Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[N:8]=1)(=O)=O.[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([Cl:35])[C:26]=1[NH2:36]>O1CCOCC1>[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[C:27]([Cl:35])[C:26]=1[NH:36][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=2)[N:8]=1
Reactant: N#Cc1ccc(Nc2nccc(OS(=O)(=O)C(F)(F)F)n2)cc1
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(Nc2nccc(Nc3c(Cl)cc(C(F)(F)F)cc3Cl)n2)cc1
Temperature: 170 °C
Yield: 9.2 %

Procedure:
2-[(4-cyanophenyl)amino]-4-pyrimidinyl trifluoromethanesulfonate (0.0022 mol) and 2,6-dichloro-4-(trifluoromethyl)-benzenamine (0.0044 mol) were combined in 1,4-dioxane (2.5 ml) and heated in a sealed tube under Ar at 170° C. for 40 hours. The reaction mixture was allowed to cool to room temperature. Silica gel was added, and the solvent was evaporated. The residue was purified by flash column chromatography over silica gel (eluent gradient: CH2Cl2:CH3OH:NH4OH 100:0:0 to 97:2.7:0.3). The desired fractions were collected and the solvent was evaporated. The residue was recrystallized from CH3CN, filtered off and dried, yielding 0.086 g (9.2%) of 4-[[4-[[2,6-dichloro-4-(trifluoromethyl)-phenyl]amino]-2-pyrimidinyl]amino]benzonitrile (compound 66).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:17].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C=O)C>[CH3:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:17])=[O:15])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1-c1ccc(CO)cc1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccnc1-c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 23.4 %

Procedure:
To a solution of [4-(3-methyl-2-pyridinyl)phenyl]methanol (12 g, 0.06 mol) in dry DMF (150 mL) was added pyridiniumdichromate (91 g, 0.24 mol) and stirred at RT for 3 days. The reaction mixture was poured into water and extracted with ethyl acetate (250 mL). The organic layer was washed with water, brine, dried and concentrated. The crude was purified by column chromatography over silica gel to give 4-(3-methyl-2-pyridinyl)benzoic acid (3 g, 25%) as white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[CH:8]1([C@H:11]([NH2:33])[C:12]([N:14]2[CH2:18][C:17]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[F:26])=[CH:16][C@H:15]2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:13])[CH2:10][CH2:9]1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:1][CH2:2][CH2:3][S:4]([NH:33][C@@H:11]([CH:8]1[CH2:10][CH2:9]1)[C:12]([N:14]1[CH2:18][C:17]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])=[CH:16][C@H:15]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:13])(=[O:6])=[O:5]
Reactant: O=S(=O)(Cl)CCCl
Reactant: N[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C([C@@H](NS(=O)(=O)CCCl)C1CC1)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
2-chloroethanesulfonyl chloride (81 μL, 0.78 mmol, 1.1 equiv) was added to a solution of (1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethanamine (16-7, 250 mg, 0.705 mmol, 1 equiv) and N,N-diisopropylethylamine (160 μL, 0.917 mmol, 1.30 equiv) in dichloromethane (5 mL) at 0° C., and the resulting mixture was stirred for 15 minutes, then warmed to 23° C. and stirred for an additional 15 minutes. Additional 2-chloroethanesulfonyl chloride (1.2 equiv) and N,N-diisopropylethylamine (1.3 equiv) were added and the mixture was stirred for 30 minutes, then partitioned between water (75 mL) and dichloromethane (2×60 mL). The combined organic layers were dried over sodium sulfate and concentrated to give 2-chloro-N-{(1S)-1-cyclopropyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}ethanesulfonamide (27-1) as a colorless oil. LRMS m/z (M+H—Cl) 445.4 found, 445.1 required.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:9])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[CH2:11][CH2:12][N:13]([CH2:21][CH2:22]Cl)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17]>C(N(C(C)C)CC)(C)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1([N:9]2[CH2:22][CH2:21][N:13]([C:14]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:20])[CH2:12][CH2:11]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(N)CC1
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-aminocyclopropane-1-carboxylic acid ethyl ester (440 mg, 2.6 mmol) was suspended in diisopropylethylamine (2 ml). Tert-Butyl bis(2-chloroethyl)carbamate (610 mg, 2.5 mmol, prepared according to Evans et al. J. Med. Chem. 1992, 35, 3919) was added at room temperature. The suspension was stirred at room temperature for 10 minutes before being heated to 100° C. for 18 h. The resulting biphasic mixture was cooled to room temperature. Brine was added and the mixture was extracted three times with EtOAc. Combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 20% EtOAc/hexanes) to give tert-butyl 4-(1-(ethoxycarbonyl)cyclopropyl)piperazine-1-carboxylate as a colorless oil (60 mg, 8% 2 steps). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm: 0.91 (m, 2 H), 1.22 (t, J=7.2 Hz, 3 H), 1.25 (m, 2H), 1.43 (s, 9 H), 2.87 (bs, 4 H), 3.27 (bs, 4 H), 4.09 (q, J=7.2 Hz, 2 H); 13C NMR (100 MHz, CHLOROFORM-D) δ ppm 14.3, 19.0, 28.4, 45.7, 49.0, 60.2, 79.4, 154.8, 174.0; ESI-MS: m/z 299.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[C:9]([NH:11][C@H:12]([CH:16]=O)[CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[N:32][CH:33]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[C:9]([NH:11][C@H:12]([CH2:16][NH:27][C:28]2[CH:33]=[N:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH:13]([CH3:14])[CH3:15])=[O:10])=[CH:4][CH:3]=1
Reactant: COc1ccc(N)cn1
Reactant: CC(C)[C@@H](C=O)NC(=O)[C@@H](CC(=O)N1CCOCC1)c1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(NC[C@@H](NC(=O)[C@@H](CC(=O)N2CCOCC2)c2ccc(F)cc2)C(C)C)cn1

