Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]([C:8]1[C:13]([OH:14])=[C:12]([CH3:15])[C:11]([CH2:16]Cl)=[C:10]([CH3:18])[CH:9]=1)([CH3:7])([CH3:6])[CH3:5].O>CN(C)C=O>[C:4]([C:8]1[CH:9]=[C:10]([CH3:18])[C:11]([CH2:16][C:1]#[N:2])=[C:12]([CH3:15])[C:13]=1[OH:14])([CH3:7])([CH3:6])[CH3:5]
Reactant: [C-]#N
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CCl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(C)(C)C)c(O)c(C)c1CC#N
Temperature: 0 °C
Reaction time: 7 h

Procedure:
To 41 grams of potassium cyanide dispersed in 300 ml of N,N-dimethylformamide, was slowly added a solution of 97.2 grams of the compound of Example 1, the reaction temperature rising from 25° to 35° C. The reaction mixture was then heated at 70° to 75° for 7 1/2 hours. Since a sample analyzed after 7 hours reaction time indicated that some unreacted staring 6-tert.-butyl-3-chloromethyl-2,4-dimethyl-phenol remained unreacted, an additional 13.7 grams of potassium cyanide was added and the reaction mixture heated for an additional 2 hours at 60° to 65° C. The reaction mixture was poured on crushed ice, and water added to made the total volume 1.8 liters. The mixture was stirred until the ice melted, the aqueous solid dispersion was filtered by suction, and the filtercake washed well with water. The filtercake was taken up in a toluene-benzene mixture, the resulting solution being successively washed with water, 6N aqueous hydrochloric acid and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration and treating the clear filtrate with activated charcoal, the solvent was evaporated at reduced pressures. The resulting residue was allowed to crystallize from toluene yielding white crystals melting at 134° to 139°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([NH2:24])[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.C([BH3-])#N.[Na+]>C1COCC1.C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([NH:24][CH2:31][C:30]3[CH:33]=[CH:34][C:27]([F:26])=[CH:28][CH:29]=3)[CH:17]=2)[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13]1)=[O:4]
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(N)c2)Cc2ccccc2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(NCc3ccc(F)cc3)c2)Cc2ccccc2C1
Temperature: 25 °C
Yield: 80 %

Procedure:
The compound of example 117, step 2 (0.042 g, 0.12 mmol) and 4-fluorobenzaldehyde (0.0115 g, 0.092 mmol) were dissolved in THF (3 ml) and acetic acid (0.5 ml). Resin-bound sodium cyanoborohydride (0.2 mmol) was added, and the mixture was stirred at room temperature until LC/MS analysis showed complete conversion. The resin was filtered off, the filtrate was subjected to preparative RP HPLC (water/ACN gradient), and the fractions containing the title compound freeze-dried to give 33 mg of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][C:6]([NH:8][C:9]1([C:12](=[O:34])[NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[C:30]([F:33])([F:32])[F:31])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:7])C.[OH-].[Na+]>C1COCC1>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:18]2[CH:17]=[CH:16][C:15]([CH2:14][NH:13][C:12]([C:9]3([NH:8][C:6](=[O:7])[CH2:5][C:4]([OH:35])=[O:3])[CH2:11][CH2:10]3)=[O:34])=[CH:20][CH:19]=2)=[C:23]([C:30]([F:31])([F:33])[F:32])[CH:24]=1
Reactant: CCOC(=O)CC(=O)NC1(C(=O)NCc2ccc(Oc3ccc(OC)cc3C(F)(F)F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)CC(=O)O)CC3)cc2)c(C(F)(F)F)c1

