, 132.65, 130.87, 130.69, 130.46, 129.54, 129.43, 128.43, 126.02, 126.26, 77.45, 51.35, 40.70, 41.77, 37.10, 32.94, 20.25; ESI MS m/z 320.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5]2.[OH:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.O1CCOCC1>[OH:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5]3)=[CH:20][C:19]=1[CH3:27]
Reactant: Cc1cc(B(O)O)ccc1O
Reactant: CCOC(=O)c1ccc2cc(Br)ccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2cc(-c3ccc(O)c(C)c3)ccc2n1
Temperature: 60 °C
Yield: 39.8 %

Procedure:
Palladium(II)acetate (4.7 mg, 21.0 μmol) was added to ethyl 6-bromo-2-quinolinecarboxylate (117.8 mg, 420.5 μmol), (4-hydroxy-3-methylphenyl)boronic acid (95.9 mg, 630.8 μmol), triphenylphosphine (11.0 mg, 42.1 μmol), and potassium phosphate (312.4 mg, 1.47 mmol). Then, dioxane (4.2 mL) was added to the mixture, followed by water (42 μL), and the reaction mixture was heated open to the atmosphere at 60° C. in an oil bath for 16 hours, then allowed to cool to room temperature. Water was added, followed by ethyl acetate, and the mixture was filtered through Celite®. The filtrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 2:3 ethyl acetate:hexanes to give 51.4 mg (40%) of ethyl 6-(4-hydroxy-3-methylphenyl)-2-quinolinecarboxylate as a solid. 1H NMR (400 MHz, d6-DMSO): δ 9.64 (s, 1H), 8.55 (d, J=9 Hz, 1H), 8.27 (s, 1H), 8.18-8.13 (m, 2H), 8.11 (d, J=8 Hz, 1H), 7.62 (s, 1H), 7.53 (dd, J=8, 2 Hz, 1H), 6.91 (d, J=8 Hz, 1H), 4.42 (q, J=7 Hz, 2H), 2.22 (s, 3H), 1.38 (t, J=7 Hz, 3H). ESI-LCMS m/z 308 (M+H)+.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].Br[C:6]1[CH:7]=[C:8]([C:12]2([CH:22]3[CH2:24][CH2:23]3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH2:21])=[N:13]2)[CH:9]=[CH:10][CH:11]=1.[N:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27][CH:26]=1>>[C:1]([OH:4])(=[O:3])[CH3:2].[CH:22]1([C:12]2([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([C:29]4[CH:30]=[N:25][CH:26]=[N:27][CH:28]=4)[CH:7]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH2:21])=[N:13]2)[CH2:24][CH2:23]1
Reactant: OB(O)c1cncnc1
Reactant: NC1=NC(c2cccc(Br)c2)(C2CC2)c2ccccc21
Solvent: CC(=O)O
Product: NC1=NC(c2cccc(-c3cncnc3)c2)(C2CC2)c2ccccc21
Yield: 85 %

Procedure:
The title compound was prepared in 85% yield as described for Example 78 (Scheme #14, N) starting from 1-(3-bromophenyl)-1-cyclopropyl-1H-isoindol-3-amine acetate (Scheme #15, O) and pyrimidine-5-ylboronic acid: 1H NMR (DMSO-d6) δ 9.19 (s, 1 H), 9.10 (s, 2 H), 8.02 (t, J=1.76 Hz, 1 H), 7.77 (t, J=8.03 Hz, 2 H), 7.64 (dd, J=7.78, 1.25 Hz, 1 H), 7.60-7.55 (m, 1 H), 7.47-7.37 (m, 3 H), 2.05-1.94 (m, 1 H), 1.87 (s, 3 H), 0.52-0.41 (m, 2 H), 0.28-0.17 (m, 1 H), −0.04-0.05 (m, 1 H); MS (ES) m/z 327 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([OH:26])=[CH:10][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:12][C:13]=2[O:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1.[F:27][C:28]1[CH:29]=[C:30]([S:36](Cl)(=[O:38])=[O:37])[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]>>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH2:15][CH3:16])=[CH:12][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:10][C:9]=2[O:26][S:36]([C:30]2[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:28]([F:27])[CH:29]=2)(=[O:37])=[O:38])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(O)c1-c1cccc(N)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1F
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)c2ccc(OC)c(F)c2)c1-c1cccc(N)c1
Yield: 76.1 %

