Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[C:21]([O:22]C)=[CH:20][N:19]=[CH:18][C:17]=2[O:24][CH3:25])=[CH:10][CH:9]=[CH:8][N:7]=1.Cl.N1C=CC=CC=1>C(=O)([O-])O.[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[C:17]([O:24][CH3:25])=[CH:18][N:19]=[CH:20][C:21]=2[OH:22])=[CH:10][CH:9]=[CH:8][N:7]=1.[Br:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[C:17]([OH:24])=[CH:18][N:19]=[CH:20][C:21]=2[OH:22])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: COc1cncc(OC)c1CCCOc1cccnc1Oc1cccc(Br)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1cncc(O)c1CCCOc1cccnc1Oc1cccc(Br)c1
Product: Oc1cncc(O)c1CCCOc1cccnc1Oc1cccc(Br)c1
Temperature: 180 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2-(3-bromophenoxy)-3-[3-(3,5-dimethoxypyridin-4-yl)propoxy]pyridine (3.15 g, 7.1 mmol) obtained in Example 19 and pyridine hydrochloride (8.0 g) is stirred at 180° C. for 1.5 hours. After being allowed to cool, to the mixture is added a saturated aqueous sodium hydrogen carbonate solution (100 ml), and the mixture is extracted with ethyl acetate (100 ml×3). The organic layer is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform/methanol) to give 2-(3-bromophenoxy)-3-[3-(3-hydroxy-5-methoxypyridin-4-yl)propoxy]pyridine and 2-(3-bromophenoxy)-3-[3-(3,5-dihydroxypyridin-4-yl)propoxy]pyridine, which are individually treated with fumaric acid to give 2-(3-bromophenoxy)-3-[3-(3-hydroxy-5-methoxypyridin-4-yl)propoxy]pyridine.0.5 fumarate (1.00 g) [m.p. 157-161° C. (recrystallized from ethanol/diethyl ether)] and 2-(3-bromophenoxy)-3-[3-(3,5-dihydroxypyridin-4-yl)propoxy]pyridine.0.5 fumarate (1.36 g) [m.p. 184-189° C. (recrystallized from ethanol)], respectively.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].[NH:62]1[CH2:66][CH2:65][CH2:64][CH2:63]1>O1CCCC1.C(OCC)C.O>[N:62]1([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[C:5]#[N:6])[CH2:66][CH2:65][CH2:64][CH2:63]1
Reactant: N#Cc1cccc(Br)c1
Reactant: C1CCNC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#Cc1cccc(N2CCCC2)c1
Temperature: 80 °C
Yield: 5.2 %

Procedure:
A reaction mixture of 3-bromo-benzonitrile (0.91 g, 5 mmol), tris(dibenzylidenecetone)-dipalladium (229 mg), (S)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (311 mg, 0.5 mmol), sodium tert-butoxide (740 mg, 7.7 mmol), pyrrolidine (0.58 mL, 6.9 mmol) in tetrahydrofuran (10 mL) was heated at 80° C. in a sealed tube for 6 h. The reaction mixture was worked up with water and diethyl ether. The organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 0-5% ethyl acetate in hexanes yielded 3-pyrrolidin-1-yl-benzonitrile (45 mg, 5%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])[C:5]([NH2:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH:41]=[CH:40][C:30]([O:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:29][CH:28]=2)O1>>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[CH2:10][O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:27]2[CH:41]=[CH:40][C:30]([O:31][CH2:32][CH2:33][N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:29][CH:28]=2)[CH:3]=1
Reactant: Nc1ncc(Br)cc1OCc1c(Cl)cccc1Cl
Reactant: CC1(C)OB(c2ccc(OCCN3CCOCC3)cc2)OC1(C)C
Product: Nc1ncc(-c2ccc(OCCN3CCOCC3)cc2)cc1OCc1c(Cl)cccc1Cl

