Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[C:32]1([N:38]2[C:42]3([CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)[C:41](=[O:48])[NH:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([N:45]3[CH2:44][CH2:43][C:42]4([N:38]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH2:39][NH:40][C:41]4=[O:48])[CH2:47][CH2:46]3)=[O:22])=[CH:17][C:9]1=2
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one as in General Procedure 10 to give the title compound. LCMS: m/z=661.00 (M+H+); retention time=0.87 minutes.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C:28]([CH3:36])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:29])[C:4]([NH:6][C@@H:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:8]([N:10]([CH3:23])[C@@H:11]([CH:20]([CH3:22])[CH3:21])/[CH:12]=[C:13](\[CH3:19])/[C:14]([O:16]CC)=[O:15])=[O:9])=[O:5].CO[C@H](C(C)(C1C=CC=CC=1)C)C(N[C@@H](C(C)(C)C)C(N(C)[C@@H](C(C)C)/C=C(\C)/C(OCC)=O)=O)=O.O.O.[OH-].[Li+]>CO.O1CCCC1>[CH3:1][O:2][C@H:3]([C:28]([CH3:36])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH3:29])[C:4]([NH:6][C@H:7]([C:8]([N:10]([CH3:23])[C@@H:11]([CH:20]([CH3:22])[CH3:21])/[CH:12]=[C:13](\[CH3:19])/[C:14]([OH:16])=[O:15])=[O:9])[C:24]([CH3:25])([CH3:26])[CH3:27])=[O:5]
Reactant: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](OC)C(C)(C)c1ccccc1)C(C)(C)C
Agent: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@H](OC)C(C)(C)c1ccccc1)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CO[C@@H](C(=O)N[C@H](C(=O)N(C)[C@H](/C=C(\C)C(=O)O)C(C)C)C(C)(C)C)C(C)(C)c1ccccc1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
According to General Procedure II, a 1:1 mixture of ethyl (E,4S)-4-[((2S)-2-{[(2S)-2-methoxy-3-methyl-3-phenylbutanoyl]amino}-3,3-dimethylbutanoyl)(methyl)amino]-2,5-dimethyl-2-hexenoate and ethyl (E,4S)-4-[((2S)-2-{[(2R)-2-methoxy-3-methyl-3-phenylbutanoyl]amino}-3,3-dimethylbutanoyl)(methyl)amino]-2,5-dimethyl-2-hexenoate (1.0 g, 2.0 mmol, from Reference Example 104) is dissolved in methanol (10 mL) and tetrahydrofuran (10 mL). To this solution is added water (5 mL) and lithium hydroxide monohydrate (0.17 g, 4.0 mmol), and the resulting mixture is stirred at 60° C. for 16 hours. Solvents are removed in vacuo and the residue is then dissolved in water. The solution is acidified to pH 1 with 2 M aqueous hydrochloric acid solution and then extracted thrice with ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, decanted, and concentrated under reduced pressure to afford a white foam. A sample of this crude material (240 mg) is subjected to HPLC purification (Prodigy OS3 column, acetonitrile/water/TFA) to give (E,4S)-4-[{N-[(2R)-2-methoxy-3-methyl-3-phenylbutanoyl]-3-methyl-L-valyl}(methyl)amino]-2,5-dimethyl-2-hexenoic acid as a clear colorless oil (80 mg). MS (ES+): (M+H)=475.0
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[OH-:20].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:13][CH2:14][CH2:15][C:16]([OH:19])=[O:20])=[CH:15][CH:14]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: [OH-]
Reactant: Oc1ccc(N2CCN(c3ccncc3)CC2)cc1
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCCOc1ccc(N2CCN(c3ccncc3)CC2)cc1

Procedure:
A solution of the product of Example 50 (0.1 g) in aqueous sodium hydroxide (1N, 0.8 ml) and ethanol (2 ml) was kept for 2 hours. The solution was evaporated and the residue dissolved in water (5 ml). Hydrochloric acid (1N, 0.8 ml) was added and the precipitate was filtered and washed with water and ether to give the title compound as a solid: m.p. 305°-306° C.; m/e 342(M+H)+ ; NMR(d6DMSO) δ 8.0(2H,d); 6.72(6H,m); 3.74(2H,t); 3.3(4H,m); 2.94(4H,m); 2.19(2H,t); 1.72(2H,m); calculated for C19H23N3O3 : C, 66.8; H, 6.8; N, 12.3. Found: C, 67.0; H, 6.8; N, 12.2%.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[S:28][C:27]([C:29]([NH:31][C:32]2[CH:40]=[CH:39][CH:38]=[C:37]3[C:33]=2[CH2:34][N:35]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][OH:50])[CH:44]=2)[C:36]3=[O:41])=[O:30])=[CH:26][CH:25]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl.N1C=CC=CC=1>[Cl:23][C:24]1[S:28][C:27]([C:29]([NH:31][C:32]2[CH:40]=[CH:39][CH:38]=[C:37]3[C:33]=2[CH2:34][N:35]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([CH:49]=[O:50])[CH:44]=2)[C:36]3=[O:41])=[O:30])=[CH:26][CH:25]=1
Reactant: O=C(Nc1cccc2c1CN(Cc1cccc(CO)c1)C2=O)c1ccc(Cl)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=Cc1cccc(CN2Cc3c(NC(=O)c4ccc(Cl)s4)cccc3C2=O)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Dess-Martin periodinane (1.9 g, 4.6 mmol) is added to a solution of 5-chloro-N-{2-[3-(hydroxymethyl)benzyl]-1-oxo-2,3-dihydro-1H-isoindol-4-yl}-2-thiophenecarboxamide (1.6 g, 3.8 mmol) in dichloromethane (38 ml) and pyridine (1.5 ml) and the mixture is stirred at room temperature for 6 h, and saturated aqueous sodium bicarbonate solution is then added. After addition of ethyl acetate and phase separation, the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried (sodium sulfate), filtered and concentrated under reduced pressure. The desired product is purified by flash chromatography (dichloromethane/methanol mixtures). Yield: 1.5 g, 97% of theory.
Reaction SMILES: C(OC([NH:8][CH:9]([C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1)=O)(C)(C)C.C(Cl)[Cl:35]>>[ClH:35].[NH2:8][CH:9]([C:29](=[O:33])[N:30]([CH3:32])[CH3:31])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1
Reactant: CN(C)C(=O)C(Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1)NC(=O)OC(C)(C)C
Reactant: ClCCl
Product: CN(C)C(=O)C(N)Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1
Product: Cl
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
The acid compound 6 (0.8 g) was dissolved in CH2Cl2 (20 mL) and cooled to 0-5° C. Hydrogen chloride gas was bubbled through this solution for 20 min. The bubbling was discontinued and the reaction mixture was stirred at room temperature for 1 h. The excess HCl was degassed and the CH2Cl2 was removed. The residual solid was triturated with EtOAc (2×25 mL), decanted, and dried to yield the desired compound 10 as a white amorphous solid (0.6 g, 87%). 1H NMR (DMSO-d6): 12.20 (br, 1H), 7.24 (d, J=8.4 Hz, 2H), 7.21 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.0 Hz, 2H), 4.53 (m, 1H), 3.04 (dd, J=13.2 and 6.0 Hz, 1H), 2.95 (dd, J=14.0 and 8.0 Hz, 1H), 2.81 (m, 5H), 2.71 (s, 3H), 2.53 (t, J=7.6 Hz, 2H). LCMS (m/e): Obsd. 357.0, Calcd. 356.42
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:5]=[C:6]([C:14]2[S:18][C:17]([NH:19][C:20]3[CH:24]=[CH:23][NH:22][N:21]=3)=[N:16][C:15]=2[CH3:25])[CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11]>C(Cl)(Cl)Cl.CO>[Br:1][C:24]1[C:20]([NH:19][C:17]2[S:18][C:14]([C:6]3[CH:7]=[CH:8][C:9]([S:10]([CH3:13])(=[O:12])=[O:11])=[C:4]([F:3])[CH:5]=3)=[C:15]([CH3:25])[N:16]=2)=[N:21][NH:22][CH:23]=1
Reactant: Cc1nc(Nc2cc[nH]n2)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Reactant: BrBr
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1nc(Nc2n[nH]cc2Br)sc1-c1ccc(S(C)(=O)=O)c(F)c1

Procedure:
Bromine (0.012 ml, 0.23 mmol) in chloroform (0.5 ml) is added dropwise to a stirred solution of [5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-(1H-pyrazol-3-yl)-amine (69) (0.10 g, 0.23 mmol) in chloroform (1 ml) and methanol (2 ml). After stirring at room temperature for 1 hour the hydrobromide salt of the titled compound precipitates. This is removed by filtration and washed with ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:11](=[O:18])[NH:10][CH2:9]2)=[CH:4][CH:3]=1.O=[CH:20][C@@H:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:22].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[C:12]3([CH2:13][CH2:14][N:15]([CH2:22][C@@H:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[CH3:20])[CH2:16][CH2:17]3)[C:11](=[O:18])[NH:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1NC[C@H](c2ccc(F)cc2)C12CCNCC2
Reactant: C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H](CN1CCC2(CC1)C(=O)NC[C@@H]2c1ccc(F)cc1)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
A reaction mixture containing 0.25 g (1.0 mmol) of (R)-4-(4-fluorophenyl)-2,8-diazaspiro[4.5]decan-1-one, 0.25 g (1.44 mmol) of the (S)-tert-butyl 1-oxopropan-2-ylcarbamate, 2 mL of THF, 1 mL of DCM, and 1 g (2.5 mmol) of MP-sodium triacetoxyborohydride resin was rotated overnight. The reaction mixture was filtered and the solvents were removed under reduced pressure. The residue was subjected to silica gel chromatography to give 250 mg (61%) of tert-butyl (S)-1-((R)-4-(4-fluorophenyl)-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)propan-2-ylcarbamate as a colorless oil. 1HNMR (400 MHz, CD3OD) δ ppm 7.35-7.31 (m, 2H), 7.10-7.06 (m, 2H), 3.85 (brs, 1H), 3.73-3.68 (m, 1H), 3.55-3.51 (m, 2H), 3.39-3.27 (m, 1H), 3.10-2.87 (m, 2H), 2.78-2.59 (m, 3H), 2.01-1.72 (m, 5H), 1.42 (s, 9H), 1.32-1.20 (m, 1H), and 1.11 (d, 3H, J=2.4 Hz); LCMS m/z: 406.2 (M+H)+.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].[Cl-].[CH2:18]([O:20][N:21]=[C:22]1[CH2:28][CH:27]2[NH2+:29][CH:24]([CH2:25][CH2:26]2)[CH2:23]1)[CH3:19].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:18]([O:20][N:21]=[C:22]1[CH2:28][CH:27]2[N:29]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[O:8][CH2:7][C:6]3=[O:15])[CH:24]([CH2:25][CH2:26]2)[CH2:23]1)[CH3:19]
Reactant: CCON=C1CC2CCC(C1)[NH2+]2
Reactant: C[C@H](CI)CN1C(=O)COc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCON=C1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccccc21
Temperature: 60 °C
Reaction time: 72 h
Yield: 24.5 %

Procedure:
A 7 ml vial was charged with 4-(3-iodo-2(S)-methyl-propyl)-4H-benzo[1,4]oxazin-3-one (330 mg, 1.0 mmol), crude 3-ethoxyimino-8-azonia-bicyclo[3.2.1]octane chloride (200 mg, 0.98 mmol), and K2CO3 (290 mg, 2.1 mmol) in dry DMF (4 ml) and the reaction was shaken at 60° C. for 3 days. The reaction was then poured into water and extracted with ether. The combined organic phases were washed brine, dried (Na2SO4), filtered, concentrated under reduced pressure and the oily residue was purified by flash column chromatography (SiO2; CH2Cl2/acetone/MeOH, 90:7:3) to yield the diastereomeric mixture of the title compound as an oil (87 mg, 0.24 mmol, 24%). 1H NMR (CD3OD) δ 7.28 (dd, J=2.0, 7.6 Hz, 1H), 7.07-6.93 (m, 3H), 4.57 (ABq, J=14.8, 19.6 Hz, 2H), 4.12 (dd, J=6.4, 14.4 Hz, 1H), 4.05-3.92 (m, 3H), 3.30-3.16 (m, 2H), 2.92-2.82 (m, 1H), 2.54-2.32 (m, 3H), 2.18-1.81 (m, 2H), 1.60-1.34 (m, 2H), 1.20 (m, 3H), 0.93 (d, J=6.8H); 13C NMR (CD3OD) δ165.8, 156.6, 146.0, 128.6, 124.0, 122.6, 116.8, 115.9, 68.5, 67.4, 60.2, 59.54, 59.48, 58.8, 56.5, 45.0, 37.0, 36.9, 31.9, 31.7, 30.99, 30.96, 27.6, 27.0, 26.7, 26.1, 15.9, 13.7; HPLC-MS (ammonium acetate) [M+H]+=372.21.