Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:15])=[N:7][N:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[CH:16]1([CH2:22][C:23](Cl)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[C:1]([C:5]1[C:6]([NH:15][C:23](=[O:24])[CH2:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:7][N:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cnc2c(C(C)(C)C)c(N)nn2c1
Reactant: O=C(Cl)CC1CCCCC1
Product: Cc1cnc2c(C(C)(C)C)c(NC(=O)CC3CCCCC3)nn2c1

Procedure:
The product from Example 178A and cyclohexylacetyl chloride were processed using the method analogous to that described in Example 105C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91-1.03 (m, 2H), 1.11-1.30 (m, 3H), 1.43 (s, 9H), 1.59-1.80 (m, 6H), 2.16-2.18 (m, 2H), 2.29 (d, J=1.0 Hz, 1H), 8.38 (d, J=2.0 Hz, 1H), 8.75 (s, 1H), 9.58 (br s, 1H); MS (DCI) m/z 329 (M+H)+.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][CH:10]([OH:48])[CH2:11][N:12]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:19][N:18]([CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:17][CH2:16][N:15]([CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:14][CH2:13]1)C1C=CC=CC=1.O>CO.[Pd]>[NH2:8][CH2:9][CH:10]([OH:48])[CH2:11][N:12]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][CH2:19][N:18]([CH2:32][C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:17][CH2:16][N:15]([CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(O)CN(Cc2ccccc2)Cc2ccccc2)CCN(CC(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(O)CN)CCN(CC(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
76.8 g (100 mmol) of 10-(3-dibenzylamino-2-hydroxypropyl)-1,4,7-tris-(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane is dissolved in 500 ml of methanol, mixed with 40 ml of water, and 10 g of palladium catalyst (20% Pd/C) is added. It is hydrogenated for 8 hours at 50° C. under normal pressure. Catalyst is filtered out, and the filtrate is evaporated to the dry state in a vacuum.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH:9]([Cl:11])[CH3:10])[N:5]=[CH:4][N:3]=1.[C:12]([C@@H:16]1[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18][CH2:17]1)([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:12]([C@@H:16]1[CH2:17][CH2:18][C@H:19]([NH:22][C:2]2[C:7]([Cl:8])=[C:6]([CH:9]([Cl:11])[CH3:10])[N:5]=[CH:4][N:3]=2)[CH2:20][CH2:21]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)[C@H]1CC[C@@H](N)CC1
Reactant: CC(Cl)c1ncnc(Cl)c1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(Cl)c1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1Cl

Procedure:
32.3 g (0.15 mol) of 4,5-dichloro-6-(1-chloroethyl)pyrimidine(EP 543 402) were stirred in 200 ml of toluene with 23.3 g (0.15 mol) of cis-4-tert-butylcyclohexylamine and 20.2 g (0.20 mol) of triethylamine at from 80° to 90° C. for 6 hours. The mixture was extracted by stirring with water and the organic phase was dried and concentrated. The residue was purified by chromatography on silica gel, to give 36.3 g (73.2% of theory) of a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:21]=[CH:20][C:14]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:43][O:42][C:38]1[CH:37]=[C:36]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:21]=[CH:20][C:14]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=4)=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:35]=[C:34]([O:33][CH3:32])[C:39]=1[O:40][CH3:41]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: CC(=O)NCc1ccc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(Br)cc23)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(-c2cnc3[nH]cc(-c4ccc(CNC(C)=O)cc4)c3c2)cc(OC)c1OC
Yield: 53.1 %

Procedure:
N-{4-[5-Bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-benzyl}-acetamide (Intermediate CC, 24 mg, 0.048 mmol), 3,4,5-trimethoxyphenyl boronic acid (13 mg, 0.058 mmol) and dichlorobis(triphenylphosphine)palladium (II) (2 mg, 0.002 mmol) were combined in CH3CN (1 ml) and 1 M Na2CO3 (2 ml) and heated in a microwave reactor at 150° C. for 20 min. EtOAc was added, washed with water, dried and purified by silica gel chromatography eluting with 0-4% MeOH:DCM to give 11 mg (53%) of the title compound. MS ESI (m/z): 432.2 (M+1)+, calc. 431.
Reaction SMILES: [C:1]([N:4]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([O:22]C)[CH:15]=2)[C:11]2[C:6](=[C:7]([O:26]C)[C:8]([O:24]C)=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].B(Br)(Br)Br.ClCCl.CO>ClCCl>[C:1]([N:4]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:22])[CH:15]=2)[C:11]2[C:6](=[C:7]([OH:26])[C:8]([OH:24])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc([C@H]2CN(C(C)=O)Cc3c2ccc(OC)c3OC)cc1OC
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N1Cc2c(ccc(O)c2O)[C@@H](c2ccc(O)c(O)c2)C1
Yield: 96.6 %

