Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=2)=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8].[C:20](Cl)(=[O:23])[CH2:21][CH3:22].O.[C:26]1(C)[CH:31]=CC=C[CH:27]=1>>[C:20]([O:19][CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]2[C:3]3=[N:4][C:5]([CH3:9])=[CH:6][C:7]([CH3:8])=[C:2]3[N:1]=[C:27]2[CH2:26][CH3:31])=[CH:12][CH:13]=1)(=[O:23])[CH2:21][CH3:22]
Reactant: CCC(=O)Cl
Reactant: Cc1cc(C)c(N)c(Nc2ccc(CCO)cc2)n1
Reactant: Cc1ccccc1
Solvent: O
Product: CCC(=O)OCCc1ccc(-n2c(CC)nc3c(C)cc(C)nc32)cc1

Procedure:
To a stirred suspension of 2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4, 1.3 g, 5.1 mmol) in toluene (30 mL) was added dropwise propionyl chloride (990 mg, 10.7 mmol) at 0° C., and the reaction mixture was heated at reflux temperature for 2 h. After cooling, the mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with 2N aqueous NaOH (50 mL) and brine (50 mL), then dried (MgSO4). Removal of solvent gave 1.8 g (quant.) of the title compound as brown solids: 1H-NMR (CDCl3) δ 7.41 (2H, d, J=8.4 Hz), 7.33 (2H, d, J=8.4 Hz), 6.90 (1H, s), 4.37 (2H, t, J=6.9 Hz), 3.04 (2H, t, J=6.9 Hz), 2.82 (2H, q, J=7.6 Hz), 2.65 (3H, s), 2.52 (3H, s), 2.35 (2H, q, J=7.6 Hz), 1.27 (3H, t, J=7.6 Hz), 1.14 (3H, t, J=7.6 Hz).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][N:40]([C:45]1[CH:50]=[CH:49][CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:46]=1)[S:41]([CH3:44])(=[O:43])=[O:42].C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:39][N:40]([C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:46]=1)[S:41]([CH3:44])(=[O:42])=[O:43]
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CN(c1cccc(B2OC(C)(C)C(C)(C)O2)c1)S(C)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cccc(N(C)S(C)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 93 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (131 mg, 0.22 mmol) was treated with N-methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (170 mg, 0.55 mmol, prepared according to WO 2006015829 A1 20060216), sodium carbonate (62 mg, 0.58 mmols) and bis(triphenylphosphine)palladium(II) dichloride (55 mg, 0.07 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl ether) to give 143 mg (92% yield) of the title compound. Purity 99%.
Reaction SMILES: COC(=O)C1C=CC=C(N[C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])C=1.C1(C2C3C=CC=CC=3N([CH2:57][C:58](C3CCCC3)=[O:59])C(=O)N(CC(O)=O)N=2)CCCCC1.C(OC(=O)CSC1C=CC=C(N)C=1)C.C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[CH2:58]([O:59][C:11](=[O:38])[CH2:12][N:13]1[N:19]=[C:18]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C:14]1=[O:37])[CH3:57]
Reactant: O=C(O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: CCOC(=O)CSc1cccc(N)c1
Agent: COC(=O)c1cccc(N)c1
Product: CCOC(=O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C(C)(C)C)C1=O

