Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:4]=2[O:3]1.[F:13][C:14]([F:25])([F:24])[C:15]1[N:20]=[CH:19][C:18]([CH2:21][C:22]#N)=[CH:17][CH:16]=1.C([O:29][C:30](=O)[C@H:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[OH:32])(=O)C>>[CH3:1][C:2]1([CH3:12])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]([CH2:22][CH2:21][C:18]3[CH:19]=[N:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=3)[C:30](=[O:29])[C@@H:31]([OH:32])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:10][C:4]=2[O:3]1
Reactant: CC(=O)OC(=O)[C@@H](O)c1ccccc1
Reactant: CC1(C)Oc2ccc(N)cc2O1
Reactant: N#CCc1ccc(C(F)(F)F)nc1
Product: CC1(C)Oc2ccc(N(CCc3ccc(C(F)(F)F)nc3)C(=O)[C@@H](O)c3ccccc3)cc2O1

Procedure:
In analogy to example 55, 2,2-Dimethyl-benzo[1,3]dioxol-5-ylamine, (6-Trifluoromethyl-pyridin-3-yl)-acetonitrile & (S)-(+)-O-acetyl-L-mandelic acid were successively coupled then hydrolysed to give the target compound. MS(m/e): 473.1 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([F:20])=[C:16]([CH:19]=1)[CH:17]=O.C([O:23][C:24](=O)[C:25](=[O:30])[CH2:26][C:27](=[O:29])[CH3:28])C>C(O)C>[C:27]([C:26]1[CH:17]([C:16]2[CH:19]=[C:12]([Br:11])[CH:13]=[CH:14][C:15]=2[F:20])[N:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)[C:24](=[O:23])[C:25]=1[OH:30])(=[O:29])[CH3:28]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: Nc1ccc2[nH]cnc2c1
Solvent: CCO
Product: CC(=O)C1=C(O)C(=O)N(c2ccc3[nH]cnc3c2)C1c1cc(Br)ccc1F
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1H-Benzoimidazol-5-ylamine (1 mmol) and 5-bromo-2-fluorobenzaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2,4-Dioxo-pentanoic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=3[N:10]=[CH:9]2)=[CH:5][CH:4]=1.[Br:20]Br.N.CO.C(Cl)(Cl)Cl>CC(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][C:15]([NH2:17])=[C:16]([Br:20])[C:11]=3[N:10]=[CH:9]2)=[CH:18][CH:19]=1
Reactant: COc1ccc(Cn2cnc3cc(N)ccc32)cc1
Reactant: BrBr
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(Cn2cnc3c(Br)c(N)ccc32)cc1
Yield: 95 %

Procedure:
To a solution of 1-(4-methoxybenzyl)-5-aminobenzimidazole (0.80 g, 2.2 mmol) in 20 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CHCl3) to provide 0.90 g (2.1 mmol, 95%) of the product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[N:14][N:15]([CH2:17][C:18]3[CH:19]=[N:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[C:23]([CH3:28])[CH:22]=4)[CH:16]=2)=[O:11])=[C:6]([CH3:29])[N:5]=[C:4]([NH:30]C(=O)OC(C)(C)C)[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[NH2:30][C:4]1[N:5]=[C:6]([CH3:29])[C:7]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[N:14][N:15]([CH2:17][C:18]3[CH:19]=[N:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[C:23]([CH3:28])[CH:22]=4)[CH:16]=2)=[O:11])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1ccc2cc(Cn3cc(C(=O)NCc4c(C)cc(NC(=O)OC(C)(C)C)nc4C)nn3)cnc2c1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2cc(Cn3cc(C(=O)NCc4c(C)cc(N)nc4C)nn3)cnc2c1
Temperature: 23 °C

