Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([F:12])=[CH:7][C:3]=1[C:4]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:6]
Reactant: C1CCNC1
Reactant: Cc1cc(F)cc(C(=O)O)c1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)cc(C(=O)N2CCCC2)c1Br
Reaction time: 8 h

Procedure:
To a solution of 2-bromo-5-fluoro-3-methylbenzoic acid (140 mg, 0.60 mmol), pyrrolidine (99 μL, 1.20 mmol) and Hunig's base (210 μL, 1.20 mmol) in DMF (2 mL) at RT was added HATU (457 mg, 1.20 mmol) and the reaction stirred at this temp overnight. The reaction was quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was then washed with water and brine (3× ea.), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography (0-60% Hex/EtOAC) to yield (2-bromo-5-fluoro-3-methylphenyl)(pyrrolidin-1-yl)methanone as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.B.CO>O1CCCC1.C(OCC)(=O)C>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:11]2([CH2:14][OH:15])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccc(F)cc2)CC1
Agent: B
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Temperature: 0 °C

Procedure:
1-(tert-Butoxycarbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylic acid (9.5 g, 29.3 mmol) was suspended in tetrahydrofuran (60 mL) and cooled to 0° C. To this solution was added borane tetrahydrofuran complex (1 M in tetrahydrofuran, 59 mL, 59 mmol) cautiously over 15 min. The reaction mixture was allowed to warm to room temperature overnight and then heated at reflux for 24 h. The mixture was cooled to 0° C., treated with excess methanol, diluted with ethyl acetate, washed with 1 N sodium hydroxide (2×), then brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (40% ethyl acetate/hexanes) gave 6.6 g (72%) as a white powder. 1H-NMR (CDCl3, 500 MHz) 7.24-7.29 (m, 2H), 7.00-7.05 (m, 2H), 3.66-3.71 (m, 2H), 3.49 (s, 2H), 2.96-3.05 (m, 2H), 2.06-2.10 (m, 2H), 1.69-1.77 (m, 2H), 1.40 (s, 9H). Mass spec.: 310.21 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:7]([F:25])[C:6]=1F)[CH3:2].[CH:28]1([NH2:31])[CH2:30][CH2:29]1>CN(C)C(=O)C>[CH2:1]([O:3][C:4](=[O:27])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[C:7]([F:25])[C:6]=1[NH:31][CH:28]1[CH2:30][CH2:29]1)[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)c(N2CCC(NC(=O)OC(C)(C)C)C2)c(F)c1F
Reactant: NC1CC1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cc(Cl)c(N2CCC(NC(=O)OC(C)(C)C)C2)c(F)c1NC1CC1
Yield: 48.7 %

Procedure:
A solution of 4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-5-chloro-2,3-difluorobenzoic acid ethyl ester (Example 21, 3.75 g, 9.3 mmol) and cyclopropylamine (14.0 mL, 201 mmol) in N,N-dimethylacetamide (5 mL) is heated in a sealed glass tube for 48 hours at 100° C. The solution is then concentrated under high vacuum and purified by column chromatography (1:9 ethyl acetate/hexanes) to afford the title compound (2.0 g). 1H NMR (CDCl3): δ 7.64 (d, 1H), 7.56 (bs, 1H), 4.98-4.90 (bd, 1H), 4.40-4.20 (m, 3H 3.78-3.63 (m, 4H), 2.97-2.83 (m, 1H), 2.35-2.21 (m, 1H), 1.93-1.81 (m, 1H), 1.46 (s, 9H), 1.38 (t, 3H), 0.75-0.61 (m, 2H), 0.57-0.50 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5](/[CH:7]=[CH:8]/[C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O1CCOCC1>[C].[Pd].CO>[CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(/C=C/c2nc(-c3ccccc3)c(C)s2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CCc2nc(-c3ccccc3)c(C)s2)cc1
Yield: 94.2 %

