Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH:3]=1.Br[C:28]1[CH:29]=[C:30]([S:34]([NH:37][C:38]([CH3:42])([CH3:41])[CH2:39][OH:40])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[OH:40][CH2:39][C:38]([NH:37][S:34]([C:30]1[CH:29]=[C:28]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:6]3[CH:5]=[C:4]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=4)[CH:3]=[C:2]([CH3:1])[N:7]=3)[CH:9]=2)[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35])([CH3:42])[CH3:41]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(B(O)O)c2)n1
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(Br)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)CO)c3)c2)n1

Procedure:
The title compound was prepared from 3-[6-methyl-4-(4-trifluoromethyl-phenyl)pyridin-2-yl]-benzeneboronic acid (example G.9) (0.442 g, 1.2 mmol) and 3-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example H.4) (0.381 g, 1.2 mmol) according to the general procedure VI. Obtained as a white solid (0.150 g, 22%). MS (ISP) 499.2 [(M+H)+]; mp 181° C.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].O.C[N:19]1CCO[CH2:21][CH2:20]1.C(Cl)(=O)OCC.C(N)C>C1COCC1>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:2]([C:7]([NH:19][CH2:20][CH3:21])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN1CCOCC1
Agent: CCN
Agent: CCOC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)[C@@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
25 g of Boc-D-Leu-OH.H2O was dissolved in 200 ml of THF. The solution was cooled to -20° C. 11 ml of N-methylmorpholine and 9.56 ml of ethyl chlorocarbonate were added to the solution. After 5 min, 12.9 g of a 70% aqueous ethylamine solution was added thereto and the mixture was stirred at about -5° C. for 2 h. After concentration, the residue was dissolved in ethyl acetate and washed with an aqueous NaHCO3 solution and water successively. After concentration to dryness, 24.5 g of Boc-D-Leu-NHC2H5 was obtained.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C(Cl)(Cl)Cl.O1CCOCC1>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[C:4]3[CH:3]=[C:2]([NH:36][C:35]4[CH:37]=[CH:38][C:32]([O:31][CH3:30])=[CH:33][CH:34]=4)[N:7]=[CH:6][C:5]=3[CH:8]=2)[CH:19]=[N:20]1)=[O:24])([CH3:27])([CH3:29])[CH3:28]
Reactant: COc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2C(=O)OC(C)(C)C)cn1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COc1ccc(Nc2cc3c(cn2)cc(-c2cnn(C(=O)OC(C)(C)C)c2)n3C(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Yield: 67.8 %

Procedure:
To tert-butyl 6-bromo-2-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (10) (50 mg, 0.108 mmole) was added 4-methoxyaniline (16 mg, 0.129 mmole, 1.2 eq) followed by cesium carbonate (70 mg, 0.216 mmole, 2 eq) and Xantphos (6.2 mg, 0.0108 mmole, 10 mole %). Dioxane (1.2 mL) was added and the flask flushed twice with nitrogen. Pd2(dba)3 complex (5 mg, 0.0054 mmole, 5 mole %) was added and the flask was flushed again with nitrogen (×3) and heated at 80° C. for 2 hours. The reaction was cooled and diluted with ethyl acetate (10 mL). The solution was washed with water (3 mL) and with brine, dried and evaporated to leave a gum. This was applied in chloroform to a 1 mm, 20×20 cm silica prep plate which was eluted with 9:1 dichloromethane:ethyl acetate. The product band was recovered with acetone. Solution evaporated and residue azeotroped with ethanol to leave the title compound (37 mg, 68%). 1H-NMR (d6-DMSO, 500 MHz): δ 1.45 (s, 9H), 1.60 (s, 9H), 3.72 (s, 3H), 6.78 (d, J=0.63 Hz, 1H), 6.87 (d, J=9.14 Hz, 2H), 7.39 (t, J=0.95 Hz, 1H), 7.48 (d, J=9.14 Hz, 2H), 8.02 (d, J=0.63 Hz, 1H), 8.41 (d, J=0.95 Hz, 1H), 8.43 (d, J=0.63 Hz, 1H), 8.73 (br s, 1H).
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[C:12]1([CH3:30])[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:28][CH:27]([OH:29])[CH2:26][C@@H:22]2[C:23](O)=[O:24])(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1COCC1>[OH:24][CH2:23][C@@H:22]1[CH2:26][C@H:27]([OH:29])[CH2:28][N:21]1[S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:30])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)N2CC(O)C[C@@H]2C(=O)O)cc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2C[C@@H](O)C[C@H]2CO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.7 %

