Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(C=O)cc2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
Combine 4-hydroxy-benzaldehyde (1 equiv), 6-chloro-nicotinonitrile (1 equiv), and potassium carbonate (1.5 equiv) in dimethylformamide (0.1 M) and warm to 130° C. with stirring. After 3 h, cool to ambient temperature, dilute reaction mixture with water and extract with ethyl acetate (3×). Wash combined organic extracts with water and brine successively, dry over anhydrous magnesium sulfate, filter, and concentrate. Purify the residue by silica gel chromatography (hexanes:ethyl acetate 6:4) to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)[N:5]=[C:4]([NH:13][C:14]2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[O:32]=[C:33]1[CH2:42][CH2:41][CH2:40][C:39]2[CH:38]=[C:37]([C:43]([O:45][CH3:46])=[O:44])[CH:36]=[CH:35][C:34]1=2>C1COCC1>[OH:32][C:33]1([C:11]2[S:12][C:8]([C:6]3[CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]([NH:13][C:14]4[CH:19]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:17]=[CH:16][N:15]=4)[N:5]=3)=[CH:9][N:10]=2)[CH2:42][CH2:41][CH2:40][C:39]2[CH:38]=[C:37]([C:43]([O:45][CH3:46])=[O:44])[CH:36]=[CH:35][C:34]1=2
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cncs2)c1
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CCCC2(O)c1ncc(-c2cc(C)cc(Nc3cc(C(F)(F)F)ccn3)n2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
To a solution of 4-methyl-6-(1,3-thiazol-5-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine (500 mg, 1.487 mmol) in THF (5.9 mL) under argon at −78° C. was added lithium diisopropylamide (2.0 M in tetrahydrofuran, 2.2 mL, 4.46 mmol), and the resulting mixture was stirred as such for 30 minutes. To this mixture was added a solution of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (379 mg, 1.858 mmol) in THF (2 mL), and the reaction was then allowed to warm to rt over a period of 2 h. After stirring for an additional 14 h, the reaction was quenched with methanol (10 mL) and directly concentrated. Chromatography on silica gel (dichloromethane-methanol) afforded (rac)-methyl 5-hydroxy-5-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]-5,6,7,8-tetrahydronaphthalene-2-carboxylate as a light brown solid (718.0 mg, 1.328 mmol, 89% yield). MS ESI calcd for C27H23F3N4O3S [M+H]+ 541, found 541. 1H NMR (500 MHz, DMSO) δ 10.20 (s, 1H), 8.63 (s, 1H), 8.48 (d, J=5.0 Hz, 1H), 8.23 (s, 1H), 7.74 (s, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.36 (s, 1H), 7.23-7.17 (m, 2H), 7.09 (s, 1H), 6.63 (s, 1H), 3.82 (s, 3H), 2.92-2.85 (m, 2H), 2.33-2.30 (m, 4H), 2.15-2.09 (m, 1H), 2.02-1.88 (m, 2H) ppm.
Reaction SMILES: [OH:1][C:2]1[C:16]([O:17][C:18]2[CH:19]=[N:20][C:21]([S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])=[CH:22][CH:23]=2)=[CH:15][C:5]2[NH:6][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[C:31]=1F>>[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[C:31]=1[O:1][C:2]1[C:16]([O:17][C:18]2[CH:19]=[N:20][C:21]([S:24]([CH2:27][CH3:28])(=[O:25])=[O:26])=[CH:22][CH:23]=2)=[CH:15][C:5]2[NH:6][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: N#Cc1cccc(F)c1F
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2O)cn1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2c(F)cccc2C#N)cn1

Procedure:
The entitled compound was obtained as a pale green solid in the same method as in Example 251 or in accordance with the method or by combining it with an ordinary method but using 5-hydroxy-2-pyridin-2-yl-6-(6-ethanesulfonyl-pyridin-3-yloxy)-1H-benzimidazole obtained in Example 397 and 1,2-difluoro-3-cyano-benzene.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[O:54]1[C:58]([C:59](Cl)=[O:60])=[CH:57][CH:56]=[N:55]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:59]([C:58]2[O:54][N:55]=[CH:56][CH:57]=2)=[O:60])[CH2:48]1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(Cl)c1ccno1
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCN(C(=O)c2ccno2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 81 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and isoxazole-5-carbonyl chloride as the starting materials in 81% yield. LCMS for C27H26ClN8O3 (M+H)+: m/z=545.0.
