Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C:11]2[CH:10]=[C:9]([Se:12][C:13]3[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23]CC)=[O:22])=[CH:15][CH:14]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)=[CH:4][CH2:3]1.O.[OH-].[Li+]>>[CH3:1][C:2]1([CH3:33])[C:11]2[CH:10]=[C:9]([Se:12][C:13]3[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:4][CH2:3]1
Reactant: CCOC(=O)/C=C/c1ccc([Se]c2ccc3c(c2)C(C)(C)CC=C3c2ccc(C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C2=CCC(C)(C)c3cc([Se]c4ccc(/C=C/C(=O)O)cc4)ccc32)cc1

Procedure:
In a manner similar to that of Example 1g, by reacting 0.11 g (0.23 mmol) of ethyl (E)-3-[4-(8,8-dimethyl-5-p-tolyl-7,8-dihydro-2-naphthylselanyl)phenyl]acrylate with 0.11 g (2.6 mmol) of lithium hydroxide hydrate, a yellow solid is obtained (0.08 g; yield=78%).
Reaction SMILES: [Br-].[CH3:2][N:3]([CH3:37])[C:4]1[CH:5]=[CH:6][C:7]2[C:16]([CH:17]=1)=[O+:15][C:14]1[C:9](=[CH:10][CH:11]=[C:12]([N:18]([CH3:20])[CH3:19])[CH:13]=1)[C:8]=2[C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([NH2:28])[C:22]=1[C:29]([O:31][CH2:32][O:33][C:34](=[O:36])[CH3:35])=[O:30].[I-:38].[CH3:39]N(C)C1C=CC2C(C=1)=[O+]C1C(=CC=C(N(C)C)C=1)C=2C1C=C(C(OC)=O)C(NC)=C(N)C=1OC(=O)C>>[I-:38].[CH3:20][N:18]([CH3:19])[C:12]1[CH:11]=[CH:10][C:9]2[C:14]([CH:13]=1)=[O+:15][C:16]1[C:7](=[CH:6][CH:5]=[C:4]([N:3]([CH3:2])[CH3:37])[CH:17]=1)[C:8]=2[C:21]1[CH:26]=[CH:25][C:24]([NH:27][CH3:39])=[C:23]([NH2:28])[C:22]=1[C:29]([O:31][CH2:32][O:33][C:34](=[O:36])[CH3:35])=[O:30]
Reactant: CC(=O)OCOC(=O)c1c(-c2c3ccc(N(C)C)cc3[o+]c3cc(N(C)C)ccc23)ccc(N)c1N
Reactant: CNc1c(C(=O)OC)cc(-c2c3ccc(N(C)C)cc3[o+]c3cc(N(C)C)ccc23)c(OC(C)=O)c1N
Agent: [Br-]
Agent: [I-]
Product: CNc1ccc(-c2c3ccc(N(C)C)cc3[o+]c3cc(N(C)C)ccc23)c(C(=O)OCOC(C)=O)c1N

Procedure:
From the above 3,6-bis(dimethylamino)-9-(2-acetoxymethoxycarbonyl-3,4-diaminophenyl)xanthylium bromide (133 mg), 3,6-bis(dimethylamino)-9-[2-acetoxy-methoxycarbonyl-3-amino-4-(N-methylamino)phenyl]xanthylium iodide was obtained (40.5 mg, 27.5%) in the same manner as in Example 1.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[C:5]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=1.C(N(CC)C1C=CC=CC=1)C.O=P(Cl)(Cl)[Cl:33]>>[Cl:33][C:6]1[C:5]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=[C:2]([CH3:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CCc1c(C(F)(F)F)nc(C)[nH]c1=O
Solvent: CCN(CC)c1ccccc1
Product: CCOC(=O)CCc1c(Cl)nc(C)nc1C(F)(F)F