Procedure:
33 mg (0.067 mmol) of N-{1-[4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylcarbamoyl]-cyclopropyl}-malonic acid monoamide monoethylester (from 109a) was stirred for 1 h at RT together with 1 mL sodium hydroxide solution 1M in 20 mL THF. The reaction mixture was evaporated down and the residue was purified by chromatography (reversed phase).
Reaction SMILES: [CH:1]1([C:4]2[S:43][C:7]3[N:8]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[C:37]5[NH:41][C:40](=[O:42])[O:39][N:38]=5)=[CH:27][CH:26]=4)[C:9](=[O:23])[N:10]([CH2:13][C:14]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)=[O:15])[C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1.O1CCCC1.[BH4-].[Na+]>CO>[CH:1]1([C:4]2[S:43][C:7]3[N:8]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[C:37]5[NH:41][C:40](=[O:42])[O:39][N:38]=5)=[CH:27][CH:26]=4)[C:9](=[O:23])[N:10]([CH2:13][CH:14]([C:16]4[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=4)[OH:15])[C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:2][CH2:3]1
Reactant: O=C(Cn1c(=O)c2cc(C3CC3)sc2n(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c1=O)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccccc2-c2ccc(Cn3c(=O)n(CC(O)c4ccc(F)cc4)c(=O)c4cc(C5CC5)sc43)cc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a mixture of 6-cyclopropyl-3-[2-(4-fluorophenyl)-2-oxoethyl]-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.1 g), tetrahydrofuran (10 mL) and methanol (10 mL) was added sodium borohydride-(0.038 g), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the residue was extracted with chloroform and saturated aqueous ammonium chloride solution. The chloroform layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.074 g, 74%).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([C@@H:20]1[N:23]([Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C:22](=[O:31])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CI>C1COCC1.CCOC(C)=O>[CH2:13]([C@@H:20]1[N:23]([Si:24]([C:27]([CH3:28])([CH3:30])[CH3:29])([CH3:25])[CH3:26])[C:22](=[O:31])[C@H:21]1[CH3:1])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@@H]1Cc1ccccc1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: C[C@@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@H]1Cc1ccccc1
Reaction time: 0.25 h
Yield: 82.9 %

Procedure:
To a solution of diisopropylamine (705 μL, 5.03 mmol) in anhydrous THF (12 mL) at −20° was added butyllithium (2.87 mL, 4.60 mmol, 1.6 M in hexane). After the reaction mixture was cooled to −78°, a solution of 4(S)-benzyl-1-(tert-butyldimethyl-silyl)azetidin-2-one (640 mg, 2.32 mmol) in THF (4 mL) was added and the mixture was stirred at −78° for 15 min followed by addition of methyl iodide (488 mg, 214 μL, 3.44 mmol). After 10 min, the reaction mixture was poured into EtOAc (125 mL). The organic phase was washed with aqueous NaHSO4 (1M) and brine, dried (MgSO4), filtered and concentrated. The residual oil was purified by flash chromatography (SiO2, 6% EtOAc in hexane) to give 4(S)-benzyl-1-(tert-butyldimethylsilyl)-3(S)-methylazetidin-2-one (557 mg , 83% yield) as a pale yellow solid. 1H-NMR (400 MHz, CDCl3) δ7.33-7.15 (m, 5H), 3.35 (ddd, J=10.8, 3.8, 2.5 Hz, 1H), 3.21 (dd, J=13.4, 3.8 Hz, 1H), 2.88 (qd, J=7.5, 2.5 Hz, 1H), 2.60 (dd, J=13.4, 10.8 Hz, 1H), 1.02 (d, J=7.5 Hz, 3H), 1.00 (s, 9H), 0.31 (s, 3H), 0.27 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=O.[NH2:11][C:12]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:13]=1[NH2:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]1[NH:11][C:12]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1nc2ccc([N+](=O)[O-])cc2[nH]1

Procedure:
2-Methylbenzoyl chloride (4.1 g, 0.027 mol) is added to 2-amino-4-nitroaniline (4 g, 0.025 mol) in toluene (100 ml), and the mixture is refluxed for 24 hours. para-Toluenesulfonic acid (1.0 g) is added, the mixture is refluxed for 36 hours and concentrated, and the residue is taken up in ethyl acetate. The solution is washed with NaHCO3 and then with water. The resulting solution is dried and concentrated, and the solid obtained is recrystallized from isopropyl ether. Yield: 3.1 g (48%); Rf (7/3 toluene/ethyl acetate): 0.58; 1H-NMR (d6-DMSO): 8.5 (d, 1H); 8.1 (dd, 1H); 7.7 (m, 2H); 7.4 (m, 3H); 2.6 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2].C(O)(=[O:17])C>C1COCC1.O>[CH2:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH:9]=[O:17])[NH:5][C:4]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(C)c(C)c1CC
Reactant: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c(C=O)c(C)c1CC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 3-ethyl-4,5-dimethyl-1H-pyrrole-2-carboxylate (Salor-Aldrich) (0.0147 g, 0.077 mmol) in acetic acid (5 mL), THF (4 mL) and water (4 mL) was added ceric ammonium nitrate (0.169 g, 0.31 mmol) and the reaction was stirred at ambient temperature. After 1.5 h, the reaction was poured into water (10 mL) and extracted with CH2Cl2 (3×5 mL). The combined organic layers were washed with saturated NaHCO3, dried over Na2SO4, filtered, and concentrated. The resultant residue was purified by normal phase chromatography. Proton NMR for the product was consistent with the title compound. 1H NMR (500 MHz, CDCl3) δ 9.78 (s, 1H); 4.36 (q, J=7.1 Hz, 2H); 2.76 (q, J=7.6 Hz, 2H); 1.62 (s, 3H); 1.38 (t, J=7.1 Hz, 3H); 1.13 (t, J=7.6 Hz, 3H). HRMS (ES) exact mass calculated for C11H16NO3 (M+H+): 209.1052. Found 209.1050.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([C@@H:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:26](=[O:45])[C@@H:27]([NH:31][C:32](=[O:44])[C@@H:33]([N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH3:36])[CH3:34])[CH:28]([CH3:30])[CH3:29])[CH:20]=2)[CH:7]=1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[C:40]([O:39][C:37]([N:35]([CH3:36])[C@@H:33]([CH3:34])[C:32]([NH:31][C@@H:27]([CH:28]([CH3:29])[CH3:30])[C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:21]1[C:19]1[CH:20]=[C:15]([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([C:4]([OH:5])=[O:3])=[CH:7]2)[CH:16]=[N:17][CH:18]=1)=[O:45])=[O:44])=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CCOC(=O)c1cn(-c2cncc([C@@H]3CCCN3C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C)c2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1c1cncc(-n2cc(C(=O)O)c3ccccc32)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.8 %

