Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:37]1(=[O:47])[NH:42][CH2:41][CH2:40][N:39]2[CH2:43][CH2:44][NH:45][CH2:46][CH:38]12.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.ClCCl>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:45]3[CH2:44][CH2:43][N:39]4[CH2:40][CH2:41][NH:42][C:37](=[O:47])[CH:38]4[CH2:46]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C1NCCN2CCNCC12
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCN3CCNC(=O)C3C2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 24 h
Yield: 61.7 %

Procedure:
To a solution of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide [WO 2005/002577] (50 mg, 0.092 mmol) in 0.5 mL of DMSO was added hexahydro-2H-pyrazino[1,2-a]pyrazin-1(6H)-one (D78, 33 mg, 0.213 mmol) and potassium carbonate (39 mg, 0.28 mmol) and the reaction was left at 150° C. for 24 h. It was worked up by diluting with dichloromethane and extracting with brine. The organics were dried (Na2SO4), and the solvent removed. The product was purified by flash chromatography: silica, cyclohexane:EtOAc 50:50 to EtOAc. Obtained 37 mg of the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14]([Cl:20])=[CH:15][CH:16]=2)[N:11]=1.C(#N)C>O>[Cl:20][C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccsc1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccsc1
Temperature: 4 °C
Yield: 27.7 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 3-thiophenecarboxylic acid (16 g), N,N'-carbonyldiimidazole (20.1 g) and 2-amino-7-chloro-1,8-naphthyridine (16.8 g). The product produced by precipitation in water (10.6 g; m.p. 250° C.) is dissolved in boiling acetonitrile (980 cc). After 2 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (2×25 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-3-thiophenecarboxamide (7.5 g) is produced, m.p. 254° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[O:13])[N:3]=1.CCN(C(C)C)C(C)C.[NH:30]1[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]1>CN(C=O)C>[NH:30]1[CH:34]=[CH:33][C:32]([NH:35][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[O:13])[N:3]=2)=[N:31]1
Reactant: O=C(c1cccc(F)c1)c1nc(Cl)c2ccccc2n1
Reactant: Nc1cc[nH]n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccc(F)c1)c1nc(Nc2cc[nH]n2)c2ccccc2n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
To a solution of (4-chloroquinazolin-2-yl)(3-fluorophenyl)methanone from Example 1 (57 mg, 0.20 mmol) in DMF (3 mL), DIEA (0.069 mL, 0.4 mmol) and 1H-pyrazol-3-amine (83 mg, 1 mmol) were added. The mixture was stirred at 50° C. for 2 h. The reaction was quenched by adding water and the precipitate was filtered. The crude solid was purified on preparative TLC using DCM/MeOH as mobile phase to afford (4-(1H-pyrazol-3-ylamino)quinazolin-2-yl)(3-fluorophenyl)methanone (18 mg, 27%). 1H NMR (300 MHz, DMSO-d6) δ 6.80 (s, 1H), 7.67-7.61 (m, 4H), 7.92-7.84 (m, 4H), 8.78 (m, 1H), 10.82 (s, 1H), 12.54 (s, 1H); LC-MS (ESI) m/z 334 (M+H)+.
Reaction SMILES: Cl.[N+:2]([C:5]1[C:6]([NH:15][C:16](=O)[CH2:17][CH2:18][CH2:19][CH3:20])=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])([O-])=O>[Fe].CO>[CH2:17]([C:16]1[NH:15][C:6]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=[CH:14][C:5]=2[N:2]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC(=O)Nc1c(C(=O)OC)cccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: CCCCc1nc2cccc(C(=O)OC)c2[nH]1
Temperature: 25 °C
Yield: 69 %

Procedure:
To a mixture of conc. HCl (5.3 ml) and methanol (35 ml) was added methyl 3-nitro-2-(N-valerylamino)benzoate (2.8 g), to which was added iron powder (1.7 g) in portions while stirring at room temperature. The resultant mixture was heated for 8 hours under reflux. Insoluble material was filtered off, and the filtrate was concentrated. To the concentrate were added water and ethyl acetate. The aqueous layer was made basic with 6N NaOH and was extracted with ethyl acetate. The organic layers were combined, washed with water and dried. The solvent was evaporated, and the residue was purified by column chromatography on silica gel. The crystals thus obtained were recrystallized from isopropyl ether to give colorless needles (1.6 g, 70%), m.p. 97-98° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23]Br)=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[CH2:34]([NH2:37])[CH2:35][NH2:36]>CS(C)=O.ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH:36][CH2:35][CH2:34][NH2:37])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: NCCN
Reactant: COc1cc(CC(=O)NCCCc2ccc(C)c(C)c2)ccc1OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1cc(CC(=O)NCCCc2ccc(C)c(C)c2)ccc1OCCNCCN
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.9 %