Procedure:
(i) 1.78 g of (R)-(-)-N-acetyl-7,8-dimethoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline was dissolved in 9 ml of dichloromethane; after adding 24 ml of 1M boron tribromide-dichloromethane solution at -30° C., the mixture was reacted at room temperature for 90 minutes. Then 4.4 ml of methanol was added at -30° C. The reaction solution was concentrated and subjected twice to azeotropic distillation with methanol. To the residue was added 17.8 ml of 0.1N hydrochloric acid. The crystals which separated out were collected by filtration, affording 1.46 g of (R)-(-)-N-acetyl-7,8-dihydroxy-4-(3,4-dihyroxyphenyl)-1,2,3,4-tetrahydroisoquinoline.1/4 hydrate, m.p. above 230° C. (decomposition); [α]D20 =-85° (C=1, CH3OH)
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].O[N:21]=[C:22]([NH2:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][OH:30])[CH:24]=1>>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:12][N:31]=[C:22]([C:23]3[CH:24]=[C:25]([CH2:29][OH:30])[CH:26]=[CH:27][CH:28]=3)[N:21]=2)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: NC(=NO)c1cccc(CO)c1
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Product: COCc1cc(-c2nc(-c3cccc(CO)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following the general procedure 3 starting from Intermediate 3 and Intermediate 70 and was isolated as a yellow oil. HPLC (Method A) Rt 5.16 min (Purity: 97.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[CH:9]=[C:10](Br)Br.[CH2:13]([NH2:16])[CH2:14][NH2:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[C:3]=1[CH2:9][C:10]1[NH:15][CH2:14][CH2:13][N:16]=1
Reactant: Clc1cccc(I)c1C=C(Br)Br
Reactant: NCCN
Product: Clc1cccc(I)c1CC1=NCCN1

Procedure:
2-(2-Chloro-6-iodo-benzyl)-4,5-dihydro-1H-imidazole was prepared from 1-chloro-2-(2,2-dibromo-vinyl)-3-iodo-benzene and ethylenediamine in analogy to Example 1e): light yellow crystals; MS (ISP): 323.1 ([M+H]+, 35%), 321.4 ([M+H]+, 100%).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:17][NH:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1.[I-].[K+]>CN(C=O)C>[CH3:17]/[N:18]=[C:19]1\[S:20][CH:21]=[CH:22][N:23]\1[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: CNc1nccs1
Reactant: CC(C)(C)OC(=O)N1CCC(CCBr)CC1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C/N=c1\sccn1CCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 22 %

Procedure:
To a solution of tert-butyl 4-(2-bromoethyl)-1-piperidinecarboxylate (D. Brundish et al., J. Med. Chem., 42, 4584 (1999); 5.0 g) and 2-methylaminothiazole (O. Kemal et al., J. Chem. Soc. Perkin I, 5, 1569 (1981); 3.9 g) in DMF (50 ml) was added potassium iodide (5.7 g), and mixed at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in chloroform and a saturated aqueous potassium hydrogen carbonate solution. The organic layer was collected by separation, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified with silica gel column to obtain the title compound as a brown oil (1.25 g, 22%).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:11](O)(=O)[CH2:12][CH3:13].Cl>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:11]([CH2:12][CH3:13])=[N:9][C:4]=2[C:3]=1[Cl:10]
Reactant: Nc1ccc(Br)c(Cl)c1N
Reactant: CCC(=O)O
Agent: Cl
Product: CCc1nc2c(Cl)c(Br)ccc2[nH]1
Temperature: 140 °C
Yield: 89 %