Procedure:
To a solution of 1-[5-((S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyryl}-pyrrolidin-2-yl)-pyridin-3-yl]-1H-indole-3-carboxylic acid ethyl ester (I-2A-2c: 0.29 g, 0.46 mmol) in THF (1 mL) and MeOH (0.3 mL) was added a solution of LiOH (0.035 g, 0.80 mmol) in water (0.3 mL). The resulting mixture was stirred at room temperature for 5 hours. More LiOH (0.065 g, 2.70 mmol) was added and stirring continued for overnight. The reaction mixture was then concentrated under reduced pressure to remove all organic solvents, then diluted with water. To this mixture 1 M HCl was added dropwise until pH=4. The white precipitate formed was filtered and dried in vacuo to give the titled compound as a white powder (0.19 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[CH:19]=O>>[Br:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1/[CH:19]=[C:6]1/[C:7](=[O:11])[C:8]2[C:4]([CH2:5]/1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2
Reactant: O=C1CCc2cc(Cl)ccc21
Reactant: O=Cc1ccncc1Br
Product: O=C1/C(=C/c2ccncc2Br)Cc2cc(Cl)ccc21

Procedure:
The title compound 94 is prepared according to the procedure reported in Example 35.3 with 5-chloro-1-indanone (0.83 g, 5 mmol) and 3-bromo-4-pyridinecarboxaldehyde (0.93 g, 5 mmol) as reactants. White solid. (Yield 0.44 g, 26%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[C:8]([C:14]([F:17])([F:16])[F:15])[C:9]([Br:13])=[CH:10][CH:11]=2)[CH2:6][CH:5]1[CH3:18])(=O)C.[OH-].[Na+]>CO.O>[Br:13][C:9]1[C:8]([C:14]([F:16])([F:15])[F:17])=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][CH:5]([CH3:18])[CH2:6]2
Reactant: CC(=O)N1c2ccc(Br)c(C(F)(F)F)c2CC1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1Cc2c(ccc(Br)c2C(F)(F)F)N1
Yield: 79.5 %

