Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([CH2:8][C:9]1([NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)=[O:21])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:18])=[O:7])C>O.C(O)C>[OH:7][C:6]([CH2:8][C:9]1([NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)=[O:21])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]1=[O:18])=[O:5]
Reactant: CCOC(=O)CC1(NC(=O)Nc2ccc(C)cc2)C(=O)Nc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(NC(=O)NC2(CC(=O)O)C(=O)Nc3ccccc32)cc1
Reaction time: 4 h
Yield: 27.2 %

Procedure:
A solution of 300 mg of potassium hydroxide (85%) in 2 ml of water was added to a solution of 0.35 g of (RS)-3-(ethoxycarbonylmethyl)-3-(N'-(4-methylphenyl)ureido)indolin-2-one in 10 ml of ethanol at room temperature, and the mixture was stirred for 4 hours, followed by concentration. The concentrate was diluted with water, and washed with chloroform. The aqueous layer was adjusted to pH 3 by addition of 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated The resulting crude product was recrystallized from isopropyl alcohol to give 0.088 g (27%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:14])=[N:7]2.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.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.[Cl-].C(O)C.C1(C)C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:2]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:3]2[C:8]=1[N:7]=[C:6]([CH3:14])[CH:5]=[CH:4]2
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(Br)c2ccc(C)nc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccccc2)c2ccc(C)nc12
Temperature: 60 °C
Yield: 54 %

Procedure:
5-Bromo-8-methoxy-2-methylquinoline (509 mg) and benzene boronic acid (323 mg) were added to a mixture of 2 M aqueous potassium carbonate (2 ml), toluene (10 ml) and ethanol (1 ml) and refluxed for 30 minutes under a nitrogen atmosphere. The mixture was cooled, triphenylphosphine (75 mg) and dichlorobis(triphenylphosphine)palladium chloride (66 mg) were added and the mixture was heated at 60° C. overnight. After cooling, the reaction mixture was diluted with ethyl acetate (30 ml). The organic phase was washed with 2 M aqueous potassium carbonate solution (2×30 ml), dried (magnesium sulphate), filtered and evaporated in vacuo to give the title compound (272 mg) as an off-white solid.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[C:11]([O:12][CH2:13][C:14]2[C:15]([C:20]3[N:21]([CH:25]([CH3:27])[CH3:26])[N:22]=[CH:23][N:24]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][N:9]=[C:8]([O:28][CH3:29])[CH:7]=1.Cl>>[CH:25]([N:21]1[C:20]([C:15]2[C:14]([CH2:13][O:12][C:11]3[C:6]([CH:2]=[O:1])=[CH:7][C:8]([O:28][CH3:29])=[N:9][CH:10]=3)=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:24][CH:23]=[N:22]1)([CH3:27])[CH3:26]
Reactant: COc1cc(C2OCCO2)c(OCc2cccnc2-c2ncnn2C(C)C)cn1
Agent: Cl
Product: COc1cc(C=O)c(OCc2cccnc2-c2ncnn2C(C)C)cn1
Temperature: 40 °C
Yield: 98.5 %