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH2:17][CH2:18][O:19][C:20]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[CH:23][C:21]=4[CH:22]=3)=[O:15])=[CH:9][CH:8]=2)[CH:2]=1.ClC1C=CC=C(C(OO)=[O:42])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[O-:42][N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH2:17][CH2:18][O:19][C:20]4[CH:26]=[CH:25][C:24]([C:27]5[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=5)=[CH:23][C:21]=4[CH:22]=3)=[O:15])=[CH:9][CH:8]=2)[CH:2]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(-c4cccnc4)cc2)CCO3)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(-c4ccc[n+]([O-])c4)cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 68 h
Yield: 52.1 %

Procedure:
To a solution of N-[4-(3-pyridyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (400 mg) in tetrahydrofuran (50 ml) was added 3-chloro-perbenzoic acid (70%, 0.34 g) at 0° C., and the mixture was stirred at room temperature for 68 hours. To the reaction mixture was added sodium thiosulfate solution, and the mixture was stirred for a few minutes and extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:1), and recrystallized from ethanol-chloroform to give N-[4-(1-oxidopyridin-3-yl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 165) (216 mg) as pale yellow crystals.
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1([C:14]([C:16]2[CH:43]=[CH:42][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:29]=3)[C:24](O)=[O:25])=[CH:18][CH:17]=2)=[O:15])[CH2:13][CH2:12][CH2:11]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:68][C:69]1[S:70][CH:71]=[CH:72][N:73]=1>CN(C=O)C.O>[N:10]1([C:14]([C:16]2[CH:43]=[CH:42][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[C:28]([O:30][C@@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:39])([CH3:40])[CH3:38])([CH3:36])[CH3:35])[CH:29]=3)[C:24]([NH:68][C:69]3[S:70][CH:71]=[CH:72][N:73]=3)=[O:25])=[CH:18][CH:17]=2)=[O:15])[CH2:13][CH2:12][CH2:11]1
Reactant: Nc1nccs1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2)cc(C(=O)Nc2nccs2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
DIPEA (0.25 mL, 1.5 mmol) was added to a suspension of 3-[4-(azetidin-1-ylcarbonyl)phenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)benzoic acid (243 mg, 0.5 mmol), HATU (248 mg, 0.65 mmol) and 2-amino-1,3 thiazole (150 mg, 1.5 mmol) in DMF (3 mL). The resulting mixture was stirred at RT for 16 hours, water (45 mL) was added and the mixture extracted with ethyl acetate. The extracts were combined, washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give the crude product which was chromatographed on silica, eluting with 75% ethyl acetate in isohexane, to give the desired compound (284 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]=[C:15]3[C:11]([NH:12][C:13](=[O:24])[N:14]3[CH2:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:10]([C:25]([O:27]C)=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Si](OC1C=C(C2N=C3C(NC(=O)N3CC3CCOCC3)=C(C(OC)=O)[N:54]=2)C=CC=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]=[C:15]3[C:11]([NH:12][C:13](=[O:24])[N:14]3[CH2:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:10]([C:25]([NH2:54])=[O:27])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2CC1CCOCC1
Reactant: COC(=O)c1nc(-c2cccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)nc2c1[nH]c(=O)n2CC1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: NC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2CC1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
