Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12]([OH:14])=[N:11][CH:10]=[N:9][C:8]=2[S:7]/[C:6]/1=[N:15]\[C:16](=[O:28])[C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1F)[CH2:2][CH2:3][CH3:4].[CH2:29]([OH:33])[C@@H:30]([OH:32])[CH3:31].CC(C)([O-])C.[K+].C1COCC1>C(O)(=O)C>[CH2:1]([N:5]1[C:13]2[C:12]([OH:14])=[N:11][CH:10]=[N:9][C:8]=2[S:7]/[C:6]/1=[N:15]\[C:16](=[O:28])[C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[O:33][CH2:29][C@@H:30]([OH:32])[CH3:31])[CH2:2][CH2:3][CH3:4]
Reactant: C[C@H](O)CO
Reactant: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)sc2ncnc(O)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OC[C@H](C)O)sc2ncnc(O)c21
Yield: 66.4 %

Procedure:
A mixture of Example 1B (65 mg, 0.16 mmol), (S)-propane-1,2-diol (28 mg, 0.36 mmol) and 1N solution of potassium tert-butoxide in THF (0.33 mL, 0.33 mmol) was heated at 45° C. for 18 hours. The mixture was acidified to pH 5 with acetic acid then concentrated under reduced pressure. The residue was stirred with saturated aqueous NaHCO3, extracted with EtOAc, concentrated, and the residue was purified by chromatography (EtOAc-EtOH 19:1) to afford 50 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90-0.96 (m, 3H) 1.19 (d, J=5.76 Hz, 3H) 1.30-1.41 (m, 2H) 1.77-1.86 (m, 2H) 3.93-4.08 (m, 3H) 4.66-4.76 (m, 2H) 4.87 (d, J=4.07 Hz, 1H) 7.36 (d, J=8.82 Hz, 1H) 7.82 (dd, J=8.82, 2.03 Hz, 1H) 8.22 (s, 2H) 13.12 (s, 1H). MS (ESI) m/z 471 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[C:9]([O:19][N:20]=C(C)C)=[C:10]3[CH:16]=[N:15][N:14]([CH2:17][CH3:18])[C:11]3=[N:12][CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.C(O)C.O>CCOCC>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]2[C:8]3[C:9](=[C:10]4[CH:16]=[N:15][N:14]([CH2:17][CH3:18])[C:11]4=[N:12][CH:13]=3)[O:19][N:20]=2)=[CH:4][CH:3]=1
Reactant: CCn1ncc2c(ON=C(C)C)c(C(=O)c3ccc(Cl)cc3)cnc21
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CCn1ncc2c3onc(-c4ccc(Cl)cc4)c3cnc21
Yield: 43.9 %

Procedure:
5-(4-chlorobenzoyl)-1-ethyl-4-isopropylideneaminooxy-1H-pyrazolo-[3,4-b]pyridine (3.54 g) was refluxed for 2 hours in 75 ml of 2:1 5% hydrochloric acid/ethanol. The reaction mixture was distributed between water and ether and then the ether layer was washed with 5% sodium hydroxide. Evaporation of the ether gave 1.30 g of product. An analytical sample was recrystallized from hexane which had mp 195°-197° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8]C=O)[C:5]([O:11][C:12]2[CH:17]=[C:16]([C:18]3[N:22]=[CH:21][O:20][N:19]=3)[C:15]([O:23][CH3:24])=[CH:14][C:13]=2[CH:25]([CH3:27])[CH3:26])=[CH:4][N:3]=1.NC1C(OC2C=C(C3N=CON=3)C(OC)=CC=2C(C)C)=CN=C(NC=O)N=1.C(NC1C(OC2C=C(C3N=CON=3)C(OC)=CC=2C(C)C)=CN=C(NC=O)N=1)=O>FC(F)(F)C(O)=O>[CH:25]([C:13]1[CH:14]=[C:15]([O:23][CH3:24])[C:16]([C:18]2[N:22]=[CH:21][O:20][N:19]=2)=[CH:17][C:12]=1[O:11][C:5]1[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1)([CH3:27])[CH3:26]
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2NC=O)cc1-c1ncon1
Agent: COc1cc(C(C)C)c(Oc2cnc(NC=O)nc2N)cc1-c1ncon1
Agent: COc1cc(C(C)C)c(Oc2cnc(NC=O)nc2NC=O)cc1-c1ncon1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1-c1ncon1

