Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][C@H:16]([OH:18])[CH2:15][CH2:14][C@H:13]1[CH2:12][S:11][C:10]([N:19]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:9]2.CI.[H-].[Na+].[C:40](OCC)(=O)C>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][C@H:16]([O:18][CH3:40])[CH2:15][CH2:14][C@H:13]1[CH2:12][S:11][C:10]([N:19]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[N:9]2
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)C2=N[C@@]3(c4ccccc4F)C[C@H](O)CC[C@H]3CS2)cc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(C(=O)OC(C)(C)C)C2=N[C@@]3(c4ccccc4F)C[C@H](OC)CC[C@H]3CS2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
tert-Butyl(±)-[(4aR*,7R*,8aS*)-8a-(2-fluorophenyl)-7-hydroxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]-(4-methoxybenzyl)carbamate obtained in Preparation Example 58-(9) (541 mg) was dissolved in DMF (5 mL). Methyl iodide (113 μL, specific gravity: 2.28 g/cm3) was added and then the mixture was cooled in an ice bath under a nitrogen atmosphere. Sodium hydride (60%, 55 mg) was added, followed by stirring for one hour and 45 minutes. Thereafter, methyl iodide (113 μL, specific gravity: 2.28 g/cm3) and sodium hydride (60%, 55 mg) were added, and the mixture was warmed to room temperature and stirred for one hour and 45 minutes. Thereafter, methyl iodide (113 μL, specific gravity: 2.28 g/cm3) was further added, followed by stirring for 13 hours. Ethyl acetate and water were added to the reaction solution, followed by further stirring. Then, the aqueous layer was separated. The organic layer was sequentially washed with a saturated ammonium chloride solution, water and brine. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solid was removed by filtration. The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography to obtain the title compound (409 mg).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][CH2:12][CH2:13]OS(C)(=O)=O)[CH:9]=[CH:10][C:4]=2[C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1.[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C)C=O>[N:29]([CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[C:3]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[C:2]([CH3:1])[S:6][C:5]=2[CH:7]=1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1sc2cc(OCCOS(C)(=O)=O)ccc2c1-c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1sc2cc(OCCN=[N+]=[N-])ccc2c1-c1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Yield: 99.6 %

Procedure:
0.300 g (0.697 mmol) Methanesulfonic acid 2-[2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yloxy]-ethyl ester dissolved in 2.0 ml of N,N-dimethylformamide were treated with 0.137 g (2.09 mmol) sodium azide and the reaction mixture heated to 80° C. for 1 hour. It was then cooled to room temperature, poured into 30 ml of ice-water and extracted 3 times with 10 ml of ether. The combined ether phases were washed with brine, dried over magnesium sulfate and evaporated under reduced pressure giving 0.262 g (99.6%) 6-(2-Azido-ethoxy)-2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophene as colorless oil, MS: 377 (M+).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:18])[C@@H:6]([CH2:16][OH:17])[NH:7][C:8](=[O:15])[C@H:9]([CH2:11][C:12](=[O:14])[OH:13])[NH2:10])([CH3:3])[CH3:2].CO[C:21](=[O:47])[C@H:22]([CH2:40][C:41]1C=CC=CC=1)[NH:23][C:24](=O)[C@](C(N1CCCCC1)=O)(CC(=O)O)N>>[CH:1]([O:4][C:5](=[O:18])[C@@H:6]([CH2:16][OH:17])[NH:7][C:8](=[O:15])[C@H:9]([CH2:11][C:12](=[O:13])[OH:14])[NH:10][C:21](=[O:47])[C@H:22]1[CH2:40][CH2:41][CH2:24][NH:23]1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)[C@@H](CO)NC(=O)[C@@H](N)CC(=O)O
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@](N)(CC(=O)O)C(=O)N1CCCCC1
Product: CC(C)OC(=O)[C@@H](CO)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H]1CCCN1

Procedure:
This compound was prepared from 1.7 g α-L-aspartyl-D-serine isopropyl ester and 2.4 g N-benzyloxycarbonyl-D-proline N-hydroxysuccinimide ester in a manner similar to Example 11 (C) and (D). Yield: 1.7 g, m.p.: 230°-233° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C)C=O.C(OCC)C>[C:25]([Si:22]([O:21][CH2:20][CH2:19][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:9])[CH:4]=1)([CH3:24])[CH3:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Cl)c(F)c1
Temperature: 100 °C
Yield: 67.5 %

Procedure:
To a solution of 4-chloro-3-fluoro-phenol (10 g, 68 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (19 g, 136 mmol), potassium iodide (11 g, 68 mmol), and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (18 g, 75 mmol, Aldrich). The reaction mixture was heated at 100° C. for 24 h. The crude was cooled, diluted with ethyl ether, washed with water, NaHCO3 solution, and brine. The organic layer was separated, dried over Na2SO4, and concentrated. The filtrate was concentrated and the residue was purified by chromatography (EtOAc:Hexanes=1:20) to give tert-butyl-[2-(4-chloro-3-fluoro-phenoxy)-ethoxy]-dimethyl-silane as colorless oil (Yield 14 g, 69%).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:16][N:15]=1.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>C1COCC1>[F:13][C:14]1[C:19]([B:25]([OH:30])[OH:26])=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:16][N:15]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COCCOc1ccc(F)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COCCOc1cnc(F)c(B(O)O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a stirred solution of diisopropylamine (Aldrich, 3.03 mL, 21.2 mmol) in THF (30 mL) in 250 mL round-bottomed flask, nBuLi (Aldrich, 2.5 M in hexanes, 8.12 mL, 20.3 mmol) was added slowly at 0° C. The mixture was stirred at 0° C. for 30 min. The mixture was cooled to −78° C. and 2-fluoro-5-(2-methoxyethoxy)pyridine (1.58 g, 9.23 mmol) in a total of 5 mL THF was added slowly. The orange mixture was stirred at that temperature for 30 min then triisopropyl borate (Aldrich, 4.72 mL, 20.3 mmol) in a total of 5 mL of THF was added slowly. The mixture was stirred at −78° C. for 10 min, then the cold bath was removed and the mixture was stirred at room temperature for 1 h. 1 N NaOH (about 70 mL) was added and the layers were separated. The aqueous phase was washed with EtOAc (50 mL) and acidified to about pH with 5N HCl. The aq phase was extracted with EtOAc (4×50 mL). The combined organic phases were washed with saturated aqueous sodium chloride (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-fluoro-5-(2-methoxyethoxy)pyridin-3-ylboronic acid (1.76 g, 89% yield) as a pale yellow residue. This material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:35])[C@@H:10]([NH:22][C:23](=[O:34])[CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.[C:43]1([C:49](Cl)([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(Cl)(Cl)Cl>[C:30]([O:29][C:27]([NH:26][CH2:25][CH2:24][C:23]([NH:22][C@H:10]([C:9]([NH:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[NH:1][C:49]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)=[O:35])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:34])=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)CCNC(=O)OC(C)(C)C)c1N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cn1ncc(NC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)CCNC(=O)OC(C)(C)C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the crude product of tert-butyl (4S)-5-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-4-{[3-(tert-butoxycarbonylamino)propionyl]amino}-5-oxopentylcarbamate and triethylamine (1.52 g) in chloroform (100 ml) was added triphenylmethyl chloride (4.20 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed successively with 10% aqueous citric acid solution, brine and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give tert-butyl (4S)-4-{[3-(tert-butoxycarbonylamino)propionyl]amino}-5-{[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}-5-oxopentylcarbamate (7.20 g) as an oil.
