Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)[C:9]=1[C:39]([O:41]CC)=[CH2:40].Cl>O1CCOCC1>[C:39]([C:9]1[C:10]([C:29]2[CH:30]=[CH:31][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:37][CH:38]=2)=[N:11][C:12]2[N:13]([N:14]=[CH:15][C:16]=2[C:17]2[CH:18]=[N:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)[C:8]=1[NH2:7])(=[O:41])[CH3:40]
Reactant: C=C(OCC)c1c(-c2ccc(C(=O)OC)cc2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N)c2C(C)=O)cc1

Procedure:
Compound, methyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)benzoate was treated with 4N HCl in dioxane for 2 hrs to result in the product, methyl 4-(6-acetyl-7-amino-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)benzoate purified by prep. HPLC. HPLC-MS tR=1.85 min (UV254 nm); mass calculated for formula C27H21N5O3 463.2, observed LCMS m/z 464.0 (M+H).
Reaction SMILES: C([O-])(=O)C.C([O:8][CH2:9][C:10]1[C:11]([N:42]2[CH2:54][CH2:53][N:45]3[C:46]4[CH2:47][CH2:48][CH2:49][CH2:50][C:51]=4[CH:52]=[C:44]3[C:43]2=[O:55])=[N:12][CH:13]=[CH:14][C:15]=1[C:16]1[CH:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH:35]4[CH2:38][O:37][CH2:36]4)[CH2:31][C@@H:30]3[CH3:39])=[CH:25][N:24]=2)[C:19](=[O:40])[N:18]([CH3:41])[CH:17]=1)(=O)C.O[Li].O>CC(O)C.C1COCC1.O>[OH:8][CH2:9][C:10]1[C:11]([N:42]2[CH2:54][CH2:53][N:45]3[C:46]4[CH2:47][CH2:48][CH2:49][CH2:50][C:51]=4[CH:52]=[C:44]3[C:43]2=[O:55])=[N:12][CH:13]=[CH:14][C:15]=1[C:16]1[CH:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH:35]4[CH2:38][O:37][CH2:36]4)[CH2:31][C@@H:30]3[CH3:39])=[CH:25][N:24]=2)[C:19](=[O:40])[N:18]([CH3:41])[CH:17]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: CC(=O)[O-]
Agent: [Li]O
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CCCC6)C4=O)c3CO)cn(C)c2=O)nc1
Yield: 85 %

Procedure:
Following the procedures as described for 118, acetate hydrolysis of 119a with LiOH.H2O in iPrOH/THF (1:1) and H2O, gave 119 as a white solid (184 mg, 85%). LCMS: [M+H]+ 651. 1H NMR (500 MHz, CDCl3) δ 8.65 (d, J=2.5, 1H), 8.50 (d, J=5.0, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.84 (d, J=2.0, 1H), 7.35 (d, J=5.0, 1H), 7.33 (d, J=7.0, 1H), 6.90 (s, 1H), 6.83 (d, J=9.0, 1H), 5.04-5.06 (m, 1H), 4.62-4.73 (m, 5H), 4.51 (s, 1H), 4.32 (s, 1H), 4.16 (s, 1H), 4.11 (s, 1H), 3.89 (s, 1H), 3.72 (s, 3H), 3.57 (t, J=6.0, 1H), 3.48 (s, 1H), 3.07-3.12 (m, 2H), 2.53-2.63 (m, 7H), 2.24 (m, 1H), 1.88-1.93 (m, 2H), 1.80 (s, 2H), 0.99 (d, J=6.5, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH:23]([CH3:25])[CH3:24]>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:10]1
Reactant: CC(C)CBr
Reactant: OC1(c2cccc(F)c2F)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CN1CCC(O)(c2cccc(F)c2F)C1
Reaction time: 4 h