Procedure:
3-(2,6-Dichloro-benzyloxy)-5-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-pyridin-2-ylamine was prepared from 5-bromo-3-(2,6-dichloro-benzyloxy)-pyridin-2-ylamine (example I(a)) and 4-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-ethyl}-morpholine (prepared in part 1) following procedure 3 as a white solid.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([CH3:16])=[C:11]([CH2:17][CH3:18])[N:10]=1.[CH3:19][CH:20]1[C:25]2[S:26][CH:27]=[CH:28][C:24]=2[CH2:23][CH2:22][NH:21]1>CN(C)C=O>[CH3:16][C:12]1[C:13]([N:21]2[CH2:22][CH2:23][C:24]3[CH:28]=[CH:27][S:26][C:25]=3[CH:20]2[CH3:19])=[N:14][C:9]([Cl:8])=[N:10][C:11]=1[CH2:17][CH3:18]
Reactant: CCc1nc(Cl)nc(Cl)c1C
Reactant: CC1NCCc2ccsc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1nc(Cl)nc(N2CCc3ccsc3C2C)c1C
Yield: 51.4 %

Procedure:
In accordance with the same procedure as in Step 1 of Example 1, except that triethylamine(2.2 ml), N,N-dimethyl formamide(20 ml), 2,4-dichloro-5-methyl-6-ethylpyrimidine (2.7 g, 14.1 mmol) prepared in Preparation 4 and 7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine(2.4 g, 15.7 mmol) prepared in Preparation 1 were used as starting materials, 2.23 g of the titled compound was prepared. (Yield: 51.3%)
Reaction SMILES: Cl.[F:2][CH:3]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[CH3:22][O:23][C:24]1[CH:31]=[C:30]([CH2:32][CH:33]=O)[CH:29]=[CH:28][C:25]=1[C:26]#[N:27].C([BH3-])#N.[Na+].CO>CC(O)=O>[F:2][CH:3]([C:11]1[CH:20]=[CH:19][C:14]2[C:15](=[O:18])[O:16][CH2:17][C:13]=2[C:12]=1[CH3:21])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:33][CH2:32][C:30]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([O:23][CH3:22])[CH:31]=2)[CH2:7][CH2:6]1
Reactant: Cc1c(C(F)CN2CCNCC2)ccc2c1COC2=O
Reactant: COc1cc(CC=O)ccc1C#N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(CCN2CCN(CC(F)c3ccc4c(c3C)COC4=O)CC2)ccc1C#N
Reaction time: 12 h

Procedure:
5-(1-Fluoro-2-piperazin-1-ylethyl)-4-methyl-2-benzofuran-1(3H)-one hydrochloride (30 mg, 0.11 mmol), 2-(methyloxy)-4-(2-oxoethyl)benzonitrile (37 mg, 0.22 mmol), sodium cyanoborohydride (67 mg, 1.078 mmol) were added to a 25 mL flask containing a stir bar; to the flask was added MeOH (3 mL) and few drops of AcOH. The reaction mixture was subsequently stirred for 12 h r; LC indicated that reaction had gone to completion. The solution was concentrated to dryness, redissolved in EtOAc (15 mL) and washed with aq. NaHCO3 and aq. NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to dryness. It was then re-dissolved in MeOH (3.5 mL) again, filtered and shot into mass-directed HPLC for separation to give the desired product. LC-MS (IE, m/z): 450 [M+1]+.
Reaction SMILES: C(N(CC)CC)C.[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C(Cl)Cl.[N:19]1([CH2:29][CH2:30][OH:31])[C@H:28]2[C@@H:23]([CH2:24][CH2:25][CH2:26][CH2:27]2)[NH:22][CH2:21][CH2:20]1>O>[Si:8]([O:31][CH2:30][CH2:29][N:19]1[C@H:28]2[C@@H:23]([CH2:24][CH2:25][CH2:26][CH2:27]2)[NH:22][CH2:21][CH2:20]1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: OCCN1CCN[C@@H]2CCCC[C@H]21
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCN1CCN[C@@H]2CCCC[C@H]21
Yield: 71 %