Procedure:
0.35 g (0.81 mmol) of N-{3-(3,4-dimethylphenyl)propyl}-4-(2-bromoethoxy)-3-methoxyphenylacetamide obtained in step 1 of Example 2 was dissolved in 3 ml of dimethylsulfoxide and 0.56 g (4.02 mmol) of potassium carbonate was added thereto. To this mixture, 0.48 g (8.06 mmol) of ethylenediamine was slowly added at room temperature, followed by stirring at room temperature for 4 hours. The reaction mixture was diluted with 40 ml of dichloromethane, washed with water and acidified with 1N HCl and the aqueous layer was separated. The aqueous layer was basified with hydrogen peroxide, extracted with 40 ml of dichloromethane, dried and the solvent was removed under a reduced pressure. The residue was triturated with a mixture of dichloromethane and hexane(1:2) to obtain 0.10 g of the title compound as a white solid(yield: 30%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].[CH3:35][N:36]([CH3:40])[C:37](Cl)=[O:38]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:35][N:36]([CH3:40])[C:37]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])=[O:38]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN(C)C(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 99.8 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0806 g, 0.175 mmol) was dissolved in dichloromethane (2.0 mL), and the solution was treated with 4-dimethylaminopyridine (0.0850 g, 0.699 mmol) and dimethylcarbamoyl chloride (0.0640 mL, 0.699 mmol) to obtain 4-dimethylcarbamoyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0930 g, yield 99%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:27]=1[C:28]([OH:30])=O.CCN(C(C)C)C(C)C.[Cl:46][C:47]1[CH:52]=[C:51]([Cl:53])[CH:50]=[CH:49][C:48]=1[C:54]1[CH:59]=[CH:58][C:57]([NH2:60])=[CH:56][CH:55]=1>CN(C=O)C>[Br:25][C:26]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:27]=1[C:28]([NH:60][C:57]1[CH:56]=[CH:55][C:54]([C:48]2[CH:49]=[CH:50][C:51]([Cl:53])=[CH:52][C:47]=2[Cl:46])=[CH:59][CH:58]=1)=[O:30]
Reactant: O=C(O)c1cc(F)c(F)cc1Br
Reactant: Nc1ccc(-c2ccc(Cl)cc2Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2ccc(Cl)cc2Cl)cc1)c1cc(F)c(F)cc1Br
Temperature: 25 °C

Procedure:
Solid HATU (501 mg, 1.3 mmol) was added to a DMF solution (1 mL) of 2-bromo-4,5-difluorobenzoic acid (250 mg, 1.1 mmol), i-Pr2NEt (0.5 mL, 3.2 mmol), and 2′,4′-dichloro-[1,1′-biphenyl]-4-amine (251 mg, 1.1 mmol) and the resulting mixture was stirred at room temperature. After 2 h the resulting mixture was directly purified via column chromatography to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([O:20][CH:21]=[C:22]([C:28](OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>CC1C=CC=CC=1C>[CH2:26]([O:25][C:23]([C:22]1[CH:28]=[N:17][C:14]2[C:15]([C:21]=1[OH:20])=[N:16][C:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[CH:12][CH:13]=2)=[O:24])[CH3:27]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc(-c2ccc(N)cn2)cc1OC
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cnc2ccc(-c3ccc(OC)c(OC)c3)nc2c1O
Temperature: 250 °C