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 22, step a) and (3-amino-phenylsulfanyl)-acetic acid ethyl ester were used instead of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively in step e, followed by reaction of the product obtained, in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid ethyl ester (Example 1, step c), according to the method of Example 1, step d. 1H NMR (CDCl3) 8.41 (1H, s), 7.45 (2H, m), 7.31-7.17 (4H, m), 7.08 (2H, m), 6.12 (1H, br s), 4.66 (1H, d), 4.21 (1H, d), 4.23 (1H, d), 4.19 (1H, d), 3.65 (2H, s), 2.96 (1H, m), 2.79 (1H, m), 1.82-1.62 (13H, m), 1.29 (5H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 52.82; H, 7.43; N, 8.12%; C31H36N4O5S.C7H17NO5.5.0H2O requires: C, 52.95; H, 7.36; N, 8.04%.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:11][C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][C:14]([OH:22])([CH2:15]3)[CH2:13]1)[CH2:19]2.ClCCCl.S(=O)(=O)(O)[OH:28].[CH:32]([OH:34])=[O:33]>>[OH:11][C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][C:14]([OH:22])([CH2:15]3)[CH2:13]1)[CH2:19]2.[C:1]12([C:14]([OH:22])=[O:28])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([C:32]([OH:34])=[O:33])([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C1C2CC3CC1CC(C2)C3
Reactant: O=CO
Reactant: O=S(=O)(O)O
Agent: OC12CC3CC(C1)CC(O)(C3)C2
Solvent: ClCCCl
Product: O=C(O)C12CC3CC(C1)CC(C(=O)O)(C3)C2

Procedure:
The synthesis of 2-methacryloyloxy-2-(3-(2-hydroxy-2-propyl)1-1-adamantyl)propane was performed by the following method. First, according to the method described in Japanese Patent Application Laid-open No. 2002-167342, 1000 g of 1,3-dihydroxyadamantane was synthesized from adamantane. Next, a four-necked flask equipped with a stirrer, a thermometer, a dropping funnel and a Dimroth condenser was charged with 100 g of 1,3-dihydroxyadamantane, 500 mL of 1,2-dichloroethane and 800 g of 96% sulfuric acid, and further 300 g of formic acid was dropped into the flask for 1 h. Thereafter, the contents of the flask were reacted at 25° C. for 10 h. The resultant reaction solution was filtered to separate precipitated crystals therefrom. The thus separated crystals were washed with water to obtain 140 g of 1,3-adamantanedicarboxylic acid. Then, a four-necked flask equipped with a stirrer, a thermometer and a Dimroth condenser was charged with 140 g of 1,3-adamantanedicarboxylic acid, 12 g of 96% sulfuric acid, 200 g of methanol and 1000 mL of 1,2-dichloroethane, and the contents of the flask were reacted at 62° C. for 10 h.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6](=[O:44])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[N:21][N:20](COCC[Si](C)(C)C)[C:17]3=[N:18][CH:19]=2)=[CH:10][C:9]=1[C:39](=[O:43])[N:40]([CH3:42])[CH3:41].Cl(O)(=O)(=O)=O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6](=[O:44])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[N:21][NH:20][C:17]3=[N:18][CH:19]=2)=[CH:10][C:9]=1[C:39](=[O:43])[N:40]([CH3:42])[CH3:41]
Reactant: COCCOC(=O)Nc1ccc(-c2cnc3c(c2)c(-c2ccccc2OC)nn3COCC[Si](C)(C)C)cc1C(=O)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: COCCOC(=O)Nc1ccc(-c2cnc3[nH]nc(-c4ccccc4OC)c3c2)cc1C(=O)N(C)C
Reaction time: 1 h
Yield: 55.9 %