Procedure:
Triethylamine (4.61 mL, 33.0 mmol) and subsequently tert-butyldimethylsilyl chloride (4.27 g, 28.3 mmol) were added to a methylene chloride (40 mL) solution of 2-(trans -decahydroquinoxalin-1-yl)ethanol (1.74 g, 9.44 mmol) with ice-cooling and stirring, and the mixture was stirred overnight at room temperature. To the reaction mixture, water (100 mL) was added to terminate the reaction. The product was extracted with methylene chloride (100 mL). The organic layer was washed with water twice and with saturated saline once, then dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride/methanol) to obtain trans-1-[2-(tert-butyldimethylsilyloxy)ethyl]decahydroquinoxaline (2.00 g, yield: 71%) in a light brown oil form.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[S:10][C:11]=2[C:12]([O:14][CH2:15]C)=[O:13])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:33])C=1.C(Cl)Cl.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][N+:20]([O-:33])=[CH:19][CH:18]=3)[S:10][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1sc(-c2cc[n+]([O-])cc2)nc1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.7 %

Procedure:
To a solution of ethyl 4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboxylate (430 mg, 1.20 mmol) in DMF (6.0 mL) was added mCPBA (322 mg, 1.44 mmol) and the mixture was stirred at room temperature overnight. To the reaction was added DCM (30 mL) and saturated sodium bicarbonate (25 mL). The layers were separated and the aqueous layer extracted with DCM (20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=50/50→100/0) to give 449 mg of the title compound as a white solid (100% yield). LC/MS (FA) ES+ 375. 1H NMR (300 MHz, CDCl3) δ: 8.23-8.20 (m, 2H), 7.84-7.81 (m, 2H), 7.33-7.23 (m, 4H), 4.51 (s, 2H), 4.38 (q, 2H, J=7.2 Hz), 1.39 (t, 3H, J=7.2 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]1[C:6]([CH:7]=[CH:8][CH:9]=[C:10]1[C:16]([OH:18])=O)=[N:5]2.[NH2:19][CH2:20][CH2:21][N:22]([CH2:33][CH3:34])[CH2:23][CH2:24][O:25][C:26]1[C:27]([F:32])=[N:28][CH:29]=[CH:30][CH:31]=1>S(Cl)(Cl)=O.ClCCl>[CH2:33]([N:22]([CH2:21][CH2:20][NH:19][C:16]([C:10]1[C:11]2[C:6](=[N:5][C:4]3[C:13]([N:12]=2)=[CH:14][CH:15]=[C:2]([Br:1])[CH:3]=3)[CH:7]=[CH:8][CH:9]=1)=[O:18])[CH2:23][CH2:24][O:25][C:26]1[C:27]([F:32])=[N:28][CH:29]=[CH:30][CH:31]=1)[CH3:34]
Reactant: CCN(CCN)CCOc1cccnc1F
Reactant: O=C(O)c1cccc2nc3cc(Br)ccc3nc12
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCN(CCNC(=O)c1cccc2nc3cc(Br)ccc3nc12)CCOc1cccnc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.5 %