Procedure:
A mixture of 6-(3,4-dimethoxy-phenyl)-pyridin-3-ylamine (Stage 249.1.4, 2.0 g, 8.69 mmol) and diethyl ethoxymethylenemalonate (Aldrich, Buchs, Switzerland, 2.087 ml, 10.42 mmol) in o-xylene (22 ml) was heated by microwaves at 150° C. for 45 min and at 250° C. for 9 h. The RM was cooled to rt and crystallized with diethylether. The suspension was filtered and the cake was triturated again in hot EtOAc and cooled after in the freezer. The suspension was filtered again. The cake was washed with EtOAc and dried in the vacuum oven to give the title compound as a brown solid. Used for next step without further purification. (HPLC: tR 2.58 min (Method A); M+H=355 MS-ES)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][C:12]3[O:13][CH2:14]O[C:11]=3[C:10]=2[C:18]([OH:20])=O)=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].S(Cl)(Cl)=[O:26]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([C:9]3[CH:17]=[CH:16][C:12]4[O:13][CH2:14][O:26][C:11]=4[C:10]=3[C:18]2=[O:20])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccc3c(c2C(=O)O)OCO3)cc1
Reactant: O=S(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)c1c-2ccc2c1OCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
Crude 5-(4-methoxyphenyl)-1,3-benzodioxole-4-carboxylic acid was dissolved in thionyl chloride (10 mL) and refluxed for 6 h. The reaction was cooled to ambient temperature and the solvent was removed by rotary evaporation to give the crude acid chloride. The acid chloride was dissolved in methylene chloride (10 mL) and added to a suspension of aluminum chloride (0.67 g, 5.00 mmol) in methylene chloride (10 mL). The reaction was stirred at ambient temperature for 4 h and quenched with a mixture of ice and concentrated HCl. The mixture was extracted with methylene chloride and dried with magnesium sulfate and concentrated by rotary evaporation to afford 89 mg of 8-methoxy-10H-fluoreno[1,2-d]-1,3-dioxol-10-one (0.35 mmol, 45% yield). 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J=8.3 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 7.06 (d, J=2.2, 1H), 6.88 (dd, J=8.3, 2.2 Hz, 1H), 6.90 (d, J=8.3 Hz, 1H), 6.15 (s, 2H), 3.86 (s, 3H). Sodium hydride (21 mg, 0.53 mmol) was suspended in THF (5 mL) and diethyl cyanomethylphosphonate (94 mg, 0.53 mmol) was slowly added to the suspension. After 15 min a yellow solution resulted and a solution of 8-methoxy-10H-fluoreno[1,2-d]-1,3-dioxol-10-one (89 mg, 0.35 mmol) in THF (5 mL) was added dropwise. The solution was allowed to stir at ambient for 16 h. The solvent was removed by rotary evaporation and the residue was taken up in methylene chloride, washed with water, and dried with magnesium sulfate. The solvent was removed by rotary evaporation to yield the crude Horner-Emmons product as an orange solid.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]([OH:33])[CH:14]([N:19]3[CH2:24][CH2:23][C:22]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)([OH:25])[CH2:21][CH2:20]3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CO>[Pd].C(O)(=O)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:22]2([OH:25])[CH2:23][CH2:24][N:19]([CH:14]3[CH:13]([OH:33])[C:12]4[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=4)[O:16][CH2:15]3)[CH2:20][CH2:21]2)=[CH:27][CH:28]=1
Reactant: OC1c2ccc(OCc3ccccc3)cc2OCC1N1CCC(O)(c2ccc(F)cc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Oc1ccc2c(c1)OCC(N1CCC(O)(c3ccc(F)cc3)CC1)C2O
Reaction time: 8 h
Yield: 54.7 %

Procedure:
A mixture of 3R*4S*7-benzyloxy-3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]-chroman-4-ol (0.80 g, 1.78 mmol), 10% palladium on carbon (0.16 g), methanol (40 mL), and acetic acid (0.8 mL) was hydrogenated for 8 hours with a starting pressure of 48.5 psi. The reaction was filtered through celite and the filtrate was concentrated. The residue was stirred vigorously with ether and saturaturated sodium bicarbonate for 1 hour. The solid was washed with water and ether and dried in vacuo. Recrystallization from ethanol yielded 0.35 g (54%) of 3R*4S*3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]-chroman-4,7-diol as a white solid which had mp 159-160° C.; NMR DMSO∂σδ7.55-7.47 (m, 2H), 7.11 (t, J=9 Hz, 2H), 7.02 (d, J=8.4 Hz, 1H)k, 6.32 (dd, J=2.3, 8.3 Hz, 1H), 6.15 (d, J=2.3 Hz 1H), 5.10-4.50 (br m with s at 4.63, 3H), 4.23 (dd, J=2.8, 10.3 Hz, 1H), 4.04 (t, J=10.5 Hz, 1H), 2.99 (br d, J=10.8 Hz, 1H), 2.86 (br d, J=10.7 Hz, 1H), 2.73-2.50 (m, 3H), 2.08-1.90 (m, 2H), 1.58 (br d, J=13 Hz, 2H).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4](O)=[N:3][CH:2]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:4]1[C:5]2[CH:9]=[CH:8][NH:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: Oc1ncnc2[nH]ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2[nH]ccc12
Temperature: 25 °C
Yield: 42 %

