Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=[O:32].Br[C:34]1[CH:35]=[C:36]([N:40]2[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[C:45]([N:50]([CH3:52])[CH3:51])[CH:46]=3)[C:41]2=[O:53])[CH:37]=[CH:38][CH:39]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:51][N:50]([CH3:52])[C:45]1[CH:46]=[C:47]2[C:42](=[CH:43][CH:44]=1)[C:41](=[O:53])[N:40]([C:36]1[CH:37]=[CH:38][CH:39]=[C:34]([C:6]3[CH:5]=[C:4]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[O:25])=[CH:20][N:19]=4)[C:3](=[O:32])[N:2]([CH3:1])[CH:7]=3)[CH:35]=1)[CH:49]=[CH:48]2
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reactant: CN(C)c1ccc2c(=O)n(-c3cccc(Br)c3)ccc2c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CN(C)c1ccc2c(=O)n(-c3cccc(-c4cc(Nc5ccc(C(=O)N6CCOCC6)cn5)c(=O)n(C)c4)c3)ccc2c1
Temperature: 100 °C
Yield: 60 %

Procedure:
To 1-Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (58 mg, 0.13 mmol), 2-(3-Bromo-phenyl)-6-dimethylamino-2H-isoquinolin-1-one (45 mg, 0.13 mmol), potassium phosphate (56 mg, 0.26 mmol), 2-(dicyclohexylphoshphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (3.7 mg, 0.0078 mmol), and bis(dibenzylidineacetone)palladium(0) (2.2 mg, 0.0038 mmol) was added 4 mL of degassed 1:3 water/n-butanol. The headspace of the vessel was evacuated and backfilled with argon 4 times. This was heated at 100° C. for 2 hours. This was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by preparative TLC (5% methanol/dichloromethane) to yield 6-Dimethylamino-2-(3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one (45 mg, 0.078 mmol). MS (ESI) 577.1 (M+H)+.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=1)[CH2:2]2.C(N(CC)CC)C.[CH2:29]([N:31]=[C:32]=[O:33])[CH3:30]>C(Cl)Cl>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:21]=[CH:20][C:18]([NH:19][C:32]([NH:31][CH2:29][CH3:30])=[O:33])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=1)[CH2:2]2
Reactant: Nc1ccc(-c2ccnc(N3CC4CCC(C3)O4)n2)cc1
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)Nc1ccc(-c2ccnc(N3CC4CCC(C3)O4)n2)cc1

Procedure:
4-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-4-yl)aniline (intermediate 26) (100 mg, 0.354 mmol) was stirred with triethylamine (74 μl, 0.532 mmol) and ethylisocyanate (42 μl, 0.531 mmol) in DCM (2 ml) overnight. The reaction mixture was concentrated in vacuo and then purified by prep HPLC at low pH. (24 mg, 19%)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][C:13]([NH:15][C:16]2[CH:29]=[CH:28][N:19]([C@@H:20]3[O:27][C@H:24]([CH2:25][OH:26])[C@@H:22]([OH:23])[CH2:21]3)[C:18](=[O:30])[N:17]=2)=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[Cl:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([N+:44]([O-:46])=[O:45])[C:39]=1[CH2:47][CH2:48][O:49][C:50](Cl)=[O:51].CC(O)C.N#N>C(Cl)Cl>[Cl:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([N+:44]([O-:46])=[O:45])[C:39]=1[CH2:47][CH2:48][O:49][C:50]([O:26][CH2:25][C@H:24]1[O:27][C@@H:20]([N:19]2[CH:28]=[CH:29][C:16]([NH:15][C:13]([O:12][CH2:11][CH2:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)=[O:14])=[N:17][C:18]2=[O:30])[CH2:21][C@@H:22]1[OH:23])=[O:51]
Reactant: O=C(Cl)OCCc1c(Cl)cccc1[N+](=O)[O-]
Reactant: O=C(Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1)OCCc1ccc([N+](=O)[O-])cc1
Agent: N#N
Solvent: c1ccncc1
Solvent: CC(C)O
Solvent: ClCCl
Product: O=C(Nc1ccn([C@H]2C[C@H](O)[C@@H](COC(=O)OCCc3c(Cl)cccc3[N+](=O)[O-])O2)c(=O)n1)OCCc1ccc([N+](=O)[O-])cc1
Temperature: -60 °C
Reaction time: 1.25 h
Yield: 68 %

