Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[N+:10]([CH2:13][C:14]([C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[F:24])=[O:15])([O-:12])=[O:11].I[CH2:26][C:27]([CH2:29]I)=[CH2:28]>CN(C)C=O>[CH2:26]=[C:27]1[CH2:29][C:13]([N+:10]([O-:12])=[O:11])=[C:14]([C:16]2[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=2[F:24])[O:15][CH2:28]1
Reactant: C=C(CI)CI
Reactant: O=C(C[N+](=O)[O-])c1cc(F)c(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=C1COC(c2cc(F)c(F)cc2F)=C([N+](=O)[O-])C1
Temperature: 60 °C

Procedure:
A mixture of 3-chloro-2-(chloromethyl)prop-1-ene (1.0 g, 8 mmol) and sodium iodide (6.6 g, 44 mmol) in acetone (60 mL) was stirred at room temperature for 20 h, evaporated under reduced pressure and dissolved in dichloromethane (150 mL) and water (50 mL). The organic layer was dried over sodium sulfate, filtered and evaporated to yield 3-iodo-2-(iodomethyl)prop-1-ene as a reddish oil. N,N-diisopropylethylamine (0.20 mL) was added to a solution of 2-nitro-1-(2,4,5-trifluorophenyl)ethanone (110 mg, 0.5 mmol) in N,N-dimethylformamide (3 mL) and 3-iodo-2-(iodomethyl)prop-1-ene (170 mg, 0.55 mmol) and the mixture was heated at 60° C. for 2.5 h, evaporated and purified by chromatography on a Biotage Horizon® system (silica gel, gradient 0-30% dichloromethane in hexane) to yield 3-methylene-5-nitro-6-(2,4,5-trifluorophenyl)-3,4-dihydro-2H-pyran.
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:38])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][S:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)(=[O:30])=[O:29])[O:24][CH2:23]2)[CH:17]([CH:39]([OH:41])[CH3:40])[C:16]3=[O:42])=[O:13])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:47].O>[Pd].O1CCOCC1>[Na+:47].[F:37][C:34]1[CH:35]=[CH:36][C:31]([S:28]([CH2:27][CH:25]2[O:24][CH2:23][CH:22]([S:21][C:20]3[CH:19]([CH3:38])[CH:18]4[N:15]([C:16](=[O:42])[CH:17]4[CH:39]([OH:41])[CH3:40])[C:14]=3[C:12]([O-:13])=[O:11])[CH2:26]2)(=[O:30])=[O:29])=[CH:32][CH:33]=1
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CS(=O)(=O)c4ccc(F)cc4)C3)C(C)C12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SC3COC(CS(=O)(=O)c4ccc(F)cc4)C3)C(C)C12
Yield: 20.1 %

Procedure:
The title compound is prepared by the procedure of Example 18 using 0.821 g of product from Example 33, 0.124 g of sodium bicarbonate, 8 ml of water, 20 ml of dioxane, and 0.380 g of 10% palladium/carbon to give 0.135 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].I[CH3:15]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([CH3:15])[C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=c1[nH]ccc(Cl)c1[N+](=O)[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc(Cl)c([N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
To a stirred solution of 4-chloro-3-nitropyridin-2(1H)-one (3.0 g, 17 mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride (60% w/w, 1.0 g, 25.5 mmol) in batches at 0° C. The mixture was stirred at room temperature for 30 minutes. Then iodomethane (2.9 g, 20.4 mmol) was added dropwise to the above solution at room temperature. The resultant solution was stirred at room temperature for 12 hours. Once starting material was consumed, the reaction mixture was quenched with ice water (100 mL) at 0-10° C., and extracted with ethyl acetate (100 mL×3). The organic phase was washed with brine (100 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give 4-chloro-1-methyl-3-nitropyridin-2(1H)-one (3 g, 94%) as a yellow solid. LRMS (M+H+) m/z: calcd 188.0. found 188.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C:10]([O:12]CC)=O)=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:16][NH2:17]>C(O)C>[C:1]([C:5]1[O:9][C:8]([C:10]([NH:16][NH2:17])=[O:12])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)c1ncc(C(C)(C)C)o1
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cnc(C(=O)NN)o1
Temperature: 85 °C
Yield: 96.1 %