Procedure:
4.14 g (109.5 mmol) of sodium borohydride was suspended in 150 ml of THF at 0° C. and 17.6 ml (142.2 mmol) of borontrifluoride etherate was added dropwise over a period of 10 minutes. 15.6 g (54.7 mmol) of 1-(4-toluenesulfonyl)-4-hydroxy-D-proline was added in portions and the mixture was allowed to stir at room temperature for 16 hours. The reaction was then cooled to 0° C. and quenched with methanol: 10% aqueous HC1 solution was then added and the mixture was gently heated to 60° C. for 1 hour. The pH of the reaction was adjusted to neutral with 50% aqueous sodium hydroxide solution and the volatiles were evaporated under reduced pressure. The product was then isolated via filtration and the filter cake was washed with water. Drying under vacuum at 60° C. for 12 hours yielded 10.2 g of the product as a white solid in 69% yield. M.P.=103°-105° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([O:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1>[C:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([O:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:9]=2)=[CH:6][CH:7]=1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(N)cc2)on1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(NC(=O)c3ccccc3)cc2)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
5-(4-Aminophenyl)-3-(2-(N-tert-butoxycarbonylamino)ethoxy)isoxazole (0.1 g) was dissolved in tetrahydrofuran (I ml), and triethylamine (0.05 ml) and benzoyl chloride (0.04 ml) were successively added dropwise thereto at 5° C. under a nitrogen atmosphere, followed by stirring of the resulting mixture at room temperature for 30 minutes. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=3/1) to obtain the title compound (0.08 g, 62%) as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][CH:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:15][OH:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH:14]([CH2:17][C:18]([F:19])([F:21])[F:20])[CH2:15][O:16][C:30]3=[O:32])[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: OCC(CC(F)(F)F)Nc1nc(-c2ccc(Br)cc2)cs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1OCC(CC(F)(F)F)N1c1nc(-c2ccc(Br)cc2)cs1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 83.2 %

Procedure:
2-{[4-(4-Bromophenyl)-1,3-thiazol-2-yl]amino}-4,4,4-trifluorobutan-1-ol (0.700 g, 1.83 mmol), prepared in the previous step, was dissolved in 20 mL of methylene chloride. Triethylamine (2.65 mL, 18.3 mmol) was added and the solution was cooled to 0° C. Triphosgene (1.36 g, 4.6 mmol) was added in two portions and the mixture was stirred at 0° C. for 45 min and then at 25° C. for 2 h. The mixture was diluted with methylene chloride and poured into 250 mL of saturated aqueous sodium bicarbonate and the layers were separated. The organics were washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (5% acetone/hexane) afforded the title compound (0.62 g, 83%) as a white solid. mp 163-165° C. HRMS: calcd for C14H10BrF3N2O2S+H+, 406.96712; found (ESI, [M+H]+), 406.9679. Analytical HPLC: retention time 10.8 min, 210-370 nm the Xterra® RP18 column, 3.5%, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)[CH:3]=[N:2]1.Br[CH2:31][CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].O.[OH-].[Cs+]>CN(C=O)C>[Si:34]([O:33][CH2:32][CH2:31][N:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[C:11]([NH:16][C:17]([C:19]4[N:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]5=[N:21][CH:20]=4)=[O:18])[CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:28][CH3:29])=[N:8]2)[CH:3]=[N:2]1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: CCc1nn(Cc2cn[nH]c2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [Cs+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nn(Cc2cnn(CCO[Si](C)(C)C(C)(C)C)c2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 3 h
Yield: 56.6 %

Procedure:
To N-(1-((1H-pyrazol-4-yl)methyl)-3-ethyl-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (20 mg, 0.052 mmol) in DMF (5 mL) was added (2-bromoethoxy)(tert-butyl)dimethylsilane (37 mg, 0.16 mmol), cesium hydroxide hydrate (17 mg, 0.10 mmol) and 4 angstrom molecular sieves (2 g). The reaction mixture was stirred for 3 hours and then concentrated. Purification by silica gel chromatography (DCM/MeOH 10:1) gave the desired product (16 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([N:25]([CH2:30][CH:31]([CH3:33])[CH3:32])[S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([N:25]([CH2:30][CH:31]([CH3:33])[CH3:32])[S:26]([CH3:29])(=[O:28])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CC(C)CN(c1ccc(C(=O)O)c(Cl)c1)S(C)(=O)=O
Product: CC(C)CN(c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1)S(C)(=O)=O

