Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[N-:20]=[N+:21]=[N-:22].[Na+].[N-]=[N+]=[N-].[Li+]>C(#N)C>[N:20]([C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1)=[N+:21]=[N-:22]
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Agent: [Na+]
Solvent: CC#N
Product: [N-]=[N+]=Nc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 264 h
Yield: 22.5 %

Procedure:
A suspension of 2-chloro-4,6-diphenyl-s-triazine (30 g, 0.112 mol), sodium azide (12.86 g, 0.199 mol) and lithium azide (1.25 g, 0.025 mol) in acetonitrile (550 ml) was stirred at room temperature for 11 days. After filtration, the filtrate on evaporation yielded 6.9 g of 2-azido-4,6-diphenyl-s-triazine, mp 115°-117° C. The residue on extraction with hot heptane, followed by crystallization from heptane, gave an additional 20 g quantity having a mp of 114°-116° C. bringing the total yield of 2-azido-4,6-diphenyl-s-triazine to 26.9 g (88% yield). The melting point and infrared spectrum were identical with that of an authentic sample.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][N:18]=[C:17](Br)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][C:29]1(C)C(C)(C)OB(C=C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][N:18]=[C:17]([CH:28]=[CH2:29])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)c1nc2cc(Br)ncc2cc1NC(=O)OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1cc2nc(C(=O)OCC)c(NC(=O)OCc3ccccc3)cc2cn1
Temperature: 95 °C
Yield: 52 %

Procedure:
A mixture of ethyl 3-{[(benzyloxy)carbonyl]amino}-7-bromo-1,6-naphthyridine-2-carboxylate (22 mg, 0.051 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (43 μL, 0.26 mmol), tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.004 mmol), and potassium carbonate (21 mg, 0.15 mmol) in 1,4-dioxane (500 μL) and water (50 μL) in a vial was deoxygenated and purged with nitrogen several times. The vial was sealed under nitrogen and then heated at 95° C. for 3 h. The crude reaction mixture was filtered through a pad of diatomaceous earth and the inorganics were washed thoroughly with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (24 g silica gel column, eluting with 0-50% EtOAc/hexanes) to afford the sub-title compound (10 mg, 50%). LCMS (ESI) calc. for C21H20N3O4 [M+H]+: m/z=378.1. found: 378.1.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[CH2:15]([OH:19])[CH:16]([CH3:18])[CH3:17]>>[CH2:15]([O:19][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CC(C)COc1cccc([N+](=O)[O-])c1C#N

Procedure:
Prepared in a similar manner as example 160c from 2,6-dinitrobenzonitrile and isobutanol to provide 2-isobutoxy-6-nitrobenzonitrile. 1H NMR (400 MHz, DMSO-d6) δ 1.05 (d, J=6.4 Hz, 6H), 2.11 (sept, J=6.6 Hz, 1H), 4.07 (d, J=6.5 Hz, 2H), 7.75 (dd, J=8.0, 1.9 Hz, 1H), 7.91 (t, J=8.2 Hz, 1H), 7.94 (dd, J=8.2, 1.9 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][C:31]1[CH:39]=[CH:38][C:34]([CH2:35][CH2:36][OH:37])=[CH:33][CH:32]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][C:31]2[CH:39]=[CH:38][C:34]([CH2:35][CH2:36][OH:37])=[CH:33][CH:32]=2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: Nc1ccc(CCO)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNc3ccc(CCO)cc3)ccc21
Yield: 99.9 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (30.0 mg, 0.0730 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 4-aminophenethyl alcohol (40 mg, 0.29 mmol), acetic acid (0.084 mL, 1.5 mmol) and sodium triacetoxyborohydride (46 mg, 0.22 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain Compound 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)phenylaminomethyl]indol-2-yl}isoindolinone (38.8 mg, yield 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].C(N(C(C)C)CC)(C)C.[Cl:21][C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[C:24]([N:26]=[C:27]=[O:28])=[O:25]>ClCCl>[Cl:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[NH:1][C:27]([NH:26][C:24](=[O:25])[C:23]1[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=1[Cl:21])=[O:28]
Reactant: O=C=NC(=O)c1ccccc1Cl
Reactant: Nc1cc(C(=O)O)ccc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC(=O)c1ccccc1Cl)Nc1cc(C(=O)O)ccc1Cl