Procedure:
Preparation according to Example 38: Enantiomer E2 of 3-(2,3-difluorophenyl)pyrrolidin-3-ol (0.5 g, 2.5 mmol), acetonitrile (20 mL), potassium carbonate (0.69 g, 5 mmol), 1-bromo-2-methylpropane (0.32 mL, 2.97 mmol). Stirred 4 h. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 2:1). Yield: 0.16 g. [α]D=−16.1° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether: M.p. 176° C.; MS m/z (relative intensity, 70 eV) 255 (M+3), 182 (45), 213 (12), 127 (6) 212 (bp).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@@H:11]2[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CN(C=O)C>O>[Cl:1][C:2]1[N:3]([CH2:10][C@@H:11]([OH:12])[CH2:13][N:17]2[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1cn(C[C@@H]2CO2)c(Cl)n1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C[C@H](O)Cn2cc([N+](=O)[O-])nc2Cl)CC1
Temperature: 70 °C
Reaction time: 6 h
Yield: 50.5 %

Procedure:
A mixture of (R)-2-chloro-1-(oxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 9 (1 g, 4.91 mmol), tert-butyl piperazine-1-carboxylate (1.01 g, 5.40 mmol) and DMF (3 ml) was stirred at 70° C. for 6 hours. The reaction mixture was allowed to return to room temperature and added water (7 ml). The precipitates were filtered off, and purified by silica gel column chromatography (methylene chloride/methanol=40/1) to afford tert-butyl (S)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxypropyl]piperazine-1-carboxylate (967 mg, 51%) as a light yellow powder.
Reaction SMILES: [OH:1]O.[OH-].[Na+].[C:5]([C:7]1[C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[NH:15][C:16](=[O:17])[C:11]=2[N:10]=[CH:9][CH:8]=1)#[N:6].Cl>C(O)C>[C:5]([C:7]1[C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[NH:15][C:16](=[O:17])[C:11]=2[N:10]=[CH:9][CH:8]=1)(=[O:1])[NH2:6]
Reactant: CCOc1ccccc1-c1nc2c(C#N)ccnc2c(=O)[nH]1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccccc1-c1nc2c(C(N)=O)ccnc2c(=O)[nH]1
Yield: 72 %

Procedure:
30% Aqueous hydrogen peroxide solution (0.5 ml) was added to a stirred aqueous sodium hydroxide solution (1M, 40 ml), followed by 8-cyano-2-(2-ethoxyphenyl)pyrido[3,2-d]pyrimidin-4(3H)-one (Preparation 14; 0.2 g, 0.00068 mol) and ethanol (2 ml). The mixture was heated under reflux for 2 hours, allowed to cool, acidified with 1N hydrochloric acid, and then extracted with a mixture of dichloromethane and methanol (10:1, 5×50 ml). The combined organic fractions were evaporated under vacuum and the resulting residue triturated with ethanol to give the title compound as a colourless solid (0.152 g, 72%), m.p. 295-297° C.
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:16][C:11]=2[N:10]=[CH:9]1)(OC(C)(C)C)=O.C([O-])([O-])=O.[K+].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C.O>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:17]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:15]2[CH:14]=[CH:13][C:12]3[N:8]=[CH:9][NH:10][C:11]=3[CH:16]=2)=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc(CNc2ccc3c(c2)ncn3C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccccc2)c2ccc3nc[nH]c3c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N1-Boc-N-(4-methoxybenzyl)benzimidazol-5-amine (353 mg; 1 mmol; 1 eq.) was dissolved in DMF (5 ml), treated with K2CO3 (166 mg; 1.2 mmol; 1.2 eq.) and benzylbromide (0.143 ml; 1.2 mmol; 1.2 eq.) and stirred at room temperature for 24 h. The mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The remains were taken up with THF (5 ml), treated with 5 N NaOCH3 and stirred for 2 h at room temperature. The mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography on silica using a CHCl3/MeOH gradient. Yield: 0.049 g (14.3%); MS m/z: 344.1 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 3.70 (s, 3H); 4.60 (s, 2H), 4.64 (s, 2H); 6.71 (d, 1H, 4J=2.1 Hz); 6.77 (dd, 1H, 4J=2.1 Hz, 3J=8.9 Hz); 6.85-6.88 (m, 2H); 7.19-7.22 (m, 3H); 7.26-7.32 (m, 4H); 7.34 (d, 1H, 3J=8.9 Hz); 7.99 (s, 1H); HPLC (METHOD [A]): rt 15.26 min (99.8%)
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.Cl[C:8]1[N:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]>>[OH:6][CH:4]1[CH2:5][N:2]([C:8]2[N:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])[CH2:3]1
Reactant: OC1CNC1
Reactant: COC(=O)c1cc(C(F)(F)F)cnc1Cl
Agent: Cl
Product: COC(=O)c1cc(C(F)(F)F)cnc1N1CC(O)C1
Yield: 82.6 %