Procedure:
To 4-(1,3-dioxolan-2-yl)-5-((2-(2-isopropyl-2H-1,2,4-triazol-3-yl)pyridin-3-yl)methoxy)-2-methoxypyridine (60 mg, 0.15 mmol, 1 eq.) in a RB flask was added HCl (6 N, 2.0 mL). The mixture was warmed to 40° C., O/N, cooled to rt, neutralized to pH 7-8 with NaHCO3(sat) solution, and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give 5-((2-(2-isopropyl-2H-1,2,4-triazol-3-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde (52.2 mg, 99%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.35 (s, 1H), 8.62 (dd, J=4.6, 1.2 Hz, 1H), 8.33 (s, 1H), 8.11 (dd, J=8.0, 1.2 Hz, 1H), 7.98 (s, 1H), 7.40 (dd, J=8.0, 4.7 Hz, 1H), 6.99 (s, 1H), 5.62 (s, 2H), 5.28 (sep, J=6.7 Hz, 1H), 3.82 (s, 3H), 1.46 (d, J=6.7 Hz, 6H). LRMS (M+H+) m/z 354.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]#[C:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=3)=[CH:9][N:8]([C@@H:23]3[CH2:27][N:26](C(OC(C)(C)C)=O)[C@H:25]([C:35](=[O:43])[N:36]([CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[CH3:37])[CH2:24]3)[C:4]=2[N:5]=[CH:6][N:7]=1.NC1C2C(C#CC3C=C(OC)C=C(OC)C=3)=CN([C@@H]3CN(C(OC(C)(C)C)=O)[C@H](C(OC)=O)C3)C=2N=CN=1>>[NH2:1][C:2]1[C:3]2[C:10]([C:11]#[C:12][C:13]3[CH:14]=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=3)=[CH:9][N:8]([C@@H:23]3[CH2:27][NH:26][C@H:25]([C:35]([N:36]([CH2:38][CH2:39][N:40]([CH3:42])[CH3:41])[CH3:37])=[O:43])[CH2:24]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1cc(C#Cc2cn([C@H]3C[C@@H](C(=O)N(C)CCN(C)C)N(C(=O)OC(C)(C)C)C3)c3ncnc(N)c23)cc(OC)c1
Agent: COC(=O)[C@@H]1C[C@H](n2cc(C#Cc3cc(OC)cc(OC)c3)c3c(N)ncnc32)CN1C(=O)OC(C)(C)C
Product: COc1cc(C#Cc2cn([C@@H]3CN[C@H](C(=O)N(C)CCN(C)C)C3)c3ncnc(N)c23)cc(OC)c1

Procedure:
In accordance with Example 66 (Step 7), except that the (2S,4S)-tert-butyl 4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-((2-(dimethylamino)ethyl)(methyl)carbamoyl)pyrrolidine-1-carboxylate obtained in Step 1 above was used in place of (2S,4S)-1-tert-butyl 2-methyl 4-(4-amino-5-((3,5-dimethoxyphenyl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1,2-dicarboxylate, the title compound was obtained as a colorless, amorphous substance. Physical properties: m/z [M+H]+ 492.4
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:17]N1C(=O)CCC1=O.O>CN(C=O)C>[NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:6][C:5]([Cl:17])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1ccc(Oc2cccnc2N)cc1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2cc(Cl)cnc2N)cc1
Temperature: 80 °C
Reaction time: 14 h
Yield: 42.2 %

Procedure:
To a solution of 4-(2-aminopyridin-3-yloxy)benzonitrile (5.6 g, 26.5 mmol) in DMF (100 mL) was added N-chlorosuccinimide (4.25 g, 31.8 mmol) and stirred at 80° C. for 14 h. The reaction mixture was cooled to ambient temperature and poured into water (100 mL). The aqueous suspension was extracted with EtOAc and the combined organic layers were washed with water. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified on silica gel (20% EtOAc/hexanes) and triturated with methanol to afford 4-(2-amino-5-chloropyridin-3-yloxy)benzonitrile (2.75 g, 42.2% yield) as a bright yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7](/[CH:8]=[CH:9]/[C:10]([CH3:12])=O)[C:6]([CH3:14])([CH3:13])[CH2:5][CH2:4][CH:3]=1.ClC[C:17](OCC)=[O:18].C[O-].[Na+].O=O.[OH-].[Na+].C(=O)=O>C1C2NC3C(=CC=CC=3)SC=2C=CC=1.O.C(O)(=O)C.CCOCC.N1C=CC=CC=1>[CH3:12][CH:10]([CH:9]=[CH:8][CH:7]1[C:6]([CH3:14])([CH3:13])[CH2:5][CH2:4][CH:3]=[C:2]1[CH3:1])[CH:17]=[O:18]
Reactant: CCOC(=O)CCl
Reactant: CC(=O)/C=C/C1C(C)=CCCC1(C)C
Agent: C[O-]
Agent: O=C=O
Agent: O=O
Solvent: O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC1=CCCC(C)(C)C1C=CC(C)C=O
Temperature: 5 °C
Reaction time: 4 h
Yield: 60.7 %