Procedure:
Starting from 3′-amino-4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-biphenyl-2-ol (100 mg; 0.28 mmol) and 3-fluoro-4-methoxy-benzenesulphonyl chloride (115 mg; 0.51 mmol), 115 mg of the title compound are obtained as a pale yellow solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][C:26]=4[N+:34]([O-])=O)=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:38][C:39]1[CH:40]=[C:41]([NH2:45])[CH:42]=[CH:43][CH:44]=1.ClC1C=CC(N)=NC=1>>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:32])[NH:45][C:41]5[CH:42]=[CH:43][CH:44]=[C:39]([F:38])[CH:40]=5)=[CH:27][C:26]=4[NH2:34])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Cl)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1cccc(F)c1
Agent: Nc1ccc(Cl)cn1
Product: Nc1cc(C(=O)Nc2cccc(F)c2)ccc1Sc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1

Procedure:
A mixture of the product from Example 19C was reacted with 3-Fluoro-phenylamine using the procedure of Example 19D substituting 3-Fluoro-phenylamine for 5-chloro-2-aminopyridine followed by reduction of the nitro group following the procedure of Example 19E to provide the title product.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:14]2[C:15]3[CH:16]=[CH:17][C:18]([C:38]([O:40]C(C)(C)C)=[O:39])=[CH:19][C:20]=3[N:21]3[CH2:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][C:24]4[CH:32]=[C:33]([O:36][CH3:37])[CH:34]=[CH:35][C:23]=4[C:22]=23)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>ClC(Cl)C>[CH:8]1([C:14]2[C:15]3[CH:16]=[CH:17][C:18]([C:38]([OH:40])=[O:39])=[CH:19][C:20]=3[N:21]3[CH2:27][C:26]([C:28]([O:30][CH3:31])=[O:29])=[CH:25][C:24]4[CH:32]=[C:33]([O:36][CH3:37])[CH:34]=[CH:35][C:23]=4[C:22]=23)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC(C)(C)C)cc3n2C1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94 %

Procedure:
Trifluoroacetic acid (30 mL) was added dropwise to a stirring slurry of 10-tert-butyl 6-methyl 13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylate (10 g, 20 mmol) in dichloroethane (30 mL) under N2. The clear dark green solution was stirred at rt for 2.5 h, concentrated to dryness and stirred with EtOAc (100 mL) overnight. The solids were collected by filtration, washed with EtOAc and Et2O to yield 13-cyclohexyl-3-methoxy-6-(methoxycarbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (8.35 g, 18.8 mmol, 94%) was as a yellow solid which was used without further purification. 1HNMR (300 MHz, CDCl3) δ 1.13-2.16 (m, 10H), 2.74-2.88 (m, 1H), 3.84 (s, 3H), 3.89 (s, 3H), 4.06-4.29 (m, 1H), 5.54-5.76 (m, 1H), 6.98 (d, J=2.6 Hz, 1H), 7.08 (dd, J=8.4, 2.6 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.78 (dd, J=8.8, 1.1 Hz, 1H), 7.80 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 8.34 (d, J=1.1 Hz, 1H). LCMS: m/e 446 (M+H)+, ret time 3.21 min, column B, 4 minute gradient.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:20][CH:19]=[CH:18][CH2:17][CH2:16]1.C([BH3-])#N.[Na+]>[Cl-].[Zn+2].[Cl-].CO>[N:15]1([CH: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)[CH2:20][CH2:19][CH:18]=[CH:17][CH2:16]1
Reactant: C1=CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2CC=CCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (797 mg, 4 mmol), 1,2,3,6-tetrahydropyridine (349 mg, 4.2 mmol), sodium cyanoborohydride (126 mg, 2 mmol), zinc chloride (410 mg, 3.2 mmol), and anhydrous methanol (20 mL) were mixed together and the mixture stirred overnight at room temperature. The solvent was evaporated from the mixture and the residue partitioned between 1 N sodium hydroxide and dichloromethane. The phases were separated and the aqueous layer extracted with dichloromethane. The organic extracts were combined, dried over magnesium sulfate, and the solvent evaporated. The residue was purified by flash column chromatography (1:1 hexanes/ethyl acetate to ethyl acetate to 1:3 methanol/ethyl acetate) to give 800 mg (75%) as a colorless oil. 1H-NMR (CDCl3, 400 MHz) δ 5.75-5.70 (m, 1H), 5.68-5.64 (m, 1H), 4.13-4.07 (m, 2H), 3.08 (m, 2H), 2.71-2.60 (m, 4H), 2.48-2.41 (m, 1H), 2.15 (m, 2H), 1.82-1.79 (m, 2H), 1.49-1.38 (m, 11H).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:27])=[C:8]([C:16]([NH:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])[C:9](=[O:15])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>O>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:27])=[C:8]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[C:9](=[O:15])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2ccc(C#N)cc2C(C)(C)C1=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2ccc(C#N)cc21
Yield: 91.1 %