Procedure:
1 g (5.8 mmol) of 3-amino-4-chlorobenzoic acid were mixed with 0.75 g (5.8 mmol) of diisopropylethylamine and 1.06 g (5.8 mmol) of 2-chlorobenzoyl isocyanate in 5 ml of dichloromethane and reacted at room temperature for 12 hours. The solvent was evaporated, the residue was mixed with 5% strength sodium bicarbonate solution and extracted twice with diethyl ether, and the aqueous phase was adjusted to pH 3 with HCl. The resulting precipitate was filtered off with suction.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[CH:8]=[C:7]([O:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:6]=12.C(N(CC)CC)C.[CH:32]1([C:35]#[CH:36])[CH2:34][CH2:33]1>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I>[CH:32]1([C:35]#[C:36][C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[C:9]([C:11]4[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=4)[CH:8]=[C:7]([O:17][CH2:18][C:19]4[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=4)[C:6]=23)[CH2:34][CH2:33]1
Reactant: C#CC1CC1
Reactant: Cn1cc(-c2cc(OCc3cccnc3)c3c(I)cnn3c2)cn1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(OCc3cccnc3)c3c(C#CC4CC4)cnn3c2)cn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-iodo-6-(1-methyl-1H-pyrazol-4-yl)-4-(pyridin-3-ylmethoxy)pyrazolo[1,5-a]pyridine from Step 2 (11.0 mg, 0.026 mmol), tetrakis(triphenylphosphine)palladium (0) (3.0 mg, 2.6 μmol), and CuI (2.9 mg, 0.02 mmol) were suspended in DMF (1 ml). Triethylamine (11 μl, 0.08 mmol) and cyclopropyl acetylene (5.1 mg, 0.08 mmol) were added and the mixture was sparged with argon for 10 minutes. After stirring at ambient temperature for 1.5 h, the reaction mixture was diluted in ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA. The fractions containing product were combined and diluted in ethyl acetate, then washed with aqueous sodium bicarbonate and dried over sodium sulfate. The solution was filtered and concentrated to afford 3-(cyclopropylethynyl)-6-(1-methyl-1H-pyrazol-4-yl)-4-(pyridin-3-ylmethoxy)pyrazolo[1,5-a]pyridine. 1H NMR (500 MHz, DMSO-d6) δ 8.79 (s, 1H); 8.65 (s, 1H); 8.57-8.60 (m, 1H); 8.30 (s, 1H); 8.00-8.05 (m, 2H); 7.98 (s, 1H); 7.49 (dd, 1H); 7.12 (s, 1H); 5.37 (s, 2H); 3.87 (s, 3H), 1.39-1.45 (m, 1H); 0.71-0.76 (m, 2H); 0.42-0.46 (m, 2H). LRMS (ESI) calculated for C22H20N5O [M+H]+, 370.2; found 370.0.
Reaction SMILES: [Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:24]=[C:23]([CH:25]([CH3:27])[CH3:26])[C:22]([OH:28])=[C:21]([CH:29]([CH3:31])[CH3:30])[CH:20]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.O[C@@H:33]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:34]([O:36]C)=[O:35]>>[Br:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:24]=[C:23]([CH:25]([CH3:26])[CH3:27])[C:22]([O:28][C@H:33]([CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:34]([OH:36])=[O:35])=[C:21]([CH:29]([CH3:31])[CH3:30])[CH:20]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: CC(C)c1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc(C(C)C)c1O
Product: CC(C)c1cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc(C(C)C)c1O[C@H](Cc1ccccc1)C(=O)O