Procedure:
To a mixture of ethyl 5-tert-butyl-1,3-oxazole-2-carboxylate (28 g, 142 mmol) in ethanol (200 mL) is added hydrazine hydrate (7.1 g, 142 mmol). The reaction mixture is heated at 85° C. for 3 h. The solvent is evaporated and the residue is washed with n-pentane to afford the title compound (25 g, 96%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[C:6]([CH3:22])=[C:5]2[C:23]([O:25][CH3:26])=[O:24].[CH3:27][S:28]([O-:30])=[O:29].[Na+].IC>[Cu]I.O>[CH3:22][C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[N:8][C:9]2[C:4]([C:5]=1[C:23]([O:25][CH3:26])=[O:24])=[CH:3][C:2]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:11][CH:10]=2
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(Br)cc12
Reactant: CS(=O)[O-]
Agent: [Cu]I
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Temperature: 120 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
Methyl 6-bromo-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (50 g, 118 mmol) was combined with copper(I) iodide (44.9 g, 236 mmol) and sodium methylsulfinate (24.07 g, 236 mmol) in a 2 L round bottom flask and the vessel was purged with N2 (3×). The solids were suspended in dimethyl sulfoxide (400 mL), the atmosphere was exchanged for nitrogen (3×Vac/N2 purges), and the reaction was heated to 120° C. overnight. The reaction was cooled to 50° C., and iodomethane (50.2 g, 354 mmol) was added. The reaction was stirred for 2 hours at 50° C. and cooled to RT. The crude reaction mixture was added slowly 1 L of water with stirring over 30 minutes. The resulting yellow slurry was filtered through a buchner funnel. The filter cake was washed with 3×500 mL water and dried overnight. The solids were suspended in 625 mL CH2Cl2, and the suspension was stirred for ca. 30 min. The solids were purified by flash chromatography eluting with 100% CH2Cl2→40% EtOAc/CH2Cl2. Fractions containing the product were further purified by trituration with MeOH. Mixed fractions were repurified using the same conditions and combined with the previously isolated solid to provide 31.9 g (64%) of the product as a white solid. MS (m/z) 423.7 (M+H+).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[C:13](C(OCC)=O)[C:12]2=[O:28])=[CH:2]1>CN(C)C=O.C(Cl)(Cl)Cl>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:28])[CH:13]=[C:14]([NH:16][CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[O:15]2)=[CH:2]1
Reactant: CCOC(=O)C1=C(NCc2cccs2)OC(=Cc2c[nH]c3ncccc23)C1=O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C1C=C(NCc2cccs2)OC1=Cc1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 22.6 %

Procedure:
A solution of the compound (0.10 g, 0.26 mmol) of Example 60 in N,N-dimethylformamide (0.80 mL) was refluxed for 16 h. Cooled to ambient temperature, the reaction mixture was diluted with chloroform and the precipitate was collected by filtration. The solid was washed with chloroform/methanol (10/1) and hexane then dried to afford the titled compound as solid (0.019 g, y. 22%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:31][O:32][C:33]1[C:34](=[O:57])[C:35]([CH3:56])=[C:36]([CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:52][C:53](=[O:55])[CH3:54])=[C:47]([CH:51]=2)[C:48](O)=[O:49])[C:37](=[O:41])[C:38]=1[O:39][CH3:40]>C(Cl)Cl>[CH3:31][O:32][C:33]1[C:34](=[O:57])[C:35]([CH3:56])=[C:36]([CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:52][C:53](=[O:55])[CH3:54])=[C:47]([CH:51]=2)[C:48]([NH:10][C:9]2[CH:11]=[CH:12][C:6]([S:3]([C:2]([F:13])([F:1])[F:14])(=[O:4])=[O:5])=[CH:7][CH:8]=2)=[O:49])[C:37](=[O:41])[C:38]=1[O:39][CH3:40]
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(S(=O)(=O)C(F)(F)F)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.1 %