Procedure:
To {2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxy-methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-carbamic acid 2-methoxy-ethyl ester (53 mg, 0.084 mmol) was added 5% v/v 70% perchloric acid in acetic acid (0.5 mL) and the resulting solution was agitated for 60 min. Saturated sodium bicarbonate (2 mL) was added and the resulting mixture was extracted with ethyl acetate (3×2 mL). The combined organic layers were concentrated and the residue was purified by mass-triggered reverse-phase HPLC to give {2-dimethylcarbamoyl-4-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-carbamic acid 2-methoxy-ethyl ester as a white solid (23 mg, 55%). MS: m/z 490 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ 3.00 (s, 6H), 3.33 (s, 3H), 3.60 (t, 2H), 3.86 (s, 3H), 4.23 (t, 3H), 7.11 (t, 1H), 7.22 (d, 1H), 7.46 (t, 1H), 7.62 (s, 1H), 7.69 (d, 1H), 7.75 (d, 1H), 7.85 (d, 1H), 8.31 (s, 1H), 8.82 (s, 1H), 13.42 (br, 1H).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[CH2:41][NH2:42].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[NH:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[CH2:41][NH:42][C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:30])([F:29])[F:31])[O:14][N:13]=2)=[CH:8][CH:7]=1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCc1nc2ccccc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCc1nc2ccccc2[nH]1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 50 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol), (1H-benzo[d]imidazol-2-yl)methanamine (10.24 mg, 0.070 mmol), HATU (22.92 mg, 0.060 mmol), and 4-methylmorpholine (18.76 mg, 0.185 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 45-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-N-((1H-benzo[d]imidazol-2-yl)methyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (12.8 mg, 0.023 mmol, 49.3% yield): LCMS=561.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.19 (2 H, d, J=8.58 Hz), 7.51-7.79 (10 H, m), 7.34 (2 H, dd, J=6.05, 3.19 Hz), 5.27 (1 H, s), 4.76-4.94 (2 H, m); HPLC peak RT=2.6 min (Method E).
Reaction SMILES: C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(=O)[NH:22][CH2:23][C@H:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35]([CH3:46])([CH3:45])[C:36]([N:38]3[CH:42]4[CH2:43][CH2:44][CH:39]3[CH2:40][CH2:41]4)=[O:37])[CH:33]=2)[NH:28][C:27]=1[C:47]1[CH:52]=[C:51]([CH3:53])[CH:50]=[C:49]([CH3:54])[CH:48]=1)[CH3:25])(C)(C)C>>[NH2:22][CH2:23][C@H:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:35]([CH3:46])([CH3:45])[C:36]([N:38]3[CH:42]4[CH2:43][CH2:44][CH:39]3[CH2:40][CH2:41]4)=[O:37])[CH:33]=2)[NH:28][C:27]=1[C:47]1[CH:52]=[C:51]([CH3:53])[CH:50]=[C:49]([CH3:54])[CH:48]=1)[CH3:25]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)CNC(=O)OC(C)(C)C)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2[C@H](C)CN)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of (S)-{2-[5-[2-(7-azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-2-oxo-ethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]-propyl}-carbamic acid tert-butyl ester (2.6 g in 90 mL methylene chloride) at 0° C. was added 5.2 mL anisole followed by 37 mL trifluoroacetic acid and the mixture stirred at 0° C. After 2 hours, the mixture was concentrated in vacuo and the residual acid removed by azeotrope with toluene. Purifiaction by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 90:7:1) gave the title compound (2.1 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[CH:38][CH:37]=2)O1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.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>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:25])[C:18]=1[N:9]1[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=2[C:7]([C:36]2[CH:37]=[CH:38][C:39]([N:42]3[CH2:43][CH2:44][O:45][CH2:46][CH2:47]3)=[CH:40][CH:41]=2)=[N:8]1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)cc2)OC1(C)C
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: CN(C)C=O
Solvent: O
Product: COc1nccc2c1c(-c1ccc(N3CCOCC3)cc1)nn2-c1c(F)cccc1F
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 93 %

Procedure:
A mixture of 1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (250 mg) obtained in Step C of Example 35, 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (265 mg), tetrakis(triphenylphosphine)palladium(0) (35.3 mg) and 2M aqueous potassium carbonate solution (169 mg) in DMF (2 mL) was stirred under microwave irradiation at 130° C. for 1.5 hr. The reaction mixture was added to water, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (240 mg).
Reaction SMILES: [CH2:1]([C@H:3]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[C:5](=[O:17])[CH2:4]1)[CH3:2].Cl.[CH2:19](O)[CH3:20].[OH2:22]>C(OCC)(=O)C>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([NH:6][C@H:3]([CH2:1][CH3:2])[CH2:4][C:5]([O:17][CH2:19][CH3:20])=[O:22])=[CH:8][CH:9]=1
Reactant: CCO
Reactant: CC[C@@H]1CC(=O)N1c1ccc(C(F)(F)F)cc1
Reactant: O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H](CC)Nc1ccc(C(F)(F)F)cc1
Temperature: 40 °C
Reaction time: 14 h