Procedure:
A mixture of methyl (E)-4-[2-(5-methyl-4-phenyl-2-thiazolyl)vinyl]benzoate (9.5 g), palladium-carbon (5%, 1.0 g) and dioxane (70 ml)-methanol (60 ml) was subjected to catalytic hydrogenation at 1 atm and room temperature. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure to yield methyl 4-[2-(5-methyl-4-phenyl-2thiazolyl)ethyl]benzoate (9.0 g, 94%), which was then recrystallized from hexane to yield colorless plates having a melting point of 52°-53° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.Br[CH2:13][CH:14]=[CH2:15].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[CH2:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: Cc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOc1ccc(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-methyl-2-nitrophenol (5.0 g, 0.033 mol), 3-bromoprop-1-ene (4.2 g, 0.034 mol) and K2CO3 (4.6 g, 0.033 mol) in acetone (20 mL) was stirred for 8 h at ambient temperature. The mixture was poured into water (50 mL), extracted with EtOAc (90 mL), washed with brine, dried and concentrated to give the title compound (7a).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](=[N:11][CH3:12])([NH2:10])=[O:9].C1(O[C:20](=[O:31])[NH:21][C:22]2[N:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([CH3:30])[N:23]=2)C=CC=CC=1.N12CCCN=C1CCCCC2.Cl>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](=[N:11][CH3:12])([NH:10][C:20]([NH:21][C:22]1[N:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([CH3:30])[N:23]=1)=[O:31])=[O:9]
Reactant: COc1nc(C)nc(NC(=O)Oc2ccccc2)n1
Reactant: CN=S(N)(=O)c1ccccc1Cl
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CN=S(=O)(NC(=O)Nc1nc(C)nc(OC)n1)c1ccccc1Cl
Reaction time: 0.75 h
Yield: 22.5 %

Procedure:
To a solution of 196.8 mg (0.96 mmol) of 2-chloro-N'-methylbenzenesulfonimidamide and 250 mg (0.96 mmol) of phenyl(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-carbamate in 5 mL of dry acetonitrile was added 0.15 mL (1.0 mmol) of 1,8-diazabicyclo[5.4.0]-undec-7-ene. After 45 minutes at room temperature, 5 mL of water and 2.5 mL of 5% HCl were added. The aqueous layer was extracted with methylene chloride (3×10 mL). The organic layer was dried (Na2SO4), filtered and the solvent was removed with a rotary evaporator. The residue was triturated with ethyl acetate to give 80 mg of a white solid; m.p. 154° to 160° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](Br)=[N:13][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([N:28]2[C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=[N:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.COCCOC>[CH2:1]([O:8][C:9]1[C:14]([C:32]2[N:28]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:29]=[CH:30][CH:31]=2)=[N:13][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccnn2-c2ccccc2)OC1(C)C
Reactant: Brc1nc(-c2ccccc2)cnc1OCc1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: c1ccc(COc2ncc(-c3ccccc3)nc2-c2ccnn2-c2ccccc2)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 104.2 %

Procedure:
A mixture of 2-(benzyloxy)-3-bromo-5-phenylpyrazine (0.17 g), 1-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.20 g), X-phos (24 mg), Pd2(dba)3 (11 mg), 2M aqueous cesium carbonate solution (0.62 mL) and 1,2-dimethoxyethane (5.0 mL) was stirred at 110° C. for 1 hr under microwave irradiation. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.21 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([N:35]=[C:36]=[S:37])=[O:34]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:35][C:33](=[O:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH3:26])=[S:37])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1ccccc1C(=O)N=C=S
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml), and ethanol (1 ml) to prepare a solution. Commercially available 2-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added thereto, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (78 mg, yield 97%).
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][NH:8][S:9]([C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[CH:16]=1)(=[O:11])=[O:10])(=[O:6])[O:4][CH3:5].[C:21](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:1][O:2][P:3]([CH2:7][N:8]([S:9]([C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[CH:16]=1)(=[O:10])=[O:11])[CH3:21])(=[O:6])[O:4][CH3:5]
Reactant: O=C([O-])[O-]
Reactant: COP(=O)(CNS(=O)(=O)c1cc2ccccc2s1)OC
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COP(=O)(CN(C)S(=O)(=O)c1cc2ccccc2s1)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.5 %