Procedure:
Prepared from of 4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-2,6-diisopropyl-phenol (Example 40) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 96). White solid: NMR (DMSO-d6); δ13.08 (broad s, 1 H), 8.27 (d, J=8 Hz, 1 H), 8.00 (d, J=8 Hz, 1 H), 7.76 (ddd, J=8, 8, 1, 1H), 7.66-7.58 (m, 2 H), 7.43 (ddd, J=8, 8, 1 Hz, 1 H), 7.40-7.34 (m, 4 H), 7.31-7.25 (m, 1 H), 7.12 (s, 2 H), 7.08 (ddd, J=8, 8, 1, 1H), 6.36 (d, J=8 Hz, 1 H), 4.55 (t, J=7 Hz, 1 H), 3.45 (septuplet, J=7 Hz, 2 H), 3.32 (d, J=7 Hz, 2 H), 1.14 (d, J=7 Hz, 3 H), 1.09 (d, J=7 Hz, 3 H), 1.05 (d, J=7 Hz, 3 H), 1.03 (d, J=7 Hz, 3 H); MS (+FAB): [M+] 636 (95%), 638 (100%); Anal. Calc. for C37H33BrO3S: C, 69.70, H, 5.11, N, 0.00. Found: C, 69.48, H, 5.11, N,0.11.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][NH:4][N:3]=1.[CH3:10][C:11]([CH3:17])=[CH:12][C:13]([O:15][CH3:16])=[O:14].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:10][C:11]([N:4]1[CH:5]=[C:6]([N+:7]([O-:9])=[O:8])[C:2]([CH3:1])=[N:3]1)([CH3:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: Cc1n[nH]cc1[N+](=O)[O-]
Reactant: COC(=O)C=C(C)C
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CC(C)(C)n1cc([N+](=O)[O-])c(C)n1
Yield: 6.8 %

Procedure:
A solution of 3-methyl-4-nitro-1H-pyrazole (1.00 g, 7.87 mmol), methyl 3-methylbut-2-enoate (2.20 g, 18.9 mmol), and DBU (3.10 g, 20.5 mmol) in DMF (5.0 mL) was stirred overnight. The mixture was purified by reverse phase Combiflash to afford the title compound (130 mg, 7%) as yellow oil. LC-MS (ESI): m/z=242 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].S(=O)(=O)(O)O.[CH3:20]O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:20])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CO
Reactant: O=C(O)Cc1ccc(F)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-Fluoro-3-nitrophenylacetic acid (31.0 g, 0.156 mol) was added to a mixture of concentrated sulfuric acid (1.6 ml) and methanol (160 ml) and the mixture was stirred for 3 days at room temperature. Most of the solvent was removed in vacuo and the residue was partitioned between diethyl ether and water. The organic phase was washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo to give methyl 4-fluoro-3-nitrophenylacetate (27.2 g) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[C:7]([C:11]([O:13]CC)=[O:12])[NH:8]2)=[CH:4][CH:3]=1.O.O.O.[OH-].[Li+]>O1CCCC1.O>[C:18]([CH2:17][CH2:16][C:6]1[C:5]2[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[NH:8][C:7]=1[C:11]([OH:13])=[O:12])([OH:20])=[O:19]
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2cc(Br)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1c(C(=O)O)[nH]c2cc(Br)ccc12
Temperature: 25 °C
Yield: 95 %