Procedure:
To a solution of tert-butyl (4,6-dimethyl-5-((1-((7-methylquinolin-3-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)pyridin-2-yl)carbamate (70 mg, 0.140 mmol) in DCM (1 ml) was added TFA (0.215 ml, 2.79 mmol). Reaction mixture was stirred over a weekend at 23° C. Reaction mixture was evaporated to afford a crude product, which was purified by preparative HPLC (Sunfire C18-ODB, 5 μm, 100×30 mm, elution with A=water+0.1% HCOOH and B=ACN+0.1% HCOOH, gradient from 10% to 100% B in 25 min, flow: 40 mL/min). Fractions were combined and solvents were evaporated to afford athe product as a formic acid salt, which was dissolved in methanol and eluted through a PL-HCO3 MP-resin column (Stratosphere SPE) in order to remove salt. The eluted solution was evaporated and dried overnight under high vacuum (dessicator, 50° C.) to afford the title compound as a free base. 1H-NMR (DMSO-d6, 400 MHz) δ 8.90 (s, 1H), 8.72 (s, 1H), 8.30 (broad s, 1H), 8.26 (s, 1H), 7.89 (d, 1H), 7.83 (s, 1H), 7.49 (d, 1H), 6.10 (s, 1H), 5.87 (s, 2H), 5.61 (broad s, 2H), 4.33 (d, 2H), 2.54 (s, 3H), 2.31 (s, 3H), 2.18 (s, 3H); HPLC (Method G) Rt=1.079 min; MS (Method V) [M+H]+=402.4.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:15]=[CH:16][C:17]=2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:10])=[CH:5][CH:4]=1.[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12.[K].[I-].[K+].O>CN(C=O)C>[O:37]=[C:35]1[C:34]2[C:33](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:32](=[O:42])[N:36]1[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:15]=[CH:16][C:17]=2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:10])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(CCl)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1

Procedure:
1,1-dimethylethyl [3-({[4-(chloromethyl)phenyl]carbonyl}amino)biphenyl-4-yl]carbamate (20 g, 45.8 mmol), potassium phthalimide (9.33 g, 50.4 mmol) and potassium iodide (1.52 g, 9.15 mmol) were stirred in DMF (81 mL) at 50° C. overnight. Room temperature was attained, H2O was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was triturated in MeOH to give 1,1-dimethylethyl {3-[({4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}carbonyl)amino]biphenyl-4-yl}carbamate as a pale yellow solid.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1.[C:22](=[O:24])=[O:23].Cl>C1COCC1>[F:9][C:10]1[C:15]([C:22]([OH:24])=[O:23])=[CH:14][CH:13]=[C:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:11]=1
Reactant: O=C=O
Reactant: Fc1cccc(-c2ccccc2)n1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccccc2)nc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Cool a solution of LDA (3.46 mmol) in anhydrous THF (6 mL) to −78° C. Cannulate the 2-fluoro-6-phenylpyridine in anhydrous THF (6 mL) to the cooled LDA solution. Stir at −78° C. for 30 minutes then bubble carbon dioxide gas through the solution for 10 minutes. Allow the reaction to come to room temperature and purge with argon. Extract the reaction with 1 M NaOH and discard the organics. Acidify the aqueous layer with conc. HCl and extract with ethyl acetate. Dry the organic layer over MgSO4, filter and evaporate to yield the title compound as a light yellow solid (405 mg, 65%). MS (ES): m/z 216.1 (M−H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:19])([F:18])[F:17])[CH:6]=[CH:7][CH:8]=1)=O.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1.O>[F:17][C:16]([F:19])([F:18])[O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[CH:1]=[C:24]1[S:20][C:21](=[O:26])[NH:22][C:23]1=[O:25]
Reactant: O=Cc1cccc(-c2ccccc2OC(F)(F)F)c1
Reactant: O=C1CSC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cccc(-c3ccccc3OC(F)(F)F)c2)S1

Procedure:
To a solution of 3-formyl-(2′-trifluoromethoxy-1,1′-biphenyl) (0.31 g, 1.16 mmol) and 2,4-thiazolidinedione (0.164 g, 1.4 mmol) in toluene (20 mL) were added piperidine (0.015 mL, 0.152 mmol) and benzoic acid (0.021 mg, 0.175 mmol), and the reaction was refluxed for 3 h with continuous removal of water. The solvent was then distilled off and the residue was crystallized from ether-pet ether to yield titled product as a solid.
Reaction SMILES: C[OH:2].[CH3:3][C:4]1[O:8][C:7]([CH2:9][CH:10]([OH:12])[CH3:11])=[CH:6][CH:5]=1.ClCl>O>[CH3:11][C:10]1[O:12][C:5]([CH2:4][CH3:3])=[C:6]([OH:2])[C:7](=[O:8])[CH:9]=1
Reactant: CO
Reactant: Cc1ccc(CC(C)O)o1
Agent: ClCl
Solvent: O
Product: CCc1oc(C)cc(=O)c1O
Temperature: -15 °C
Yield: 30 %