Procedure:
N4 -(2-(4-nitrophenyl)ethoxycarbonyl)-2'-deoxycytidine (5 g, 11.9 mmol) was co-evaporated with pyridine (2×60 ml, pro analysi quality, additionally dried over molecular sieve 4 Å), dissolved in pyridine (60 ml, see above) and cooled to -60° C. (i-PrOH/N2). A solution of 2-(2-chloro-6-nitrophenyl)ethoxycarbonyl chloride (4.7 g, 17.8 mmol) in CH2Cl2 (60 ml, dist. over CaH2) was added dropwise thereto for 75 min and was stirred for 1 h 45 min in conditions of i-PrOH/N2 cooling (-40° to -25° C.). The mixture was diluted with CH2Cl2 (150 ml) and washed with H2O (100 ml). The aqueous phases were post-extracted with CH2Cl2 (100 ml). Drying the organic phases over Na2SO4, filtering, evaporating the solvent under reduced pressure and co-evaporating with toluene (3×50 ml) yielded the crude product (9.8 g) which was purified by column chromatography (440 g SiO2, 32×5.9 cm, solvent: CH2Cl2 /MeOH 100:4). 5'-O-(2-(2-chloro-6-nitrophenyl)ethoxycarbonyl)-N4 -(2-(4-nitrophenyl)ethoxycarbonyl)-2'-deoxycytidine (5.247 g, 680%) was obtained as a colourless foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[CH2:24]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:8][C:9]1[C:10]([CH:11]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:13][CH:14]=[CH:15][C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1cccc(-c2ccccc2)c1OCc1ccccc1
Agent: [Br-]
Product: C(=Cc1cccc(-c2ccccc2)c1OCc1ccccc1)c1ccccc1

Procedure:
2-Benzyloxy-3-phenylbenzaldehyde was reacted with benzyl triphenylphosphonium bromide using a similar method to that of Example 48 to give 2-benzyloxy-1-phenyl-3-styrylbenzene, which was hydrogenated using a similar method to that of Reference Example 29 to give 2-(2-phenethyl)-6-pherylphenol.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][CH:15]1[CH:19]([CH3:20])[N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:17](=[O:30])[CH2:16]1.O>C(Cl)Cl>[CH3:8][S:9]([O:13][CH2:14][C@H:15]1[CH2:16][C:17](=[O:30])[N:18]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C@@H:19]1[CH3:20])(=[O:11])=[O:10]
Reactant: COc1ccc(CN2C(=O)CC(CO)C2C)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)C[C@H](COS(C)(=O)=O)[C@H]2C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylamine (1.47 g, 14.57 mmol) and methanesulfonyl chloride (1.25 g, 10.93 mmol) were added to a solution of rac-(4R,5S)-4-(hydroxymethyl)-1-(4-methoxybenzyl)-5-methylpyrrolidin-2-one (1.8 g, 7.29 mmol) in DCM (36 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour, and then water (70 mL) was added and the mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to afford [(2R,3S)-1-(4-methoxybenzyl)-2-methyl-5-oxopyrrolidin-3-yl]methyl rac-methanesulfonate. MS ESI calc'd. for C15H22NO5S [M+H]+ 328. found 328. 1H NMR (400 MHz, CDCl3): δ 7.17 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 4.96-4.91 (m, 1H), 4.10-4.05 (m, 2H), 3.91-3.86 (m, 1H), 3.81 (s, 3H), 3.36-3.30 (m, 1H), 2.92 (s, 3H), 2.76-2.68 (m, 1H), 2.39-2.29 (m, 1H), 2.27-2.20 (m, 1H), 1.24 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.B(Cl)([C@H]1[C@H](C)C2C(C)(C)C(CC2)C1)[C@H]1[C@H](C)C2C(C)(C)C(CC2)C1.N(CCO)CCO>C1COCC1.CCOCC>[OH:8][C@H:7]1[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C:2]1([CH3:16])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Agent: C[C@@H]1C2CCC(C[C@H]1B(Cl)[C@@H]1CC3CCC([C@H]1C)C3(C)C)C2(C)C
Solvent: OCCNCCO
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC[C@H](O)C(C)(C)C1
Temperature: 5 °C
Reaction time: 96 h