Reaction SMILES: CC[O-].[Na+].Cl.[F:6][C:7]([F:17])([F:16])[C:8]1[N:9]=[C:10]([C:13]([NH2:15])=[NH:14])[S:11][CH:12]=1.[C:18](OCC)(=[O:25])[CH2:19][C:20](OCC)=[O:21]>CCO>[F:17][C:7]([F:6])([F:16])[C:8]1[N:9]=[C:10]([C:13]2[N:15]=[C:20]([OH:21])[CH:19]=[C:18]([OH:25])[N:14]=2)[S:11][CH:12]=1
Reactant: N=C(N)c1nc(C(F)(F)F)cs1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Oc1cc(O)nc(-c2nc(C(F)(F)F)cs2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a stirred solution of NaOEt (32 g, 5 eq.) in EtOH (200 mL) was slowly added compound 282 (22 g, 1 eq.). The reaction mixture was stirred at room temperature for 30 min and diethyl malonate (11.5 mL, 0.8 eq.) was then added. The suspension was refluxed for 24 hrs. The solvent was removed under reduced pressure. The residue was suspended in H2O (200 mL) and acidified to pH 5 with 2 N aqueous HCl. The resulting solid was filtered, washed with water, and dried under reduced pressure to yield compound 283 as a brown solid in 98% yield. 1H NMR (DMSO-d6, 400 MHz) δ 5.77 (s, 1H), 8.68 (s, 1H).
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:7][CH2:6][CH:5]([CH2:8]O)[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:31]>C(Cl)Cl>[Br:31][CH2:8][CH:5]1[CH2:6][CH2:7][C:2]([F:10])([F:1])[CH2:3][CH2:4]1
Reactant: BrC(Br)(Br)Br
Reactant: OCC1CCC(F)(F)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC1(F)CCC(CBr)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
(4,4-Difluorocyclohexyl)methanol (7.22 g, 48.08 mmol) and triphenylphosphine (25.2 g, 96.16 mmol) were dissolved in DCM (75 mL) and cooled to 0° C. under nitrogen atmosphere. Carbon tetrabromide (31.9 g, 96.16 mmol) was dissolved in DCM (75 mL) and added to the reaction mixture. The mixture was stirred at room temperature overnight. The solvent was evaporated. Pentane (250 mL) was added to the orange residue, which caused triphenylphosphineoxide to precipitate. The off-white solids were filtered off. The filtrate was evaporated and purified on a ISOLUTE Silica Flash column (50 g). Pentane followed by EtOAc:pentane (1% EtOAc) was used as eluent. 4-(Bromomethyl)-1,1-difluorocyclohexane (5.48 g, 54%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.32-1.46 (m, 2H), 1.64-1.84 (m, 3H), 1.90-1.99 (m, 2H), 2.05-2.18 (m, 2H), 3.31 (d, 2H).
Reaction SMILES: [N:1]1[C:5]2[C@H:6]3[C@H:11]([CH2:12][CH2:13][C:4]=2[O:3][C:2]=1[NH2:14])[NH:10][CH2:9][CH2:8][CH2:7]3.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH2:23][CH3:24]>C(#N)C>[CH2:22]([N:10]1[C@@H:11]2[C@H:6]([C:5]3[N:1]=[C:2]([NH2:14])[O:3][C:4]=3[CH2:13][CH2:12]2)[CH2:7][CH2:8][CH2:9]1)[CH2:23][CH3:24]
Reactant: CCCI
Reactant: Nc1nc2c(o1)CC[C@@H]1NCCC[C@@H]21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC[C@H]2c3nc(N)oc3CC[C@@H]21

Procedure:
A mixture of (±) trans-4,5,5a,6,7,8,9,9a-octahydrooxazolo[4,5-f]quinolin-2-amine, 1.46 g (5.0 mmol), 3.6 g (26 mmol) of finely ground potassium carbonate and 2.5 ml (25.6 mmol) of 1-iodopropane in 250 ml of acetonitrile is refluxed, under nitrogen, for 24 hours. The mixture is cooled, filtered through a pad of Celite, concentrated and partitioned between brine and chloroform. The organic extract is dried and concentrated. Chromatography of the mixture on silica gel gives (±) trans-4,5,5a,6,7,8,9,9a-octahydro-6-propyloxazolo[4,5-f]quinolin-2-amine. The procedure just described can be applied to (±) trans-4,5,5a,6,7,8,9,9a-octahydrooxazolo[5,4-f]quinolin-2-amine to give (±) trans-4,5,5a,6,7,8,9,9a-octahydro-6-propyloxazolo [5,4-f]quinolin-2-amine.