Procedure:
A mixture of 192 g of α-ionone, 165.4 g of ethyl chloroacetate, 500 mg of phenothiazine and 100 ml of pyridine is treated with 81 g of sodium methylate within 30 minutes at -10° C to -15° C with the exclusion of moisture and oxygen from the air. After the addition of 100 ml of absolute ether, the mixture is stirred for 4 hours at - 5° C and treated with 400 ml of 15% methanolic sodium hydroxide while cooling. The mixture is stirred for 1 hour at 10° C, cooled to -30° C and adjusted to a pH of about 4 by the addition of 600 ml of glacial acetic acid. After warming to room temperature, 1 liter of water is added and the mixture stirred again for 15 minutes (CO2 evolution). Extraction with hexane, washing the organic phase neutral, drying over anhydrous sodium sulphate and removal of the solvent under reduced pressure yields 190 g of a brown, liquid crude product which is subjected to fractional distillation in vacuo and produces 125 g of 2-methyl-4-(2,6,6-trimethyl-2-cyclohexenyl)-3-butenal; b.p.0.15 = 90° C; nD20 = 1.4880. Odour: woody, ionone-like, flowery.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[CH:18]=3)=[CH:15][C:14]([C@H:43]([N:45]3[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][C@@H:46]3[CH3:55])[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].OS(C(F)(F)F)(=O)=O>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[CH:18]=3)=[CH:15][C:14]([C@H:43]([N:45]3[CH2:50][CH2:49][N:48]([S:51]([CH3:54])(=[O:53])=[O:52])[CH2:47][C@@H:46]3[CH3:55])[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3Nc3cnc(OC)c(F)c3)nc(C)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc([C@@H](C)N3CCN(S(C)(=O)=O)C[C@@H]3C)cc2-c2cc(N)nc(C)n2)cc1F
Temperature: 80 °C
Yield: 29.2 %