Procedure:
To 200 mg (0.822 mmol) of (R)-4-ethyl-1-[4-(trifluoromethyl)phenyl]-2-azetidinone produced in Example 6, 2.0 g (16.45 mmol) of 30 wt % hydrogen chloride/ethanol solution was added dropwise for 5 minutes. On completion of the addition, the resulting solution was heated to 40° C. and stirred for 14 hours. Water (5 mL) was added to the solution and extraction with ethyl acetate was carried out. The extracted organic layer was washed with saturated brine and the product was dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain ethyl (R)-3-[4-(trifluoromethyl) phenylamino]-pentanoate as a yellow oil (193.8 mg, crude yield: 82%). 1H-NMR (CDCl3, 400 MHz/ppm): 6 0.98 (3H, t), 1.23 (3H, t), 1.55-1.71 (2H, m), 2.53 (2H, m), 3.75-3.82 (1H, m), 4.11 (2H, q), 6.61 (2H, d), 7.38 (2H, d)
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[H][H]>C(O)C.O.[Pt]=O>[F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Reactant: [H][H]
Agent: O=[Pt]
Solvent: O
Solvent: CCO
Product: O=C(O)CCc1ccc(F)cc1F
Yield: 99.7 %

Procedure:
A mixture of 2,4-difluorocinnamic acid (30.0 g, 0.16 mol, Aldrich ) and platinum oxide hydrate (0.5 g, EM Scientific) in 95% ethanol (140 mL) was placed on a Parr hydrogenation apparatus. After the appropriate amount of hydrogen was taken up, the catalyst was filtered and the filtrate was concentrated in vacuo to give 29.7 g (98%) of 3-(2,4-difluorophenyl)propanoic acid as a white solid. Recrystallization of 1.0 g from acetonitrile: water mixtures gave 0.61 g of 3-(2,4-difluorophenyl)propanoic acid as a white solid: mp 104°-106° C.; NMR (DMSO-d6); d 12.2 (br, 1H), 6.98-7.40 (m, 3H), 2.81 (t, 2H), 2.51 (t, 2H).
Reaction SMILES: [CH:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:60][C:61]1[CH:67]=[CH:66][CH:65]=[C:64]([CH3:68])[C:62]=1[NH2:63]>CN(C)C=O.O>[CH:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:63][C:62]4[C:64]([CH3:68])=[CH:65][CH:66]=[CH:67][C:61]=4[CH3:60])=[O:23])=[CH:25][CH:26]=3)[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cccc(C)c1N
Reactant: O=C(O)c1ccc(Nc2nc(C3CCCCC3)c3ccccc3n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(C)c1NC(=O)c1ccc(Nc2nc(C3CCCCC3)c3ccccc3n2)cc1
Temperature: 50 °C
Yield: 25.8 %