Reaction SMILES: O.NN.[NH:4]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:7](=O)[C:5]1=[O:6].N1C2C(=CC=CC=2)C(=O)C1=NN.N1(C2CCCCCCC2)CCCCCCN1.N1(C2CCCCCCCCCC2)CCCCCCCCCN1>C(N(C(C)C)C(C)C)C>[NH:4]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:7][C:5]1=[O:6]
Reactant: O=C1Nc2ccccc2C1=O
Agent: C1CCCC(N2CCCCCCN2)CCC1
Agent: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Agent: NN
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Cc2ccccc2N1

Procedure:
in a polar solvent with hydrazine hydrate in the presence of a tertiary amine catalyst, characterized in that the isatin is converted to the corresponding isatin hydrazone at a temperature of from 15 to 185° C. which is directly reacted further by adding a diazabicyclooctane and/or diazabicycloundecane and/or ethyldiisopropylamine catalyst at temperatures of from 100 to 185° C. while distilling off the water of reaction formed to give the corresponding 2-oxindole of the formula which is then isolated by distilling off the solvent and crystallizing out of the reaction mixture.
Reaction SMILES: [C:1]([CH:4]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH2:14][CH2:13][C:12]=2[CH:16]=1)[C:5]([OH:7])=[O:6])([OH:3])=[O:2].O.Cl[CH2:19][O:20][C:21](=[O:23])[CH3:22].C(OCC)(=O)C>[OH-].[Na+].CCOCC>[C:21]([O:20][CH2:19][O:6][C:5]([CH:4]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH2:14][CH2:13][C:12]=2[CH:16]=1)[C:1]([OH:3])=[O:2])=[O:7])(=[O:23])[CH3:22]
Reactant: O=C(O)C(C(=O)O)c1ccc2c(c1)CCO2
Reactant: CC(=O)OCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OCOC(=O)C(C(=O)O)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
α-Carboxy(2,3-dihydro-5-benzofuranyl)acetic acid (10 mmole) is dissolved in 50 ml of water containing 10 mmole of sodium hydroxide. This mixture is stirred for 30 minutes at room temperature and then 10 mmole of chloromethylacetate in 25 ml of ether is added. The temperature during the addition is 10° C.; after the addition is complete, the temperature is raised to 20° C. and the mixture stirred for an additional 30 minutes. The pH is adjusted to 2 and ethyl acetate is added. The organic phase is removed, dried over magnesium sulfate, filtered and evaporated to give the title compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:11][C@H:6]1[O:7][CH2:8][CH2:9]Br)(=[O:3])[CH3:2].[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([SH:35])=[CH:31][CH:30]=1.[OH-].[Na+].O>[Cl-].C[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC.C1C=CC=CC=1.C(OCC)(=O)C.C(CC(C)(C)C)(C)C>[C:1]([O:4][C@@H:5]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@@H:13]([O:19][C:20](=[O:22])[CH3:21])[C@@H:12]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:11][C@H:6]1[O:7][CH2:8][CH2:9][S:35][C:32]1[CH:33]=[CH:34][C:29]([NH2:28])=[CH:30][CH:31]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc(S)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](OCCBr)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](OCCSc2ccc(N)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