Procedure:
Ethyl 6-bromo-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate (3.68 g, 10 mmol) was dissolved in 25 ml tetrahydrofurane (THF) with stirring at rt. Then a solution of 1.26 g of lithium hydroxide trihydrate (3 equiv.) in 25 ml water was added and the resulting mixture was let to stir at rt for 24 h. After completion of the reaction THF was removed under reduced pressure and the pH was adjusted to 4-5, and the product was extracted with diethyl ether (3×30 ml). The organic layers were dried over magnesium sulfate, filtered, and evaporated to dryness to yield a light-beige-colored solid in 95-100% yield. mp. 234-235° C. 1H-NMR (DMSO-d6) δ 2.50 (m, 2H, 2′-H); 3.23 (m, 2H, 1′-H); 7.16 (dd, 1H, J=1.8 Hz, 5-H); 7.54 (dd, 1H, J=1.8 Hz, 7-H); 7.64 (dd, 1H, J=8.5 Hz, 4-H); 11.57 (s, 1H, NH); 12.54 (b, 1H, 2CO2H). 13C-NMR (DMSO-d6) δ 19.9 (C-2′); 35.2 (C-1′); 114.9 (C-7); 117.6 (C-4); 121.6 (C-3); 122.5 (C-6, C-5); 125.0 (C-2); 126.2 (C-3a); 136.8 (C-7a); 163.0 (2′-CO2H); 174.0 (2-CO2H). LC-MS (m/z): 329 [M-NH4+]+, 312 [M]+, 312 [M]−. Purity (LC-MS): 99%.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([N:20]1[CH2:34][C:23]2=[C:24]3[N:29]([N:30]=[C:22]2[CH2:21]1)[C:28]([CH3:31])=[C:27]([Cl:32])[C:26]([CH3:33])=[N:25]3)=[O:19])C)(C)(C)C.O1CCOCC1.Cl>C(Cl)Cl>[Cl:32][C:27]1[C:26]([CH3:33])=[N:25][C:24]2[N:29]([N:30]=[C:22]3[CH2:21][N:20]([C:18]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[O:11][CH2:10][CH2:9][NH:7][CH3:6])=[O:19])[CH2:34][C:23]3=2)[C:28]=1[CH3:31]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OCCN(C)C(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNCCOc1ccccc1C(=O)N1Cc2nn3c(C)c(Cl)c(C)nc3c2C1
Yield: 97.4 %

Procedure:
A solution of {2-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-phenoxy]-ethyl}-methyl-carbamic acid tert-butyl ester (1.54 mg; 3.08 mmol; 1 eq.) in a 4M solution of HCl 1,4-dioxane (7.7 mL; 30.8 mmol; 10 eq.) and DCM (25 mL) was stirred at room temperature for 2 hours then concentrated in vacuo. After dilution with DCM, the solution was washed with sat. aq. Na2CO3, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (1.2 g, 89%) as a yellow powder. 1H NMR (DMSO-d6) δ 10.12 (br s, 2H), 7.46-7.35 (m, 1H), 7.35-7.26 (m, 1H), 7.18-7.10 (m, 1H), 7.04 (t, J=7.4 Hz, 1H), 4.85 (d, J=8.3 Hz, 2H), 4.67-4.28 (m, 3H), 4.22-3.74 (m, 4H), 3.62-3.45 (m, 2H), 2.85 (s, 1.5H), 2.81 (s, 1.5H), 2.62 (s, 1.5H), 2.56 (s, 1.5H), 2.34-2.19 (m, 1H), 2.17-1.98 (m, 1H). HPLC (max plot) 94.7%, Rt 2.61 min. UPLC/MS: (MS+) 400.2 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([O:9]CC2C=CC=CC=2)=[CH:4][C:3]=1[O:17][CH3:18].[H][H]>C(O)(=O)C.[Pd]>[Cl:8][C:7]1[CH:6]=[C:5]([OH:9])[CH:4]=[C:3]([O:17][CH3:18])[C:2]=1[Cl:1]
Reactant: COc1cc(OCc2ccccc2)cc(Cl)c1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc(O)cc(Cl)c1Cl
Yield: 25.9 %