Procedure:
A mixture of N-[2-amino-5-(2-isopropyl-4-methoxy-5-[1,2,4]oxadiazol-3-yl-phenoxy)-pyrimidin-4-yl]formamide, N-[4-amino-5-(2-isopropyl-4-methoxy-5-[1,2,4]oxadiazol-3-yl-phenoxy)-pyrimidin-2-yl]formamide and N-[4-formylamino-5-(2-isopropyl-4-methoxy-5-[1,2,4]oxadiazol-3-yl-phenoxy)-pyrimidin-2-yl]-formamide (0.164 g) in trifluoroacetic acid (10 mL) was heated at reflux for 24 h. The mixture was then cooled and concentrated in vacuo. The residue was purified by flash chromatography (0-5% methanol in dichloromethane) to yield 76 mg of 5-(2-isopropyl-4-methoxy-5-[1,2,4]oxadiazol-3-yl-phenoxy)-pyrimidine-2,4-diamine as its trifluoroacetic acid salt. (M+H)+=343; MP 135-138.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](/[C:11]2[CH:12]=[C:13]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)\[OH:10])[CH:5]=[CH:4][N:3]=1.[Cl:29]C1C(NS(C2C(F)=CC=CC=2F)(=O)=O)=CC=CC=1C(OC)=O.ClC1N=C(C)C=CN=1>>[Cl:29][C:12]1[C:11](/[C:9](/[OH:10])=[CH:8]\[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)=[CH:16][CH:15]=[CH:14][C:13]=1[NH:17][S:18]([C:21]1[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=1[F:28])(=[O:19])=[O:20]
Reactant: O=S(=O)(Nc1cccc(/C(O)=C/c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1Cl
Agent: Cc1ccnc(Cl)n1
Product: O=S(=O)(Nc1cccc(/C(O)=C\c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F
Yield: 73.5 %

Procedure:
Following a procedure analogous to Intermediate 5, Step B using methyl 2-chloro-3-(2,6-difluorophenylsulfonamido)benzoate (31 g, 85.9 mmol) and 2-chloro-4-methylpyrimidine (12.2 g, 94.5 mmol) the title compound was obtained (33 g, 73.5% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.47-13.52 (br, 0.96H), 8.50-8.56 (m, 0.13H), 8.38 (d, J=5.3 Hz, 1H), 7.78-7.82 (m, 0.15H), 7.62-7.73 (m, 2H), 7.40-7.50 (m, 1.18H), 7.17-7.30 (m, 1.77H), 6.90-6.97 (m, 2.29H), 6.83 (d, J=5.3 Hz, 1H), 5.65 (s, 1H), 4.28 (s, 0.26H). MS (ES+): 458 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][C:19]3[C:24](=[O:25])[N:23]([CH3:26])[CH:22]=[C:21]([C:27]4[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([N:34]5[CH2:46][CH2:45][N:37]6[C:38]7[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=7[CH:44]=[C:36]6[C:35]5=[O:47])[C:28]=4[CH2:48][O:49][C:50](=[O:52])[CH3:51])[N:20]=3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[C:50]([O:49][CH2:48][C:28]1[C:29]([N:34]2[CH2:46][CH2:45][N:37]3[C:38]4[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=4[CH:44]=[C:36]3[C:35]2=[O:47])=[CH:30][C:31]([F:33])=[CH:32][C:27]=1[C:21]1[N:20]=[C:19]([NH:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:17][CH2:16]3)[C:24](=[O:25])[N:23]([CH3:26])[CH:22]=1)(=[O:52])[CH3:51]
Reactant: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)C4)n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc4c(c3)CCNC4)n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.5 %