Procedure:
A solution of 7-bromophenazine-1-carboxylic acid (81) (333 mg, 1.10 mmol) (Madelmont, J. C.; Chezal, J. M.: Moins, N.; Teulade, J. C.; Chavignon, O. Labelled analogues of halobenzamides as radiopharmaceuticals, WO 2008/012782A3) in thionyl chloride (8 mL) was refluxed, under argon, for 1 h. After cooling to room temperature, the solvent was evaporated under reduce pressure and the residue was dissolved in anhydrous toluene (5 mL). The solvent was evaporated under vacuum and the residue was dissolved in anhydrous dichloromethane (11 mL). A solution of compound 5 (300 mg, 1.32 mmol) in anhydrous dichloromethane (5 mL) was added, at 0° C. and the mixture was then stirred at room temperature for 24 h. The solvent was evaporated under reduce pressure and the residue was chromatographed (Al2O3, AcOEt) to give compound 82 (537 mg, 1.05 mmol) as a yellow oil. Yield 95%; Rf (Al2O3, AcOEt) 0.69; IR (CCl4) ν 1190, 1249, 1283, 1466, 1517, 1663, 2800-3000, 3250-3350 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.09 (t, 3H, J=7.1 Hz), 2.80 (q, 2H, J=7.1 Hz), 2.86 (t, 2H, J=6.0 Hz), 3.00 (t, 2H, J=5.5 Hz), 3.70 (q, 2H, J=6.0 Hz), 4.04 (t, 2H, J=5.5 Hz), 6.75 (ddd, 1H, 5JH-F=0.8 Hz, J=4.8, 7.9 Hz), 6.93 (ddd, 1H, 4JH-F=10.1 Hz, J=1.5, 7.9 Hz), 7.45 (td, 1H, 4JH-F=1.5 Hz, J=1.5, 4.8 Hz), 7.71 (dd, 1H, J=2.0, 9.2 Hz), 7.82 (dd, 1H, J=7.1, 8.7 Hz), 7.89 (d, 1H, J=9.2 Hz), 8.15 (dd, 1H, J=1.5, 8.7 Hz), 8.23 (d, 1H, J=2.0 Hz), 8.84 (dd, 1H, J=1.5, 7.1 Hz), 10.79 (m, 1H); ESI-MS m/z 512.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH2:21][CH:20]=3)=[CH:18][C:13]=2[O:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+]>>[O:10]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:30][CH2:29][N:28]([CH2:4][C:3]5[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=5[Cl:1])[CH2:27][CH2:26]4)[CH2:21][CH:20]=3)=[CH:18][C:13]=2[O:12][CH2:11]1
Reactant: C1=C(c2ccc3c(c2)OCO3)CCC(N2CCNCC2)C1
Reactant: ClCc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccccc1CN1CCN(C2CC=C(c3ccc4c(c3)OCO4)CC2)CC1

Procedure:
The title compound was prepared from 2-chlorobenzyl-chloride (0.16 g, 1 mmole), 1-[4-(1,3-benzodioxol-5-yl)-3-cyclohexen-1-yl]piperazine (0.29 g, 1 mmole), and excess powdered K2CO3 as described in example 45 to give the product (78%, mp: 115-116° C.). Calc'd for C24H27ClN2O2 : C, 70.14%; H, 6.62%; N, 6.82%. Found: C, 70.25; H, 6.69%; N, 6.83%.
Reaction SMILES: [Cl:1][C:2]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C@@H:5]1[CH3:18])=[O:3].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][OH:23]>>[ClH:1].[CH3:18][C@H:5]1[CH2:6][NH:7][CH2:8][C@@H:9]([CH3:10])[N:4]1[C:2]([O:23][CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=1[Cl:19])=[O:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Reactant: OCc1ccccc1Cl
Product: C[C@@H]1CNC[C@H](C)N1C(=O)OCc1ccccc1Cl
Product: Cl