Procedure:
4-Bromo-3-chloro-1,2-benzenediamine (0.17 g, 0.766 mmol), propionic acid (0.17 g, 2.298 mmol), and 4 N HCl (1.724 ml, 6.894 mmol) were combined and heated to 140° C. for 3 h. Treatment with 1N NaOH was followed by extraction with EtOAc (×3), and washing with brine. The dried (Na2SO4) organic portions were filtered, concentrated, and chromatographed (SiO2, MeOH/CH2Cl2) to obtain 0.177 g of the title compound: 1HNMR (400 MHz, CDCl3) δ 9.50 (broad s, 1H), 7.43 (d, J=8.31 Hz, 1H), 7.35 (broad s, 1H), 2.96 (q, J=7.5 Hz, 2H), 1.43 (t, J=7.5 Hz, 3H); MS (ESI) m/z 261 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=O)[CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[OH:32])=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[OH:32])=[CH:20][CH:21]=1
Reactant: COc1cc2ncnc(Oc3ccc(NC(=O)COc4ccccc4O)cc3)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3ccc(NCCOc4ccccc4O)cc3)c2cc1OC
Temperature: 0 °C
Yield: 80 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]phenyl}-2-(2-hydroxyphenoxy)acetamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%).
Reaction SMILES: [CH3:1][Si:2]([CH3:31])([CH3:30])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][CH:13]([CH2:16][C:17]1[N:18]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:19]=[CH:20][N:21]=1)[CH2:14][NH2:15].[CH2:32]([N:36]1[CH2:54][CH2:53][C:39]2([CH2:43][N:42]([CH2:44][C:45]3[CH:52]=[CH:51][C:48]([CH:49]=O)=[CH:47][CH:46]=3)[CH2:41][CH2:40]2)[CH2:38][CH2:37]1)[CH:33]([CH3:35])[CH3:34]>>[CH2:32]([N:36]1[CH2:54][CH2:53][C:39]2([CH2:43][N:42]([CH2:44][C:45]3[CH:46]=[CH:47][C:48]([CH2:49][NH:15][CH2:14][CH:13]([CH2:16][C:17]4[N:18]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[CH:19]=[CH:20][N:21]=4)[CH2:12][C:8]4[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:30])[CH3:31])[CH:11]=[CH:10][N:9]=4)=[CH:51][CH:52]=3)[CH2:41][CH2:40]2)[CH2:38][CH2:37]1)[CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)CN1CCC2(CC1)CCN(Cc1ccc(C=O)cc1)C2
Reactant: C[Si](C)(C)CCOCn1ccnc1CC(CN)Cc1nccn1COCC[Si](C)(C)C
Product: CC(C)CN1CCC2(CC1)CCN(Cc1ccc(CNCC(Cc3nccn3COCC[Si](C)(C)C)Cc3nccn3COCC[Si](C)(C)C)cc1)C2
Yield: 43.3 %

Procedure:
Except for using the compound (200 mg) produced in Example 29 in place of 8-isobutyl-2,8-diazaspiro[4.5]decane and using the compound (135 mg) produced in Example 27 in place of 4-(diethoxymethyl)benzaldehyde, the same operation as in Example 26 was performed to obtain the title compound (142 mg) having the following physical properties.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:10]1.C[O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH2:35]Cl>>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:35][CH2:34][O:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[C:26]([OH:37])=[O:25])[CH2:20][CH2:19]2)=[CH:10]1
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2CCC1COCCO1
Reactant: COC(=O)c1ccccc1OCCCl
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(CCC3COCCO3)c3ccccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 0.58 g (1.84 mmol) of 1-(2-[1,4]dioxan-2-yl-ethyl)-3-piperidin-4-yl-1H-indole (example 71, part B) and 0.51 g (2.39 mmol) of 2-(2-chloro-ethoxy)-benzoic acid methyl ester. After standard work-up and purification by flash chromatography over silica gel, 0.18 g (20% of yield) of the expected acid were obtained.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])=[C:16]([CH:26]([CH3:28])[CH3:27])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[C:29]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39]Br)[CH:34]=1)(=[O:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:29]([O:32][C:33]1[CH:34]=[C:35]([CH:36]=[CH:37][CH:38]=1)[CH2:39][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:17]1[C:13]([O:12][C@@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]2[OH:3])=[N:14][NH:15][C:16]=1[CH:26]([CH3:28])[CH3:27])(=[O:31])[CH3:30]
Reactant: CC(=O)Oc1cccc(CBr)c1
Reactant: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1cccc(COc2ccccc2Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)n[nH]c2C(C)C)c1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a solution of 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-5-isopropyl-1H-pyrazole (150 mg) in N,N-dimethylformamide (1 mL) were added 3-bromomethylphenyl acetate (131 mg) and potassium carbonate (105 mg), and the mixture was stirred at room temperature for 13 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1˜5/1) to give 4-[2-(3-acetyloxybenzyloxy)benzyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole. To a solution of 4-[2-(3-acetyloxybenzyloxy)benzyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole (12 mg) in methanol (2 mL) was added sodium methoxide (28% methanol solution, 5 μL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (8 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([N:27]2[C:32](=[O:33])[CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[N:29]([CH3:38])[C:28]2=[O:39])=[CH:22][C:21]=1[OH:40].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([N:27]2[C:32](=[O:33])[CH:31]=[C:30]([C:34]([F:35])([F:37])[F:36])[N:29]([CH3:38])[C:28]2=[O:39])=[CH:22][C:21]=1[O:40][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([N+:16]([O-:18])=[O:17])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1OCc1ccccc1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc([N+](=O)[O-])c(OCc4ccccc4)n3)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.4 %

