Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.C(N(CC)CC)C.[F:20][C:21]([F:28])([F:27])[C:22](=[CH2:26])[C:23](Cl)=[O:24]>O1CCCC1>[F:20][C:21]([F:28])([F:27])[C:22](=[CH2:26])[C:23]([O:12][C:2]1([CH3:1])[CH:3]2[CH2:11][CH:7]3[CH2:6][CH:5]([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2)=[O:24]
Reactant: C=C(C(=O)Cl)C(F)(F)F
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(C(=O)OC1(C)C2CC3CC(C2)CC1C3)C(F)(F)F
Temperature: 0 °C
Reaction time: 10 h
Yield: 70.3 %

Procedure:
A 500 ml flask was flushed with nitrogen to displace the air with nitrogen, and was charged with 83.1 g (0.50 mol) of 2-methyl-2-adamantanol, 101.2 g (1.0 mol) of triethylamine and 200 g of tetrahydrofuran. Then 118.9 g (0.75 mol) of α-trifluoromethylacryloyl chloride was dropwise added to the content in the flask over a period of about 1 hour, while the content was maintained at a reaction temperature of about 0° C. Then the content was stirred for 10 hours at room temperature. After completion of the reaction, the reaction mixture was washed with water and then with an aqueous saturated sodium chloride solution. The thus-obtained organic phase was subjected to column chromatography, and further, analyzed by NMR and mass spectrometry. Thus, 101.2 g (yield: 70.3%) of the object 2-methyl-2-adamantyl α-trifluoromethylacrylate was obtained.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](O)=[O:8])=[CH:3][CH:2]=1.Cl.[NH2:17][OH:18]>>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:17][OH:18])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: NO
Agent: Cl
Product: O=C(NO)c1ccc(-c2ccccc2)cc1

Procedure:
Using the procedure of Example 1 part (b), but using 4-biphenyl carboxylic acid and hydroxylamine hydrochloride the desired compound was obtained.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@H:5]([CH3:18])[CH2:4][CH2:3]1.CN(C)C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N+:41]([C:44]1[CH:52]=[CH:51][C:47]([C:48](O)=[O:49])=[CH:46][CH:45]=1)([O-:43])=[O:42].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:18][C@@H:5]1[CH2:4][CH2:3][C@@H:2]([O:1][C:48]([C:47]2[CH:46]=[CH:45][C:44]([N+:41]([O-:43])=[O:42])=[CH:52][CH:51]=2)=[O:49])[CH2:7][N:6]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: C[C@@H]1CC[C@H](O)CN1C(=O)OCc1ccccc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: CN(C)c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a THF (909 ml) solution of benzyl (2R,5S)-5-hydroxy-2-methylpiperidine-1-carboxylate (34 g, 136 mmol), 4-(dimethylamino) phenyldiphenylphosphine (58.3 g, 191 mmol), and 4-nitrobenzoic acid (29.6 g, 177 mmol) was added, under N2, DEAD (30.0 ml, 191 mmol) dropwise at −15 to −25° C. over 20 min. The reaction was allowed to warm to RT overnight. The reaction was concentrated in vacuo, removing most THF, then diluted with Et2O (500 mL). The mixture was cooled at 0° C. and washed with 1 N HCl (5×200 mL). The combined aqueous phases were back-extracted twice with Et2O. The combined organic phases were subsequently washed twice more with 1 N HCl. The organics were dried over MgSO4, filtered, and concentrated. The crude material was purified by silica gel gradient chromatography (0-40% ethyl acetate in hexanes), providing the titled compound as a light yellow oil which slowly solidified. LRMS m/z (M+H) 399.3 found, 399.1 required.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2C(=O)C3C(=CC=CC=3NC=O)N=C2C)[CH2:6][CH2:5][C:4](=[O:23])[NH:3]1.[CH3:24][C:25]1O[C:27](=[O:38])[C:28]2[C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.NC1CCC(=O)NC1=O>>[CH3:24][C:25]1[N:8]([CH:7]2[CH2:6][CH2:5][C:4](=[O:23])[NH:3][C:2]2=[O:1])[C:27](=[O:38])[C:28]2[C:29](=[CH:31][CH:32]=[CH:33][C:34]=2[N+:35]([O-:37])=[O:36])[N:30]=1