2-Bromoethyl 2,3,4,6-tetra-O-acetyl-β-D-galactopyranoside (1) (2.05 g; 4.50 mmol), p-aminothiophenol (1.2 g; 9.6 mmol), methyltrioctylammonium chloride (20 mg) and sodium hydroxide (0.3 g; 7.5 mmol) were dissolved in benzene (5 ml) and water (5 ml) The reaction mixture was stirred vigorously for 9 h (TLC: SiO2, ethyl acetate:isooctane 3:1) and worked up as above Chromatography (SiO2, ethyl acetate:isooctane 2:1) gave the title compound (20) as an amorphous solid. Yield: 1.6 g (71%). [α]D21 +7.7° (c 1.0; CHCl3); 1H-NMR (CDCl3, TMS) δ 7.25, 6.63 (ABq, 4H, JAB =8.6 Hz, aromatic H), 5.39 (d, 1H, J3,4 =3.5 Hz, H4), 5.22 (dd, 1H, J1,2 =7.9 Hz, J2,3 =10.4 Hz, H2), 5.01 (dd, 1H, H3), 4.45 (d, 1H, H1), 2.92 (t, 1H, J=6.8 Hz, S--CH2), 2.15, 2.08, 2.05, 2.00 (s, 3H each, CH3CO) ppm. 13C-NMR (CDCl3, TMS) δ 170.4, 170.3, 170.2, 169.5 (CO), 146.4, 134.5, 122.0, 115.6 (aromatic C), 101.5 (Cl), 70.9, 70.6, 68.8, 68.7, 67.0 (C2-C5, O--CH2), 61.2 (C6), 35.7 (S--CH2), 20.9, 20.7, 20.6 (CH3 --CO) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14])[CH2:6][N:7]=[C:8]=[O:9].[N+:17](=[C:19]1[N:23]=[CH:22][N:21]=[C:20]1[C:24]([NH2:26])=[O:25])=[N-:18]>CS(C)=O>[O:9]=[C:8]1[N:7]([CH2:6][C:5]2[CH:10]=[C:11]([O:15][CH3:16])[C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:18]=[N:17][C:19]2=[C:20]([C:24]([NH2:26])=[O:25])[N:21]=[CH:22][N:23]12
Reactant: COc1cc(CN=C=O)cc(OC)c1OC
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Solvent: CS(C)=O
Product: COc1cc(Cn2nnc3c(C(N)=O)ncn3c2=O)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4,5-Trimethoxybenzyl isocyanate (Sigma Aldrich) (0.536 g, 2.4 mmol) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (0.274 g, 2 mmol) in dry dimethylsulfoxide (2.5 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of ice and the solid product removed by filtration, washed with water and ethyl acetate, and then recrystallised from chloroform/hexane to give an off-white powder. Yield: 0.323 g, 45%. IR vmax/cm−1 1740, 1690, 1589. 1H NMR δH (DMSO-d6) 3.64 (3H, s, 4-OMe), 3.76 (6H, s, 3,5-OMe), 5.42 (2H, s, CH2Ar), 6.75 (2H, s, ArH), 7.68 (1H, br s, NH), 7.81 (1H, br s, NH), 8.84 (1H, s, 6-H). δC (DMSO-d6) 52.5, 56.4, 60.4, 105.9, 129.4, 131.3, 131.7, 134.9, 137.6, 139.7, 153.4, 162.0. MS Found 361.1300. Calc for (M+H): 361.1260. Found C, 49.5; H, 4.4; N, 23.2. Calc. for C15H16N6O5C, 50.0; H, 4.5; N, 23.3%.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:27]1[CH:31]=[C:30]([CH:32]=[O:33])[CH:29]=[N:28]1>CN(C1C=CN=CC=1)C.ClCCCl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:27]3[CH:31]=[C:30]([CH:32]=[O:33])[CH:29]=[N:28]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Reactant: O=Cc1cn[nH]c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C=O)cn3)ccc2n1CC1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (0.8 g, 1.9 mmol) was added to a solution of 1H-pyrazole-4-carbaldehyde (0.6 g, 6.2 mmol) and DMAP (1.5 g, 12 mmol) in DCE (70 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. The solvent was concentrated and the product was purified by flash chromatography on silica gel using DCM/EtOAc (1:1) as eluent to provide the title compound as white solid. Yield: 0.34 g (36%); MS (ESI) (M+H)+=465.0.