Reaction SMILES: C(C=P(CCCC)(CCCC)CCCC)#N.[C:17]([O:21][C:22]([N:24]1[C@H:29]([CH2:30]O)[CH2:28][O:27][C@H:26]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[NH:40][C:41](=[O:61])[C@@H:42]([NH:56][C:57]([O:59][CH3:60])=[O:58])[CH:43]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].[C:62]1([SH:68])[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>C1(C)C=CC=CC=1>[CH3:60][O:59][C:57]([NH:56][C@H:42]([C:41]([NH:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][CH2:32][C@H:26]1[O:27][CH2:28][C@@H:29]([CH2:30][S:68][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[N:24]([C:22]([O:21][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:23])[CH2:25]1)=[O:61])[CH:43]([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:58]
Reactant: Sc1ccccc1
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)CO1)C(c1ccccc1)c1ccccc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CSc2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Cyanomethylenetributylphosphorane (2 eq) was added to a stirred mixture of (2R,5R)-5-hydroxymethyl-2-{2-[2-((S)-2-methoxycarbonylamino-3,3-diphenyl-propionylamino)-phenyl]-ethyl}-morpholine-4-carboxylic acid tert-butyl ester (1 eq) and thiophenol (1.5 eq) in toluene (0.04 M). The mixture was stirred at 90° C. for 2 h, cooled to room temperature and evaporated to dryness. The residue was purified by automated silica gel flash chromatography system eluted with a gradient 0% to 100% of EtOAc/Hex to afford tert-butyl (2R,5S)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]-5-[(phenylsulfanyl)methyl]morpholine-4-carboxylate which was then treated with TFA following the procedure described in step 2 of Example 2 to afford the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11]4=[C:12]([O:18][CH2:19][CH:20]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:10]4[C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH:13]=[CH:14][CH:15]=3.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:21]1([CH:20]2[N:10]3[C:11]4[C:16]([C:17]5[C:5]([O:4][CH2:3][CH2:2][N:27]6[CH2:32][CH2:31][O:30][CH2:29][CH2:28]6)=[CH:6][CH:7]=[CH:8][C:9]=53)=[CH:15][CH:14]=[CH:13][C:12]=4[O:18][CH2:19]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(C2COc3cccc4c5c(OCCN6CCOCC6)cccc5n2c34)cc1
Temperature: 100 °C
Reaction time: 72 h
Yield: 60.6 %

Procedure:
To a mixture of 7-(2-chloroethoxy)-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazole (0.278 g, 0.764 mmol) in dry DMF (10 mL) is added morpholine (0.133 g, 1.53 mmol), sodium iodide (0.114 g, 0.764 mmol), and potassium carbonate (0.211 g, 1.53 mmol). The mixture is heated to 100° C. for 6 h. The mixture is removed from heat and stirred at room temperature for three days. The mixture is then partitioned between water and Et2O. The layers are separated and the organic layer is washed twice with water (50 mL) and then dried over anhydrous sodium sulfate and concentrated. Column chromatography (50 mL silica) using CH2Cl2/acetone/hexanes (7:2:1) gave 0.192 g (61%) of 2-(4-morpholinyl)ethyl 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:12].[NH3:13]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([S:8](=[O:10])(=[O:9])[NH2:13])[CH:5]=[CH:4][C:3]=1[CH3:12]
Reactant: N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1Cl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(N)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
8 g of 2-chloro-toluene-4-sulfonic acid chloride is dissolved in 25 ml of CHCl3 and slowly stirred into 100 ml of concentrated NH3 solution. After 10 minutes of stirring at room temperature, the solution is concentrated by evaporation to one-half of its original volume. The substance is suctioned off, washed with water and dried. 2-Chloro-4-sulfamoyltoluene is obtained.