Procedure:
4-(Trifluoromethylsulfonyl)aniline (0.452 g, 2.005 mmol), triethylamine (0.203 g, 2.005 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.339 g, 2.005 mmol) were added to a methylene chloride solution (70 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.250 g, 0.668 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.140 g, 0.241 mmol, 36%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]1[CH2:22][C@H:21]1[CH2:23][OH:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].C1COCC1>O>[CH3:25][S:26]([O:24][CH2:23][C@@H:21]1[CH2:22][C@H:20]1[CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:28])=[O:27]
Reactant: CC(C)(C)[Si](OC[C@@H]1C[C@H]1CO)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](OC[C@@H]1C[C@H]1COS(C)(=O)=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
TEA (0.450 mL, 3.23 mmol) was added to a mixture of trans-(2-((tert-butyldiphenylsilyloxy)methyl)cyclopropyl)methanol (1 g, 2.94 mmol), methanesulfonyl chloride (0.250 mL, 3.23 mmol) and THF (10 mL) at 0° C., and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give trans-(2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl methanesulfonate (1.230 g, 2.94 mmol, 100%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:17][CH:18]([O:24][CH:25]([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]=[CH:14][C:15]=1[OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:35])C(=O)C1>C(#N)C.C(OCC)(=O)C>[Br:35][C:14]1[CH:13]=[C:12]([CH2:17][CH:18]([O:24][CH:25]([CH3:26])[CH3:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:11]=[C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:15]=1[OH:16]
Reactant: CCOC(=O)C(Cc1ccc(O)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(Cc1cc(Br)c(O)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
402 mg of ethyl 3-(3-[(tertiary butoxycarbonyl)amino]methyl-4-hydroxyphenyl)-2-isopropoxypropionate was dissolved in 5 ml acetonitrile, and 200 mg N-bromosuccimide was added. After stirring at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate. The organic layer was successively washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was purified by silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (5:1), 433 mg of ethyl 3-(3-bromo-5-[(tertiary butoxycarbonyl)amino]methyl-4-hydroxyphenyl)-2-isopropoxypropionate was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:64])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[C:57]([CH3:63])=[N:58][C:59](Cl)=[CH:60][CH:61]=1)(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1>>[CH3:1][O:2][C:3](=[O:64])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:41][CH:42]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[C:57]([CH3:63])=[N:58][C:59]([N:65]2[CH2:70][CH2:69][O:68][CH2:67][CH2:66]2)=[CH:60][CH:61]=1)(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1ccc(Cl)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: C1COCCN1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1ccc(N2CCOCC2)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(S)-7-(6-Chloro-2-methyl-pyridine-3-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (30 mg) was treated with morpholine according to General Procedure U to give (S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-(2-methyl-6-morpholin-4-yl-pyridine-3-sulfonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]amino}-propionic acid methyl ester (24 mg).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33](O)=[O:34])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:18]([C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][C:33]([NH:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:9]=[CH:10]3)=[O:34])=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc2c(cnn2CCN2CCCC2)c1
Reactant: O=C(O)CCc1ccc(Oc2ccccc2)cc1
Product: O=C(CCc1ccc(Oc2ccccc2)cc1)Nc1ccc2c(cnn2CCN2CCCC2)c1

Procedure:
1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-ylamine and 3-(4-phenoxy-phenyl)-propionic acid were processed as described in Example 17 to provide the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 1.83 (m, 2 H), 1.99 (m, 2 H), 2.60 (t, J=7.64 Hz, 2 H), 2.87 (t, J=7.49 Hz, 2 H), 3.04 (m, 2 H), 3.52 (m, 2 H), 3.70 (m, 2 H), 4.73 (t, J=6.08 Hz, 2 H), 5.06 (s, 2 H), 6.92 (m, 2 H), 7.17 (m, 2 H), 7.32 (m, 1 H), 7.40 (m, 4 H), 7.49 (m, 1 H), 7.66 (m, 1 H), 8.13 (m, 2 H), 9.93 (s, 1 H); MS (DCI/NH3) m/z 469 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH:10]([C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1)[CH2:11][C:12]([C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)=O.CC(O)=O.C[N:34](C)C=O>>[O:25]1[C:22]2[CH:23]=[CH:24][C:19]([C:10]3[CH:11]=[C:12]([C:14]4[CH:18]=[CH:17][S:16][CH:15]=4)[N:34]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[OH:1])[CH:9]=3)=[CH:20][C:21]=2[O:27][CH2:26]1
Reactant: O=C(CC(CC(=O)c1ccccc1O)c1ccc2c(c1)OCO2)c1ccsc1
Reactant: CN(C)C=O
Solvent: CC(=O)O
Product: Oc1ccccc1-c1cc(-c2ccc3c(c2)OCO3)cc(-c2ccsc2)n1
Temperature: 100 °C