Procedure:
The title compound (D67) (4.0 g) was prepared according to the experimental procedure described in Description 62 starting from azetidin-3-ol hydrochloride (2.3 g, 21.03 mmol) and methyl 2-chloro-5-(trifluoromethyl)nicotinate (D66) (4.2 g, 17.53 mmol)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11])[CH:7]=1.[C:18]([O:22][C:23]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=2)/[C:27](=[CH:35]/[C:36]2[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=2[O:43][CH2:44][C:45]2([C:50]#[N:51])[CH2:49][CH2:48][CH2:47][CH2:46]2)/[C:26]1=[O:52])=[O:24])([CH3:21])([CH3:20])[CH3:19].CO>C1(C)C=CC=CC=1>[C:18]([O:22][C:23]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=2)[C:27]2([CH:35]([C:36]3[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=3[O:43][CH2:44][C:45]3([C:50]#[N:51])[CH2:49][CH2:48][CH2:47][CH2:46]3)[CH2:12][C:10](=[O:11])[NH:9][CH:8]2[C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:17])[C:26]1=[O:52])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cc(Cl)ccc2OCC2(C#N)CCCC2)c2ccc(Cl)cc21
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OCC2(C#N)CCCC2)C12C(=O)N(C(=O)OC(C)(C)C)c1cc(Cl)ccc12
Temperature: 70 °C
Yield: 6.2 %

Procedure:
To a solution of 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (30 mmol) in toluene (30 mL) was added E/Z-6-Chloro-3-[5-chloro-2-(1-cyano-cyclopentylmethoxy)-benzylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (6 g, 11.7 mmol). Then the reaction mixture were heated at 70° C. overnight. After the solution was cooled to room temperature, methanol was added. The solution was concentrated and the residue was purified by flash column to give the title compound as a white solid (500 mg).
Reaction SMILES: C([O-])(=O)CO.[Cl:6][C:7]1[CH:8]=[C:9]([NH:14][C:15]([O:17][CH2:18][C:19]([O-:21])=O)=[O:16])[CH:10]=[C:11]([Cl:13])[CH:12]=1.ClC1C=C(N(C(NC2C=C(Cl)C=C(Cl)C=2)=O)C([O-])=O)C=C(Cl)C=1>>[Cl:6][C:7]1[CH:8]=[C:9]([N:14]2[C:19](=[O:21])[CH2:18][O:17][C:15]2=[O:16])[CH:10]=[C:11]([Cl:13])[CH:12]=1
Reactant: O=C([O-])COC(=O)Nc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])CO
Agent: O=C([O-])N(C(=O)Nc1cc(Cl)cc(Cl)c1)c1cc(Cl)cc(Cl)c1
Product: O=C1COC(=O)N1c1cc(Cl)cc(Cl)c1
Yield: 90 %