Procedure:
1,1-Dimethylethyl N-((7-cyano-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-yl)carbonyl)glycinate (163 mg, 440 μmol) was stirred in TFA (1 mL, 13462 μmol) at room temperature for 20 minutes. Water was added. The resulting precipitate was filtered and washed with water to give the desired product as an off-white solid (126 mg). MS (m/e)=315.1 (M+H)+. Calculated for C16H14N2O5 314.09.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([OH:13])=[CH:6][CH:5]=1.N1C=CC=CC=1>ClCCl>[N+:10]([C:8]1[CH:9]=[C:4]([Cl:3])[CH:5]=[C:6]([Br:1])[C:7]=1[OH:13])([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Reactant: BrBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)cc(Br)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Bromine, Br2 (63.9 g) in 50 ml of dichloromethane was added dropwise to a solution of 4-chloro-6-nitrophenol (34.7 g) in 300 ml of dichloromethane. After the addition was completed, the mixture was stirred at room temperature for 30 min. Pyridine (19.0 g, 240 mmol) in 50 ml of dichloromethane was added. This mixture was stirred at room temperature for 2 hours and a white precipitate was formed. The reaction mixture was quenched with 200 ml of water and the white precipitate was dissolved. The organic layer was then washed with water (2×150 ml), 150 ml of brine and dried over MgSO4. The solvent was evaporated under vacuum to give the crude product which was recrystallized from ethyl acetate to afford 41.5 g (82%) yellow crystalline 2-nitro-4-chloro-6-bromophenol. 1H NMR (300 MHz, CDCl3) δ8.11 (d, J=2.5 Hz, 1 H), 7.87 (d, J=2.5 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=[O:8])([O-:3])=[O:2].[CH3:18][NH:19]C=O.O>C1(C)C(C)=CC=CC=1>[CH3:18][N:19]=[C:7]([OH:8])[C:6]1[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=1)[C:10]([OH:9])=[O:11]
Reactant: CNC=O
Reactant: O=C1OC(=O)c2c1cc([N+](=O)[O-])cc2[N+](=O)[O-]
Solvent: O
Solvent: Cc1ccccc1C
Product: CN=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C(=O)O
Yield: 77.8 %

Procedure:
238.11 g (1 mol) of 3,5-dinitrophthalic anhydride are dissolved under reflux in 1 liter of xylene. 62.02 g (1.05 mols) of N-methylformamide are added dropwise under reflux in the course of 30 minutes. After 18 hours under reflux, the water formed and the formic acid, together with some xylene (total 140 ml), are distilled off, the boiling point rising to 137° C. The solution is filtered hot. After slow cooling and concentration of the mother liquor, 209.42 g (83% of theory) of 3,5-dinitrophthalic acid N-methylimide are obtained; melting point: 174°-6° C.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:21]([CH3:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Cl:23][C:19]1[CH:20]=[C:21]([CH3:22])[C:7]2[N:6]3[C:2]([N:28]4[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]4)=[N:3][N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc(Cl)cc2c1-n1c(Br)nnc1CN=C2c1ccccn1
Product: Cc1cc(Cl)cc2c1-n1c(nnc1N1CCN(C)CC1)CN=C2c1ccccn1