Procedure:
A mixture of ethyl 3-(2-methyl-6-trifluoromethyl-3H-pyrimidine-4-on-5-yl)propionate (0.61 g, 2.20 mmol), N,N-diethylaniline (0.33 g, 2.2 mmol), and POCl3 (8 mL) was heated under reflux for 2 h. The mixture was concentrated, poured onto ice, and extracted with ether. The combined extracts were dried (MgSO4) and concentrated to give 0.65 g of product as a brown oil.
Reaction SMILES: [O:1]([C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:36][CH2:37][O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.O>CN(C)C=O>[O:1]([C:13]1[CH:18]=[C:17]([O:19][CH2:36][CH2:37][O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:16]=[CH:15][C:14]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[CH:23][CH:22]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: BrCCOCc1ccccc1
Reactant: CCc1ccc(Cc2ccc(O)cc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(Cc2ccc(OCCOCc3ccccc3)cc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
To a suspension of 2-(4-ethylbenzyl)-5-hydroxyphenyl β-D-glucopyranoside (0.039 g) and cesium carbonate (0.098 g) in N,N-dimethylformamide (1 mL) was added (2-bromoethyl)benzyl ether (0.025 mL), and the mixture was stirred at 50° C. for 3.5 hours. The reaction mixture was cooled to ambient temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (eluent: dichloromethane/methanol=6/1) to give 5-[2-(benzyloxy)ethyloxy]-2-(4-ethylbenzyl)phenyl β-D-glucopyranoside (0.022 g).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[N:18]=[CH:19][C:20]([C:23]([OH:25])=O)=[N:21][CH:22]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)([N:28]1C=CN=C1)=O.N>CN(C)C=O>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([O:16][C:17]4[N:18]=[CH:19][C:20]([C:23]([NH2:28])=[O:25])=[N:21][CH:22]=4)=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
5-[(3-Cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-2-pyrazinecarboxylic acid (E123a) (168 mg, 0.47 mmol) was dissolved in dry dimethylformamide (5 ml), treated with 1,1′-carbonyldiimidazole (230 mg, 1.42 mmol) and the resulting mixture stirred at room temperature for 1.5 hours. The mixture was treated with 0.880 ammonia (0.14 ml, 2.84 mmol) and stirred for 4 hours. The reaction mixture was concentrated in vacuo and the resulting residue purified by column chromatography eluting with a mixture of (0.5:4.5:95) to afford the title compound; MS (ES+) m/e 339 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][O:12][C:13]3[CH:45]=[CH:44][C:16]([CH2:17][CH:18]4[S:22][C:21](=[O:23])[N:20](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:19]4=[O:43])=[CH:15][CH:14]=3)[N:8]([CH3:46])[C:5]2=[N:6][CH:7]=1.C(O)(=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][O:12][C:13]3[CH:45]=[CH:44][C:16]([CH2:17][CH:18]4[S:22][C:21](=[O:23])[NH:20][C:19]4=[O:43])=[CH:15][CH:14]=3)[N:8]([CH3:46])[C:5]2=[N:6][CH:7]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cc(Cl)cnc21
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2cc(Cl)cnc21

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 1.40 g of 5-{4-(6-chloro-3-methylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 65) and 20 ml of a 3:1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. This crude product was crystallized by trituration with ethyl acetate, to give 0.75 g of the title compound, melting at 203°-205° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:19])[CH:9]([NH2:18])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[S:28](Cl)(=[O:30])=[O:29].CCN(CC)CC.C(=O)([O-])[O-].C(O)C(N)(CO)CO>ClCCCl>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[S:28]([NH:18][CH:9]([C:8]([N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1)=[O:19])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)(=[O:29])=[O:30]
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Reactant: CC1CCN(C(=O)C(N)CCc2ccccc2)CC1
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cccc(Cl)c1S(=O)(=O)NC(CCc1ccccc1)C(=O)N1CCC(C)CC1
Reaction time: 16 h