Procedure:
To a stirred mixture of 4-(4-cyclohexylquinazolin-2-ylamino)benzoic acid (300 mg, 0.86 mmol), HATU (327 mg, 0.86 mmol) and Hunig's base (555 μL, 4.3 mmol) in dimethylformamide (1 mL) was added 2,6-dimethylaniline (620 mg, 5.12 mmol) and the reaction was heated to 50° C. overnight. The mixture was cooled to rt, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with 1 N sodium bicarbonate and a 5% aqueous solution of lithium chloride, then was extracted with 1 N hydrochloric acid. The combined acidic washes were neutralized with 1 N sodium hydroxide and extracted with dichloromethane. These combined organic extracts were dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The residue obtained was purified by recrystallization from methanol to give 4-[(4-cyclohexylquinazolin-2-yl)amino]-N-(2,6-dimethylphenyl)benzamide as a white solid (99.8 mg, 27%). 1H NMR (400 MHz, CDCl3): δ 8.06-7.94 (m, 5H), 7.82-7.71 (m, 2H), 7.58-7.49 (br s, 1H), 7.39-7.33 (m, 2H), 7.16-7.12 (m, 3H), 3.53-3.44 (m, 1H), 2.65-2.59 (s, 5H), 2.31 (s, 6H), 2.04-1.91 (m, 4H), 1.89-1.70 (m, 3H), 1.60-1.31 (m, 3H). MS (EI) for C29H30N4O: 451.0 (MH+).
Reaction SMILES: C([N:8]1[CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH:13]2[CH:9]1[CH2:10][N:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:12]2)C1C=CC=CC=1>[Pd].C(O)C>[CH:9]12[CH2:10][N:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:12][CH:13]1[CH2:14][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:8]2
Reactant: CCOC(=O)C1CC2CN(C(=O)OCC)CC2N1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CC2CN(C(=O)OCC)CC2N1

Procedure:
96.5 g (0.279 mol) of diethyl 2-benzyl-2,7-diazabicyclo[3.3.0]octane-3,7-dicarboxylate in 1 1 of ethanol are hydrogenated at 100 C and 100 bar on 5 g of palladium-active carbon (10% Pd). The catalyst is filtered off with suction, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.O1CCOCC1.[C:16](=[O:19])([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)[C:29]2C=CC=[CH:31][C:30]=2[C:35]2C(OC)=CC=CC=2OC)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCCCCCC.O>[C:30]([O:19][CH2:16][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1)([CH3:35])([CH3:31])[CH3:29]
Reactant: O=C([O-])[O-]
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: COc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCCCCCC
Product: COc1cccc(COC(C)(C)C)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 406.3 %

Procedure:
To a mixture of 3-bromoanisole (30 mg, 0.16 mmol) and 1,4-dioxane (2 ml) were added water (0.2 ml), cesium carbonate (0.26 g, 0.80 mmol), potassium t-butoxymethyl trifluoroborate (62 mg, 0.32 mmol), palladium (II) acetate (3.6 mg, 0.016 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (13 mg, 0.032 mmol). Then, the reaction mixture was stirred at 100° C. (external temperature) overnight. After the reaction mixture was cooled at room temperature, water and heptane were added to the mixture, and the resultant was filtered using Celite. The separated organic layer was washed with an aqueous saturated sodium chloride solution. The organic layer was separated, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=40:1) to obtain the title compound (26 mg, 0.13 mmol, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.CO.S(=O)(=O)(O)O.[C:19](=O)(O)[O-].[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:19])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: COC(=O)Cc1ccc(Cl)cc1
Yield: 94 %

Procedure:
To a solution of 100 g (0.59 mole) of 4-chlorophenylacetic acid in 165 ml of 1,2-dichloroethane and 96 ml (2.4 moles) of methanol was added 2.75 ml of concentrated sulfuric acid, and the mixture was refluxed for 6 hours. It was then cooled, poured into an aqueous sodium bicarbonate solution and stirred. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to give 102 g (94% yield) of methyl (4-chlorophenyl)acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:15]=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].C1C[O:27][CH2:26]C1.[Li]CCCC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:15]([CH:26]=[O:27])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1CCOC1
Reactant: CC(C)(c1ccc(Cl)c(Cl)c1)c1cncn1-c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(C=O)n1-c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a solution of 5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (770 mg, 2.2 mmol) in anhyd THF (10 mL) at −78° C. was added n-BuLi (1.4 mL, 2.0M in hexane, 2.8 mmol) dropwise. After stirring 1 h at −78° C., anhyd DMF (0.85 mL) was added in one portion. After stirring another 3 h at −78° C., the reaction was quenched with water. After warming to ambient temperature, the mixture was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by column chromatography (silica gel, 0-90% EtOAc/Hex) to give 5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-carbaldehyde as a white solid (740 mg, 89% yield).