Reaction SMILES: [N:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]([O:5][C:6]2=[O:11])=O.C(N1C2C(=CC=CC=2)C=C1C)CCCCCCC.C(N(CC)C1C=C(OCC)C=CC=1)C.C(OC(=O)C)(=O)C>[Cl-].[Zn+2].[Cl-].[Cl-].[Ca+2].[Cl-].C(O)(=O)C>[C:6]1([C:7]2[C:2](=[N:1][CH:10]=[CH:9][CH:8]=2)[CH2:3][O:5]1)=[O:11]
Reactant: O=C1OC(=O)c2ncccc21
Agent: CCCCCCCCn1c(C)cc2ccccc21
Agent: CCOc1cccc(N(CC)CC)c1
Agent: [Ca+2]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C1OCc2ncccc21
Temperature: 20 °C
Reaction time: 5 h
Yield: 279.6 %

Procedure:
1.5 g of quinolinic anhydride, 2.3 g of N-octyl-2-methylindole, 10 ml of glacial acetic acid and a mixture of 0.11 g of calcium chloride and 0.14 g of zinc chloride are stirred at 20° C. for 5 hours. 1.6 g of 3-diethylaminophenetole and 2 ml of acetic anhydride are then added, after which the reaction mixture is stirred at 50° C. for 21/2 hours. The product is precipitated with 30% aqueous ammonia, separated from the aqueous phase and recrystallised from isopropanol, affording 3.8 g of the isomer-free 4-azaphthalide compound of the formula (12) of melting point 114°-117° C.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([NH:35][CH2:36][C:37](O)=[O:38])([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[C:31]([O:30][C:28](=[O:29])[NH:35][CH2:36][C:37]([N:13]1[CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9][C@@H:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:38])([CH3:34])([CH3:32])[CH3:33]
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCN(C(=O)CNC(=O)OC(C)(C)C)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 2 h
Yield: 81.2 %

Procedure:
A solution of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (73 mg, 0.2 mmol) and BOC-glycine (35 mg, 0.2 mmol) in DMF (1.0 mL) at room temperature was treated with diisopropylethylamine (35 μL, 0.2 mmol) followed by 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (84 mg, 0.22 mmol). The reaction mixture was stirred for 2 h then partitioned between EtOAc (10 mL) and a saturated aqueous NaHCO3 solution (10 mL). The organic component was isolated and further washed with brine (10 mL) then dried over MgSO4, filtered, and evaporated to an oil which was purified by silica gel flash chromatography with 40% EtOAc/hexane as eluant to afford intermediate {2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester as a foam (85 mg, 81%). LC/MS 7.46 min, [M+1]+ 524.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:21]=[C:20]3[C:16]([C:17]([CH:22]=O)=[N:18][NH:19]3)=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][O:11][CH3:12].C(O)(=O)C.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH2:35]>C(O)C.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[NH:28]1[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:35]=[C:22]1[C:17]1[C:16]2[C:20](=[CH:21][C:13]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH2:10][O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:14][CH:15]=2)[NH:19][N:18]=1
Reactant: COCOc1ccc(-c2ccc3c(C=O)n[nH]c3c2)cc1OC
Reactant: Nc1ccccc1N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: COCOc1ccc(-c2ccc3c(-c4nc5ccccc5[nH]4)n[nH]c3c2)cc1OC
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
6-(3-Methoxy-4-methoxymethoxy-phenyl)-1H-indazole-3-carbaldehyde (from Example 1(a), step (vi)) (20 mg, 0.064 mmol, 1 equiv) was dissolved in degassed 1:1 MeOH-water (0.7 mL) and was treated with acetic acid (19 μL, 5 equiv), 1,2-diaminobenzene (8.3 mg, 1.2 equiv) and copper(II) acetate (18 mg, 1.4 equiv) at 23° C. The mixture stirred for 30 min, was diluted with ethanol (3 mL) and water (2 mL) and was treated with a bubbling stream of SH2 for 3 min, which gave a black precipitate. The mixture was allowed to stir for 12 h. The mixture was filtered and concentrated. Purification by silica gel chromatography (6:4 ethyl acetate-hexane) gave 3-(1H-benzoimidazol-2-yl)-6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole as a solid (14 mg, 54%); Rf sm 0.39, p 0.24 (ethyl acetate-hexane 6:4); 1H NMR (CDCl3) δ 8.69 (d, 1H, J=8 Hz), 7.70 (bs, 2H), 7.58 (s, 1H), 7.53 (d, 1H, J=8 Hz), 7.30–7.15 (m, 7H), 5.30 (s, 2H), 3.97 (s, 3H), 3.58 (s, 3H); MS (ES) [m+H]/z Calc'd 401. found 401. [m−H]/z Calc'd 399. found 399.