Procedure:
To the solution of 129a (360 mg 0.51 mmol) in DCM (30 mL) was added 3M HCl in dioxane (8 mL) at room temperature. The mixture was stirred at room temperature for 5 h. After the reaction was completed, the solvent was removed at reduced pressure to afford 129b as a yellow solid (310 mg, 99%).
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([C:20](=O)[CH:21]=[CH:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[C:26]=2[O:35][CH3:36])[CH2:16][CH2:15]1)([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.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>CCOCC>[CH:1]([N:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH:21]=[CH:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[C:26]=2[O:35][CH3:36])[CH2:18][CH2:19]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C=CC=CC(=O)N2CCN(C(c3ccccc3)c3ccccc3)CC2)c(OC)c1OC
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: COc1ccc(C=CC=CCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c(OC)c1OC
Yield: 96.5 %

Procedure:
To 10.0 g (20.1 mmol) of said 1-benzhydryl-4-(5-(2,3,4-trimethoxyphenyl)-2,4-pentadienoyl)piperazine was added 250 ml of dry ether, and the mixture was stirred. After addition of 760 mg (20.1 mmol) of lithium aluminum hydride, the mixture was heated under reflux for 1 hour To the reaction mixture were added a saturated aqueous solution of ammonium chloride followed by extraction with ether. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure There was obtained a residue, which was subjected to column chromatography on silica gel to give 9.40 g (19.4 mmol) of 1-benzhydryl-4-(5-(2,3,4-trimethoxyphenyl)-2,4-pentadienyl)piperazine. Spectrophotometric data of the product support the structure (VIII). ##STR8##
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:10][C:6]=2[CH:5]=[C:4]([Br:16])[C:3]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[C:20]([C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH:19]=1.[Al+3].[Cl-].[Cl-].[Cl-].C(S)C>CCOCC>[Br:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[O:10][C:6]=2[CH:5]=[C:4]([Br:16])[C:3]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH:19]=1
Reactant: CCOC(=O)c1cc2c(Br)c(Oc3ccc(OC)c(C(=O)c4ccc(F)cc4)c3)c(Br)cc2o1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: CCOCC
Product: CCOC(=O)c1cc2c(Br)c(Oc3ccc(O)c(C(=O)c4ccc(F)cc4)c3)c(Br)cc2o1
Yield: 46.5 %

Procedure:
Ether cleavage of 108 mg of ethyl 4,6-dibromo-5-[3-(4-fluorobenzoyl)-4-methoxyphenoxy]-1-benzofuran-2-carboxylate with AlCl3/ethanethiol, in analogy with example . . . , yields 49 mg (47%) of ethyl 4,6-dibromo-5-[3-(4-fluorobenzoyl)-4-hydroxyphenoxy]-1-benzofuran-2-carboxylate.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([O:33][CH3:34])=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[CH:19]=[C:18]2[NH:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[CH:27][C:26]=1[Cl:32]>>[C:1]([O:4][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([O:33][CH3:34])=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[CH:19]=[C:18]2[NH:24][C:25]1[C:30]([Cl:31])=[CH:29][N:28]=[CH:27][C:26]=1[Cl:32])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Reactant: CC(=O)[O-]
Agent: [K+]
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCOC(C)=O

Procedure:
The title compound can be prepared from potassium acetate and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6): δ 9.53 (s, 1H), 8.83 (s, 2H), 7.95 (d, 1H), 7.22 (s, 1H), 4.65 (s, 1H), 4.00 (m, 4H), 3.93 (s, 3H), 2.00 (s, 3H), 1.73-1.52 (m, 6H); MS (ESI): 480.9.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][C:17]([F:20])([F:19])[F:18])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:28][CH3:29].N1CCOCC1>CN(C=O)C.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>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:28][CH3:29])[C:6](=[O:15])[N:5]([CH2:16][C:17]([F:18])([F:19])[F:20])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CC(F)(F)F
Reactant: CCI
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: CN(C)C=O
Solvent: C1COCCN1
Product: CCn1c(=O)c2[nH]c(Cl)nc2n(CC(F)(F)F)c1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 8-chloro-7-(2-propen-1-yl)-3-(2,2,2-trifluoroethyl)-3,7-dihydro-1H-purine-2,6-dione (0.070 g, 0.23 mmol) in anhydrous DMF (2 ml) was added caesium carbonate (0.085 g, 0.26 mmol) followed by 1-iodoethane (0.061 g, 0.39 mmol). The mixture was heated for 5 h at 80° C. then stirred for 16 h at ambient temperature under an atmosphere of nitrogen. The solvent was removed under reduced pressure using a vacuum centrifuge and the residue dissolved in anhydrous THF (2.5 ml). To the mixture was added palladium tetrakis (0.030 g, 0.026 mmol) and morpholine (0.040 g, 0.45 mmol) and the reaction mixture degassed using nitrogen then stirred at ambient temperature for 72 h. The mixture was partitioned between chloroform and 2N HCl aq., and the aqueous layer re-extracted. Organic extracts were combined and evaporated under a stream of nitrogen then purified using aminopropyl SPE (eluting with acetic acid:methanol:DCM, 1:2:2) to give the title compound as a white solid in >95% purity (0.041 g, 60%). NMR δH (400 MHz, d4-MeOD) 1.20 (t, 3H, J=7 Hz), 4.03 (q, 2H, J=7 Hz), 4.73 (q, 2H, J=8.5 Hz), m/z 297 [MH+].
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15](C(OC(C)(C)C)=O)[N:14]=[CH:13]3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:26].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>O1CCCC1>[Br:26][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[CH:13]2)=[O:9]
Reactant: [Br-]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(C(=O)Cc3ccccc3)ccc21
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: O=C(c1ccc2[nH]ncc2c1)C(Br)c1ccccc1