Procedure:
In a three necked round bottom flask were combined 28 ml of methanol and 38 ml of water. The solution was cooled to -15° C. and 0.166 mole of 5-methyl2-(2-hydroxy-propyl)furan (J. Org. Chem., 26, 1973, 1960) and 0.416 mole of chlorine were added simultaneously. During the addition, the reaction was maintained between -16° and -8° C. When addition was completed, the solution was warmed to 80° C. and refluxed for about 3 hours. Upon cooling to room temperature, the pH was adjusted to 2.1 and extracted with chloroform (3 × 100 ml). The combined organic layers were washed with water, brine and dried over magnesium sulfate. The organic solution was filtered and evaporated to give a thick dark solid. The solid was recrystallized twice from methanol to give 8.06 grams (30% yield) of white solid. Sublimation yielded pure product, m.p. 157°-159° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.CS(C)=O.[CH:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:16])[CH3:15]>O>[CH:14]([N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=2)[CH2:19][CH2:18]1)([CH3:16])[CH3:15]
Reactant: CC(C)N1CCNCC1
Reactant: N#Cc1ccc(Cl)nc1
Solvent: O
Solvent: CS(C)=O
Product: CC(C)N1CCN(c2ccc(C#N)cn2)CC1
Temperature: 100 °C
Yield: 81.8 %

Procedure:
A mixture of 2-chloropyridine-5-carbonitrile (5.0 g, 36.1 mmol), DMSO (10 mL) and 1-isopropylpiperazine (10.7 mL, 75.8 mmol) was stirred under an atmosphere of nitrogen and heated on a 100° C. oil-bath for 3 h. The reaction mixture was allowed to cool, and then poured into cold water (500 mL). The solid was isolated by filtration, washed with water and dried to give 6.8 g (82%) of 6-(4-isopropylpiperazin-1-yl)nicotinonitrile.
Reaction SMILES: [CH2:1]1[O:24][C:23]2[CH:22]=[CH:21][C:5]([CH2:6][CH:7]3[C:16]4[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=4[O:17][CH3:18])[CH2:10][CH2:9][NH:8]3)=[CH:4][C:3]=2[O:2]1.Br[CH2:26][C:27](Br)=[O:28].[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][NH2:37]>>[CH2:1]1[O:24][C:23]2[CH:22]=[CH:21][C:5]([CH2:6][CH:7]3[C:16]4[C:11](=[C:12]([O:19][CH3:20])[CH:13]=[CH:14][C:15]=4[O:17][CH3:18])[CH2:10][CH2:9][N:8]3[CH2:26][C:27]([NH:37][CH2:36][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=3)=[O:28])=[CH:4][C:3]=2[O:2]1
Reactant: NCc1ccccn1
Reactant: COc1ccc(OC)c2c1CCNC2Cc1ccc2c(c1)OCO2
Reactant: O=C(Br)CBr
Product: COc1ccc(OC)c2c1CCN(CC(=O)NCc1ccccn1)C2Cc1ccc2c(c1)OCO2

Procedure:
prepared by reaction of 1-(3,4-Methylenedioxy-benzyl)-5,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-picolylamine
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([NH2:11])[CH2:3][CH2:2]1.F[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[S:20]([CH3:23])(=[O:22])=[O:21].C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[F:19][C:17]1[CH:18]=[CH:13][C:14]([S:20]([CH3:23])(=[O:22])=[O:21])=[C:15]([NH:11][CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[O:1][CH2:2][CH2:3]2)[CH:16]=1
Reactant: NC1CCOc2ccccc21
Reactant: CS(=O)(=O)c1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(F)cc1NC1CCOc2ccccc21
Yield: 58.6 %