Procedure:
The conventional reaction of equimolar amounts of 3,5-DCI and a glycolate gives a mixture of 85-90% of an N-(3,5-dichlorophenyl)-carbamyloxyacetate (I) and 10-15% of an N,N'-bis-(3,5-dichlorophenyl)-allophanate (II), the percentages being based on 3,5-DCI employed. Both the N-(3,5-dichlorophenyl)-carbamyloxyacetate and the N,N'-bis-(3,5-dichlorophenyl)-allophanate undergo cyclization in the presence of a basic catalyst to give an N-(3,5-dichlorophenyl)-oxazolidine-2,4-dione (III), this product being obtained in a yield of about 90%, based on 3,5-DCI employed, in the case of the above mixture.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[NH:24][CH2:25][CH3:26])=[O:15])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][N:37]=2)[CH2:32][CH2:31]1.C(=O)(O)[O-].[Na+].COCCOC>O>[CH2:25]([NH:24][C:23]1[CH:22]=[C:21]([CH3:27])[NH:20][C:19](=[O:28])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:6]=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=[C:2]([C:39]2[CH:38]=[N:37][C:36]([N:33]3[CH2:32][CH2:31][N:30]([CH3:29])[CH2:35][CH2:34]3)=[CH:41][CH:40]=2)[CH:3]=1)=[O:15])[CH3:26]
Reactant: CCNc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1ccn2C(C)C
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCNc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCN(C)CC3)nc2)cc2c1ccn2C(C)C
Temperature: 85 °C
Yield: 59.4 %

Procedure:
To a 20 mL microwave vial was added 6-bromo-N-{[4-(ethylamino)-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl]methyl}-1-(1-methylethyl)-1H-indole-4-carboxamide (70 mg, 0.170 mmol), and 1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (59.9 mg, 0.198 mmol). PdCl2(dppf)-CH2C12 adduct (14.67 mg, 0.018 mmol) and sodium bicarbonate (45.3 mg, 0.539 mmol) were added followed by 1,2-Dimethoxyethane (DME) (5 mL) and Water (2 mL). The vial was sealed and the reaction was heated to 85° C. for 1 hr. The reaction was cooled and evaporated. The material was taken into Methanol/DMSO and was filtered through an acrodisk and purified by reverse phase Gilson HPLC (5-80% acetonitrile/water+0.1% TFA, YMC ODS-A C18 Column 75×30 mm ID S-5 um, 12 nM Column, 6 minutes) the desired fractions were collected and evaporated from 0.1N NaOH which provided the desired product N-{[4-(ethylamino)-6-methyl-2-oxo-1,2-dihydro-3-pyridinyl]methyl}-1-(1-methylethyl)-6-[6-(4-methyl-1-piperazinyl)-3-pyridinyl]-1H-indole-4-carboxamide (57 mg, 0.101 mmol, 56.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.68 (s, 1H) 8.89 (t, J=5.94 Hz, 1H) 8.66 (d, J=2.02 Hz, 1H) 8.09 (dd, J=8.59, 2.02 Hz, 1H) 7.91 (s, 1H) 7.80 (s, 1H) 7.60 (d, J=3.03 Hz, 1H) 6.99 (d, J=8.84 Hz, 1H) 6.89-6.96 (m, 2H) 5.66 (s, 1H) 4.85-4.98 (m, 1H) 4.39 (d, J=5.81 Hz, 2H) 3.63 (br. s., 4H) 3.11-3.24 (m, 2H) 2.7 (bs, 4H) 2.08 (s, 3H) 1.47 (d, J=6.57 Hz, 6H) 1.20 (t, 3H). MS(ES) [M+H]+ 542.4.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]I.[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[N:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:6][C:7]1[CH:8]=[C:9]2[CH:10]=[CH:11][N:12]([CH2:3][CH:2]([F:5])[F:1])[C:13]2=[N:14][CH:15]=1
Reactant: FC(F)CI
Reactant: Brc1cnc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)Cn1ccc2cc(Br)cnc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
1,1-Difluoro-2-iodoethane (2.19 g, 11.42 mmol) was added to a solution of 5-bromo,7-azaindole (1.5 g, 7.61 mmol) in DMF (30 mL) followed by cesium carbonate (4.96 g, 15.2 mmol), and the mixture was stirred at 70° C. for 1 h. Insoluble solids were filtered off, and filtrate was concentrated. Residue was partitioned between ethyl acetate and water. Organic layer was separated, washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in reduced pressure and purified by flash chromatography using 5% ethyl acetate in hexane to afford title compound (1.3 g, 65%) as oil. 1H NMR (300 MHz, CDCl3): δ 8.33 (d, J=2.1 Hz, 1H), 8.04 (d, J=2.4 Hz, 1H), 7.26 (d, J=2.1 Hz, 1H), 6.46 (d, J=3.6 Hz, 1H), 6.28-5.88 (tt, J1=3.9 Hz, J2=55.8 Hz, 1H), 4.60 (dt, J1=4.2 Hz, J2=14.1 Hz, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:51])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C@H:23]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH2:24]2)[CH:17]=[C:16]([C:36]([O:38]CC)=[O:37])[C:15]3=[O:41])=[C:8]([C:42]2[S:43][CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[N:46]=2)[CH:7]=1)[CH3:2].[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([NH:3][C:4](=[O:51])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C@H:23]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH2:24]2)[CH:17]=[C:16]([C:36]([OH:38])=[O:37])[C:15]3=[O:41])=[C:8]([C:42]2[S:43][CH:44]=[C:45]([C:47]([F:50])([F:48])[F:49])[N:46]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C[C@H]2CCN(CCN3CCOCC3)C2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3C[C@H]2CCN(CCN3CCOCC3)C2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
(S)-ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-((1-(2-morpholinoethyl)pyrrolidin-3-yl)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Example 236, 380 mg) was dissolved in methanol (3 mL) and tetrahydrofuran (3 mL). To this solution was added 24 wt % sodium hydroxide (1 mL) and the reaction was stirred at room temperature overnight. The solution was then concentrated to remove the organic solvents. Water (10 mL) was added and the aqueous layer was carefully acidified to pH 6˜7 with 1N hydrochloric acid. The solution was centrifuged to help isolate the solid that precipitated which was washed with cold water once to give a light yellow solid (300 mg, 82.1%) after drying.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17](I)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:22])[NH2:21]>>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][NH:11][C:10]2[N:15]=[CH:16][C:17]([C:26]3[CH:27]=[CH:28][C:23]([C:20]([NH2:21])=[O:22])=[CH:24][CH:25]=3)=[CH:18][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CNc2ncc(I)cc2N1Cc1ccccc1
Reactant: NC(=O)c1ccc(B(O)O)cc1
Product: NC(=O)c1ccc(-c2cnc3c(c2)N(Cc2ccccc2)C(=O)CN3)cc1
Yield: 24 %