Procedure:
A mixture of 6-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-((2S)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.050 g, 0.065 mmol) in TFA (1 mL) was treated with triflic acid (5.76 μL, 0.065 mmol) and heated to 80° C. for 1 h. The reaction mixture was concentrated and then ice cubes were added to the brown residue. Saturated NaHCO3 (aq.) was added followed by CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (4 g), eluting with a gradient of 0% to 5% MeOH in CH2Cl2, to provide 6-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-((2S)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-2-methyl-4-pyrimidinamine (0.010 g, 0.019 mmol, 29.1% yield) as a brown solid. m/z (ESI, +ve) 531.2 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 12.14 (s, 1H); 8.36 (dd, J=12.91, 2.35 Hz, 1H); 8.22-8.25 (m, 1H); 8.16 (d, J=2.35 Hz, 1H); 7.95 (dd, J=1.96, 0.39 Hz, 1H); 7.04 (s, 2H); 6.79 (s, 1H); 4.02 (q, J=6.65Hz, 1H); 3.94 (s, 3H); 3.05-3.20 (m, 2H); 2.77-2.95 (m, 5H); 2.53 (br. s., 3H); 2.45 (dd, J=11.35, 5.28 Hz, 1H); 1.40 (d, J=6.65 Hz, 3H); 1.10 (d, J=6.26 Hz, 3H).
Reaction SMILES: [H-].[Na+].[O-:3][CH2:4][CH3:5].[Na+].[Cl:7][C:8]1[C:9]([C:40]([NH2:42])=[O:41])=[N:10][CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[C:25](=[O:38])[N:26]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:27]=[CH:28][C:29]=2I)=[O:23])=[CH:17][C:16]=1[F:39]>C1COCC1.CCO>[Cl:7][C:8]1[C:9]([C:40]([NH2:42])=[O:41])=[N:10][CH:11]=[CH:12][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[C:25](=[O:38])[N:26]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH:27]=[CH:28][C:29]=2[O:3][CH2:4][CH3:5])=[O:23])=[CH:17][C:16]=1[F:39]
Reactant: CC[O-]
Reactant: NC(=O)c1nccc(Oc2ccc(NC(=O)c3c(I)ccn(-c4ccc(F)cc4)c3=O)cc2F)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1ccc(Oc2ccnc(C(N)=O)c2Cl)c(F)c1
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a suspension of NaH (1.87 g, 77.9 mmol) in THF (26 mL) under nitrogen was slowly added EtOH (80 mL, Aldrich>99.5%, 200 proof) and the resulting homogeneous solution was stirred for 10 minutes. The sodium ethoxide solution was then added to a mixture of 3-Chloro-4-(2-fluoro-4-(1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)picolinamide (37.3 g, 59.9 mmol) in THF (100 mL) and EtOH (46 mL), and the resulting mixture was stirred at room temperature for 1 h before being concentrated in vacuo. The residue was suspended in water (500 mL) and the mixture was sonicated and stirred for about 1 h at room temperature until the remaining solid became a filterable powder. The resulting powder was collected, triturated with ethyl ether (50 mL) and dried under high vacuum for 48 h to afford 3-Chloro-4-(4-(4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-2-fluorophenoxy)picolinamide (30.8 g, 95%) as a pale yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.34 (d, 1H, J=5.6 Hz), 7.94 (dd, 1H, J=12.4, 2.4 Hz), 7.80 (d, 1H, J=8 Hz), 7.48-7.46 (m, 3H), 7.31-7.28 (m, 3H), 6.86 (d, 1H, J=5.6 Hz), 6.61 (d, 1H, J=7.2 Hz), 4.34 (q, 2H, J=7.2 Hz), 1.45 (t, 3H, J=7.2 Hz); MS (ESI+) m/z 541.11 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][NH:5][C:6]1[NH:10][C:9]2[C:11]3[CH2:12][C:13]([CH3:23])([CH3:22])[O:14][C:15]=3[C:16]([C:18](OC)=[O:19])=[CH:17][C:8]=2[N:7]=1.[F:28][C:29]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:30]=1[NH2:31].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][NH:5][C:6]1[NH:10][C:9]2[C:11]3[CH2:12][C:13]([CH3:23])([CH3:22])[O:14][C:15]=3[C:16]([C:18]([NH:31][C:30]3[CH:32]=[C:33]([C:36]([F:37])([F:38])[F:39])[CH:34]=[CH:35][C:29]=3[F:28])=[O:19])=[CH:17][C:8]=2[N:7]=1
Reactant: Nc1cc(C(F)(F)F)ccc1F
Reactant: COC(=O)c1cc2nc(NCc3ccccc3Cl)[nH]c2c2c1OC(C)(C)C2
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2c(c(C(=O)Nc3cc(C(F)(F)F)ccc3F)cc3nc(NCc4ccccc4Cl)[nH]c23)O1
Yield: 4.7 %

Procedure:
The title compound was prepared following the procedure described for Example-137 using methyl 2-((2-chlorobenzyl)amino)-7,7-dimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Intermediate-52, 0.200 g, 0.519 mmol), 2-fluoro-5-trifluoromethyl aniline (0.237 g, 1.0389 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL). The obtained crude was purified by column chromatography eluting with 0.5% DCM:MeOH to afford 0.013 g of the desired product. 1HNMR (DMSO-d6): δ 1.55 (s, 6H), 3.14 (s, 2H), 4.61 (m, 2H), 7.32 (m, 2H), 7.40 (m, 1H), 7.49-7.62 (m, 5H), 7.69 (m, 1H), 8.93 (d, J=6.3 Hz, 1H), 10.34 (bs, 1H), 11.00 (bs, 1H). [M+H]+: 533.08.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:8]2[CH:9]=[N:10][C:11]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])=[O:15])=[CH:12][C:7]=2[N:6](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:5]=1)[CH3:2].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH2:1]([NH:3][C:4]1[C:8]2[CH:9]=[N:10][C:11]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH3:18])=[O:15])=[CH:12][C:7]=2[NH:6][N:5]=1)[CH3:2]
Reactant: CCNc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCNc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12