Procedure:
A mixture of 20 mg (0.077 mmol) of 1-(4-methylpiperidin-1-yl)-1-oxo-4-phenylbutan-2-amine, 0.11 mmol of 2-chloro-6-methylbenzene-sulfonyl chloride, and 0.2 mmol of Et3N in 1 mL of DCE is stirred for 16 h, and 240 mg of MP-carbonate and 170 mg of PS-trisamine are added. The mixture is shaken for 2 days, filtered, and concentrated to provide Example 54.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:9])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[Na].[Cl:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:30])[C:28]=1[SH:29]>>[Cl:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:30])[C:28]=1[S:29][C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:9])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: Sc1c(Cl)cncc1Cl
Reactant: CN1CCC(NC(=O)Nc2cc([N+](=O)[O-])c(Cl)s2)CC1
Agent: [Na]
Product: CN1CCC(NC(=O)Nc2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for step A of example 18 from 1-(5-chloro-4-nitrothiophen-2-yl)-3-(1-methylpiperidin-4-yl)urea (100 mg, 0.31 mmol) and 3,5-dichloropyridine-4-thiol sodium salt (62 mg, 0.35 mmol). The title compound was obtained as a white solid (120 mg, 85% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.01 (1H, m), 8.92 (2H, m), 6.91 (1H, m), 3.43 (2H, m), 2.87 (2H, m), 2.33 (3H, m), 1.91 (1H, m), 1.74 (2H, m), 1.46 (2H, m). MS m/z: 459.94, 461.94 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:8][NH2:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.C[O:18][C:19](=O)[N:20]=[C:21](SC)[C:22]([C:36]1[CH:37]=[C:38]2[C:43](=[C:44]([O:46][CH3:47])[CH:45]=1)[O:42][CH2:41][CH2:40][CH2:39]2)=[N:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:34]=[C:33]([CH3:35])[O:32][N:31]=2)=[CH:26][CH:25]=1>CN(C=O)C>[F:1][C:2]1[C:3]([N:8]2[C:19](=[O:18])[NH:20][C:21]([CH:22]([C:36]3[CH:37]=[C:38]4[C:43](=[C:44]([O:46][CH3:47])[CH:45]=3)[O:42][CH2:41][CH2:40][CH2:39]4)[NH:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[N:34]=[C:33]([CH3:35])[O:32][N:31]=4)=[CH:26][CH:25]=3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1ncccc1F
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc2c(c(OC)c1)OCCC2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccc3F)c(=O)[nH]2)cc2c1OCCC2
Temperature: 85 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
After adding 25 mg of (3-fluoropyridin-2-yl)hydrazine and 50 μl of triethylamine to a solution of 100 mg of {2-(8-methoxychroman-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester (Example (24a)) in 2 ml of DMF, the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 2 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 2-(3-fluoro-pyridin-2-yl)-5-{(8-methoxychroman-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2,4-dihydro-[1,2,4]triazol-3-one (60 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])(C)(C)C.C(O[C:23](=[O:41])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([NH2:40])[N:34]=2)[CH:28]=1)=O)(C)(C)C>>[NH2:40][C:35]1[N:34]=[C:33]([C:29]2[CH:28]=[C:27]([C:25]3[CH2:24][C:23](=[O:41])[NH:16][C:9]4[CH:10]=[C:11]([Cl:15])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:32]=[CH:31][CH:30]=2)[CH:38]=[C:37]([CH3:39])[N:36]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nc(N)n1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc(-c2cccc(C3=Nc4cc(C)c(Cl)cc4NC(=O)C3)c2)nc(N)n1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-methyl-phenyl)-carbamic acid tert-butyl ester (Example J22) (128 mg, 0.5 mmol) and 3-[3-(2-amino-6-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K45) (180 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (108 mg).
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1)(=[O:5])[CH3:4].[CH3:19]I.O>CN(C)C=O>[CH3:19][N:6]([C:7]1[N:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1)[C:3](=[O:5])[CH3:4]
Reactant: CI
Reactant: COC(=O)/C=C/c1ccc(NC(C)=O)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)/C=C/c1ccc(N(C)C(C)=O)nc1
Reaction time: 1 h
Yield: 60.1 %

Procedure:
To a suspension of sodium hydride (60% in oil, 20.6 mg) in N,N-dimethylformamide (1 ml) was added dropwise a solution of methyl (E)-3-(6-acetylaminopyridin-3-yl)acrylate (180 mg) in N,N-dimethylformamide (2 ml) at 0° C. under nitrogen and the mixture was stirred for 1 hour. Methyl iodide (116 mg) was added to the mixture under the same condition and the mixture was stirred for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was collected by vacuum filtration and washed with diisopropyl ether to give methyl (E)-3-[6-(N-methyl-N-acetylamino)pyridin-3-yl]acrylate (115 mg) as a powder.
Reaction SMILES: C[Mg]Br.[CH:4]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][C:13]([CH3:16])=[CH:12]2)([CH3:6])[CH3:5].[Cl:17][C:18]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21].[NH4+].[Cl-]>CCOCC.C1COCC1>[CH:4]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][C:13]([CH3:16])=[C:12]2[C:20]([C:19]1[CH:23]=[CH:24][CH:25]=[C:26]([Cl:27])[C:18]=1[Cl:17])=[O:21])([CH3:6])[CH3:5]
Reactant: Cc1cc2cccc(C(C)C)c2[nH]1
Reactant: O=C(Cl)c1cccc(Cl)c1Cl
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1[nH]c2c(C(C)C)cccc2c1C(=O)c1cccc(Cl)c1Cl
Temperature: -30 °C
Reaction time: 1 h