Procedure:
A reaction mixture consisting of 290 mg (0.83 mmol) of [(2-benzothiophenesulfonylamino)-methyl]-phosphonic acid dimethyl ester, 380 mg (1.16 mmol) of anhydrous cesium carbonate, 0.11 mL (1.16 mmol) of methyl iodide and 5 mL of anhydrous DMF stirred for 16 hours at room temperature. After the reaction was complete, DMF was evaporated in vacuum, and the residue was suspended in 15 mL of water and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate, filtered and evaporated, providing an oily residue which was chromatographed on a silica gel column, eluent EtOAc/hexane (7:3), then dichloromethane/MeOH (20:1), to yield the title compound as a yellowish oil (190 mg, 63%): 1H NMR: (300 MHz, CDCl3) δH 3.00 (s, CH3), 3.48 (d, J=11.5 Hz, 2H), 3.83 (d, J=10.9 Hz, 6H, 2CH3), 7.45-7.50 (m, 2H, Ar—H), 7.83-7.89 (m, 3H, Ar—H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9].[N+:12]([O-])([OH:14])=[O:13].C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][C:2]1[C:6]([N+:12]([O-:14])=[O:13])=[C:5]([CH3:7])[S:4][C:3]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1sc(C)cc1C
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1sc(C)c([N+](=O)[O-])c1C
Temperature: 0 °C

Procedure:
To a well stirred, chilled (0°) solution of 51.4 g (0.3 mol) of methyl 3,5-dimethylthiophene-2-carboxylate in 200 ml of glacial acetic acid are added dropwise over a period of 40 minutes, a mixture of 30 ml of fuming nitric acid (specific gravity=1.5) and 120 ml of acetic anhydride. After the addition is completed the resulting brown solution is stirred a further two hours at 5° and then poured into 3000 ml of ice water.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][NH2:19])=[CH:14][CH:13]=1.CCCCC>C(O)C.C(O)(=O)C>[C:2]([C:3]1[CH:4]=[C:5]([NH2:6])[N:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[N:19]=1)([CH3:9])([CH3:8])[CH3:1]
Reactant: COc1ccc(NN)cc1
Reactant: CC(C)(C)C(=O)CC#N
Solvent: CCO
Solvent: CCCCC
Solvent: CC(=O)O
Product: COc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reaction time: 8 h
Yield: 82.5 %

Procedure:
4,4-Dimethyl-3-oxo-pentanenitrile (14.28 g, 114 mmol) and 4-methoxyphenyl hydrazine (19.89 g, 114 mmol) were dissolved in a mixture of absolute ethanol (170 mL) and glacial acetic acid (5.0 mL) then heated to reflux for 3 h, before allowing to standing overnight at RT. The resulting red/brown solid was filtered off, and the filtrate was then diluted with water (500 mL), and basified with 880 ammonia solution until the pH=5. This aqueous solution was extracted into diethyl ether (3×). The combined organics were dried (MgSO4) and evaporated in vacuo to a brown oil. Trituration (pentane) gave the title compound as a light purple/brown solid (23.07 g, 94.1 mmol, 82%). LCMS (method 1): Rt 2.87 min, m/z 246/247 [MH+].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=O)(C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:29][CH:30]1[CH2:48][C:34]2[C:35]3[NH:36][C:37](=[O:47])[C:38](=[O:46])[NH:39][C:40]=3[CH:41]=[C:42]([N+:43]([O-:45])=[O:44])[C:33]=2[CH2:32][CH2:31]1.C(N(CC)CC)C>O1CCCC1.CN(C)C=O>[N+:43]([C:42]1[C:33]2[CH2:32][CH2:31][CH:30]([NH:29][C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:16])[CH2:48][C:34]=2[C:35]2[NH:36][C:37](=[O:47])[C:38](=[O:46])[NH:39][C:40]=2[CH:41]=1)([O-:45])=[O:44]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NC1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NC1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1)C1CCNCC1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 39.6 %