Procedure:
2-Chlorobenzyl cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared from cis 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and 2-chloro-benzyl alcohol according to the methods described for Examples 52 and 54 to give the product as a white solid (0.0901 g, 14% overall); νmax (nujol)/cm−1 3375, 2689, 2577, 1699, 1592, 1380, 1328, and 1300; δH (400 MHz, DMSO-d6) 9.62 (2 H, br), 7.50 (2 H, m), 7.40 (2 H, m), 5.19 (2 H, s), 4.33 (2 H, m), 3.18–3.06 (4 H, m), and 1.31 (6 H, d, J 7.2).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[N+:15]([O-])([OH:17])=[O:16].O>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=1)[CH3:6])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(C)c1ccc(O)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(4-hydroxy-phenyl)-propionic acid ethyl ester (9.02 g) in acetic acid (75 mL) was added nitric acid (60%, 5.24 g in AcOH) at room temperature. The reaction mixture was stirred for 30 minutes at room temperature and added water. The mixture was extracted with EtOAc and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (n-Hex:EtOAc=10:1) to afford the product as yellow oil. (9.71 g)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:37])=[C:4]([C:29]2[CH:30]=[CH:31][C:32]([C:35]#N)=[N:33][CH:34]=2)[C:5]([O:26][CH2:27][CH3:28])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3C2CCCCO2)[CH3:9])[CH:7]=1.[OH-:38].[Na+].[OH2:40].Cl>C(O)C>[Cl:1][C:2]1[C:3]([F:37])=[C:4]([C:29]2[CH:30]=[CH:31][C:32]([C:35]([OH:40])=[O:38])=[N:33][CH:34]=2)[C:5]([O:26][CH2:27][CH3:28])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH3:9])[CH:7]=1
Reactant: O
Reactant: [OH-]
Reactant: CCOc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(F)c1-c1ccc(C#N)nc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(F)c1-c1ccc(C(=O)O)nc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A solution of 5-[3-chloro-6-ethoxy-2-fluoro-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]pyridine-2-carbonitrile (0.070 g, 0.13 mmol) in ethanol (1.2 mL) was treated with 3 M sodium hydroxide in water (0.6 mL, 2 mmol) and stirred at 90° C. for 4 h in a sealed tube. The reaction mixture was cooled to 0° C., quenched with 12 M HCl in water (0.1 mL, 2 mmol), and stirred at 20° C. for 30 minutes. The reaction mixture was treated with additional 12 M HCl in water (0.2 mL, 2 mmol) and stirred at 20° C. for 15 minutes. The reaction mixture was concentrated to give the desired product (61 mg, quantitative) which was used without further purification. LCMS for C21H19ClFN6O3 (M+H)+: m/z=457.1. Found: 457.1.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[CH2:15][C:16]1[CH:17]=[N:18][C:19]([N:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[N:20][CH:21]=1.CCOC(C)=O>CN(C=O)C>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH2:15][C:16]1[CH:17]=[N:18][C:19]([N:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])=[N:20][CH:21]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(CBr)cn1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1)C(=O)OCC
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
A solution of diethyl malonate (0.704 mL, 4.64 mmol) in DMF (2 mL) was added dropwise to a suspention of NaH (200 mg, 4.64 mmol, 55% in mineral oil) in DMF (4 mL) at 0° C. under argon. The reaction mixture was stirred for 30 min and a solution of 5-bromomethyl-2-[N,N-bis(tert-butoxycarbonyl)amino]-pyrimidin (1.5 g, 3.86 mmol) in DMF (4 mL) was added dropwise. The mixture was stirred at room temperature for 3 h. EtOAc was added and the solution was washed with water and brine, dried and concentrated under reduced pressure. Flash chromatography (heptane/EtOAc, 3:2) gave 2-(2-[N,N-bis(tert-butoxycarbonyl)amino]-pyrimidin-5-ylmethyl)-malonic acid diethyl ester (0.87 g, 40%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)=[CH:8]2)=[O:4].CO.C1COCC1>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ccc2[nH]c(-c3ccc([N+](=O)[O-])cc3)cc2c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc2[nH]c(-c3ccc(N)cc3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
An oven dried 2L round bottom flask with magnetic stirbar under argon was charged with 2-(4-Nitro-phenyl)-1H-indole-5-carboxylic acid methyl ester (9.33 g, 31.52 mmol), methanol (600 mL), and THF (300 mL). The palladium catalyst (3.358, 10% wt, 3.152 mmol) was carefully added in portions then acetic acid (2 ml) was added. The mixture was evacuated then a balloon filled with H2 (g) was placed over the mixture. The reaction mixture was stirred at room temperature overnight. The mixture was filtered through a pad of celite. The celite pad was washed with ethyl acetate. The filtrate was concentrated to about 250 ml then filtered through a plug of silica gel and eluted with 70% Ethyl acetate:30% Hexanes then with ethyl acetate. The filtrate was concentrated and slurried in about 70 ml boiling methanol. The crude product was then purified on silica gel using 7:3 ethylacetate:hexanes as eluant to give 4.5 g of the pure product. Yield (4.5 g, 53.7%)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[N:12][C:11]=1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22]>>[CH2:1]([O:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[N:12][C:11]=1[C:26]1[CH:27]=[CH:28][C:23]([C:21]([O:20][CH3:19])=[O:22])=[CH:24][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(C(=O)OCc2ccccc2)c(Cl)n1
Product: COC(=O)c1ccc(-c2nc(C)ccc2C(=O)OCc2ccccc2)cc1
Yield: 81.8 %