Reactant: Cc1nc2cccc(NC=O)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: Cc1nc2cccc([N+](=O)[O-])c2c(=O)o1
Agent: NC1CCC(=O)NC1=O
Product: Cc1nc2cccc([N+](=O)[O-])c2c(=O)n1C1CCC(=O)NC1=O

Procedure:
In one specific embodiment, provided herein is a method for preparing 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof; comprising the steps of (a) reacting 2-amino-6-nitrobenzoic acid with an activated acetic acid in a solvent to form 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one; (b) reacting 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one with 3-aminopiperidine-2,6-dione or a salt thereof in a solvent in the presence of a coupling reagent to form 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione; (c) reducing 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione in a solvent in the presence of formic acid via transfer hydrogenation to form N-(3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-5-yl)formamide; and (d) hydrolyzing N-(3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-5-yl)formamide in a solvent to form 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof; wherein the molar ratio of the activated acetic acid versus 2-amino-6-nitrobenzoic acid is ranging from about 1 to about 10, from about 1 to about 5, from about 1.5 to about 5, or from about 1.5 to about 2.5; and wherein steps (a), (b), (c), and (d) are each as described herein elsewhere.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[C:15]([C:29](O)=[O:30])[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)=[CH:17][CH:18]=2)=[CH:11][C:10]([C:32]([F:35])([F:34])[F:33])=[N:9]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:26])=[O:27])[CH:20]=3)=[C:15]([C:29]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[O:30])[CH:14]=2)=[CH:11][C:10]([C:32]([F:34])([F:35])[F:33])=[N:9]1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)cc2C(=O)O)c1
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)cc2C(=O)N2CCOCC2)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a suspension of 4-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3′-(methylsulfonyl)biphenyl-2-carboxylic acid (0.52 g, 1 mmol) in DCM (6 mL) was added carbonyldimidazole (2.43 mg, 1.5 mmol) and the mixture was stirred for 2 h at 20° C. Morpholine (0.175 mL, 2 mmol) was added and the mixture was stirred overnight at 20° C. Evaporation of solvent gave a crude, which was purified by column chromatography on silica gel eluting with EtOAc-hexane (1:4 to 4:1) to afford (4-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3′-(methylsulfonyl)biphenyl-2-yl)(morpholino)methanone (0.52 g). 1H-NMR (CDCl3): δ 7.97 (m, 2H), 7.77 (d, 1H), 7.64 (m, 1H), 7.58 (m, 1H), 7.46-7.24 (m, 5H), 6.89 (s, 1H), 3.55 (m, 3H), 3.33 (m, 2H), 3.08 (s, 3H), 2.87 (m, 2H), 2.69 (m, 1H). MS(ES): 590 [M+H]+.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[NH2:45][C:46]1[CH:47]=[N:48][C:49]([N:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[CH:50][CH:51]=1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:45][C:46]4[CH:47]=[N:48][C:49]([N:52]5[CH2:53][CH2:54][O:55][CH2:56][CH2:57]5)=[CH:50][CH:51]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: Nc1ccc(N2CCOCC2)nc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(N5CCOCC5)nc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 3-amino-6-morpholinopyridine as the aniline component. (29%, MS=556.3 (M+H))