Procedure:
A solution of chroman-4-amine (0.38 g, 2.55 mmol), 2,4-difluoro-1-(methylsulfonyl)benzene (0.49 g, 2.55 mmol) and diisopropylethylamine (2.2 mL, 12.74 mmol) in N,N-dimethylformamide (10 mL) was stirred at 90° C. for 16 h. The reaction mixture was diluted with water and extracted with diethyl ether. The combined extracts were washed with water and brine, dried, and concentrated under reduced pressure to yield 0.48 g of a yellow oil. The residue was purified by PTLC (25% ethyl acetate in hexanes) to give 0.45 g (55%) of the desired aniline: 1H NMR (400 MHz, CDCl3) δ 7.62 (dd, 1H), 7.35 (d, 1H), 7.28 (m, 1H), 6.91 (m, 1H), 6.85 (d, 1H), 6.57 (dd, 1H), 6.42 (dd, 1H), 4.49 (m, 1H), 4.34 (bs s, 1H), 4.29 (m, 2H), 2.86 (s, 3H), 2.23 (m, 2H). MS (ESI) m/z: Calculated: 321.08; Observed: 322.2 (M++1).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11](B3OC(C)(C)C(C)(C)O3)[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=2[O:7][C:6]=1[C:29]1C=N[C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=1)=[O:4].Cl[C:40]1[CH:49]=[CH:48][C:47]2[CH2:46][CH2:45][N:44]3[C:50]4[CH:51]=[CH:52][CH:53]=[C:54]([F:57])[C:55]=4[CH:56]=[C:43]3[C:42]=2[N:41]=1.[CH3:58][CH:59](C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(=O)OCC>O1CCOCC1.O.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]>[F:57][C:54]1[C:55]2[CH:56]=[C:43]3[C:42]4[N:41]=[C:40]([C:13]5[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:10]6[O:7][C:6]([C:29]7[CH:59]=[CH:58][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=7)=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[C:9]=6[CH:8]=5)[CH:49]=[CH:48][C:47]=4[CH2:46][CH2:45][N:44]3[C:50]=2[CH:51]=[CH:52][CH:53]=1
Reactant: Fc1cccc2c1cc1n2CCc2ccc(Cl)nc2-1
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Reactant: CNC(=O)c1c(-c2ccc(C(F)(F)F)nc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(C(F)(F)F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CC4)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 264.1 %