Procedure:
2-Chloro-6-methylnicotinic acid benzyl ester (1.0 g) and 4-methoxycarbonylphenylboronic acid (722 mg) were treated in a similar manner to Step b) of Reference Example 1 to give the title compound (1.13 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:5]=1[C:19]1[N:23]([C@H:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[N:22]=[CH:21][C:20]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])([O-:3])=[O:2].Br[C:35]1[C:36]([CH3:45])=[N:37][C:38]([O:42][CH2:43][CH3:44])=[CH:39][C:40]=1[CH3:41].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:43]([O:42][C:38]1[N:37]=[C:36]([CH3:45])[C:35]([C:8]2[CH:7]=[CH:6][C:5]([C:19]3[N:23]([C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)[N:22]=[CH:21][C:20]=3[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=2)=[C:40]([CH3:41])[CH:39]=1)[CH3:44]
Reactant: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1ccc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Reactant: CCOc1cc(C)c(Br)c(C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cnn([C@H]2CCOC2)c1-c1ccc(-c2c(C)cc(OCC)nc2C)cc1[N+](=O)[O-]

Procedure:
Ethyl 5-[2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl][(S)-tetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate obtained in Preparation Example 7-(2) (200 mg) was dissolved in a mixed solution of 1,4-dioxane (4 mL) and water (1 mL). 3-bromo-6-ethoxy-2,4-dimethylpyridine obtained in Preparation Example 51 (121 mg), Pd(PPh3)4 (25 mg) and cesium carbonate (428 mg) were added, and the mixture was reacted using a microwave reactor at 130° C. for three hours. The reaction mixture was returned to room temperature, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 30% to 100%) to give the title compound (97 mg).
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([O:17]CC)=[O:16].[Li+].[OH-]>C1COCC1.CO.O>[O:20]=[S:2]1(=[O:1])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)CN1CCCN(c2ccccc2)S1(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CN1CCCN(c2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
To ethyl 2-(1,1-dioxido-6-phenyl-1,2,6-thiadiazinan-2-yl)acetate (260 mg, 0.872 mmol) in THF (5 mL) and MeOH (5 mL), was added LiOH (182.9 mg, 4.36 mmol) in H2O (5 mL). The reaction mixture was agitated for 3 hr at room temperature and evaporated. The residue was introduced into ice water, its pH was adjusted down to 1 with 2 N HCl, and extracted with ethyl acetate. The organic layer was dried over MgSO4 to give 2-(1,1-dioxido-6-phenyl-1,2,6-thiadiazinan-2-yl)acetic acid (230 mg, 97%, yellow solid). 1H NMR (300 MHz, DMSO-d6): δ 12.81 (s, 1H), 7.43-7.26 (m, 5H), 3.96 (s, 2H), 3.68-3.62 (m, 4H), 1.92-1.85 (m, 2H).