Procedure:
To a solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (10.0 g, 44.0 mmol) in THF (45 mL) at 0° C. was added dropwise (−)-DIP-Chloride (50-65 wt. % in heptane, 48.9 mL, 79.0 mmol), and the reaction mixture was stirred at 5° C. for 4 days. The reaction mixture was then diluted with Et2O (250 mL) and diethanol amine (8.0 g) was added to give a massive amount of white precipitate. The resulting mixture was vigorously stirred at room temperature for 3 h. The heterogeneous mixture was then filtered through a Buchner funnel packed with Celite®, and the resulting filtrate was concentrated to give a yellow residue. The residue was purified by silica gel chromatography (25-70% EtOAc/heptane) to provide (S)-tert-butyl 4-hydroxy-3,3-dimethylpiperidine-1-carboxylate. (90% ee). Enantiomeric excess determined by Mosher ester analysis. 1H NMR (400 MHz, CDCl3) δ ppm 3.79-3.94 (m, 1 H), 3.53 (d, J=13.4 Hz, 1 H), 3.42 (dd, J=9.2, 4.2 Hz, 1 H), 3.05 (ddd, J=13.2, 9.8, 3.5 Hz, 1 H), 2.74 (d, J=13.1 Hz, 1 H), 1.69-1.80 (m, 2 H), 1.58 (m, 1 H), 1.46 (s, 9 H), 0.97 (s, 3 H), 0.90 (s, 3 H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([O:12]CC)=[O:11])=[CH:5][CH:4]=1)=[CH2:2].C(C1C=C(C=C(C(C)(C)C)C=1O)CC1C(C)=C(CC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)C(C)=C(CC2C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=2)C=1C)(C)(C)C.[OH-].[Na+]>C1COCC1>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:15])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(C(C)C(=O)OCC)cc1
Agent: Cc1c(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)c(Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C)c1Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=Cc1ccc(C(C)C(=O)O)cc1
Temperature: 25 °C
Yield: 68.1 %

Procedure:
20 g (0.1 mol)of ethyl 4-vinylphenylpropionate was fed to a 1-liter three-necked flask, 100 ml of THF was added and well dissolved, and further 0.3 g of 2,4,6-tris(3′,5′-di-t-butyl-4′-hydroxybenzyl)mesitylene was added. 100 ml of a 1.5 N aqueous solution of sodium hydroxide was added dropwise under stirring at room temperature and stirred at 50° C. for 1.5 hours. After THF was distilled off under reduced pressure and the reaction product was extracted with 100 ml of n-hexane twice, 15 ml of 37% concentrated hydrochloric acid was added dropwise under stirring to produce a white precipitate. The precipitate was separated by filtration, washed in cold water completely and vacuum dried at 50° C. for 12 hours to obtain 12 g of 4-vinylphenylpropionic acid (C11H12O2). The yield was 68%. According to elemental analysis (wt %), C: 74.76 (calculated value: 74.98) and H: 6.91 (calculated value: 6.86). FIG. 3 shows a nuclear magnetic resonance spectrum of this compound and FIG. 4 shows an infrared absorption spectrum of this compound.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[CH:3]=1.ClC1[CH:35]=[C:34]([O:36]C2C=CC([N+]([O-])=O)=CC=2)[N:33]=CN=1.C(N)(=O)C>O1CCOCC1.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:26][C:25]([F:28])([F:27])[C:21]1[CH:20]=[C:19]([NH:18][C:16](=[O:17])[NH:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:33][C:34](=[O:36])[CH3:35])[CH:3]=3)=[CH:10][CH:11]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Reactant: O=C(Nc1ccc(Oc2cc(Cl)ncn2)cc1)Nc1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: CC(N)=O
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)Nc1cc(Oc2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)ncn1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
1-[4-(6-Chloro-pyrimidin-4-yloxy)-phenyl]-3-(3-trifluoromethyl-phenyl)-urea (compound of Example 56) (100 mg, 0.245 mmol)1 acetamide (40 mg1 0.678 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-xanthrene (9 mg), and tris(dibenzylideneacetone)dipalladium (6 mg) dissolved in dioxane (3 mL) are stirred at 55° C. under Ar for 8 h. After evaporating the solvent under reduced pressure, the residue is partitioned between H2O (60 mL) and AcOEt (200 mL). The organic phase is separated, dried (MgSO4) and concentrated under reduced pressure. The product is purified by preparative thin layer chromatography (four 20×20 cm silica gel plates, acetone/CH2Cl2=3:7): M+H=431.9; Rf (acetone/CH2Cl2=3:7): 0.29; 1H-NMR (400 MHz, DMSO-d6): 10.85 (s, 1H, pyrimidinyl), 9.03/8.84 (s/s, 1H/1H, urea), 8.45 (s, 1H, NH), 7.98 (s, 1H, pyrimidinyl), 7.56 (d, 8.5 Hz, 1H, phenyl-CF3), 7.50 (d/s, 9.0 Hz, 2H/1H, phenyl/phenyl-CF3), 7.49 (t, 1H, phenyl-CF3), 7.29 (d, 8.5 Hz, 1H, phenyl-CF3), 7.06 (d, 9.0 Hz, 2H, phenyl), 7.39 (d, 8.5 Hz, 2H), 7.13 (s, 1H), 7.11 (d, 8.5 Hz, 2H), 6.86 (d, 8.5 Hz, 2H), 5.94 (s, 1H, pyrimidinyl), 2.09 (s, 3H, CH3).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([N:9]=[C:10]([NH:19][CH:20]([CH3:22])[CH3:21])[C:11]3[N:12]2[C:15](=[O:18])[NH:16][N:17]=3)=[CH:7][CH:6]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:2][CH2:3][C:5]1[CH:14]=[C:13]2[C:8]([N:9]=[C:10]([NH:19][CH:20]([CH3:22])[CH3:21])[C:11]3[N:12]2[C:15](=[O:18])[NH:16][N:17]=3)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc2nc(NC(C)C)c3n[nH]c(=O)n3c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Nc1nc2ccc(CO)cc2n2c(=O)[nH]nc12
Temperature: 65 °C