Reaction SMILES: [NH:1]1[CH:8]=[N:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].C[Si](N[Si](C)(C)C)(C)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.C(O[C@@H:34]1[O:46][C@H:45]([CH2:47][O:48]C(=O)C)[C@@H:40]([O:41]C(=O)C)[C@H:35]1[O:36]C(=O)C)(=O)C.C(=O)(O)[O-].[Na+].C[O-].[Na+].CO>C(#N)C>[C@@H:34]1([N:1]2[CH:8]=[N:7][C:5]([NH2:6])=[N:4][C:2]2=[O:3])[O:46][C@H:45]([CH2:47][OH:48])[C@@H:40]([OH:41])[C@H:35]1[OH:36]
Reactant: Nc1nc[nH]c(=O)n1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: CO
Product: Nc1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Temperature: 2.5 °C
Reaction time: 20 h

Procedure:
A mixture of 5-azacytosine (5.0 g, 44.6 mol), HMDS (6.3 mL, 29.8 mol), and TMSC1 (6 mL, 47.3 mmol) in acetonitrile (78 mL) was heated to reflux for 20 hours under an inert atmosphere. TMS-triflate (9 mL, 50 mmol) and 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose (14.2 g, 44.6 mmol were added directly to the silylated 5-azacytosine in acetonitrile. The addition was performed at ambient temperature and under an inert atmosphere. The reaction mixture was maintained under stirring for 20 hours, then poured over a pre-cooled (0-5° C.) sodium bicarbonate solution (10%, 500 mL). The resulting mixture was extracted with dichloromethane (3×75 mL). The combined organic extract was washed with cooled (0-5° C.) 10% sodium bicarbonate (2×25 mL) and brine (2×25 mL), then dried over magnesium sulfate (10.0 g), filtered, and the filtrate concentrated in vacuum to dryness. The off-white foam dissolved in methanol (120 mL) was treated with a solution of 25% sodium methoxide in methanol (1.0 g, 4.62 mmol). Soon a white solid started to separate. The suspension was stirred at ambient temperature for 15 hours, then the solid was filtered off, washed with methanol (3×5 mL) and anhydrous ether (2×5 mL), then dried in vacuum. The crude 5-azacytidine (4.5 g, 41.3%) was further purified from DMSO and methanol (for details see Example 4).
Reaction SMILES: ClC(OCC(C)C)=O.[CH3:9][N:10]([CH3:17])[CH2:11][C:12]#[C:13][C:14](O)=[O:15].CN1CCOCC1.[NH2:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[N:32]=[CH:31][C:30]([C:36]#[N:37])=[C:29]2[NH:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([Br:45])[CH:40]=1>N1C=CC=CC=1>[Br:45][C:41]1[CH:40]=[C:39]([NH:38][C:29]2[C:28]3[C:33](=[CH:34][CH:35]=[C:26]([NH:25][C:14](=[O:15])[C:13]#[C:12][CH2:11][N:10]([CH3:17])[CH3:9])[CH:27]=3)[N:32]=[CH:31][C:30]=2[C:36]#[N:37])[CH:44]=[CH:43][CH:42]=1
Reactant: CN(C)CC#CC(=O)O
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Product: CN(C)CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 16.9 %

Procedure:
Isobutyl chloroformate (0.342 g, 2.5 mmol) was dropwise added into an ice cold solution of 4-dimethylamino-2-butynoic acid (0.9 g, 3.8 mmol) and N-methyl-morpholine (0.384 g, 3.8mmol) in 50 mL of tetrahydrofaan under N2. After stirring for 30 min, a solution of 0.644 g (1.9 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 10 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 2.5 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by thin-layer chromatography eluted with 15% methanol in ethyl acetate. The product was collected, and dried in vacuo to give 0.144 g (21%) of yellow solid; mass spectrum (electrospray, m/e,): 447.9, 450.2 (M+H+); mp 180° C. (dec.).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH2:26][CH2:25][CH2:24][C@@H:20]1[C:21]([OH:23])=[O:22]>CN(C)C(=O)C.O.[Cu]I>[CH2:8]([O:7][C:5]([C:4]1[CH:3]=[C:2]([N:19]2[CH2:26][CH2:25][CH2:24][C@@H:20]2[C:21]([OH:23])=[O:22])[CH:12]=[CH:11][CH:10]=1)=[O:6])[CH3:9]