Procedure:
A mixture of 1-acetyl-5-bromo-2-methyl-4-(trifluoromethyl)-2,3-dihydro-1H-indole (0.130 g, 0.404 mmol; step B above) and NaOH (0.086 g; 2.15 mmol) in MeOH/H2O (4:1; 13 mL) was heated at reflux 3 h. The solvent was removed, the residue was partitioned between Et2O/H2O, and the layers were separated. The aqueous layer was extracted with Et2O (×2). Combined organics were washed (H2O, brine), dried over Na2SO4, filtered and concentrated in vacuo, affording 0.090 g of the title compound as a pale yellow oil which was used without further purification: MS (APCI) m/z 282 (M+H, 81Br).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[C:51]([O:55][C:56](=[O:77])[NH:57][C@H:58]([CH2:64][NH:65][C:66]([C:68]1[C:73]([NH2:74])=[N:72][C:71]([NH2:75])=[C:70]([Cl:76])[N:69]=1)=[O:67])[CH2:59][CH2:60][CH2:61][CH2:62][NH2:63])([CH3:54])([CH3:53])[CH3:52]>CN(C=O)C>[C:51]([O:55][C:56](=[O:77])[NH:57][C@H:58]([CH2:64][NH:65][C:66]([C:68]1[C:73]([NH2:74])=[N:72][C:71]([NH2:75])=[C:70]([Cl:76])[N:69]=1)=[O:67])[CH2:59][CH2:60][CH2:61][CH2:62][NH:63][C:17](=[O:19])[CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)CNC(=O)c1nc(Cl)c(N)nc1N
Reactant: O=C(O)CCc1ccc(OCc2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)CCc1ccc(OCc2ccccc2)cc1)CNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(4-benzyloxyphenyl)propionic acid (0.19 g, 0.74 mmol) and HATU (0.29 g, 0.75 mmol) in DMF (10 mL) is added N-methylmorpholine (0.32 mL, 2.91 mmol) followed by ((S)-5-amino-1-{[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-methyl}-pentyl)-carbamic acid tert-butyl ester (Intermediate B) (0.30 g, 0.75 mmol). The resulting mixture is stirred at RT for 16 h. The solvent is removed in vacuo and the residue is purified by column chromatography (basic alumina, 2% MeOH in DCM) to afford the title compound as yellow solid. [M-Boc+H]+ 540.
Reaction SMILES: C([O:3][C:4](=[O:41])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][CH2:22][C@H:23]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1)C.C([O-])=O.[NH4+]>CO.[Pd]>[CH2:34]([O:33][C@H:23]([CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=1)[CH2:22][NH:21][CH2:20][CH:17]1[CH2:16][CH2:15][N:14]([C:12]([NH:11][C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:4]([OH:41])=[O:3])=[O:13])[CH2:19][CH2:18]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(=O)c1cccc(NC(=O)N2CCC(CNC[C@@H](COc3ccc(O)cc3)OCc3ccccc3)CC2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C(O)c1cccc(NC(=O)N2CCC(CNC[C@@H](COc3ccc(O)cc3)OCc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
A mixture of 3-[(4-{[(2S)-2-benzyloxy-3-(4-hydroxy-phenoxy)-propylamino]-methyl}-piperidine-1-carbonyl)-amino]-benzoic acid ethyl ester (0.112 g, 0.43 mmol) and ammonium formate (0.063 g, 1 mmol) in 5 mL of methanol over 0.112 g of 10% palladium on carbon was stirred at ambient temperature overnight. The catalyst was filtered (solka floc) and the filtrate concentrated in vacuo. Trituration of the crude solid foam with Et2O provided 0.057 g of the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([NH:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C1N=CN([C:21](N2C=NC=C2)=[O:22])C=1>C1COCC1>[C:7]([N:6]1[C:4](=[O:5])[C:3]2[C:2](=[C:14]([CH3:15])[CH:13]=[CH:12][CH:11]=2)[NH:1][C:21]1=[O:22])([CH3:10])([CH3:9])[CH3:8]
Reactant: Cc1cccc(C(=O)NC(C)(C)C)c1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1cccc2c(=O)n(C(C)(C)C)c(=O)[nH]c12

Procedure:
The compounds of this invention can be prepared as illustrated by the exemplary reaction in Scheme 3. Reaction of 2-amino-3-methylbenzoic acid with triphosgene in THF produced 8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione, which was treated with tert-butylamine and DMAP in DMF to produce 2-amino-N-tert-butyl-3-methylbenzamide. Reaction of the benzamide with CDI in THF produced 3-tert-butyl-8-methylquinazoline-2,4(1H,3H)-dione, which was reacted with methyl 3-(bromomethyl)benzoate and MeONa in DMF, followed by treatment with hydrochloric acid aqueous solution, to produce 8-methyl-1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione. Coupling of the acid with 2-(piperazin-1-yl)pyrimidine in the presence of coupling agents, such as HATU and DIPEA in DMF, produced the targeted compound 8-methyl-1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH:11]1([OH:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([O:17][C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: OC1CCCCC1
Product: Cn1ncc([N+](=O)[O-])c1OC1CCCCC1
Yield: 47 %