Procedure:
N-t-butyloxycarbonylpiperidine-4-carboxylic acid (0.35 g, 1.5 mmol) and carbonyldiimidazole (0.24 g, 1.5 mmol) were refluxed in tetrahydrofuran (5 mL) for 15 min. The mixture was added to a solution of 9-amino-6-nitro-1,4,7,8,9,10-hexahydro-benzo[f]quinoxaline-2,3-dione (0.15 g, 1.5 mmol) in dimethylformamide (5 mL) and heated to 70° C. After 15 min, triethylamine (0.15 g, 1.5 mmol) was added and heating continued at 70° C. for 6 h. The solvent was removed by rotoevaporation in vacuo and the residue triturated with diethyl ether to form a solid. The solid was collected by filtration, washed with water and dried to give the crude product (0.23 g, 94% yield). For further purification, the solid was suspended and stirred in 2N HCl, and then filtered and dried. Anal. calc'd for C23H29N5O7.1.5 NaCl.H2O: C, 40.82; H, 4.57; N, 13.22; found-C, 40.35; H, 4.70:N, 12.91.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1B(O)O.C(O)(=[O:16])C.OO>O1CCCC1>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[OH:16]
Reactant: COc1ccc(F)c(B(O)O)c1F
Reactant: CC(=O)O
Agent: OO
Solvent: C1CCOC1
Product: COc1ccc(F)c(O)c1F
Reaction time: 120 h
Yield: 88 %

Procedure:
To a solution of 2,6-difluoro-3-methoxy-phenylboronic acid (10.0 g, 0.053 mol) in tetrahydrofuran (160 mL) was added glacial acetic acid (60 mL). The resulting mixture was cooled to 0° C. before hydrogen peroxide (50% aqueous solution, 8 mL) was added. The resulting mixture was allowed to come to room temperature and stirred for 120 h. The mixture was evaporated and the residue was dissolved in ethyl acetate, washed with hydrochloric acid (0.5N), water and brine. The organic phase was dried, filtered and evaporated which afforded 2,6-difluoro-3-methoxy-phenol (7.50 g, 88%) as a pale brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH2:19][CH2:18][CH2:17][CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>O.CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH2:19][CH2:18][CH2:17][CH:16]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](CC1=CCCC1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC1=CCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(cyclopent-1-en-1-yl)propanoate (62 g, 0.23 mol) in water/methanol (900 mL, 2:1) was added lithium hydroxide hydrate (19.3 g, 0.460 mol). The reaction mixture was stirred at ambient temperature overnight and then concentrated to remove most of the methanol. The residue was washed with DCM (400 mL) and the aqueous phase was acidified with dilute HCl to pH=3-4. The resulting mixture was extracted with DCM (3×300 mL). The organic layers were combined and concentrated to afford (S)-2-((tert-butoxycarbonyl)amino)-3-(cyclopent-1-en-1-yl)propanoic acid (56 g, 95% yield) as viscous oil, which was used in the next step without further purification.
Reaction SMILES: [CH:1]1([CH2:13][C:14]#N)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.[OH-].[NH4+:17]>CO.[Ni]>[CH:1]1([CH:13]([NH2:17])[CH3:14])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: [NH4+]
Reactant: N#CCC1Cc2cccc3cccc1c23
Agent: [Ni]
Agent: [OH-]
Solvent: CO
Product: CC(N)C1Cc2cccc3cccc1c23
Reaction time: 23 h

Procedure:
The nitrile obtained in Step B (900 mg, 4.66.10−3 mol), diluted with methanol (30 ml), is hydrogenated with vigorous stirring at ambient temperature in the presence of ammonium hydroxide (2 ml) and Raney nickel. After 23 hours, the starting material has disappeared. After filtering over Celite, then rinsing and evaporating off the solvent under reduced pressure, the title amine is obtained in the form of an oil, which is used without being purified.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][C:6]1([CH2:19][CH3:20])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[CH:17][CH:16]=[CH:15][CH:14]=3)C.O.[OH-].[Li+].Cl>O1CCOCC1.O>[CH2:19]([C:6]1([CH2:5][C:4]([OH:21])=[O:3])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:20]
Reactant: CCOC(=O)CC1(CC)OCCc2c1[nH]c1ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCC1(CC(=O)O)OCCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
To a solution of (1-ethyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester (2.50 g, 8.7 mmol) in 1,4-dioxane was added a solution of lithium hydroxide monohydrate (1.50 g, 35.7 mmol) in water (5 mL). The mixture was stirred at room temperature overnight. It was neutralized with 5% HCl solution and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulfate, and evaporated to dryness. Flash chromatography on silica gel provided 0.954 g (42%) of the title compound as a solid. mp. 135-136° C. 1H NMR (500 MHz, CDCl3) δ 10.0 (br, 1H), 8.55 (br, 1H), 7.51 (d, 1H), 7.34 (d, 1H), 7.18 (t, 1H), 7.12 (t, 1H), 4.12 (m, 1H), 4.06 (m, 1H), 3.01 (d, 1H), 2.99 (d, 1H), 2.85 (m, 2H), 2.10 (m, 1H), 2.03 (m, 1H), 0.86 (t, 3H); ESI (+) MS m/e=260 (MH+), ESI (−) MS m/e=258 (MH−).
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([O:16][C:17]([NH:19][C@@H:20]([C:25]([OH:27])=O)[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1([NH:34]C2CCCCC2)CCCCC1.CN1CCOCC1.N.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.COCCOC>[CH2:9]([O:16][C:17]([NH:19][C@@H:20]([C:25]([NH2:34])=[O:27])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C1CCC(NC2CCCCC2)CC1
Agent: CC(C)COC(=O)Cl
Agent: N
Agent: O=C([O-])O
Solvent: CN1CCOCC1
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](NC(=O)OCc1ccccc1)C(N)=O
Reaction time: 1 h
Yield: 111.4 %