Procedure:
175 μL of 1-iodo-2-methylpropane and 740 mg of Cesium Carbonate were added to 200 mg of methyl 2-chloro-4-(methylsulfonamido)benzoate in 2 mL of DMF and stirred in the microwave at 140° C. for 30 minutes. The reaction mixture was extracted in Ethyl Acetate twice with water, dried over Magnesium Sulfate, filtered, concentrated and purified on ISCO Combi-Flash to give methyl 2-chloro-4-(N-isobutylmethylsulfonamido)benzoate. 120 mg of methyl 2-chloro-4-(N-isobutylmethylsulfonamido)benzoate was hydrolyzed via Procedure M to yield 110 mg of crude 2-chloro-4-(N-isobutylmethylsulfonamido)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(N-isobutylmethylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-isobutylmethylsulfonamido)benzamide. MS (Q1) 492 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][F:11])[C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[OH-:12].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][F:11])[C:5]([C:8]([OH:12])=[O:9])=[N:6][CH:7]=1
Reactant: O=Cc1ncc(Cl)cc1CF
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ncc(Cl)cc1CF
Reaction time: 0.17 h

Procedure:
To a solution of 5-chloro-3-(fluoromethyl)picolinaldehyde (55 mg, 0.32 mmol) in THF (2 mL) and water (4 mL) was added solid NaOH (13 mg) at 0° C. After 10 min, KMNO4 (100 mg) was added in one portion. After additional 10 min, the reaction mixture was filtered through a pad of celite. The celite was washed with 1 M HCl (10 mL), water and EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over MgSO4 and the filtrate was concentrated under reduced pressure. The title compound was obtained as a yellow residue and taken onto the next step without further purification. LC/MS m/z=172.1 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]([NH2:12])=O)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[BH4-].[Na+].II.CO>C1COCC1>[O:1]1[C:5]2[C:6]([CH2:10][NH2:12])=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: NC(=O)c1cccc2c1OCC2
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: NCc1cccc2c1OCC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 20.1 %