Procedure:
(R)-1-(3-(Ethylamino)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (187 mg, 0.330 mmol) and triethylsilane (0.080 mL, 0.501 mmol) were stirred in TFA (2 mL) at room temperature for 30 min. The solvent was removed in vacuo, saturated NaHCO3 was added, and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered through Celite, and concentrated in vacuo. Purification of the residue by flash chromatography (0-10% MeOH-EtOAc) gave (R)-1-(3-(ethylamino)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. For C17H20N6O [M+1]+ 325. found 325. 1H NMR (500 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.86 (s, 1H), 8.57 (s, 1H), 8.09 (br s, 1H), 7.34-7.31 (m, 4H), 7.25-7.20 (m, 2H), 6.21 (t, J=5.5 Hz, 1H), 4.89-4.83 (m, 1H), 3.25-3.19 (m, 2H), 1.39 (d, J=7.0 Hz, 3H), 1.18 (t, J=7.0 Hz, 3H). Examples 3-38 (Table 1) were prepared according to Scheme 1 following a similar procedure to that described for Example 1 using the appropriate pyrazolopyridine (Intermediate 1C), the appropriate aryl chlorides, and commercial or synthesized ureas (prepared using the same procedure as intermediates 20C-24C), which can be achieved by those of ordinary skill in the art of organic synthesis. The compounds of examples 6, 8, 9, 11, 12, 16, 17, 18, 21, 25, 27, 28, 30, and 38 were obtained as the trifluoroacetic acid salt.
Reaction SMILES: [C:1]([C:9]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.O>[OH:8][CH:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10]1
Reactant: CCOC(=O)C1(C(=O)c2ccccc2)CC1
Reactant: [H][H]
Solvent: CO
Solvent: O
Product: CCOC(=O)C1(C(O)c2ccccc2)CC1
Temperature: 70 °C
Yield: 694.6 %

Procedure:
(S)-tBuBisP*-RuBr2 (25 mg) was placed in a reaction vessel and deaerated. After substitution with argon, a mixture of ethyl 1-benzoylcyclopropanecarboxylate (3.3 g, 1.0 mmol) and methanol-water (10/1) (33 ml) was added. The mixture was stirred at 70° C. and hydrogen pressure (6 kg/cm2) for 24 h, after which the reaction mixture was concentrated. This was concentrated to dryness, diluted with ethyl acetate, washed with water and purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (1.53 g, 46.3%) as a colorless oil. The enantiomer excess of this product was measured by high performance liquid chromatography (Condition F) and found to be 85%.
Reaction SMILES: [C:1]1([N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:24]1[CH:36]=[CH:35][C:27]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:26][CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O>[C:1]1([N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:32]3[CH:33]=[CH:34][C:29]([NH:28][C:27]4[CH:35]=[CH:36][CH:24]=[CH:25][CH:26]=4)=[CH:30][CH:31]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Brc1ccc(Nc2ccccc2)cc1
Reactant: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccc(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)cc2)cc1
Temperature: 25 °C
Yield: 81.4 %

Procedure:
4-(diphenylamino)phenylboronic acid (4.87 g, 16.8 mmol), 4-bromo-N-phenylaniline (3.5 g, 14 mmol), potassium phosphate (9.2 g, 42 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.23 g, 0.56 mmol) were added to a three-neck flask under nitrogen. 200 mL of toluene and 20 mL of water was then added. The solution was degassed with nitrogen for 20 minutes. Pd2(dba)3 (0.13 g, 0.14 mmol) was added to the mixture. The mixture was then heated up to reflux overnight. After cooled to room temperature, the organic layer was separated and dried over magnesium sulfate. After evaporating solvent, the residue was purified by column chromatography using 1:2 dichloromethane and hexanes as eluent. 4.7 g of desired product was obtained. (81% yield)
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[S:10][C:11]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[O:7])=[CH:4][N:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>O1CCOCC1>[CH3:25][O:24][C:14]1[C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:26]=[CH:27][C:2]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[N:3][CH:4]=3)[S:10][C:11]=2[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=O)c3ccc(Cl)nc3)nc12
Reactant: C1CCNC1
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)c3ccc(N4CCCC4)nc3)nc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of 6-chloro-N-(4-methoxy-7-phenyl-benzothiazol-2-yl)-nicotinamide (297 mg, 0.75 mmol) in dioxane (10 ml) was added pyrrolidine (266 mg, 3.7 mmol, 5 eq.) and the mixture stirred at 100° C. for 2 h. After cooling the solvent was evaporated and the residue suspended in methanol (20 ml) at r.t., the solid was then filtered, washed with methanol and finally dried under vacuum (0.05 mmHg, 60° C.) to obtain the title compound as a white solid (230 mg, 71% yield), MS: m/e=431.4 (M+H+).
Reaction SMILES: [C:1]([O:4][CH:5]([O:7][C:8](=[O:36])[C@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:26](=[O:35])[N:27]([CH3:34])[C:28](=[O:33])[N:29]([CH3:32])[C:30]=2[CH3:31])=[CH:21][CH:20]=1)[NH:10]C(OC(C)(C)C)=O)[CH3:6])(=[O:3])[CH3:2].[ClH:37].O1CCOCC1>C(OCC)C.ClCCl>[ClH:37].[C:1]([O:4][CH:5]([O:7][C:8](=[O:36])[C@H:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[C:26](=[O:35])[N:27]([CH3:34])[C:28](=[O:33])[N:29]([CH3:32])[C:30]=2[CH3:31])=[CH:23][CH:24]=1)[NH2:10])[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)OC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(=O)OC(C)OC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Reaction time: 2 h
Yield: 99 %