Procedure:
To a solution of 2,3-dichloro-5-benzyloxyanisole (3.4 g, 0.02 mole) in acetic acid (60 ml) was added 5% palladium on carbon (2.0 g) and the mixture hydrogenated using a Parr apparatus at 20 p.s.i. of hydrogen for 3 hours. The catalyst was removed by filtration and the acetic acid evaporated at reduced pressure. The residue was dissolved in ether, extracted with 2N sodium hydroxide acidified, extracted into ether, washed with water, brine, dried over magnesium sulfate and the solvent removed by evaporation in vacuo to give 1.0 g of 3,4-dichlor-5-methoxyphenol which melted at 119°-120° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[C:19]([F:20])=[C:18]([F:21])[C:17]([C:22]4[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][CH:23]=4)=[C:16]([F:30])[C:15]=3[F:31])[NH:10][C:9]=2[CH:8]=[C:7]([CH3:32])[CH:6]=1)=[O:4].[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[C:15]([F:31])=[C:16]([F:30])[C:17]([C:22]4[CH:23]=[CH:24][C:25]([CH2:28][N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:26][CH:27]=4)=[C:18]([F:21])[C:19]=3[F:20])[NH:10][C:9]=2[CH:8]=[C:7]([CH3:32])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(C)cc2[nH]c(-c3c(F)c(F)c(-c4ccc(C=O)cc4)c(F)c3F)nc12
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)cc2[nH]c(-c3c(F)c(F)c(-c4ccc(CN5CCCCC5)cc4)c(F)c3F)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
To a solution of 6-methyl-2-(2,3,5,6-tetrafluoro-4′-formyl-biphenyl-4-yl)-1H-benzoimidazole-4-carboxylic acid methyl ester (0.13 g, 0.29 mmol) in tetrahydrofuran (100 mL) was added piperidine (0.03 g, 0.35 mmol). The reaction mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (0.374 g, 1.76 mmol) was added and stirring continued for another 1 hour. The progression of the reaction was monitored by TLC. The reaction mixture quenched with sodium bicarbonate solution (3 mL) and concentrated. The residue was then extracted with ethyl acetate and the combined organic layered were washed with water and brine, dried over anhydrous sodium sulphate and concentrated to get the title compound (0.145 g, 96.66%) which was directly taken to next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N+:15]([O-:18])=[C:14]([CH3:19])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].C(=O)([O-])O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[CH3:27])[CH2:9]/[C:10](/[C:12]2[CH:17]=[CH:16][N+:15]([O-:18])=[C:14]([CH3:19])[CH:13]=2)=[N:29]\[OH:30])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1cc(Cl)ccc1[C@H](CC(=O)c1cc[n+]([O-])c(C)c1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1[C@H](C/C(=N\O)c1cc[n+]([O-])c(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 132, step 6, from (R)-4-(3-(4-bromophenyl)-3-(4-chloro-2-methyl-phenyl)propanoyl)-2-methylpyridine 1-oxide (example 383, step 1) and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=459.1 ([M+H]+).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4].C(N(CC)C(C)C)(C)C.[F:20][C:21]([F:36])([F:35])[C:22]([O:25][C:26](=O)[O:27]C1C=CC=CN=1)([CH3:24])[CH3:23]>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[C@@H:2]([NH:1][C:26]([O:25][C:22]([CH3:24])([CH3:23])[C:21]([F:36])([F:35])[F:20])=[O:27])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(OC(=O)Oc1ccccn1)C(F)(F)F
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](NC(=O)OC(C)(C)C(F)(F)F)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
To an ice-cooled solution of (S)-methyl 2-amino-3,3-dimethylbutanoate (0.411 g, 2.262 mmol) in DCM (20 mL) was added N,N-Diisopropylethylamine (1.182 mL, 6.79 mmol). The formed solution was stirred for 5 min before addition of carbonic acid pyridin-2-yl ester 2,2,2-trifluoro-1,1-dimethyl-ethyl ester (1.24 g, 4.98 mmol, from step 1a) in DCM (10 mL). The final light yellow solution was stirred at room temperature overnight. The reaction mixture was washed with 5% citric acid aqueous solution, 0.1 M NaOH aqueous solution, and brine, then dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by silica gel column, eluted with (4:1) hexane-EtOAc to afford a colorless oil as the product (673 mg, 99%).
Reaction SMILES: [NH2:1][C:2](=[S:17])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([O:12]C(C)(C)C)=[O:11])[CH:6]=[N:5]1.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=1)=O>>[Cl:29][C:24]1[CH:23]=[C:22]([C:20]2[N:1]=[C:2]([CH2:3][N:4]3[C:8]([CH3:9])=[C:7]([C:10]([OH:12])=[O:11])[CH:6]=[N:5]3)[S:17][CH:19]=2)[CH:27]=[CH:26][C:25]=1[Cl:28]
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Reactant: Cc1c(C(=O)OC(C)(C)C)cnn1CC(N)=S
Product: Cc1c(C(=O)O)cnn1Cc1nc(-c2ccc(Cl)c(Cl)c2)cs1
Yield: 79.8 %