Procedure:
To 7H-pyrrolo[2,3-d]pyrimidin-4-ol (0.425 g, 3.14 mmol) was added phosphorus oxychloride (4 ml). The mixture was heated at reflux for 90 minutes and then cooled to room temperature. The solution was poured onto cracked ice, and extracted with chloroform (3×50 ml) and ethyl acetate (100 ml). The extracts were then dried and concentrated, and the residue obtained triturated with hot ethyl acetate (200 ml) to yield the title compound (0.204 g, 42%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:44]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52](O)=[C:51]([O:56][CH3:57])[CH:50]=1)(=[O:46])[CH3:45].N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[C:44]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([O:7][C@@H:6]2[O:8][C@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:5]2[O:4][C:1](=[O:3])[CH3:2])=[C:51]([O:56][CH3:57])[CH:50]=1)(=[O:46])[CH3:45]
Reactant: CC(=O)OC[C@H]1OC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COc1cc(COC(C)=O)ccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cc(COC(C)=O)ccc1O[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.3 %

Procedure:
Under an argon atmosphere, 2,3,4,6-tetra-O-acetyl-D-glucopyranose (2) (576 mg, 1.65 mmol) was dissolved in toluene (5 ml) at room temperature, and triphenylphosphine (423 mg, 1.61 mmol) and 4-acetoxymethyl-2-methoxyphenol (6) (204 mg, 1.04 mmol) were added. Then, the reaction mixture was cooled in an ice bath, diethyl azodicarboxylate 2.2 M toluene solution (0.75 ml, 1.65 mmol) was added dropwise, the ice bath was removed and the mixture was warmed to room temperature and stirred for 3 hours. The reaction solution was concentrated under reduced pressure, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient; ethyl acetate:n-hexane=20:80→61:39) to give 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-methoxybenzyl acetate (7) (335 mg, 0.637 mmol, yield 61%) as a colorless oil.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=1)#[N:2]
Reactant: NCCc1ccc(Cl)cc1
Reactant: CC(C)OC(=NC#N)c1ccncc1
Solvent: CO
Product: N#CNC(=NCCc1ccc(Cl)cc1)c1ccncc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 57.7 %

Procedure:
Isopropyl N-cyano-4-pyridinecarboximidate (0.5 g, 2.6 mmol) was dissolved in methanol (5 ml), and 2-(4-chlorophenyl)ethylamine (0.46 g, 3.0 mmol) having been diluted with methanol (5 ml) was added. The mixture was stirred at room temperature for 40 minutes. After the reaction was completed, the reaction solution was then concentrated under reduced pressure. The residual concentrate was further crystallized from methanol-diethyl ether to give the title compound (0.44 g, 1.5 mmol, yield: 58%) as colorless needles.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[CH2:34][O:35][CH3:36])[NH:28][C:27](=[O:38])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[CH2:34][O:35][CH3:36])[NH:28][C:27](=[O:38])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Reactant: COCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Product: COCC(=O)Nc1cc2c(cc1F)C(=Cc1[nH]c3c(c1C)C(=O)N(CCN1CCCCC1)CC3)C(=O)N2
Yield: 55 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide as starting materials to give N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxy-acetamide (55 mg, 55.0%) as a brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[O:9])[CH:5]=[N:4][CH:3]=1.[CH3:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C1C=CC=CC=1>[CH3:16][CH:17]1[CH2:22][CH2:21][N:20]([C:2]2[N:7]=[C:6]([C:8]([NH:10][C:11]3[NH:15][N:14]=[N:13][N:12]=3)=[O:9])[CH:5]=[N:4][CH:3]=2)[CH2:19][CH2:18]1
Reactant: O=C(Nc1nnn[nH]1)c1cncc(Cl)n1
Reactant: CC1CCNCC1
Solvent: c1ccccc1
Product: CC1CCN(c2cncc(C(=O)Nc3nnn[nH]3)n2)CC1