Procedure:
120 ml of anhydrous THF are cooled to −5° C. and 36 ml of 3M methylmagnesium bromide in ether are added. The mixture is cooled to −30° C. and then 15 g of 7-isopropyl-2-methyl-1H-indole are added dropwise. The mixture is left stirring for 1 hour between −20° C. and −30° C. and then 30.9 g of 2,3-dichlorobenzoyl chloride, dissolved in 120 ml of THF, are added dropwise. The medium is left to return to AT and is then poured onto 300 ml of a saturated NH4Cl solution. Separation is carried out by settling, the organic layer is evaporated and then the residue is taken up in DCM. The organic phase is washed with a saturated NaCl solution and then it is dried and evaporated. The residue is chromatographed on silica while eluting with an AcOEt/cyclohexane (3/7, v/v) mixture.
Reaction SMILES: [CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:14]([OH:16])=O)=[N:6]2)[CH2:4][CH2:3][CH2:2]1.[NH2:17][C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:21]([CH2:31][C:32]2([OH:38])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:20][CH2:19]1.C(P(=O)(OCC)OCC)#N.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:14]([NH:17][C@H:18]3[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C@@H:21]([CH2:31][C:32]4([OH:38])[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)[CH2:20][CH2:19]3)=[O:16])=[N:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(O)c1nn(C2CCC2)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1C[C@H](N)CC[C@@H]1CC1(O)CCOCC1
Agent: CCOP(=O)(C#N)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2nn(C3CCC3)c3ccccc23)CC[C@@H]1CC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.7 %

Procedure:
The mixture of 1-cyclobutyl-1H-indazole-3-carboxylic acid (135 mg, 0.63 mmol, step 2 of Example 4), tert-butyl cis-5-amino-2-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidine-1-carboxylate (197 mg, 6.27 mmol, step 5 of Example 2), diethyl cyanophosphonate (0.13 mL, 0.75 mmol), and N,N-diisopropylethylamine (0.16 mL, 0.94 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 12 h. Then the mixture was poured onto aqueous saturated sodium hydrogencarbonate (100 mL), and the aqueous layer was extracted with ethyl acetate/toluene (3:1, 100 mL×3). The combined organic layer was concentrated under reduced pressure. The residue was chromatographed on a column of silica gel eluting with ethyl acetate/n-hexane (1:2) to give 112 mg (35%) of the title compound as a pale yellow amorphous.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:20]2[CH2:25][CH2:24][N:23]([C:26]3[N:31]=[CH:30][N:29]=[C:28]([NH2:32])[C:27]=3Br)[CH2:22][CH2:21]2)[CH2:4][CH2:3][CH2:2]1.[C:34]([O:38][C:39]([N:41]1[C:45](B2OC(C)(C)C(C)(C)O2)=[CH:44][CH:43]=[N:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].C([O-])([O-])=O.[Cs+].[Cs+]>>[C:34]([O:38][C:39]([N:41]1[C:45]([C:27]2[C:28]([NH2:32])=[N:29][CH:30]=[N:31][C:26]=2[N:23]2[CH2:24][CH2:25][CH:20]([C:8]3[N:7]([CH2:6][CH2:5][N:1]4[CH2:4][CH2:3][CH2:2]4)[CH:11]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[CH:13]=4)[N:9]=3)[CH2:21][CH2:22]2)=[CH:44][CH:43]=[N:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: Cc1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4Br)CC3)n2)ccc1F
Reactant: CC(C)(C)OC(=O)n1nccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4-c4ccnn4C(=O)OC(C)(C)C)CC3)n2)ccc1F
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The mixture of 6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-bromo-pyrimidin-4-ylamine (90.00 mg; 0.17 mmol; 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (61.75 mg; 0.21 mmol; and Cs2CO3 (114.00 mg; 0.35 mmol; in dioxane (5 ml) and water (0.5 ml) was purged with argon, and then added Pd (0) (t-Bu3)2 (6.26 mg; 0.01 mmol; 0.07 eq.). The resulting mixture was stirred at 50° C. overnight. The curde was purified by prep HPLC to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[Br:10][C:11]1[CH:16]=[C:15](F)[CH:14]=[C:13]([Cl:18])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][C:15]1[CH:14]=[C:13]([Cl:18])[CH:12]=[C:11]([Br:10])[CH:16]=1
Reactant: Fc1cc(Cl)cc(Br)c1
Reactant: Oc1cc(F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Fc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1
Temperature: 140 °C