Procedure:
In the manner given in Example 1, 1-bromo-8-chloro-10-methyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with 1-methylpiperazine to give 8-chloro-10-methyl-1-(4-methylpiperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([OH:15])=[C:10]([F:16])[CH:9]=1.[Cl:17][C:18]1[CH:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1.O>CN(C)C(=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([O:15][C:11]2[C:12]([F:14])=[CH:13][C:8]([NH2:7])=[CH:9][C:10]=2[F:16])[CH:21]=[CH:20][N:19]=1
Reactant: Nc1cc(F)c(O)c(F)c1
Reactant: Clc1ccnc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1cc(F)c(Oc2ccnc(Cl)c2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
Potassium tert-butoxide (2.4 g, 22 mmol) was added to a solution of 4-amino-2,6-difluorophenol (2.9 g, 20 mmol) in N,N-dimethyl-acetamide (50 mL) and the mixture was stirred at RT under nitrogen for 0.5 h. A solution of 2,4-dichloro-pyridine (2.9 g, 20 mmol) in N,N-dimethyl-acetamide was added, and the reaction was heated to 100° C. under nitrogen for 10 h. After cooling to RT, the reaction was poured into water (100 mL) and the aqueous solution was extracted with ethyl acetate (3×70 mL). The combined organics were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by silica gel chromatography to give 4-(2-chloropyridin-4-yloxy)-3,5-difluoroaniline (3.0 g, 59% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.31 (d, J=5.7 Hz, 1H), 7.10 (d, J=2.1 Hz, 1H), 7.01 (dd, J=5.7 Hz, 2.1 Hz, 1H), 6.38 (d, J=10.8 Hz, 2H), 5.86 (s, 2H).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:13][CH:14]([CH2:16][CH:17]1[CH:24]2[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:26][CH:18]1[CH2:19]3)[CH2:23]2)[CH3:15])(=[O:12])[CH:10]=[CH2:11].C(N(CC)CC)C.C(OCC)(=O)C>CO>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:11][CH2:10][C:9]([O:13][CH:14]([CH2:16][CH:17]2[CH:24]3[CH2:23][CH:22]4[CH2:21][CH:20]([CH2:19][CH:18]2[CH2:26]4)[CH2:25]3)[CH3:15])=[O:12])=[CH:3][CH:4]=1
Reactant: C=CC(=O)OC(C)CC1C2CC3CC(C2)CC1C3
Reactant: Oc1ccc(S)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(CC1C2CC3CC(C2)CC1C3)OC(=O)CCSc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.2 %