Procedure:
A solution of 4-isopropylamino-1-oxo-1,2-dihydro-[1,2,4]triazolo[4,3-a]quinoxaline-8-carboxylic acid methyl ester (200 mg) in THF (5.0 mL) was stirred as LAH (76 mg) was added. The mixture was heated to 65° C. for two hr. and cooled to 23° C. prior to quenching with water (100 μL), 15% sodium hydroxide (100 μL); and water (300 μL). The solids were removed by filtration through diatomaceous earth, and the filtrate was concentrated. The residue was purified by silica gel chromatography to provide the title compound as a white solid. MS (M+H)+=329.0.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22].CN(C)C1C=CC=CC=1.[C:32](Cl)(=[O:36])[C:33](Cl)=[O:34]>C1(C)C=CC=CC=1>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH2:14][N:13]1[C:3]2[C:2](=[CH:12][CH:11]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:4]=2)[NH:1][C:33](=[O:34])[C:32]1=[O:36]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1ccc(N)c(NCc2ccc(Cl)cc2Cl)c1
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1ccc2[nH]c(=O)c(=O)n(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 4-amino3-(2,4-dichlorobenzylamino)benzoate (1.53 g) and dimethylaniline (0.71 g) in toluene was added oxalyl dichloride (0.51 ml). After stirring at room temperature for 1.5 hr, ice was added to the reaction mixture. The toluene layer was separated and washed with 6N hydrochloric acid. The toluene layer was concentrated, and the residue was washed with methyl t-butyl ether and dried to give the object compound (1.03 g) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:26][C:25](=[O:27])[C:24]4[C:15](=[C:16]([O:32][CH3:33])[C:17]5[C:22]([CH:23]=4)=[N:21][C:20]([C:28]([F:31])([F:30])[F:29])=[CH:19][CH:18]=5)[N:14]=3)=[CH:11][C:10]([C:34]([F:37])([F:36])[F:35])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:38][NH2:39]>C1COCC1>[CH3:38][NH:39][C:25]([C:24]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20]([C:28]([F:29])([F:30])[F:31])=[N:21]2)=[C:16]([O:32][CH3:33])[C:15]=1[NH:14][C:13]([C:12]1[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=[C:10]([C:34]([F:35])([F:37])[F:36])[CH:11]=1)=[O:26])=[O:27]
Reactant: CN
Reactant: COc1c2ccc(C(F)(F)F)nc2cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Solvent: C1CCOC1
Product: CNC(=O)c1cc2nc(C(F)(F)F)ccc2c(OC)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl

Procedure:
2-[2-(3-Chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-9-methoxy-6-trifluoromethyl-3-oxa-1,5-diaza-anthracen-4-one is reacted with methylamine in THF analogously to the procedure given in step i) of example H-18. The title product is obtained as yellow crystals after flash column chromatography eluting with 1:1 hexane:ethyl acetate. m.p.: 209-211° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=2)[C:5]2[N:15]([CH2:30][C@H:31]3[CH2:36][CH2:35][C@H:34]([CH3:37])[CH2:33][CH2:32]3)[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][C@H:19]3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:17][C:4]=2[CH:3]=1.[CH3:38][O:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([Sn](CCCC)(CCCC)CCCC)[N:41]=1>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>[Cl:14][C:12]1[CH:13]=[C:8]([C:6]2[C:5]3[N:15]([CH2:30][C@H:31]4[CH2:36][CH2:35][C@H:34]([CH3:37])[CH2:33][CH2:32]4)[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][C@H:19]4[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[N:17][C:4]=3[CH:3]=[C:2]([C:42]3[CH:43]=[CH:44][CH:45]=[C:40]([O:39][CH3:38])[N:41]=3)[N:7]=2)[CH:9]=[N:10][CH:11]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OC)n1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCOC[C@H]3c3ccccc3)nc3cc(Cl)nc(-c4cncc(Cl)c4)c32)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cccc(-c2cc3nc(N4CCOC[C@H]4c4ccccc4)n(C[C@H]4CC[C@H](C)CC4)c3c(-c3cncc(Cl)c3)n2)n1
Temperature: 100 °C