Procedure:
To a suspension of 1.13 g of 6-chloro-N-(1H-5-tetrazolyl)pyrazine-2-carboxamide in 20 ml of benzene, 2.96 ml of 4-methylpiperidine was added, and the mixture was refluxed for 5 hours. The reaction mixture was evaporated, ethanol was added to the residue, and then the ethanol solution was adjusted with ethanolic hydrogen chloride to pH 3. The precipitate was collected by filtration, and recrystalized from a mixture of dimethylsulfoxide and methanol affording 1.02 g of the desired compound as yellow columns, m.p. 246.5°-248.5° C. (decomp.).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:35])[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCN(c4ccccc4Cl)CC3)cnc12
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCN(c4ccccc4Cl)CC3)cnc12
Yield: 24.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(2-chlorophenyl)piperazine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.087 g, 0.177 mmol) obtained in step 2 and methanesulfonamide (0.084 g, 0.855 mmol), the title compound (0.025 g, 25%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([NH2:7])=[N:4][N:3]=1.[CH:8]1[C:21]2[CH:20]([C:22](Cl)=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:13][C:12]=2[CH:11]=[CH:10][CH:9]=1>>[CH3:1][C:2]1[O:6][C:5]([NH:7][C:22]([CH:20]2[C:21]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[O:13][C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:23])=[N:4][N:3]=1
Reactant: Cc1nnc(N)o1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Product: Cc1nnc(NC(=O)C2c3ccccc3Oc3ccccc32)o1

Procedure:
The title compound, white solid, m.p. 261-263° C. and MS: m/e=307.1 (M+) was prepared in accordance with the general method of example 44a from 5-methyl [1,3,4]oxadiazol-2-ylamine and 9-xanthene-carboxylic acid chloride.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]1(=[O:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][NH:12]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1>C1COCC1.CN(C=O)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:12]2[CH:13]=[CH:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]2=[O:21])=[CH:25][CH:26]=1
Reactant: O=c1[nH]ccc2ccccc12
Reactant: Fc1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=c1c2ccccc2ccn1Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
According to Scheme 11: To a solution of NaHMDS (2 eq, 3.00 mmol, 0.50 g) in THF (3 mL) at 0° C. was added isoquinolin-1(2H)-one (1 eq, 1.00 mmol, 0.20 g) dissolved in THF (3 mL) and DMF (5 mL). The reaction mixture was stirred for 10 min at 0° C. then cooled at −70° C. The 1-(bromomethyl)-4-fluorobenzene (4 eq, 4.00 mmol, 0.80 g) was added in one portion to the reaction mixture. The reaction mixture was allowed to warm to room temperature, for one hour. Upon completion the reaction mixture was concentrated under vacuum and the crude residue partitioned between water and AcOEt, the aqueous layer was extracted with AcOEt. The combined organic layers were successively washed with water (2.30 mL), HCl (1M, 2.30 mL), brine (2.20 mL), dried over Na2SO4, filtered and evaporated to afford a yellow oil. The crude compound was purified on silica gel using cyclohexane/AcOEt 80/20 as eluent to afford 2-(4-fluorobenzyl)isoquinolin-1(2H)-one as a white solid (0.70 mmol, 0.26 g, 74%).
Reaction SMILES: N.[OH:2][C@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([C:9]#[N:10])[CH2:4]1>CO.[Ni]>[NH2:10][CH2:9][C@H:5]1[CH2:6][CH2:7][CH2:8][C@H:3]([OH:2])[CH2:4]1
Reactant: N#C[C@H]1CCC[C@H](O)C1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NC[C@H]1CCC[C@H](O)C1
Reaction time: 15 h
Yield: 77.4 %

Procedure:
To a 2 N solution of NH3 in MeOH (15 mL) in a high pressure Parr bottle was added trans-3-hydroxy-cyclohexanecarbonitrile (0.12 g, 1.0 mmol) and W-7 Raney Nickel (0.2 g, 3.4 mmol). The mixture was placed under 45 psi H2 and shaken for 15 h. The pressure was released and the reaction filtered through a pad of diatomaceous earth. The filter pad was washed with MeOH and the filtrate was concentrated under reduced pressure to provide 0.1 g (79%) of trans-3-aminomethyl-cyclohexanol as a white solid.