Procedure:
To a solution of Example 75D (336 mg, 1 mmol) in tetrahydrofuran (20 mL) heated at 40° C. with an oil bath was added dropwise with an addition funnel a solution of pyridinium tribromide (352 mg, 1.1 mmol) in tetrahydrofuran (20 mL) over 10 minutes. The reaction mixture was heated for an extra 2 hours, and was cooled, filtered, and the filtrate was evaporated to afford the title compound. MS (ESI−) m/z 212.9 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[NH:11][C:12](=[O:39])[CH2:13][N:14]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:29]([CH3:38])([CH3:37])[C:30]([O:32]C(C)(C)C)=[O:31])=[CH:24][CH:23]=1)[CH2:15][C:16]1[O:17][CH:18]=[CH:19][CH:20]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[NH:11][C:12](=[O:39])[CH2:13][N:14]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([S:28][C:29]([CH3:37])([CH3:38])[C:30]([OH:32])=[O:31])=[CH:26][CH:27]=1)[CH2:15][C:16]1[O:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1cc(C)c(NC(=O)CN(Cc2ccc(SC(C)(C)C(=O)OC(C)(C)C)cc2)Cc2ccco2)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C)c(NC(=O)CN(Cc2ccc(SC(C)(C)C(=O)O)cc2)Cc2ccco2)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
190 mg of tert-butyl 2-[[4-[[[2-[(2,5-dimethyl-4-methoxyphenyl)amino]-2-oxoethyl](2-furanyl-methyl)amino]methyl]phenyl]thio]-2-methyl-propanoate are dissolved in 5 ml of dichloromethane and reacted with 1 ml of trifluoroacetic acid. The mixture is stirred at room temperature for 20 h and then concentrated and purified chromatographically (dichloromethane/methanol 50+1). This gives 166 mg of the title compound as a solid foam.
Reaction SMILES: C1C=C2C=C[C:9](O)=[C:10]([C:11]3[C:20]4[C:15](=CC=CC=4)[CH:14]=[CH:13][C:12]=3[OH:21])[C:4]2=CC=1.[CH2:23]([Al](CC)CC)C>C1(C)C=CC=CC=1>[CH3:23][C@H:14]1[CH2:13][C@@H:12]([OH:21])[C@H:11]([C:10]([CH3:9])=[CH2:4])[CH2:20][CH2:15]1
Reactant: CC[Al](CC)CC
Reactant: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Solvent: Cc1ccccc1
Product: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
In a 300-ml reaction flask, 2.29 g (8.0 mmol) of (R)-1,1′-bi-2-naphthol was placed and the air in the flask was replaced with nitrogen gas. Then, 116 ml of toluene and 5 ml (5.0 mmol) of a toluene solution of triethylaluminum (1.0 mol/L) were successively added thereto and the mixture was stirred at room temperature for 1 hour, to give a catalyst solution. After the catalyst solution was cooled to a temperature of 0 to 5° C., 38.6 g (250 mmol) of d-citronellal was slowly added dropwise thereto, and the mixture was stirred at a temperature of 0 to 5° C. for 9 hours. After completion of the reaction, the reaction mixture was concentrated in vacuo, and continuously toluene was distilled off at a temperature of 110 to 115° C. at a pressure of 2.93 to 3.33 kPa (22 to 25 mmHg), to give 31.0 g of the objective l-isopulegol at the yield of 80.3%. The GC analysis results show that the purity was 99.0% and that the ratio of l-isopulegol to the other isomers was 98.7:1.3.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40]([OH:42])=O)=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C@H:47]([CH2:50][CH2:51][CH2:52][CH2:53][NH:54]C(OCC1C=CC=CC=1)=O)[CH2:48][OH:49].Cl.NCC(N)=O>>[NH2:54][CH2:53][CH2:52][CH2:51][CH2:50][C@@H:47]([NH:46][C:40]([CH2:39][CH2:38][CH2:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:43]([CH3:44])[CH3:45])=[CH:36][CH:35]=1)=[O:42])[CH2:48][OH:49]
Reactant: N[C@@H](CO)CCCCNC(=O)OCc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: Cl
Agent: NCC(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)N[C@@H](CO)CCCCN)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 1 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazole and (R)-2-amino-6-benzyloxycarbonylamino-1-hexanol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and glycinamide hydrochloride, respectively.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])[CH:7]=[CH:8][CH:9]=1.[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>>[CH2:34]([NH:36][C:37]([N:30]1[CH2:31][CH2:32][CH:27]([N:12]2[C:13]3[C:22]4[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[C:17]=4[N:16]=[CH:15][C:14]=3[C:25](=[O:26])[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=3)[C:11]2=[O:33])[CH2:28][CH2:29]1)=[O:38])[CH3:35]
Reactant: CCN=C=O
Reactant: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCNCC3)c12
Agent: Cl
Product: CCNC(=O)N1CCC(n2c(=O)n(-c3cccc(Cl)c3)c(=O)c3cnc4c(OC)cccc4c32)CC1