Procedure:
A mixture of 5.29 g of 6-chloro-2-benzyloxy-3-nitropyridine, 6.77 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol, 3.32 g of potassium carbonate and 30 ml of N,N-dimethylformamide was stirred for 30 minutes at room temperature, then at 50° C. for 2.5 hours. The resulted residue was added to ice water, extracted with ethyl acetate, and organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was recrystallized from ethyl acetate and hexane to obtain 9.11 g of 6-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-benzyloxy-3-nitropyridine.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][C:7]([NH:9][CH2:10][C@:11]1([CH2:26][OH:27])[O:15][C@@H:14]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:13][C@@H:12]1[OH:25])=[O:8])=O>N>[NH2:5][CH2:6][C:7]([NH:9][CH2:10][C@:11]1([CH2:26][OH:27])[O:15][C@@H:14]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:13][C@@H:12]1[OH:25])=[O:8]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@](CO)(CNC(=O)CNC(=O)C(F)(F)F)O2)c(=O)[nH]c1=O
Agent: N
Product: Cc1cn([C@H]2C[C@H](O)[C@](CO)(CNC(=O)CN)O2)c(=O)[nH]c1=O
Reaction time: 8 h

Procedure:
4′-C-(N-trifluoroacetylglycylaminomethyl)thymidine (5) (17 mg, 0.4 mmol) was dissolved in concentrated aqueous ammonia solution (1 mL) and allowed to stand overnight at ambient temperature. The reaction mixture was then lyophilised to give the title compound (22) as a colourless resin (0.0088 g, 67%). δH(300 MHz, D2O) 7.46(1H, s, H-6), 6.14(1H, dd, H-1′), 4.48(1H, dd, H-3′), 3.70(2H, s, glycyl CH2), 3.47(2H, 2d, H-5′), 3.40(2H, 2d, 4′-C—CH2), 2.35(2H, m, H-2′), 1.73(3H, s, 5-CH3); ES +ve m/z 329(M+H)+.
Reaction SMILES: CO.Cl[C:4]1[CH:31]=[CH:30][C:7]2[S:8][C:9]([S:12]([NH:15][C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=3[S:26]([CH3:29])(=[O:28])=[O:27])(=[O:14])=[O:13])=[C:10]([CH3:11])[C:6]=2[CH:5]=1>[Pd].O1CCOCC1>[CH3:11][C:10]1[C:6]2[CH:5]=[CH:4][CH:31]=[CH:30][C:7]=2[S:8][C:9]=1[S:12]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[S:26]([CH3:29])(=[O:28])=[O:27])(=[O:13])=[O:14]
Reactant: COC(=O)c1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c(S(C)(=O)=O)c1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1ccc(NS(=O)(=O)c2sc3ccccc3c2C)c(S(C)(=O)=O)c1
Reaction time: 0.17 h
Yield: 22.9 %