Procedure:
A mixture of 1-(2-hydroxyphenyl)-3-(3,4-methylenedioxyphenyl)-5-(thiophen-3-yl)-1,5-pentanedione on Wang resin (2.0 g, 1.76 mmol), NH4OAc (1.0 g), and AcOH (1.5 mL) in dimethylformamide (40 mL) was heated at 100° C. for 18 h. The resin was filtered, and washed with dimethylformamide (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight. The dried resin was treated with 50% TFA/CH2Cl2 (15 mL) for 1 h. After filtration of the reaction mixture, the filtrate was concentrated to dryness. The residue was repeatedly dissolved in CH2Cl2 (10 mL) and concentrated to remove traces of TFA. Purification by flash chromatography gave 2-(4-benzo[1,3]dioxol-5-yl-6-thiophen-3-yl-pyridin-2-yl)-phenol; mp 120-121° C.; 1H NMR (DMSO-d6) d 6.15 (s, 2 H), 6.97 (m, 2 H), 7.13 (d, j=8.2 Hz, 1 H), 7.35 (m, 1 H), 7.66 (dd, J=8.2, 1.9 Hz, 1 H), 7.80 (m, 3 H), 8.16 (d, J=1.1 Hz, 1 H), 8.31 (m, 2 H), 8.37 (dd, J=2.9, 1.4 Hz, 1 H), 14.58 (s, 1 H); IR (KBr) 1602 cm−1; MS [M+H]+m/z=374. Anal. calcd for C22H15NO3S: C, 70.76; H, 4.05; N, 3.75; Found: C, 70.66; H, 4.02; N, 3.59.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O.C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1/[CH:12]=[CH:19]/[C:20]([OH:22])=[O:21]
Reactant: O=Cc1ccccc1Sc1ccc(Cl)cc1Cl
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1ccccc1Sc1ccc(Cl)cc1Cl
Temperature: 110 °C
Yield: 90.6 %

Procedure:
A mixture of the aldehyde (1.50 g, 5.3 mmol) from Example 1A, malonic acid (1.21 g, 11.6 mmol), piperidine (78.6 μL, 0.80 mmol) in 8.0 mL of anhydrous pyridine was heated at 110° C. for 2 hours. Gas evolution ceased during this period. Pyridine was then removed under vacuum. Water and 3N aq. HCl were then added with stirring. The desired cinnamic acid was then collected through filtration, washed with cold water and dried in a vacuum oven overnight to give 1.56 g (4.8 mmol, 91%) of white solid.
Reaction SMILES: [CH2:1]([CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16](C3N=CC(O)=CN=3)[CH:17]=2)C1)[CH2:2][CH2:3]CCCCCCC.C(C1C=CC(C2C=CC3C(=CC=C(O)C=3)N=2)=CC=1)CCCC.[C:49]1([CH3:68])[CH:54]=[CH:53][C:52]([S:55]([O:58]CCCC2C=CC=CC=2)(=[O:57])=[O:56])=[CH:51][CH:50]=1>>[C:49]1([CH3:68])[CH:50]=[CH:51][C:52]([S:55]([O:58][CH2:3][CH2:2][CH2:1][CH2:11][CH2:19][C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:56])=[O:57])=[CH:53][CH:54]=1
Reactant: CCCCCCCCCCC1Cc2ccc(-c3ncc(O)cn3)cc2C1
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccccc2)cc1
Agent: CCCCCc1ccc(-c2ccc3cc(O)ccc3n2)cc1
Product: Cc1ccc(S(=O)(=O)OCCCCCc2ccccc2)cc1
Yield: 58.3 %