Methyl 2-(3-hydroxyphenyl)-8-oxo-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9-dihydro-7H-purine-6-carboxylate. Methyl 2-(3-(tert-butyldiphenylsilyloxy)phenyl)-8-oxo-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9-dihydro-7H-purine-6-carboxylate (0.202 g, 0.367 mmol) was dissolved in tetrahyrdrofuran (10 mL) and tetrabutylammonium fluoride on silica gel (0.294 g, 0.404 mmol) was added to the solution. The solution stirred at ambient temperature for two h. LCMS confirms product and no starting materials. The solution was filtered and condensed to give the crude title compound (0.110 g, 58%).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].[CH2:24]([N:31]=[C:32]=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH:21][C:32]([NH:31][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:33])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Reactant: O=C=NCc1ccccc1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)NCc3ccccc3)cc2)n1

Procedure:
Following the procedure described in Example 1 with 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and benzyl isocyanate provided the title compound. ESMS [M+H]+: 437.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C>C(O)C>[Cl-:1].[N+:11]([C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N+:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: c1ccncc1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-[n+]2ccccc2)c([N+](=O)[O-])c1
Product: [Cl-]
Temperature: 30 °C
Yield: 70 %

Procedure:
1-Chloro-2,4-dinitrobenzene (10 g, 49.4 mmol) and pyridine (40 ml, 495 mmol) were mixed in a 100 ml round-bottom flask; the resultant solution turned orange and became very cold. The flask was then warmed to 30° C, by which time the solution was dark brown, and the solution was left to react overnight. The resulting solid was broken up, washed with ether and collected on a fritted glass funnel to yield 12.3 g of a pale pink, semicrystalline solid. This solid was dissolved in 120 ml of hot ethanol, and the resultant solution decolorized with charcoal and filtered. The crystals obtained were washed with a 1:1 v/v ethanol:ether mixture. A second crop of crystals was collected and combined with the first crop, to give an overall yield of 70% of theoretical.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:3]=1[C:4]([O:6]C)=O.[C:13]([C:19]([O:21][CH3:22])=[O:20])#[C:14][C:15]([O:17][CH3:18])=[O:16].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[Cl:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:2]2[C:3]=1[C:4]([OH:6])=[C:13]([C:19]([O:21][CH3:22])=[O:20])[C:14]([C:15]([O:17][CH3:18])=[O:16])=[N:1]2
Reactant: COC(=O)C#CC(=O)OC
Reactant: COC(=O)c1c(N)cccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)c1nc2cccc(Cl)c2c(O)c1C(=O)OC
Temperature: 25 °C
Yield: 80.4 %

Procedure:
A solution of methyl 2-amino-6-chlorobenzoate (3.00 g, 16.2 mM) and dimethyl acetylenedicarboxylate (2.64 g, 18.6 mM) in t-butanol (25 mL) was refluxed under a nitrogen atmosphere for 18 hr. The reaction mixture was cooled to room temperature and potassium t-butoxide (2.09 g, 18.6 mM) was added in one portion whereupon a precipitate formed. After refluxing this mixture for 1.5 hr, it was cooled to room temperature and filtered to separate the solids. The solids were dissolved in rarer and the resulting solution acidified with 1N H2SO4 to form a precipitate. The mixture was filtered and the collected solids were washed with water and air dried to give dimethyl 5-chloro-4-hydroxyquinoline-2,3-dicarboxylate (3.84 g, 80.2%) as a tan solid. An 0.25 g portion of this material was recrystallized from ethyl acetate to provide an analytical sample (0.152 g) of the title compound as an off-white solid, mp 174°-176° C.; MS(CI): 296 (M+H). Analysis for C13H10ClNO5.0.01 H2O: Calculated: C, 52.78; H, 3.41; N, 4.73 Found: C, 52.39; H, 3.38; N, 4.67