Procedure:
The solid N-[(1,1-dimethylethoxy)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine 1-(acetoxy)ethyl ester (1.4 mmol, 0.705 g) was treated with 4N hydrochloric acid in dioxane (20 mmol, 5 mL) at room temperature and the solution was stirred for 2 h as a white precipitate was formed. The mixture was diluted with diethyl ether and dichloromethane and the solids were collected by filtration washing with diethyl ether. After air drying, 0.63 g (99% yield) of 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine 1-(acetoxy)ethyl ester hydrochloride was obtained as an amorphous gray solid. ES-HRMS m/e calcd for C20H26N3O6 (M+H) 404.1816, found 404.1818.
Reaction SMILES: Br[C:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[O:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[C:15]#[N:16].CC1(C)C(C)(C)OB([C:28]2[CH:45]=[CH:44][C:31]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:30][CH:29]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:8][C:5]1([CH3:9])[O:4][C:3]([C:10]2[CH:11]=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=2)[C:15]#[N:16])=[C:2]([C:28]2[CH:29]=[CH:30][C:31]([O:32][CH2:33][C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)=[CH:44][CH:45]=2)[C:6]1=[O:7]
Reactant: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Reactant: COc1ccc(C2=C(Br)C(=O)C(C)(C)O2)cc1C#N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)C(C)(C)O2)cc1C#N

Procedure:
A solution of 5-(3-bromo-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)-2-methoxybenzonitrile (0.15 g, 0.465 mmol), 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (0.17 g, 0.465 mmol), and Cs2CO3 (0.75 g, 2.32 mmol) in toluene (6 mL) and water (3 mL) was degassed. Then, Pd(dppf)Cl2 (0.76 g, 0.090 mmol) was added under an inert atmosphere and the solution was again degassed. The reaction was then refluxed for 2 h, filtered through a pad of Celite® and the filtrate was diluted with EtOAc (40 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl)-2-methoxybenzonitrile (125 mg, 58%( as a pale yellow solid. 1H NMR (500 MHz, d6-DMSO): δ 8.43 (d, J=8.5 Hz, 1 H), 8.02 (t, J=7.9 Hz, 2 H), 7.90 (s, 1 H), 7.81-7.77 (m, 2 H), 7.70 (d, J=8.2 Hz, 1 H), 7.62 (t, J=8.2 Hz, 1 H), 7.32 (d, J=8.1 Hz, 1 H), 7.19 (d, J=7.4 Hz, 2 H), 7.12 (d, J=7.5 Hz, 2 H), 5.40 (s, 2 H), 3.95 (s, 3H), 1.46 (s, 6 H). MS: [M+Na]: m/z=499.3, [M+H]: m/z=477.2. HPLC: 98%, Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), AcN (B), Flow rate: 0.5 ml/min (Gradient).