Procedure:
4-Mercaptophenol (5.08 g) (40.3 mmol) and 10.0 g (40.3 mmol) of 2-adamantylpropan-2-yl acrylate were dissolved in 100 ml of MeOH. To the solution was added 4.08 g (40.3 mmol) of triethylamine and the solution was stirred at room temperature for 4 hours. Ethyl acetate (200 ml) was added to the solution, the organic layer was washed four times with saturated sodium hydrogencarbonate and two times with water in order, and the organic layer was dried with sodium sulfate. The solvent was concentrated to obtain 11.2 g (29.9 mmol) of 2-adamantylpropan-2-yl 3-(4-hydroxyphenylthio)propanoate as a white solid. A mixture comprising 3.0 g (8.0 mmol) of the solid, 2.53 g (8.0 mmol) of 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl difluoride, 1.22 g (8 mmol) of 7,11-diazabicyclo[5.4.0]undec-11-ene, and 100 ml of acetonitrile was stirred under nitrogen current at room temperature for 2 hours. Two hundred (200) ml of water and 200 ml of ethyl acetate were added to the solution, and the organic layer was washed with water, a saturated sodium chloride aqueous solution, and water in order, and the organic layer was dried with sodium sulfate. The solvent was concentrated, and the residue was dissolved in 50 ml of methanol and 50 ml of acetone. Sodium hydrogencarbonate (12.0 g) was added and the solution was stirred at 40° C. for 3 hours. Two hundred (200) ml of water and 200 ml of ethyl acetate was added thereto and the organic layer was washed with water, a saturated sodium chloride aqueous solution, and water in order, and the organic layer was dried with sodium sulfate. The solvent was concentrated to obtain brown oil. The oil was recrystallized with diisopropyl ether, and 3.08 g (4.46 mmol) of sodium 3-[4-{2-[(2-adamantylpropan-2-yloxy)carbonyl]ethylthio}-phenoxysulfonyl]-1,1,2,2,3,3-hexafluoropropane-1-sulfonate was obtained as a white solid. The white solid (1.80 g) (2.61 mmol) was dissolved in 100 ml of methanol, 0.895 g (2.61 mmol) of triphenylsulfonyl bromide was added thereto, and the solution was stirred at room temperature for 3 hours. Chloroform (200 ml) was added to the solution, the organic layer was washed with water, and the solvent was concentrated to obtain 2.63 g of a colorless transparent oily compound (A-79).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.B>C1COCC1>[OH:3][CH2:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2ccccc12
Agent: B
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2ccccc2c1CCCO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of ethyl 3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate (2.82 g) in THF (40 mL) was added 1M borane.THF (40 mL). The mixture was stirred at room temperature for 16 hours, quenched with methanol (100 mL) and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5-25% ethyl acetate/hexanes.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=O)[NH:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.CO.Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[CH2:6][NH:8][CH2:9]2
Reactant: Cc1ccc2c(c1)C(=O)NC2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)CNC2
Temperature: 60 °C
Reaction time: 8 h
Yield: 26.9 %

Procedure:
The 4-methylphthalimide (1.8 g) obtained above was suspended in tetrahydrofuran (3 ml), then 1 N borane tetrahydrofuran complex (30 ml) was added thereto at room temperature and stirred overnight at 60° C. The mixture was cooled to 0° C., then methanol (2.8 ml) and 6 N hydrochloric acid (3.2 ml) were added thereto, and the mixture was refluxed for 1 hour. The reaction mixture was cooled to 0° C., then 6 N sodium hydroxide solution was added thereto, and the reaction solution was extracted with ethyl acetate and then the extract was dried over sodium sulfate anhydrous. The resulting product was concentrated under reduced pressure, and the residue was purified by column chromatography (eluting solvent; dichloromethane→dichloromethane:methanol 10:1→5:1) to give the title compound (400 mg, Y.:27%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Li])CCC.[CH3:14][C:15]([CH3:17])=[O:16]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]([OH:16])([CH3:17])[CH3:14])=[N:3][CH:4]=1
Reactant: CC(C)=O
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)(O)c1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 2,5-dibromopyridine in toluene (12 ml/mmol) cooled to −78° C. was added n-butyllithium 2.5M in hexanes (1.05 eq) and the resulting mixture was stirred in the cold for 2.5 hours. Acetone (2 eq) was added and stirring was continued for 1.5 h. After quenching with saturated aqueous ammonium chloride solution, the mixture was warmed to room temperature and partitioned between ethyl acetate and water. The product from the organic phase was chromatographed on silica gel eluting with 20% ethyl acetate in hexane to afford the 5-Bromo-2-(1-hydroxy-1-methylethyl)pyridine compound as a syrup.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)[CH3:12]>O1CCCC1>[C:1]([NH:9][N:10]=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CC(=O)c1ccccc1
Solvent: C1CCOC1
Product: CC(=NNC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of benzoic acid hydrazide (5.70 g, 0.042 mol) in tetrahydrofuran (75 mL) was added acetophenone (5.5 g, 0.046 mol) followed by concentrated. HCl (3 drops). The reaction was allowed to stir for 12 h at 25° C. during which time the product precipitated as a colorless crystalline solid. The product was filtered, washed with tetrahydrofuran (1×30 mL), diethyl ether (3×60 mL) and pentane (2×60 mL), and the crystalline solids were dried in vacuo (6.65 g, 64%). 1H NMR (CD2Cl2): δ2.35 (s, 3H, CH3), 7.30-8.0 (m, 10H, Ph), 9.0 (br, 1H, NH). All other substrates were prepared in a similar fashion.