Procedure:
4-[3-(3-Chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl]-piperidine-1-carboxylic acid ethylamide (40 mg) was prepared according to general procedure H from 3-(3-chloro-phenyl)-7-methoxy-1-piperidin-4-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione.dihydrochloride (50 mg, 0.1 mmol) and ethyl isocyanate. LCMS: m/z 508 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:22])([CH3:21])[C:18]([OH:20])=O)=[CH:13][CH:12]=2)[CH:8]=[N:9][CH:10]=1)[CH3:2].[CH2:23]([NH2:27])[CH:24]([CH3:26])[CH3:25]>>[CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([CH3:22])([CH3:21])[C:18]([NH:27][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])=[CH:15][CH:16]=2)[CH:8]=[N:9][CH:10]=1)[CH3:2]
Reactant: CC(C)CN
Reactant: CCOCc1cncc(-c2ccc(C(C)(C)C(=O)O)cc2)c1
Product: CCOCc1cncc(-c2ccc(C(C)(C)C(=O)NCC(C)C)cc2)c1
Yield: 80 %

Procedure:
Prepared in a similar manner to Example 3 from 2-(4-(5-(ethoxymethyl)pyridin-3-yl)phenyl)-2-methylpropanoic acid (example 26a) and isobutylamine. Yield: 80%. 1H NMR (400 MHz, dMSO): δ 0.72 (s, 3H); 0.74 (s, 3H); 1.15 (t, 3H, J=6.8); 1.46 (s, 6H); 1.68 (m, 1H); 2.83 (t, 2H, J=5.6); 3.51 (q, 2H, J=7.2); 4.54 (s, 2H); 7.4 (t, 1H); 7.41 (d, 2H, J=6.4); 7.66 (d, 2H, J=6.8); 7.95 (t, 1H, J=2.4); 8.49 (d, 1H, J=1.6); 8.78 (d, 1H, J=2.8). MS (M+H, 355).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCBr
Reactant: O=Cc1ccc(O)cc1
Product: CCCCCCCCCOc1ccc(C=O)cc1
Yield: 79.3 %