Reaction SMILES: [Br:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[O:4][C:5]1[C:6]([NH:20][C:21]2[S:22][CH:23]=[C:24]([CH:26]3[CH2:31][CH2:30][N:29](C([O-])=O)[CH2:28][CH2:27]3)[N:25]=2)=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1.C(O)(C(F)(F)F)=O.O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[O:4][C:5]1[C:6]([NH:20][C:21]2[S:22][CH:23]=[C:24]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:25]=2)=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1
Reactant: COc1cccc(Sc2cnc(Nc3nc(C4CCN(C(=O)[O-])CC4)cs3)c(Oc3ccc(F)cc3Br)c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(Sc2cnc(Nc3nc(C4CCNCC4)cs3)c(Oc3ccc(F)cc3Br)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 103.3 %

Procedure:
A 20 mL vial was charged with tert-butyl. 4-(2-(3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate (100 mg, 0.145 mmol) and CH2Cl2 (2 mL). TFA (2 mL) was added and stirred at ambient temperature for 5 minutes. The reaction was poured into water and diluted with CH2Cl2. Solid Na2CO3 added slowly to neutralize the TFA. The reaction was extracted and dried to afford 3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)-N-(4-(piperidin-4-yl)thiazol-2-yl)pyridin-2-amine (88 mg, 103% yield) as a yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]3=[N:11][N:12]([CH2:23][C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=5)[NH:26][CH:25]=4)[C:13]([C:14]4[N:18]([CH3:19])[CH:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=4)=[C:9]3[C:8](=[O:34])[N:7]([CH3:35])[C:6]2=[O:36])[CH2:3][CH2:2]1.Cl.[O:38]([NH2:40])[CH3:39].C(P(=O)(OCC)OCC)#N>>[CH:1]1([CH2:4][N:5]2[C:10]3=[N:11][N:12]([CH2:23][C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[C:30]([CH3:33])[CH:31]=5)[NH:26][CH:25]=4)[C:13]([C:14]4[N:18]([CH3:19])[CH:17]=[C:16]([C:20]([NH:40][O:38][CH3:39])=[O:22])[CH:15]=4)=[C:9]3[C:8](=[O:34])[N:7]([CH3:35])[C:6]2=[O:36])[CH2:3][CH2:2]1
Reactant: Cc1ccc2[nH]cc(Cn3nc4c(c3-c3cc(C(=O)O)cn3C)c(=O)n(C)c(=O)n4CC3CC3)c2c1
Reactant: CON
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Product: CONC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC4CC4)c3nn2Cc2c[nH]c3ccc(C)cc23)n(C)c1

Procedure:
This compound was synthesized by the reaction of 5-{7-(cyclopropylmethyl)-5-methyl-2-[(5-methyl-1H-indol-3-yl)methyl]-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and methoxylamine hydrochloride using diethyl cyanophosphonate as a coupling reagent. Mass: 516.21 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:30]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:4]2[N:3]=1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>CN(C)C(=O)C.C(OCC)(=O)C>[CH:31]1([C:34]([NH:1][C:2]2[N:30]=[C:5]3[CH:6]=[CH:7][C:8]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=5)[CH:14]=[CH:15][CH:16]=4)=[CH:9][N:4]3[N:3]=2)=[O:35])[CH2:33][CH2:32]1
Reactant: Nc1nc2ccc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)cn2n1
Reactant: O=C(Cl)C1CC1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
To a solution of N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (100 mg, 0.24 mmol) in N,N-dimethylacetamide (2.0 mL) was added cyclopropanecarbonyl chloride (33 μL, 0.36 mmol), and the mixture was stirred at room temperature for 4 hr. Cyclopropanecarbonyl chloride (15 μL, 0.17 mmol) was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (150 mL), washed with 1N hydrochloric acid (15 mL), 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), fractions containing the object product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate, hexane and diisopropyl ether to give the title compound (108 mg, 92%) as a colorless powder.