Procedure:
To a solution of 2-chloro-5-fluorophenol (82.3 g, 562 mmol) and 1-bromo-3-chloro-5-fluorobenzene (124 g, 590 mmol) in NMP (200 mL) was added potassium carbonate (155 g, 1.123 mol). The resulting mixture was then heated to 140° C. and maintained at 140° C. for hours, after which the mixture was poured into water (1500 mL) and extracted with EtOAc (2500+1500 mL). The combined extracts were washed with water and brine. This solution was concentrated on the rotary evaporator and the residue was distilled at high vacuum at 135-190° C. to give the title compound as a clear, colorless liquid. 1H NMR (CDCl3) δ 7.45 (dd, 1H, J=9.0 and 4.5 hz), 7.28 (dd, 1H, J=1.7 Hz), 7.26 (s, 1H), 7.00 (dd, 1 h, J=1.95 Hz), 6.92 (ddd, 1H, J=10.5, 7.6 and 2.7 Hz), 6.89 (dd, 1H, J=1.95 Hz).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:25][CH2:26][CH:27]([CH2:29]O)[OH:28].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([O:22][CH2:29][CH:27]([OH:28])[CH2:26][OH:25])=[O:21])=[CH:18][CH:17]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC(O)CO
Reactant: O=C(O)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C(OCC(O)CO)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Reaction time: 120 h

Procedure:
A solution of 11.8 g. of 4-(8-cyclohexyloctylamino)benzoic acid, 1.00 g. of glycerol, and 5.35 ml. of boron trifluoride etherate in 200 ml. of toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml. of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords the product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1.C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[S:36]
Reactant: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)c1c(C)cccc1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=S)c1c(C)cccc1Cl
Temperature: 95 °C
Reaction time: 24 h

Procedure:
To a mixture of N-[(2-chloro-6-methylphenyl)carbonyl]-4-nitro-L-phenylalanine methyl ester (9.66 mmol, 3.64 g) and Lawesson's reagent (6.0 mmol, 2.46 g, 0.62 equiv.) was added toluene (15 mL, which had been stored over 4 Å molecular sieves) at room temperature. The suspension was heated to 90-100° C. and was stirred for 24 h. Examination of the resulting clear solution by TLC failed to detect the presence of starting material. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL), saturated sodium bicarbonate solution (50 mL), and brine (50 mL). The organic extract was dried (MgSO4) filtered and evaporated under reduced pressure. The crude compound was purified by careful silica gel column chromatography (hexane:ethyl acetate, 4:1 to 2:1) to obtain 1.52 g (40%) of N-[(2-chloro-6-methylphenyl)thioxomethyl]-4-nitro-L-phenylalanine methyl ester as a yellow solid, mp 150-153° C. (triturated from diethyl ether/hexane 3:1 ratio). HRMS: Obs. mass, 393.0685. Calcd. mass, 393.0677 (M+H).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CC(=O)CC>[Cl:23][CH2:22][CH2:21][CH2:20][O:12][C:9]1[CH:8]=[CH:7][C:6]([C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:5])=[CH:11][CH:10]=1
Reactant: ClCCCBr
Reactant: O=C(c1ccc(O)cc1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(c1ccc(OCCCCl)cc1)C1CC1
Temperature: 25 °C

Procedure:
Cyclopropyl(4-hydroxyphenyl)methanone (10 g, 61.7 mmol), K2CO3 (12.7 g, 91.9 mmol), and 1-bromo-3-chloropropane (10.74 g, 68.2 mmol) in 2-butanone (100 mL) were refluxed for 24 hours, allowed to cool to ambient temperature, filtered, and concentrated. The residue was heated at 40° C. under reduced pressure for three hours to provide the title compound of sufficient purity for subsequent use without further purification (13.25 g, 90%).
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[CH3:14][C:15]1([CH3:36])[C:19]([CH3:21])([CH3:20])[O:18][B:17](C2C=CC(OC3C=CC=CC=3)=CC=2C)[O:16]1>>[CH3:10][N:9]([CH3:11])[CH2:8][CH2:7][O:6][C:5]1[CH:12]=[CH:13][C:2]([B:17]2[O:18][C:19]([CH3:21])([CH3:20])[C:15]([CH3:36])([CH3:14])[O:16]2)=[CH:3][CH:4]=1
Reactant: Cc1cc(Oc2ccccc2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(C)CCOc1ccc(Br)cc1
Product: CN(C)CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1

Procedure:
Prepared from [2-(4-bromo-phenoxy)-ethyl]-dimethyl-amine according to general Method I for borylation described above for preparation of 4,4,5,5-tetramethyl-2-(2-methyl-4-phenoxy-phenyl)-[1,3,2]dioxaborolane.