Procedure:
An objective product was prepared in the same manner as in Example 2 except that 2-(2-decylindan-5-yl)pyrimidine-5-ol was changed to 2-(4-pentylphenyl)quinoline-6-ol and 3-phenylpropyl p-toluenesulfonate was changed to 5-phenylpentyl p-toluenesulfonate (Yield: 58.3%).
Reaction SMILES: [H-].[Na+].C([O:10][C:11](=O)[NH:12][C@@H:13]([C@@H:27]([F:30])[CH2:28][CH3:29])[CH2:14][NH:15][C:16]1[C:21]([F:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=1)C1C=CC=CC=1.O>C1COCC1>[F:30][C@H:27]([C@H:13]1[CH2:14][N:15]([C:16]2[C:21]([F:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=2)[C:11](=[O:10])[NH:12]1)[CH2:28][CH3:29]
Reactant: CC[C@H](F)[C@@H](CNc1ncc(C(F)(F)F)cc1F)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@H](F)[C@H]1CN(c2ncc(C(F)(F)F)cc2F)C(=O)N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
Sodium hydride (about 60%, 546 mg) was added to a solution of benzyl[(2R,3S)-3-fluoro-1-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]amino}pentan-2-yl]carbamate (2.85 g) in THF (35 mL), and the mixture was stirred at room temperature for 6 hr. Water was added to the reaction mixture, the resulting mixture was extracted with ethyl acetate, and the organic layer was washed with brine. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel cartridge, hexane/ethyl acetate=80:20-40:60) to afford the title compound (2.07 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@H:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][C@H:9]1[CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31]1(=[O:41])[C:35]2([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:34][CH2:33][O:32]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:20][C@H:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@H:12]1[CH2:11][CH2:10][C@@H:9]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([N:38]3[CH2:39][CH2:40][C:35]4([C:31](=[O:41])[O:32][CH2:33][CH2:34]4)[CH2:36][CH2:37]3)=[O:27])=[CH:24][CH:23]=2)[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: O=C1OCCC12CCNCC2
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)N3CCC4(CCOC4=O)CC3)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a solution of 30 mg (0.07 mmol) 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid (i-1) in 1 ml anhydrous DMF at ambient temperature was added 20 mg (0.1 mmol) 2-oxa-8-azaspiro[4.5]decan-1-one, followed by 20 mg (0.1 mmol) EDCl, 15 mg (0.10 mmol) HOBt, and 0.070 ml (0.35 mmol) diisopropylethylamine. The solution was stirred for 2 h. It was then filtered and purified by reverse-phase HPLC (TMC Pro-Pac C18; 35-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). The pure fractions were lyophilized overnight to give 28 mg (70%) of the title compound as a white solid. LC/MS 549.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](N)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.N(OC(C)(C)C)=O.C(Br)(Br)[Br:20]>>[Br:20][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)[NH:8][N:9]=1
Reactant: Nc1n[nH]c2ncc(F)cc12
Reactant: BrC(Br)Br
Agent: CC(C)(C)ON=O
Product: Fc1cnc2[nH]nc(Br)c2c1
Temperature: 61 °C

Procedure:
To a mixture of 5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine, 132a, (0.88 g, 5.79 mmol) in bromoform (8.8 mL) was added tert-butyl nitrite (1.38 mL, 11.57 mmol). This mixture was heated to 61° C. for 1 h and then heated to 90° C. for an additional hour. The mixture was cooled to room temperature and bromoform was removed under reduced pressure. The resulting crude residue was purified by silica gel chromatography (5-50% ethyl acetate/hexanes) to afford 970 mg of the desired product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 14.22 (s, 1H), 8.67 (dd, J=2.7, 1.9 Hz, 1H), 8.07 (dd, J=8.2, 2.7 Hz, 1H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.42 minutes (M+H) 216.11.
Reaction SMILES: [H][H].[NH2:3][C:4]1[C:9]([N+:10]([O-])=O)=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[C:16]([F:27])[CH:15]=2)[CH:7]=[CH:6][N:5]=1>C(O)C.CCOC(C)=O.[Pd]>[NH2:3][C:4]1[C:9]([NH2:10])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:26])[C:22]([F:23])([F:24])[F:25])=[C:16]([F:27])[CH:15]=2)[CH:7]=[CH:6][N:5]=1
Reactant: [H][H]
Reactant: Nc1nccc(Oc2ccc(NC(=O)C(F)(F)F)c(F)c2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1nccc(Oc2ccc(NC(=O)C(F)(F)F)c(F)c2)c1N
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Method D2 (using hydrogen). N-(4-(2-amino-3-nitropyridin-4-yl-oxy)-2-fluorophenyl)-2,2,2-trifluoroacetamide (540 mg, 1.5 mmol) was dissolved in ethanol (15 mL) and AcOEt (5 mL). Palladium 10% on activated carbon (150 mg) was added and the reaction mixture was stirred for 2 hours under hydrogen atmosphere. The catalyst was filtered off and the filtrate evaporated to afford the title compound (490 mg, 100%). 1H-NMR (δ, ppm, DMSO-d6): 4.65 (s, 2H, NH2,Py3), 5.86 (s, 2H, NH2,Py2), 6.23 (d, 1H, HPy,6, J=5.71 Hz), 6.85 (d, 1H, Harom,Ph, J=8.80 Hz), 7.01 (d, 1H, Harom,Ph, J=11.51 Hz), 7.32 (d, 1H, HPy,5, J=5.71 Hz), 7.45 (t, 1H, Harom,Ph, J=8.76 hz), 11.37 (s, 1H, NHCOCF3).