Procedure:
A mixture of 6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine (Example 2.1, Step 3; 130 mg, 0.242 mmol), 2-methoxy-6-(tri-n-butylstannyl)pyridine (122 mg, 0.308 mmol), and Pd(PPh3)4 (28.0 mg, 0.0242 mmol) in DMF (2.9 mL) was degassed and heated at 100° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and diluted with water (10 mL). The reaction mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with saturated aqueous KF solution (10 mL), water (2×10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated. Purification of the residue on a silica gel column (0 to 50% EtOAc/hexanes) afforded 4-(5-chloropyridin-3-yl)-6-(6-methoxypyridin-2-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-[(3R)-3-phenylmorpholin-4-yl]-3H-imidazo[4,5-c]pyridine. MS ES calc'd. for C35H37ClN6O2 [M+H]+ 609. found 609.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:12])[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]=1.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:12][N:4]1[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]=[C:3]1[CH2:2][O:1][C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1c(CO)nc2cnccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cnccc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 1.94 g of 2-hydroxymethyl-1-methylimidazo[4,5-c]pyridine (prepared as described in Preparation 73), 5.71 g of 5-(4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione, 3.1 ml of tributylphosphine, 3.09 g of 1,1'-(azodicarbonyl) dipiperidine and 50 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 10:1 by volume as the eluent, to give 3.55 g of the title compound having Rf=0.08 (on silica gel thin layer chromatography using ethyl acetate as the developing solvent).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:9]([O:13][C:14]([NH:16][C@@H:17]([CH2:20][CH2:21][CH2:22][CH3:23])[CH:18]=O)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:18][C@@H:17]([NH:16][C:14]([O:13][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:15])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: Cc1ccccc1N
Reactant: CCCC[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCC[C@@H](CNc1ccccc1C)NC(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Example 39, Step C, except using o-toluidine (0.32 mL, 3.00 mmol), 2(S)-(tert-butoxycarbonylamino)hexanal (0.538, 2.50 mmol), sodium triacetoxyborohydride (0.795 g, 3.75 mmol) in dichloroethane (10 mL) The crude product was purified by column chromatography to yield the title compound.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9](B(O)O)=[C:8]([O:17][CH3:18])[CH:7]=1.[CH3:19][O:20][C:21](=[O:49])[C@H:22]([CH2:34][C:35]1[CH:40]=[CH:39][C:38](OS(C(F)(F)F)(=O)=O)=[CH:37][CH:36]=1)[NH:23][C:24](=[O:33])[C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:32]>>[CH3:19][O:20][C:21](=[O:49])[C@H:22]([CH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:9]2[C:10]([O:12][CH3:13])=[CH:11][C:6]([CH:2]3[O:3][CH2:4][CH2:5][O:1]3)=[CH:7][C:8]=2[O:17][CH3:18])=[CH:39][CH:40]=1)[NH:23][C:24](=[O:33])[C:25]1[C:26]([Cl:32])=[CH:27][CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: COc1cc(C2OCCO2)cc(OC)c1B(O)O
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)cc(C3OCCO3)cc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl

Procedure:
4-(1,3-Dioxolan-2-yl)-2,6-dimethoxybenzeneboronic acid was reacted with N-(2,6-dichlorobenzoyl)-O-(trifluoromethanesulfonyl)-L-tyrosine methyl ester in a similar manner as described in Example 7-2) to give N-(2,6-dichlorobenzoyl)-4-[4-(1,3-dioxolan-2-yl)-2,6-dimethoxyphenyl]-L-phenylalanine methyl ester.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH3:16])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:25]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>O1CCCC1>[C:25]([C:29]1[CH:30]=[CH:31][C:32]([O:35][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH3:16])=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])=[CH:33][CH:34]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)C(Br)c1ccc(OCC(C)Oc2ccc(F)cc2)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Solvent: C1CCOC1
Product: COC(=O)C(Oc1ccc(C(C)(C)C)cc1)c1ccc(OCC(C)Oc2ccc(F)cc2)cc1

Procedure:
As described in Example 71, methyl bromo{p-[2-(p-fluorophenoxy)propoxy]phenyl}acetate (0.017 mole) is reacted with 2.55 g of p-tert-butylphenol in 75 ml of tetrahydrofuran at 80° C. for 18 hrs to give the product as a gum.