Procedure:
1-Benzyl-7-iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (50 mg) was reacted with 4-carbamoylphenyl boronic acid as in General Procedure 4B to give the title compound as a white solid (24% yield). M.p.>200° C., LCMS: m/z=359.22 (M+H+), 1H-NMR (DMSO-d6, 400 MHz) δ 4.22 (2H, s), 5.28 (2H, s), 7.24 (1H, m), 7.33 (5H, m), 7.41 (1H, s), 7.56 (2H, d, J=8.6 Hz), 7.88 (2H, d, J=8.3 Hz), 7.96 (1H, bs), 8.04 (1H, d, J=1.8 Hz).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:26])=[CH:11][CH:10]=1)=O)(C)(C)C.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[F:30][C:29]([F:32])([F:31])[C:27]([OH:33])=[O:28].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:26])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1
Reaction time: 1 h
Yield: 99 %

Procedure:
To a chilled suspension of (tert-butoxy)-N-[4-(2,4-dioxo(1,3-dihydroquinazolin-3-yl))phenyl]carboxamide (0.35 g, 1 mmol) in CH2Cl2 (2 mL) was added neat TFA (2 ML). The resulting solution was stirred cold for 1 hr, concentrated in vacuo, azeotroped with heptane and dried to give desired compound (0.376 g, 99%) as the mono TFA salt. ES-MS (M+H)+=254.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[C:22]1([CH:28]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:29][CH2:30][C:31](O)=[O:32])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:34]1([CH:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:29][CH2:30][C:31]([N:19]2[CH2:20][CH2:21][N:16]([CH2:15][C:2]3([CH3:1])[CH2:6][C:5]4[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=4[O:3]3)[CH2:17][CH2:18]2)=[O:32])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCNCC1)O2
Reactant: O=C(O)CCC(c1ccccc1)c1ccccc1
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCN(C(=O)CCC(c3ccccc3)c3ccccc3)CC1)O2
Yield: 29 %