Reactant: CCOC(=O)c1cccc(I)c1
Reactant: O=C(O)[C@H]1CCCN1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cccc(N2CCC[C@@H]2C(=O)O)c1
Temperature: 25 °C
Yield: 19.2 %

Procedure:
Add ethyl 3-iodobenzoate (1.5 mL, 8.9 mmol), potassium carbonate (1.3 g, 9.4 mmol) and copper (I) iodide (0.17 g, 0.89 mmol) to a solution of D-proline (1.00 g, 8.69 mmol) in N,N-dimethylacetamide (20 mL). Bubble Argon through the mixture for 30 min then heat the reaction to 90° C. for 15 hours. Cool the mixture to room temperature, dilute with water, and filter to remove insoluble material. Wash the filtrate with diethyl ether and adjust the pH of the aqueous phase to slightly acidic by the addition of a 2 N solution of hydrochloric acid. Extract the mixture with methylene chloride and wash the combined organic phase with brine. Dry over anhydrous sodium sulfate and concentrate under reduced pressure to provide an oil. Re-dissolve the material in methylene chloride and concentrate under a stream of nitrogen to provide 0.44 g (19.2%) of (R)-1-(3-ethoxycarbonyl-phenyl)-pyrrolidine-2-carboxylic acid as an oil.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1([CH2:20][OH:21])[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=[O:6])[CH3:3]>O1CCOCC1>[CH2:2]([O:4][C:5]([C:7]1([CH2:20][OH:21])[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)C1(CO)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C1(CO)CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of hydrochloric acid (12N, 2.5 mL) in dioxane (4.5 mL) is added to 4-hydroxymethylpiperidine-1,4-dicarboxylic acid-1-tert-butyl ester-4-ethyl ester (1.35 g, 0.0047 mol) and stirred at room temperature for 30 minutes. The reaction mixture is concentrated under reduced pressure and the residue is treated with aqueous solution of sodium bicarbonate to adjust the pH to 8-9. It is again concentrated under reduced pressure and the residue is treated with dichloromethane. After drying over sodium sulfate solvent is removed to get 4-hydroxymethylpiperidine-4-carboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.[H-].[Na+].[CH2:22]([O:29][C:30]1[C:35]([CH2:36]Cl)=[C:34]([CH3:38])[CH:33]=[C:32]([CH3:39])[N:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C=O)C>[CH2:22]([O:29][C:30]1[C:35]([CH2:36][N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([Cl:1])[C:3]([O:13][CH:14]([CH3:19])[C:15]([F:18])([F:16])[F:17])=[CH:4][CH:5]=3)[C:10]2=[O:12])=[C:34]([CH3:38])[CH:33]=[C:32]([CH3:39])[N:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(Oc1ccc2c(c1Cl)C(=O)NCC2)C(F)(F)F
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)c(CN2CCc3ccc(OC(C)C(F)(F)F)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.3 %

Procedure:
To a solution of 8-chloro-7-[(1,1,1-trifluoropropan-2-yl)oxy]-3,4-dihydroisoquinolin-1(2H)-one (58a, 50 mg, 0.17 mmol) in dry DMF (6 mL) was added portionwise NaH (60% in oil, 21 mg, 0.51 mmol) at 0° C. under N2 atmosphere. The resulting mixture was stirred at 0° C. for 10 minutes and then 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 76 mg, 0.29 mmol) was added. The resulting mixture was stirred at room temperature overnight. To the reaction mixture was added H2O (20 mL). The mixture was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (4×15 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc=6:1) to give 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-7-[(1,1,1-trifluoropropan-2-yl)oxy]-3,4-dihydroisoquinolin-1(2H)-one (58b, 70 mg, 80%) as a colorless oil.