Procedure:
Into a mixed solvent of 30 mL of methanol and 30 mL of dioxane was dissolved 640 mg of 5% palladium/carbon, followed by 10 minutes of stirring under a hydrogen atmosphere. Under an argon atmosphere, 330 mg of Compound 1 was added, followed by 3 days of stirring under a hydrogen atmosphere at 5 atm. After confirmation of disappearance of the starting material, the reaction mixture was filtered and purified by silica gel column chromatography (ethyl acetate/hexane=2/1) to obtain 70 mg of the title compound as colorless powder.
Reaction SMILES: Br[CH2:2]C1CCCCC1.C([O-])([O-])=O.[K+].[K+].[Cl:15][C:16]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:17]=1[CH2:18][N:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[S:22](=[O:30])(=[O:29])[N:21]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34]N=2)[C:20]1=[O:38]>>[Cl:15][C:16]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:17]=1[CH2:18][N:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[S:22](=[O:29])(=[O:30])[N:21]([CH2:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:2]2)[C:20]1=[O:38]
Reactant: BrCC1CCCCC1
Reactant: O=C1N(Cc2c(F)cccc2Cl)c2ccccc2S(=O)(=O)N1Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1N(Cc2c(F)cccc2Cl)c2ccccc2S(=O)(=O)N1CC1CCCCC1

Procedure:
The title compound (25 mg, 0.06 mmol) was prepared from (IntE1) (0.3 g, 0.88 mmol), 2-(bromomethyl)cyclohexane (0.18 g, 1.05 mmol) and K2CO3 (0.36 g, 2.60 mmol) using the methods of (128).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48]>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH2:44][CH2:45][CH2:46][O:47][CH3:48])=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCOc1ccccc1CCl
Product: COCCCOc1ccccc1COC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Method D, 0.200 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.113 g of 1-chloromethyl-2-(3-methoxypropoxy)benzene are reacted. The title compound is obtained as a yellowish oil. Rf=0.44 (1:2 EtOAc-heptane); Rt=6.25.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=2)[C:20]([O:22][CH3:23])=[O:21])[CH:5]=[CH:4][N:3]=1.[F:27][C:28]1[C:29]([CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:30][C:31]([O:35][CH3:36])=[C:32]([CH:34]=1)[NH2:33].C1(C)C=CC(S(O)(=O)=O)=CC=1.CC(O)C>C(Cl)Cl>[F:27][C:28]1[C:29]([CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:30][C:31]([O:35][CH3:36])=[C:32]([NH:33][C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]4=[N:10][C:9]=3[C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([O:22][CH3:23])=[O:21])[CH:5]=[CH:4][N:3]=2)[CH:34]=1
Reactant: COC(=O)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(CCN2CCCCC2)c(F)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2nc3ccccn3c2-c2ccnc(Nc3cc(F)c(CCN4CCCCC4)cc3OC)n2)c1
Temperature: 180 °C
Yield: 51.4 %

Procedure:
Methyl 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzoate (Intermediate Example 3) (300 mg, 0.82 mmol), 5-fluoro-2-(methyloxy)-4-[2-(1-piperidinyl)ethyl]aniline (Example 127, step D) (187 mg, 0.74 mmol), and p-toluenesulfonic acid (375 mg, 1.97 mmol) were weighed into a 10 mL microwave vial. 7 mL of iPrOH was added and the mixture was heated in the microwave to 180° C. for 17 min. The mixture was transferred to a 50 mL round bottom and diluted with 10 mL of DCM. 2 g of silica gel was added. The solvent was rotovaped down and the residue purified by flash chromatography to give the title compound of step A (220 mg, 0.38 mmol, 46%). 1H NMR (400 MHz, CDCl3) δ ppm 9.51 (d, J=6.97 Hz, 1H), 8.37-8.39 (m, 1H), 8.23-8.30 (m, 2H), 8.08-8.11 (m, 1H), 7.84-7.87 (m, 1H), 7.79 (s, 1H), 7.74 (d, J=8.80 Hz, 1H), 7.50 (t, J=7.70 Hz, 1H), 7.35-7.41 (m, 1H), 6.95 (t, J=6.97 Hz, 1H), 6.76 (d, J=6.97 Hz, 1H), 6.60 (d, J=5.50 Hz, 1H), 3.91 (s, 3H), 3.90 (s, 3H), 2.79-2.86 (m, 2H), 2.54-2.60 (m, 2H), 2.46-2.54 (m, 4H), 1.60-1.66 (m, J=5.68, 5.68, 5.68, 5.68 Hz, 4H), 1.43-1.50 (m, J=5.13 Hz, 2H).