Procedure:
At 0° C., a solution of 2,3-dihydrobenzofuran-7-carboxylic acid amide (5.2 g, 31 mmol) in THF (100 ml) was added drop wise to a suspension of sodium borohydride in THF. The mixture was stirred for 20 min at 0° C. A solution of iodine (4.1 g, 16 mmol) in THF (100 ml) was added drop wise. After the addition was finished, the reaction mixture was heated for 16 hours to reflux. It was cooled to room temperature. Methanol (260 ml) was added drop wise. The solvent was removed in vacuo. The residue was dissolved in a 20% aqueous solution of sodium hydroxide (200 ml) and tert-butyl methyl ether (200 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (2×100 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (90 g), using DCM/methanol/25% aqueous ammonia (100:10:1) as eluent to give 0.93 g of ((2,3-dihydrobenzofuran-7-yl)methyl)amine
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.O[NH:38][C:39]([C:41]1[C:50]2[CH2:49][CH2:48][CH2:47][C@@H:46]([OH:51])[C:45]=2[CH:44]=[CH:43][CH:42]=1)=[NH:40]>CN(C=O)C.CC(=O)OCC>[OH:51][C@@H:46]1[CH2:47][CH2:48][CH2:49][C:50]2[C:41]([C:39]3[N:38]=[C:6]([C:5]4[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:15])[CH3:14])=[C:3]([CH:4]=4)[C:1]#[N:2])[O:8][N:40]=3)=[CH:42][CH:43]=[CH:44][C:45]1=2
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: N=C(NO)c1cccc2c1CCC[C@H]2O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4O)no2)cc1C#N
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
Prepared using General Procedure 2. To a stirring solution of 3-cyano-4-isopropoxybenzoic acid (16.7 mg, 0.08 mmol) in DMF (1 mL) were added HOBt (14.3 mg, 0.11 mmol) and EDCI (20.3 mg, 0.11 mmol). After stirring for 30 min, (R)-N,5-dihydroxy-5,6,7,8-tetrahydronaphthalene-1-carboximidamide INT-4 (27.3 mg, 0.09 mmol) was added as a solution in DMF (1.5 mL). After stirring at room temperature for an additional 60 min, the mixture was heated to 90° C. for 15 h. The mixture was diluted with EA and washed with NaHCO3. The combined organic layers were dried, concentrated, chromatographed (EA/hexanes) to provide 12.72 mg (42.4%) (R)-5-(3-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 1 as a white solid. LCMS-ESI (m/z) calculated for C22H21N3O3: 375.4; found 376.1 [M+H]+, tR=3.73 min. 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J=2.2 Hz, 1H), 8.33 (dd, J=8.9, 2.2 Hz, 1H), 7.97 (dd, J=7.7, 1.3 Hz, 1H), 7.66 (d, J=7.2 Hz, 1H), 7.38 (t, J=7.7 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 4.91-4.83 (m, 1H), 4.79 (dq, J=12.0, 6.0 Hz, 1H), 3.20 (dt, J=17.8, 5.4 Hz, 1H), 3.01 (dt, J=13.3, 6.4 Hz, 1H), 2.13-1.81 (m, 4H), 1.79 (d, J=7.2 Hz, 1H), 1.47 (d, J=5.6 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 172.70, 169.48, 162.75, 140.10, 137.4, 134.13, 133.88, 131.68, 129.96, 126.18, 125.97, 116.82, 115.26, 113.54, 103.95, 72.73, 68.47, 31.62, 28.50, 21.73, 18.57. Chiral HPLC: (R)-5-(3-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile was eluted with 10% IPA/hexane: 99.4% ee, tR=40.85 min.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][N:9]=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[N:5]=1)(=[O:3])[NH2:2].[CH:17]1(C2C=C3C=NNC3=CN=2)[CH2:19][CH2:18]1>>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][N:9]=[C:10]([CH:17]3[CH2:19][CH2:18]3)[CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[N:5]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1nn(CC(=O)O)c2cnccc12
Reactant: c1n[nH]c2cnc(C3CC3)cc12
Product: NC(=O)c1nn(CC(=O)O)c2cnc(C3CC3)cc12

Procedure:
was prepared by using the same procedure as described for the preparation of 2-(3-carbamoyl-1H-pyrazolo[3,4-c]pyridin-1-yl)acetic acid and by starting from 5-cyclopropyl-1H-pyrazolo[3,4-c]pyridine (Scheme A26). MS (LC-MS): 261 [M+H]+, tR (HPLC conditions c): 1.84 min.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[CH2:19]([NH:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][NH:26][CH2:25]2)[CH3:20].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH2:19]([NH:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([C:10]1[CH:11]=[C:12]3[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=1[F:14])[CH2:25]2)[CH3:20]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: CCNc1ccc2c(c1)CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCNc1ccc2c(c1)CN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3CC)C2
Yield: 49.9 %

Procedure:
177 mg of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 136 mg of 5-ethylaminoisoindoline, 213 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 1 to produce 138 mg of the target compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[OH:10].[Cl-].[Al+3].[Cl-].[Cl-].[C:15](Cl)(=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18].Cl>[N+](C1C=CC=CC=1)([O-])=O.O>[OH:1][C:2]1[C:3]([OH:10])=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[C:7]=1[C:15]([CH2:16][CH:17]([CH3:19])[CH3:18])=[O:20]
Reactant: Oc1cc(O)c(O)c(O)c1
Reactant: CC(C)CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: CC(C)CC(=O)c1c(O)cc(O)c(O)c1O
Reaction time: 5 h
Yield: 27.2 %