Procedure:
A reaction similar to Example 1c was performed using the compound (200 mg, 0.783 mmol) obtained in Example 11b and 2-bromo-1-(3,4-dichlorophenyl)ethanone (210 mg, 0.783 mmol). As a result, the title compound (230 mg, 79%) wherein tert-butyl ester was hydrolyzed by hydrobromic acid produced under the reaction conditions was obtained as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[C@H:4]([CH3:12])[CH2:3]1.[H][H]>C1(C)C=CC=CC=1.[C].[Pd]>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([NH2:11])[CH:7]=[CH:8][CH:9]=2)[CH:4]([CH3:12])[CH2:3]1
Reactant: [H][H]
Reactant: C[C@@H]1CC(C)(C)c2cccc(N)c21
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CC1CC(C)(C)c2cccc(N)c21
Reaction time: 1 h

Procedure:
2.88 parts by weight of the recovered palladium-carbon and 0.64 part, by weight of fresh 5% palladium-carbon (E-type, manufactured by N. E. Chemcat Corporation) were charged into an autoclave reaction vessel, and 104.0 parts by weight of (3R)-1,1,3-trimethyl-4-aminoindane (optical purity of 67.0% ee) and 1.5 parts by weight of toluene were added thereto, thereby obtaining a mixture. The reaction vessel was sealed and the gas in the reaction vessel was replaced with nitrogen. While the mixture was stirred, into the reaction vessel was charged hydrogen until the internal pressure of hydrogen in the reaction vessel reached 0.5 MPa, and the mixture was stirred at an internal temperature of 60° C. After 1 hour, the gas in the reaction vessel was replaced with nitrogen, and the mixture was stirred at an internal temperature of 150° C. and an internal pressure of 0.1 MPa for 14 hours, thereby obtaining a reaction mixture. The obtained reaction mixture was cooled and filtered using Celite. The obtained solid was washed with 150 parts by weight of toluene. The washing liquid recovered after washing and the filtrate obtained by filtration were combined to obtain a solution of 244.6 parts by weight of 1,1,3-trimethyl-4-aminoindane in toluene. The combined 1,1,3-trimethyl-4-aminoindane had an optical purity of 0.11% ee and a recovery rate of 98.5%.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>O>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(F)cc2F)cc1
Temperature: 40 °C
Reaction time: 72 h
Yield: 92.8 %

Procedure:
Dissolve 2′,4′-difluoro-biphenyl-4-carboxylic acid methyl ester (0.426 g, 1.716 mmol) in THP (5 mL) and add a solution of NaOH (0.164 g, 4.12 mmol) in water (5.0 mL). Stir the mixture for 3 d at 40° C. Concentrate in vacuo to remove THF, add 1.0M HCl until pH 2, adsorb the mixture onto silica gel, and subject the mixture to flash column chromatography (40 g column, eluting with 50% ethyl acetate/n-hexane to 100% ethyl acetate) to yield the desired-product (0.373 g, 93%). mass spectrum (m/e): 233.3 (M−1).