Reaction SMILES: [CH3:1][C:2]1[N:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:3]=1[C:4](OCC)=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:9][CH:10]=[C:11]([CH3:13])[N:12]=1
Reactant: CCOC(=O)c1ccc(C)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(CO)c(C)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of ethyl 2,6-dimethylnicotinate (1.0 g, 5.6 mmol) in THF (20 mL) at 0° C. was added LiAlH4 (318 mg, 8.4 mmol). The resulting mixture was stirred at 0° C. for 5 min and then warmed to room temperature for 1 hour. Quenched with 0.3 mL water, 0.3 mL 15% NaOH solution and then with 1 mL water sequentially. After stirred at room temperature for 15 min, sodium sulfate was added to the mixture and stirred for another 15 min and then filtered. The resulting solution was concentrated to afford the crude product which was used for next step directly without further purification. LCMS (ESI) m/z=138.1 138.1 (M+H)+.
Reaction SMILES: C(O)C(N)(CO)C[OH:4].Cl.[NH2:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[C@@H:20]2[O:25][C@:24]([C:28]#[CH:29])([CH2:26][OH:27])[C@@H:22]([OH:23])[CH2:21]2)=[C:13](N)[N:12]=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O>O>[C:28]([C@:24]1([CH2:26][OH:27])[O:25][C@@H:20]([N:17]2[C:18]3[N:19]=[C:11]([NH2:10])[NH:12][C:13](=[O:4])[C:14]=3[N:15]=[CH:16]2)[CH2:21][C@@H:22]1[OH:23])#[CH:29]
Reactant: NC(CO)(CO)CO
Reactant: C#C[C@]1(CO)O[C@@H](n2cnc3c(N)nc(N)nc32)C[C@@H]1O
Agent: Cl
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: O
Product: C#C[C@]1(CO)O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a Tris-HCl buffer solution (7.8 ml, pH 7.5) of Compound 28 (0.03 g, 0.103 mmol), adenosine deaminase (0.057 ml, 20 unit) was added, and the mixture was stirred for 2 hours at 40° C., followed by cooling to room temperature. The reaction mixture was applied to a reverse-phase ODS silica gel column (50 g), desalted by water (500 ml) flow, and through use of aqueous 2.5% ethanol, Compound 30 was eluted. Recrystallization from water yielded Compound 30 in an amount of 0.015 g (50%).
Reaction SMILES: [CH2:1]([CH:9]([C:18]#[N:19])[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.[CH2:26]=[O:27].[OH-].C([N+](CC)(CC)CC)C1C=CC=CC=1>O>[C:18]([C:9]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[Cl:17])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:26][OH:27])#[N:19]
Reactant: CCCCCCCCC(C#N)c1ccc(Cl)cc1Cl
Reactant: C=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCC(C#N)(CO)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To an ice cold stirred solution of α-n-octyl-2,4-dichlorobenzyl cyanide (40 g., 0.14 mole) in 250 ml. of pyridine containing a suspension of paraformaldehyde (21 g., 0.7 mole) is added 1 ml. of benzyl triethylammonium hydroxide. The mixture is stirred under nitrogen at room temperature for 72 hours. The reaction mixture is poured into 2 liters of water and extracted with ether. The combined ether extracts are washed with water, saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to give 40 g. of a thick oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([CH2:12][OH:13])=[CH:10][CH:11]=1)=[O:5])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:9]([CH:12]=[O:13])=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(CO)n(-c2ccccc2)c1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C=O)n(-c2ccccc2)c1=O

Procedure:
1,2-dihydro-6-hydroxymethyl-2-oxo-1-phenylpyridine-3-carboxylic acid ethyl ester (5.0 g, 18 mmol) was dissolved in dichloromethane (50 mL), and a DMP reagent (1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one) (8.5 g, 20 mol) was added thereto at room temperature. The mixture was allowed to react for 4 hours. The reaction mixture was poured into an aqueous sodium bicarbonate solution, and extracted with chloroform. The organic layer was washed with water, dried, and concentrated, to obtain crude 6-formyl-1-phenyl-1,2-dihydro-2-oxopyridine-3-carboxylic acid ethyl ester. This crude product was dissolved in dichloromethane (50 mL), and a DAST reagent (diethylamino sulfur trifluoride) (4.8 g, 30 mmol) was added to this solution at 5° C. under a nitrogen atmosphere. The mixture was allowed to react overnight at room temperature. The reaction mixture was poured into water, and the organic layer was washed with an aqueous sodium bicarbonate solution and water, dried, and concentrated. Thus obtained residue was purified by column chromatography (elution solvent: hexane/ethyl acetate: 4/1 to 3/2), and thus obtained solid was washed with a mixed solution of hexane/ethyl acetate=1/1, to obtain 2.29 g of a desired product (yield: 57%, two stages).