Procedure:
Isobutyl chloroformate (811 μl) was added dropwise to a mixture of N-benzyloxycarbonyl-D-leucine•dicyclohexylamine salt (2.23 g), 1,2-dimethoxyethane (25 ml), and N-methylmorpholine (687 μl) under ice cooling, followed by stirring at the same temperature for 1 hour. 25% aqueous ammonia solution (3.4 ml) was added to the reaction mixture under ice cooling, followed by stirring at the same temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction mixture. The organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. Hexane was added to the obtained residue and solid matter was collected by filtration, and a white solid of N2-benzyloxycarbonyl-D-leucinamide (1.47 g) was thus obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([N:25]([CH3:27])[CH3:26])=[C:14]([NH:16][C:17](=[O:24])[CH2:18][NH:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH:15]=2)[CH:5]=[C:4]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34]CC2C=CC(OC)=CC=2)[N:3]=1.FC(F)(F)C(O)=O.[ClH:51]>C1(OC)C=CC=CC=1.O.C1(C)C=CC=CC=1.O1CCOCC1>[ClH:51].[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([N:25]([CH3:27])[CH3:26])=[C:14]([NH:16][C:17](=[O:24])[CH2:18][NH:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH:15]=2)[CH:5]=[C:4]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[OH:34])[N:3]=1
Reactant: COc1ccc(COc2ccccc2-c2cc(-c3ccc(N(C)C)c(NC(=O)CNCC4CC4)c3)c(C#N)c(N)n2)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(C)c1ccc(-c2cc(-c3ccccc3O)nc(N)c2C#N)cc1NC(=O)CNCC1CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77 %

Procedure:
To a suspension of N1-[5-(2-amino-3-cyano-6-{2-[(4-methoxybenzyl)oxy]phenyl}-4-pyridinyl)-2-(dimethylamino)-phenyl]-N2-(cyclopropylmethyl)glycinamide (0.130 g, 0.448 mmol) in anisole (1 mL) and water (1 mL) was added trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 20 hrs. The reaction mixture was diluted with toluene and concentrated under reduced pressure. The residue was suspended in hexane and the precipitate was collected by filtration. The solid obtained was dissolved in TB and 4N HCl in 1,4-dioxane was added to the solution. The resulting solid was collected by filtration, washed with THF and 1,4-dioxane, and dried under reduced pressure to give N1-[5-[2-amino-3-cyano-6-(2-hydroxyphenyl)-4-pyridinyl]-2-(dimethylamino)phenyl]-N2-(cyclopropylmethyl)glycinamide hydrochloride as a yellow solid (0.085 g, yield 77%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](Br)=[CH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:15]2[CH:16]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:18]=[C:13]([F:12])[CH:14]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1cc(F)cc(C(F)(F)F)c1
Reactant: Cc1c(Br)cnc(N)c1C#N
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(F)cc(C(F)(F)F)c2)cnc(N)c1C#N

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 4, using 1.7 grams (0.008 mole) of 2-amino-5-bromo-3-cyano-4-methylpyridine, 2.5 grams (0.012 mole) of 3-fluoro-5-trifluoromethylphenyl-boronic acid, 4,3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(O) in 150 mL of toluene, yielding 2-amino-3-cyano-4-methyl-5-[3-fluoro-5-trifluoromethylphenyl]pyridine.