Reaction SMILES: [Br-].[NH2:2][C:3]1[N:4]([CH2:20][C:21](=[O:27])[C:22]2[S:26][CH:25]=[CH:24][CH:23]=2)[C:5]2[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=2[N+:7]=1[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.O.[CH3:29][C:30](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>>[CH3:29][C:30]1[N:2]=[C:3]2[N:4]([C:20]=1[C:21](=[O:27])[C:22]1[S:26][CH:25]=[CH:24][CH:23]=1)[C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[N:7]2[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Nc1n(CC(=O)c2cccs2)c2ccccc2[n+]1CCN1CCCCC1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [Br-]
Solvent: O
Product: Cc1nc2n(CCN3CCCCC3)c3ccccc3n2c1C(=O)c1cccs1

Procedure:
The bromide obtained in Step A is heated at reflux in 15 ml of acetic anhydide until completely dissolved. Cool and pour into 50 ml of cold water. Neutralise with a solution of sodium carbonate and extract twice with 10 ml of chloroform each time. Combine the organic phases, pass over a column of alumina and evaporate. Recrystallise the residue from ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].CC1(C)C(C)(C)OB([C:37]2[N:38](C(OC(C)(C)C)=O)[CH:39]=[CH:40][CH:41]=2)O1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.CCO.O>[OH:28][C@@H:24]1[C@@H:25]([OH:27])[CH2:26][N:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[C:37]2[NH:38][CH:39]=[CH:40][CH:41]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Reactant: CC(C)(C)OC(=O)n1cccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(-c2ccc[nH]2)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
3-Bromo-4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 28.1, 100 mg, 0.217 mmol), tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate (127 mg, 0.434 mmol), Pd(PPh3)2Cl2 (15.22 mg, 0.022 mmol), Na2CO3 (92 mg, 0.867 mmol), DME (920 μL), water (263 μL) and EtOH (131 μL) were added to a MW vial, which was sealed, evacuated/purged with argon and the RM was stirred at 80° C. for 16 h. MeOH (0.5 mL) was added and the RM was subjected to MW at 150° C. for 5 min. The RM was diluted with DME (3 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 90 mg, 0.130 mmol), centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 4 g, cyclohexane/EtOAc from 40% to 100% EtOAc) followed by preparative SFC (Column NH2, from 25% to 30% in 10 min) to yield the title compound as a grey solid. UPLC-MS (Condition 3) tR=0.98 min, m/z=448.1 [M+H]+, m/z=446.1 [M−H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.82 (d, J=11.00 Hz, 2H) 3.28-3.34 (m, 6H) 3.86 (br. s, 2H) 4.97 (d, J=3.42 Hz, 2H) 6.03-6.07 (m, 1H) 6.07-6.12 (m, 1H) 6.75-6.77 (m, 1H) 6.78 (d, J=8.80 Hz, 1H) 7.31 (d, J=8.80 Hz, 2H) 7.82 (dd, J=8.80, 2.45 Hz, 1H) 7.85 (d, J=2.20 Hz, 1H) 7.86-7.91 (m, 2H) 10.07 (s, 1H) 10.97 (d, J=1.71 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH2:9][CH2:10][O:11][N:12]1C(=O)C2C(=CC=CC=2)C1=O)[CH3:8])([CH3:4])([CH3:3])[CH3:2].CNN.C(OCC)C>ClCCl>[C:1]([O:5][C:6](=[O:23])[N:7]([CH2:9][CH2:10][O:11][NH2:12])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCON1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Agent: CNN
Solvent: ClCCl
Solvent: CCOCC
Product: CN(CCON)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 106.3 %

Procedure:
A solution of [2-(1,3-dioxo-1,3-dihydro-isoindol-2-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester (4.50 g, 14.0 mmol) in dichloromethane (40 mL) was treated with methylhydrazine (0.78 mL, 14.7 mmol) and the reaction mixture was stirred 6 h at ambient temperature. Diethyl ether (80 mL) was added and the heterogeneous solution was allowed to stand overnight. The precipitate was removed by filtration and was washed with ether (80 mL). The filtrate was further concentrated and the resultant precipitate was filtered and the second filtrate concentrated to afford (2-Aminooxy-ethyl)-methyl-carbamic acid tert-butyl ester (2.83 g) as a viscous oil: 1H NMR (400 MHz, CDCl3) δ 3.73 (t, J=5.2 Hz, 2 H), 5.45 (br s, NH2), 3.46 and 3.42 (br s, 2 H), 2.86 br s, 3 H), 1.25 (br s, 9 H); MS (APCI+)=191.1.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:27]2[CH2:39][CH2:38][N:30]3[C:31]4[CH2:32][CH2:33][CH2:34][CH2:35][C:36]=4[CH:37]=[C:29]3[C:28]2=[O:40])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[N:20]=[N:21][CH:22]=[CH:23][N:24]=2)[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[N:21]1[CH:22]=[CH:23][N:24]=[C:19]([NH:18][C:16]2[C:15](=[O:25])[N:14]([CH3:26])[CH:13]=[C:12]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([N:27]4[CH2:39][CH2:38][N:30]5[C:31]6[CH2:32][CH2:33][CH2:34][CH2:35][C:36]=6[CH:37]=[C:29]5[C:28]4=[O:40])[C:6]=3[CH2:5][OH:4])[CH:17]=2)[N:20]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3nccnn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2nccnn2)c1=O
Temperature: 36 °C
Reaction time: 0.5 h
Yield: 27.8 %

Procedure:
A mixture of 172b (350 mg, 0.65 mmol) and lithium hydroxide (273 mg, 6.5 mmol) in i-propanol/THF (1:1, 5 mL) and water (0.5 mL) was stirred at 36° C. for 0.5 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was washed by reverse-phase prep-HPLC to afford 172 (90 mg, 28%). MS-ESI: [M+H]+ 499.2. 1H NMR (500 MHz, CDCl3) δ 8.77 (d, J=2.5 Hz, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.67 (s, 1H), 8.50 (d, J=5.0 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.05 (d, J=2.5 Hz, 1H), 7.35 (d, J=5.0 Hz, 1H), 6.89 (s, 1H), 5.10 (t, J=6.5 Hz, 1H), 4.65-4.51 (m, 2H), 4.31-4.27 (m, 1H), 4.16-4.08 (m, 2H), 3.90-3.87 (m, 1H), 3.75 (s, 3H), 2.62-2.56 (m, 4H), 1.92-1.87 (m, 2H), 1.79-1.78 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[NH:9][C:8]([C:13]2[C:17]([NH:18][C:19](=[O:28])[C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[F:27])=[CH:16][NH:15][N:14]=2)(C(O)=O)[NH:7][CH:6]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN([CH:46]=[O:47])C>ClCCl>[F:27][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([F:26])[C:20]=1[C:19]([NH:18][C:17]1[C:13]([C:8]2[NH:9][C:5]3[CH2:4][CH2:3][CH2:2][NH:1][C:46](=[O:47])[C:6]=3[N:7]=2)=[N:14][NH:15][CH:16]=1)=[O:28]
Reactant: CN(C)C=O
Reactant: NCCCC1=CNC(C(=O)O)(c2n[nH]cc2NC(=O)c2c(F)cccc2F)N1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C1NCCCc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 13 %

Procedure:
To a stirred solution of 5-(3-amino-propyl)-2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-imidazole carboxylic acid (200 mg, 0.51 mmoles) in DMF (10 ml) and dichloromethane (10 ml) was added EDC (118 mg, 0.62 mmoles), HOBt (84 mg, 0.62 mmoles) and NEM (260 μl, 2.04 mmoles). The solution was stirred at ambient temperature for 48 hours and then partitioned between EtOAc and water. The organic portion was dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by flash column chromatography [silica, 3% MeOH in DCM to 5% to 10%] to give 2,6-difluoro-N-[3-(4-oxo-1,4,5,6,7,8-hexahydro-1,3,5-triaza-azulen-2-yl)-1H-pyrazol-4-yl]-benzamide as a pale yellow solid (10 mg, 13%). (LC/MS: Rt 1.93, [M+H]+ 372.99).