Procedure:
Under an atmosphere of argon, 4.28 g (30.14 mmol) of 1,2,3,5-tetrahydroxybenzene (3) was dissolved by stirring in 70 ml of nitrobenzene. The solution was cooled with water. To the cold solution, 16.1 g (120.56 mmol, 4.00 equivalents) of granular aluminum chloride was added piecemeal and stirred. To the stirred mixture, 3.67 ml (30.1 mmol, 1.00 equivalent) of isovaleryl chloride was added dropwise. After 5 hours, the reaction solution was poured into 100 ml of a cold.2 M hydrochloric acid solution, stirred for 20 minutes, and extracted from ether. The organic layer was washed with water, distilled to remove ether, combined with a large volume of water, and distilled under reduced pressure to remove nitrobenzene. The residue was extracted from ether, washed with saturated brine, dried over sodium sulfate, and distilled under a reduced pressure to obtain a crude reaction product. By purifying the crude product by silica gel column chromatography (300 g of Wako Gel C-200, hexane:ethyl acetate=2:1), 1.85 g (yield 27.2%) of the product (9) was obtained in the form of yellow powder crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:15]=2[Cl:22])[N:11]([CH3:23])[N:10]=1.[H-].[Na+].Cl[C:27]1[C:32]([Cl:33])=[CH:31][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:29][N:28]=1.O>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:27]3[C:32]([Cl:33])=[CH:31][C:30]([C:34]([F:37])([F:35])[F:36])=[CH:29][N:28]=3)=[CH:16][C:15]=2[Cl:22])[N:11]([CH3:23])[N:10]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CO)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ncc(C(F)(F)F)cc2Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
3-(2-chloro-6-fluorophenyl)-5-(2-chloro-4-hydroxymethylphenyl) 1-methyl-1H-1,2,4-triazole (0.50 g) is dissolved in 1,2-dimethoxyethane (20 ml) and cooled to 0° C., to which is added sodium hydride (60%, 0.07 g) and the reaction mixture is stirred for 15 minutes. Then, a solution of 2,3-dichloro-5-trifluoromethyl pyridine (0.34 g) in 1,2-dimethoxyethane (10 ml) is added dropwise and stirred for 3 hours. On completion of the reaction, the reaction solution is warmed to room temperature and poured into water and extracted with ether. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 0.62 g of desired compound.
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[C:4]([CH3:13])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:10][C:8]1([CH3:11])[CH2:7][C:6]2[CH:12]=[C:2]([N:30]3[CH2:31][CH2:32][N:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:28][CH2:29]3)[C:3]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[C:4]([CH3:13])[C:5]=2[O:9]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(-c2c(Br)cc3c(c2C)OC(C)(C)C3)cc1
Product: Cc1ccc(-c2c(N3CCN(c4ccccc4)CC3)cc3c(c2C)OC(C)(C)C3)cc1
Yield: 3.3 %

Procedure:
By using 5-bromo-2,2,7-trimethyl-6-(4-methylphenyl)-2,3-dihydro-1-benzofuran (150 mg, 1.49 mmol) synthesized in Reference Example 157 and 1-phenylpiperazine (73.5 mg, 2.23 mmol), the reaction was carried out in the same manner as Example 129 to obtain 20 mg of the title compound as a colorless solid (yield 11%).
Reaction SMILES: Cl[C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19](Cl)=[O:20])=[CH:15][CH:14]=2)([CH3:12])[CH3:11])=[CH:6][CH:5]=1)=[O:3].[Cl-].[Al+3].[Cl-].[Cl-].Cl.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]([C:4]2[CH:9]=[CH:8][C:7]([C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19](=[O:20])[C:31]4[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=4)=[CH:15][CH:14]=3)([CH3:12])[CH3:11])=[CH:6][CH:5]=2)=[O:3])=[CH:30][CH:29]=1
Reactant: CC(C)(c1ccc(C(=O)Cl)cc1)c1ccc(C(=O)Cl)cc1
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)(c1ccc(C(=O)c2ccc(F)cc2)cc1)c1ccc(C(=O)c2ccc(F)cc2)cc1
Temperature: 55 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
A 250-ml, round-bottom flask was purged with argon and filled with 15.8653 g (0.0494 mol) of 2,2-bis-(4-chloroformylphenyl)propane (6HDAC) and 100 mL of fluorobenzene. To this solution was added with stirring 18.5 grams of anhydrous aluminum chloride in small portions over a 5-minute period. A small amount of heat was given off as evidenced by a slight rise in the temperature of the solution. The yellow reaction mixture was heated to 50-60° C. for 1.5 hours. The reaction progress was monitored by observing the HCl gas adsorption in a water trap. The reaction mixture was allowed to cool and then poured slowly into 700 ml of stirred, ice-cold 1M HCl. The lower organic layer was collected and concentrated to a light-red solid under reduced pressure. The solid was digested in 100 mL of ethanol for 12 hours and the resulting white solid was collected by filtration. Recrystallization from isopropyl alcohol yielded 15.8 g(73%) of 2,2-Bis-[4-(4-fluorobenzoyl)phenyl]propane (6HBFP), m.p. 167-168° C.