Procedure:
Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl)methyl]-5-benzofuranamine and 4,4-diphenylbutyric acid, the procedure of Example 10 was otherwise repeated to provide the title compound.
Reaction SMILES: [C:1]([C:5]1[C:10]([F:11])=[C:9]([S:12][CH3:13])[N:8]=[C:7]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[NH:16][CH:15]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:32])C=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]([C:5]1[C:10]([F:11])=[C:9]([S:12]([CH3:13])=[O:32])[N:8]=[C:7]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[NH:16][CH:15]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CSc1nc(-c2c[nH]c3ncc(Cl)cc23)nc(C(C)(C)C)c1F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nc(-c2c[nH]c3ncc(Cl)cc23)nc(C(C)(C)C)c1F
Reaction time: 1 h

Procedure:
To the solution of 3-(tert-butyl-5-fluoro-6-(methylthio)pyrimidin-2-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridine, 40b, (0.05 g, 0.11 mmol) in CH2Cl2 (3.4 mL) was added mCPBA (0.02 g, 0.11 mmol). The reaction mixture was stirred for 1 h. The reaction mixture was diluted with CH2Cl2 (10 mL) and saturated NaHCO3 solution (5 mL). The aqueous layer was extracted with CH2Cl2 (10 mL). The combined organic phases were washed again with aqueous saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated in vacuo to afford the desired product that was used without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:24]([F:27])([F:26])[F:25])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)[N:10]=2)[CH:7]=1.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.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.C(O)(C)C.O>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:24]([F:26])([F:25])[F:27])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:20])[CH3:22])[CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1cc(-c2cn3cc(Cl)ncc3n2)ccc1C(F)(F)F
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)C(=O)Nc1cc(-c2cn3cc(-c4ccccc4F)ncc3n2)ccc1C(F)(F)F
Temperature: 70 °C
Reaction time: 16 h
Yield: 10.1 %

Procedure:
An 8 mL vial is charged with N-[5-(6-chloroimidazo[1,2-a]pyrazin-2-yl)-2-(trifluoromethyl)phenyl]-2,2-dimethyl-propanamide (0.0516 g, 0.13 mmol), 2-fluorophenylboronic acid (Combi-Blocks, 32 mg, 0.26 mmol), Na2CO3 (0.0413 g, 0.39 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.009 g, 0.01 mmol), and isopropanol-water (1 mL, 3:1). The mixture is stirred at 70° C. for 16 hr. The reaction mixture is concentrated, taken up into EtOAc and CH2Cl2 (1:1) and purified by preparative plate TLC (1:1 Hexanes:EtoAc) to give the title compound (6 mg, 10% yield). LCMS m/z=457.5 [M+H]+, tR=3.06 min. (compound same as Example 86)
Reaction SMILES: [C:1]1([CH:7]=[N:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23]Cl>CC(C)=O>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][O:9][N:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ON=Cc1ccccc1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C(=NOCc1ccccn1)c1ccccc1

Procedure:
(E)-(5-mthyl-1, 2, 3-thiadiazol-4-yl) phenylmethanone oxime (0.30 g, 1.4 mmol) was dissolved in acetone (20 ml), potassium carbonate (0.32 g, 2.0 mmol) and hydrochloride of 2-picolylchloride (0.34 g, 2.0 mmol) were added and heated for 3 days with refluxing. After concentrating the thus reacted solution, the residue was extracted with ethylacetate, and after washing with water, the residue was dried with magnesium sulfate. The solvent was removed by distillation, the residue was refined in a column chromatography, and yielded (E)-(5-mthyl-1, 2, 3-thiadiazol-4-yl)phenyl-methanone O-(2-pyridyl) methyloxime.