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:11][C:12]1[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=1[C:14]([NH:16][C:17]1[CH:21]=[CH:20][NH:19][N:18]=1)=[O:15].[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[C:28]=1[CH2:29]Br>C1COCC1.CS(C)=O>[Cl:11][C:12]1[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=1[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH2:29][C:28]2[C:31]([C:35]([F:36])([F:38])[F:37])=[CH:32][CH:33]=[CH:34][C:27]=2[F:26])[N:18]=1)=[O:15]
Reactant: Fc1cccc(C(F)(F)F)c1CBr
Reactant: O=C(Nc1cc[nH]n1)c1ccccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccn(Cc2c(F)cccc2C(F)(F)F)n1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 M lithium bis(trimethylsilyl)amide (100 μl, 0.1 mmol, Aldrich) was slowly added to a solution of 2-chloro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 45)(22 mg, 0.1 mmol) in THF (400 μl). The resulting solution was then transferred to a solution of 2-fluoro-6-(trifluoromethyl)benzyl bromide (26 mg, 0.1 mmol, Aldrich) in THF (200 μl) and stirred for 2 h under nitrogen at ambient temperature. The mixture was diluted with DMSO (0.6 ml) and purified by MDAP using a Sunfire C18 column (Method D) using Acetonitrile-Water with a TFA modifier. The solvent was removed under a stream of nitrogen to give the title compound (27 mg); LCMS (System 4) MH+=398, tRET=2.96 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:27])=[C:4]([F:26])[C:5]([NH:17][C:18]2[CH:23]=[CH:22][C:21](I)=[CH:20][C:19]=2[F:25])=[C:6]([CH:16]=1)[C:7]([NH:9][O:10][CH2:11][CH:12]([OH:15])[CH2:13][OH:14])=[O:8].C(N(CC)CC)C>O1CCCC1.[Ni]>[Br:1][C:2]1[C:3]([F:27])=[C:4]([F:26])[C:5]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])=[C:6]([CH:16]=1)[C:7]([NH:9][O:10][CH2:11][CH:12]([OH:15])[CH2:13][OH:14])=[O:8]
Reactant: O=C(NOCC(O)CO)c1cc(Br)c(F)c(F)c1Nc1ccc(I)cc1F
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NOCC(O)CO)c1cc(Br)c(F)c(F)c1Nc1ccccc1F
Yield: 28.9 %

Procedure:
A solution of 5-bromo-N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (0.240 g, 0.429 mmol) and triethylamine (0.2 g, 1.98 mmol) in tetrahydrofuran (16 mL) was hydrogenated over Raney Nickel (0.12 g, pre-rinsed with tetrahydrofuran) at 10 psig at room temperature for a total of 7 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The afforded residue was partitioned between ethyl acetate and water. The organics were washed twice with water, twice with saturated brine, collected, dried over sodium sulfate, filtered and concentrated in vacuo. HPLC purification was performed using a YMC 30×100 mm 5 u (C18) column in 0-100% acetonitrile (3.0% n-propanol)/100-0% water (3.0% n-propanol)at 30 mL/min. The desired fractions were collected, concentrated and dried in a vacuum oven overnight at 50° C. to afford 5-bromo-N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-phenylamino)-benzamide as a white solid (0.054 g, 30%): m.p.=143.5-144.5° C.; 1NMR (400 MHz, DMSO-d6) δ 11.95 (bs, 1H), 8.74 (bs, 1H), 7.68 (d, 1H, J=6.1 Hz), 7.17 (t, 1H, J=9.8 Hz), 7.01-7.04 (m, 1H), 6.94 (m, 2H), 4.81 (m, 1H), 4.57 (m, 1H), 3.86 (m, 1H), 3.69-3.71 (m, 2H), 3.3, (2H, under HDO); MS(APCI+)=435.0/437.0.