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][C:14]=1[C:22]([F:25])([F:24])[F:23].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[O:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=2)=[CH:15][C:14]=1[C:22]([F:23])([F:24])[F:25]
Reactant: CCOC(=O)c1ccc(Br)o1
Reactant: OB(O)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2ccc(F)c(C(F)(F)F)c2)o1
Yield: 83.4 %

Procedure:
To a solution of ethyl 5-bromofuran-2-carboxylate (150 mg, 0.69 mmol) in DME (5 mL) were added 4-fluoro-3-(trifluoromethyl)phenylboronic acid (171 mg, 0.82 mmol), 2M Na2CO3 (1.03 mL, 2.06 mol), and catalytic amounts of Pd(Ph3)4 (158 mg, 0.14 mmol). The reaction mixture was refluxed for 5 h, diluted with water and extracted with EtOAc. The extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel (EtOAc/n-Hex=1:5) to give title compound (174 mg, 70%).
Reaction SMILES: [C:1]1([C:7](=O)[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH:14][NH3+:15].C(OCC)(=O)C.O>N1C=CC=CC=1>[OH:14][N:15]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C(=O)c1ccccc1
Reactant: [NH3+]O
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)C(=NO)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.5 %

Procedure:
41.0 g (0.25 mol) of methyl phenylglyoxalate are dissolved in 300 ml of pyridine. 19.1 g (0.27 mol) of hydroxylammonium hydrochloride are added in portions to this solution. When the addition is complete, the reaction mixture is stirred at room temperature for 20 hours. After addition of ethyl acetate and water, the organic layer is separated, washed with diluted HCl and water and dried over magnesium sulfate. Evaporation of the solvent gives 45 g (100%) of crude methyl α-(hydroxyimino)-2-phenylacetate as a slightly brownish liquid. This compound is used without further purification in the next reaction step. 1H-NMR (CDCl3), δ [ppm]:7.55-7.30 (m, 5 aromatic H); 3.96 and 3.87 (s, 3H, CH3O of the trans and cis isomers). The trans/cis isomer ratio is approximately 3:1.
Reaction SMILES: OO.[C:3]([O:22][CH:23]1[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([OH:31])[C:25]([CH3:33])([CH3:32])[CH2:24]1)(=[O:21])[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([OH:18])[C:12]([CH3:20])([CH3:19])[CH2:11]1)=[O:8].S([O-])([O-])=O.[Na+].[Na+].[C:40]([OH:44])([CH3:43])([CH3:42])[CH3:41]>>[OH:44][C:40]([CH3:43])([CH3:42])[CH2:41][O:18][N:13]1[C:14]([CH3:17])([CH3:16])[CH2:15][CH:10]([O:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]([O:22][CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[N:26]([O:31][CH2:41][C:40]([OH:44])([CH3:43])[CH3:42])[C:25]([CH3:33])([CH3:32])[CH2:24]2)=[O:21])[CH2:11][C:12]1([CH3:20])[CH3:19]
Reactant: CC1(C)CC(OC(=O)CCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Reactant: CC(C)(C)O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CC(C)(O)CON1C(C)(C)CC(OC(=O)CCCC(=O)OC2CC(C)(C)N(OCC(C)(C)O)C(C)(C)C2)CC1(C)C

Procedure:
Aqueous hydrogen peroxide is added to a mixture of bis(1-oxyl-2,2,6,6-tetramethyl-pieridin-4-yl) glutarate and ferrous chloride tetrahydrate in tert-butyl alcohol at 30-50° C. Excess peroxide is decomposed with aqueous sodium sulfite solution. The organic layer is concentrated and the crude product is purified by flash chromatography on silica gel to afford the title compound.