Procedure:
Following the procedure for Example 230 reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and cyclohexanol gave 5-(cyclohexyloxy)-1-methyl-4-nitro-1H-pyrazole as off-white solid (132 mg, 47%). 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 4.76-4.67 (m, 1H), 3.70 (s, 3H), 2.10-2.02 (m, 2H), 1.85-1.78 (m, 2H), 1.64-1.52 (m, 2H), 1.43-1.22 (m, 3H), 0.96-0.81 (m, 1H)
Reaction SMILES: C(O[C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])C.[CH3:18][C:19]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>CS(C)=O>[CH3:18][C:19]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:4]1[C:5](=[O:17])[C:6](=[O:16])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15]
Reactant: CCOc1c(Nc2ccccc2O)c(=O)c1=O
Reactant: Cc1cccc(N)c1C
Solvent: CS(C)=O
Product: Cc1cccc(Nc2c(Nc3ccccc3O)c(=O)c2=O)c1C
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a solution of 3-ethoxy-4-(2-hydroxyanilino)-cyclobut-3-ene-1,2-dione (50 mg, 0.21 mmol) in DMSO (1.5 mL) was added 2,3-dimethylaniline (0.026 mL, 0.21 mmol) and reaction was stirred at 110° C. overnight. Reaction was purified on HPLC (acetonitrile:water) and product was concentrated down. Solid was dried in vacuo. LC-MS (m/z) 309 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([CH:9]([CH3:32])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[C:15]([C:20]#[C:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[N:14]=1)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35]1[CH:36]=[N:37][CH:38]=[C:39]([CH3:50])[C:40]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.O>[C:1]([O:5][C:6](=[O:33])[N:7]([CH:9]([CH3:32])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:40]2[C:39]([CH3:50])=[CH:38][N:37]=[CH:36][C:35]=2[CH3:34])=[C:15]([C:20]#[C:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[N:14]=1)=[O:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cncc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C(=O)Nc1ccc(Br)c(C#C[Si](C(C)C)(C(C)C)C(C)C)n1)N(C)C(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cncc(C)c1-c1ccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)nc1C#C[Si](C(C)C)(C(C)C)C(C)C
Temperature: 90 °C
Reaction time: 17 h

Procedure:
A mixture of tert-butyl-N-[1-[[5-bromo-6-[2-tri(propan-2-yl)silylethynyl]pyridin-2-yl]-amino]-1-oxopropan-2-yl]-N-methylcarbamate C1a (300 mg, 0.56 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (169 mg, 0.72 mmol), Na2CO3 (118 mg, 1.11 mmol), 1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (40.8 mg, 0.06 mmol), dioxane (2 ml) and water (0.4 ml) is stirred under argon atmosphere for 17 h at 90° C. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 26 mg (51%). HPLC-MS: M+H=565; tR=2.32 min (*Method—4).
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[S:11][C:12](=[O:16])[N:13]([CH3:15])[CH3:14].O.[OH-].[Li+]>C1COCC1.CO.O>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:17])=[O:2])=[C:5]([S:11][C:12](=[O:16])[N:13]([CH3:14])[CH3:15])[CH:6]=1
Reactant: COC(=O)c1ccc(Br)cc1SC(=O)N(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)Sc1cc(Br)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.5 %

Procedure:
A mixture of 4-bromo-2-dimethylcarbamoylsulfanyl-benzoic acid methyl ester (2.04 g, 6.42 mmol) and lithium hydroxide hydrate (404 mg, 9.62 mmol) in (1/1/1) THF/MeOH/H2O (21 mL) was stirred at room temperature for 6 h. The reaction mixture was concentrated to remove most organic solvents. The residue was diluted with water (100 mL) and extracted with EtOAc (20 mL), which is discarded. The aqueous layer was acidified to pH 3-4 using 1 N HCl and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to provide 4-bromo-2-dimethylcarbamoylsulfanyl-benzoic acid (1.67 g). 1H NMR (200 MHz, CDCl3): δ ppm)=7.76 (m, 2H), 7.61 (dd, J=8.2, 2.0 Hz, 1H), 3.15 (br s, 3H), 3.06 (br s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31][O:32]C3CCCCO3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18].ClC1C=C([NH:47]C2C=CC(F)=CC=2F)C=CC=1C(C1C=C(C#C)C=CC=1C)=O.N(CC(N)=O)=[N+]=[N-]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][C:31]([NH2:47])=[O:32])[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18]
Reactant: C#Cc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3F)cc2Cl)c1
Reactant: Cc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: [N-]=[N+]=NCC(N)=O
Product: Cc1ccc(-c2cn(CC(N)=O)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 101, using compound 407 (0.44 mmol) and compound 411. The crude product was purified by continuous gradient flash chromatography using MeOH/DCM 0:100 to 10:90 as the eluent to afford the title compound as yellow solid. 13C NMR (DMSO-d6) δ 194.9, 167.1, 158.7 (dd), 155.7 (dd), 149.3, 145.2, 139.8, 135.9, 133.7, 133.7, 131.7, 128.2, 127.1, 126.6, 126.4 (dd), 125.0, 124.2 (dd), 123.0, 114.9, 112.0 (dd), 111.8, 105.0 (dd), 51.5, 19.4