Procedure:
General procedure K was used to convert 4-hydroxybenzaldehyde (8.2 mmols) and 1-bromononane (12.3 mmols) to 6.5 mmols (79%) of the title product was recovered. 1H NMR (300 MHz, CDCl3) δ 9.88 (s, 1H), 7.83 (d, J=8.9 Hz, 2H), 6.99 (d, J=8.7 Hz, 2H), 4.04 (t, J=6.6 Hz, 2H), 1.76-1.85 (m, 2H), 1.14-1.53 (m, 12H), 0.88 (t, J=6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 164.40, 132.11, 114.86, 68.55, 31.98, 29.47, 29.37, 29.18, 28.90, 28.31, 26.08, 22.79, 14.23.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15]>Cl.C1C=CC=CC=1>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15]
Reactant: N#CCCCCCCO
Reactant: C1=COCCC1
Agent: Cl
Solvent: c1ccccc1
Product: N#CCCCCCCOC1CCCCO1
Yield: 87.1 %

Procedure:
3,4-Dihydro-2H-pyran (272 g.) was added dropwise at 40° C. with stirring to a mixture of 7-hydroxyheptanenitrile (284 g.) and concentrated hydrochloric acid (10 drops). The temperature was allowed to rise to 65° C. and was maintained at this level for one hour. The solution was cooled and benzene (500 ml.) was added. The solution was washed with aqueous sodium bicarbonate and then water, and dried over sodium sulphate. The solvent was removed in vacuo, and the residue distilled under reduced pressure to give 7-(2-tetrahydropyranyloxy)heptanenitrile (411 g.), b.p. 100°-130° C./0.1 mm.Hg, nD25 1.455.
Reaction SMILES: [C:1]([CH2:3]C(OCC)=O)#[N:2].[H-].[Na+].[CH3:11][O:12][C:13]1[CH:31]=[CH:30][C:16]([CH2:17][N:18]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:21](=[O:28])O[C:19]2=[O:29])=[CH:15][CH:14]=1>CN(C)C(=O)C>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][N:18]2[C:23]3[C:22](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:21](=[O:28])[CH:3]([C:1]#[N:2])[C:19]2=[O:29])=[CH:30][CH:31]=1
Reactant: COc1ccc(Cn2c(=O)oc(=O)c3ccccc32)cc1
Reactant: CCOC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(CN2C(=O)C(C#N)C(=O)c3ccccc32)cc1
Temperature: 120 °C
Reaction time: 19 h

Procedure:
To a solution of ethyl cyanoacetate (7.9 ml) in N,N-dimethylacetamide (150 ml) was added sodium hydride (an oily, about 66%, 3.0 g), and added a solution of 1-(4-methoxybenzyl)2H-3,1-benzoxazine-2,4(1H)-dione (21.0 g) in N,N-dimethylacetamide (50 ml), stirred at 120° C. for 19 hours. After cooling, the reaction mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was washed with ether. The aqueous layer was acidified by adding 1N hydrochloric acid. The precipitated solid was collected by filtration, washed with water, and dried to obtain the target compound (8.1 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]2=[O:30])=[CH:9][CH:8]=1)(=O)=O.[N:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2B(O)O)[CH:36]=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>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.CC#N>[N:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][C:41]=2[C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C:17]4=[N:18][CH:19]=[CH:20][CH:21]=[C:16]4[N:15]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])[C:14]3=[O:30])=[CH:11][CH:12]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: OB(O)c1cccc2cccnc12
Reactant: C[Si](C)(C)CCOCn1c(=O)n(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)c2ncccc21
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: [Na+]
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1c(=O)n(-c2ccc(-c3cccc4cccnc34)cc2)c2ncccc21
Temperature: 150 °C
Yield: 85.7 %

Procedure:
The mixture of 4-(2-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)phenyl trifluoromethanesulfonate (500 mg), 8-quinolineboronic acid (265 mg), Pd(Ph3P)4 (35.4 mg), 2 M Na2CO3 (1.02 mL) and CH3CN (10 mL) was heated at 150° C. for 20 min under microwave irradiation. The mixture was diluted with sat.NaHCO3aq. at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-50% EtOAc in hexane) to give 3-(4-quinolin-8-ylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (410 mg) as white crystals.