Procedure:
A mixture of N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)benzofuran-3-carboxamide (121 mg, 0.22 mmol), 2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (50 mg, 0.18 mmol) and K3CO3 (51 mg, 0.37 mmol) in dioxane/water (2 mL/0.4 mL) was stirred at room temperature for 10 min under N2 protection. Then Pd2(dba)3 (18 mg, 0.02 mmol) and X-Phos (17 mg, 0.04 mmol) were added to the reaction solution. The mixture was stirred at 90° C. for 2 hours under N2 protection. The mixture was then cooled to room temperature, added EA (10 mL) and then filtered through a Celite pad. The combined organic phase was washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford the desired product (crude: 70 mg, yield: 58%). 1H-NMR (CDCl3, 400 MHz) δ 9.29 (s, 1H), 8.63 (d, J=7.2 Hz, 1H), 7.95 (s, 1H), 7.67˜7.79 (m, 3H), 7.45 (d, J=7.6 Hz, 3H), 7.14˜7.24 (m, 3H), 6.78˜6.80 (m, 1H), 6.14˜6.15 (m, 1H), 4.33 (t, J=6.8 Hz, 1H), 3.29˜3.33 (m, 5H), 3.02 (d, J=4.8 Hz, 3H), 2.74 (s, 3H). MS (M+H)+: 663.
Reaction SMILES: [OH:1][C@@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>O1CCCC1>[O:1]([C@H:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc([C@@H](C)O)cc1
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc([C@H](C)Oc2ccccc2)cc1
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of (R)-methyl 4-(1-hydroxyethyl)benzoate (360 mg, 2 mmol) in anhydrous tetrahydrofuran (20 mL) was added phenol (188 mg, 2 mmol) and triphenylphosphine (524 mg, 2 mmol) at 0° C., then stirred for 1 hour, (E)-diisopropyl diazene-1,2-dicarboxylate (404 mg, 2 mmol) was added, then stirred at room temperature for 12 hours. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=4:1) to give (S)-methyl 4-(1-phenoxyethyl)benzoate (410 mg, 80%). LRMS (M+H+) m/z: calcd 256.11. found 256.
Reaction SMILES: [C:1]([NH:11][C:12]1([C:17]([OH:19])=O)[CH2:16][CH2:15][CH2:14][CH2:13]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.[NH2:40][CH2:41][CH2:42][CH2:43][CH2:44][OH:45]>CN(C)C=O>[OH:45][CH2:44][CH2:43][CH2:42][CH2:41][NH:40][C:17]([C:12]1([NH:11][C:1]([O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])[CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:19]
Reactant: O=C(NC1(C(=O)O)CCCC1)OCc1ccccc1
Reactant: NCCCCO
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC1(C(=O)NCCCCO)CCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a stirred suspension of 12.9 g (0.010 mole) of 1-amino-1-cyclopentane carboxylic acid in 500 ml of methylene chloride is added 25 ml (0.10 mole) of N,O-bis(trimethylsilyl)acetamide. The mixture is stoppered and stirred at room temperature for 3 days, whereupon complete solution is obtained. 17 g (0.10 mole) of benzylchloroformate is added and the mixture stirred for an additional 1 hour. It is then washed with 300 ml each 2N HCl, water and saturated brine and dried over sodium sulfate. Filtration, evaporation and trituration with hexane gives 24 g of 1-carbobenzoxyamino-1-cyclopentane carboxylic acid, mp. 93°-5° C. 5.3 g (0.020 mole) of 1-carbobenzoxyamino-1-cyclopentane carboxylic acid is dissolved in 100 ml dimethylformamide and 3.1 g (0.020 mole) of 1-hydroxybenzotriazole hydrate and 2.5 g (0.020 mole) of 1,3-diisopropylcarbodiimide are added. The mixture is stirred at room temperature for three hours and 1.8 g (0.020 mole) of 4-amino-1-butanol is added. Stirring at room temperature is continued for 24 hours. The solvent is removed in vacuo and replaced with 500 ml of methylene chloride. The mixture is washed with 2N HCl, saturated sodium bicarbonate solution and water and dried over sodium sulfate. Filtration and evaporation gives 6.7 g of 1-carbobenzoxyamino-1-cyclopentane carboxylic acid, 4-hydroxybutylamide, m.p 117°-8° C.
Reaction SMILES: C([O:4][C:5]1[C:6]([C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][CH:13]=[CH2:14])[CH:10]=1)C=C.B(Br)(Br)Br.CCCCCC.CO>ClCCl>[CH2:12]([O:11][C:9]1[CH:10]=[C:5]([OH:4])[C:6]([C:20](=[O:29])[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=1)[CH:13]=[CH2:14]
Reactant: C=CCOc1cc(CC(=O)OC)c(C(=O)c2ccc(OC)cc2)c(OCC=C)c1
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: CO
Solvent: ClCCl
Product: C=CCOc1cc(O)c(C(=O)c2ccc(OC)cc2)c(CC(=O)OC)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
Methyl 3,5-diallyloxy-2-(4-methoxybenzoyl)phenyl-acetate (100 mg, 0.25 mmol) obtained in Example 15, Step 1 was dissolved in dichloromethane (10 mL). After the solution was cooled to −78° C., a 1.0 mol/L solution of boron tribromide in hexane (0.50 mL, 0.5 mmol) was added thereto, followed by stirring at −78° C. for 30 minutes. To the reaction mixture were successively added methanol and a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by preparative thin layer chromatography (chloroform/methanol=20/1) to obtain Compound 18 (54 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH:32]1([CH2:38][N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:42]4[CH2:43][CH2:44][N:39]([CH2:38][CH:32]5[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]5)[CH2:40][CH2:41]4)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: C1CCC(CN2CCNCC2)CC1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(CC2CCCCC2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(cyclohexylmethyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=611.96 (M+H+); retention time=0.64 minutes.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:27]3[CH2:32][CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][C:12]=3[F:26])[C:3]=12>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:25][C:19]1[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@@H:27]3[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]3)[N:9]=2)=[C:12]([F:26])[CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4F)cc3F)c3c(N)ncnc32)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3F)cc1F)nn2[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.3 %

Procedure:
To a solution of (R)-tert-butyl 3-(4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (1.7 g, 3.15 mmol) in 20 ml of DCM, TFA (20 ml) was added. The reaction mixture was stirred at RT for 4 h. The mixture was washed with sat. NaHCO3 (10 mL) and concentrated to give (R)-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.1 g, 80% yield).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6](C)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([F:14])=[CH:9][CH:8]=2)=O.CNC(C1N(C)C2C(C=1)=CC=CC=2)=O>>[F:14][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5]([CH2:3][NH:2][CH3:1])=[CH:13]2
Reactant: CNC(=O)c1cc2cc(F)ccc2n1C
Agent: CNC(=O)c1cc2ccccc2n1C
Product: CNCc1cc2cc(F)ccc2[nH]1
Yield: 78 %

Procedure:
According to the procedure of Preparation 1(c), except substituting N,1-dimethyl-5-fluoro-1H-indole-2-carboxamide for the N, 1-dimethyl-1H-indole-2-carboxamide, the title compound (1.5 g, 78%) was prepared as a white solid: MS (ES) t/e 193 (M+H)+.