Procedure:
2-(S)-(4-Fluoro-phenyl)-N-(1-(S)-formyl-2-methyl-propyl)-4-morpholin-4-yl-4-oxo-butyramide (350 mg, 0.96 mmol, 1.0 eq.) and 5-Amino-2-methoxy-pyridine (240 μL, 1.92 mmol, 2.0 eq.) dissolved in MeOH (2.5 mL) and acetic acid (106 mL, 1.92 mmol, 2.0 eq.) added via syringe at room temperature. Sodium cyanoborohydride (121 mg, 1.92 mmol, 2.0 eq.) added in portion and the reaction monitored the reaction by LC/MS. Upon completion, solvents were evaporated and dissolved in EtOAc (100 mL) washed with brine, dried over MgSO4, filtered and evaporated. Purification by preparative mass-directed HPLC provided the title compound as a white solid after evaporation and lyophilization (2.6 mg, 5.6 □mol, 0.6%). HPLC-MS calcd. for C25H33FN4O4 (M+H+) 473.3, found 473.5.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][CH2:9][CH:10]([OH:13])[CH2:11][CH3:12])=[CH:5][CH:4]=1.[C:16]([C:24]1[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27])(=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[Br:33][C:31]1[CH:32]=[C:24]2[C:25](=[CH:29][CH:30]=1)[C:26](=[O:27])[N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:15][CH:14]=1)[C:9]([C:10](=[O:13])[CH2:11][CH3:12])=[C:16]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCC(O)CNCc1ccc(SC)cc1
Reactant: O=C(O)c1ccc(Br)cc1C(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 35.4 %

Procedure:
To a solution of 1-(4-methylsulfanylbenzylamino)butan-2-ol (8.5 g) and 2-benzoyl-4-bromobenzoic acid (14.7 g) and 1-hydroxy-1H-benzotriazole (7.4 g) in DMF (100 ml) was added triethylamine (8.4 ml) and then WSC (11.5 g) was added at room temperature. The mixture was stirred at room temperature for 4 days. The solvent was evaporated under reduced pressure, and the residue was partitioned between dichloromethane and water, washed with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1-+13/7). The resulting colorless amorphous form was dissolved in dimethyl sulfoxide (100 ml) and triethylamine (25.3 ml) was added. Under ice-cooling, pyridine sulfur trioxide complex (14.5 g) was added, and the mixture was stirred at room temperature for 8 hrs. Water (300 ml) was added, and the mixture was extracted with ethyl acetate and washed with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine. Sodium sulfate was added to dry the mixture. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1→2/3). The obtained colorless amorphous form was dissolved in 0.1N potassium hydroxide-ethanol solution (75 ml) and heated under reflux for 12 hrs. 1N Hydrochloric acid (7.5 ml) was added and the mixture was stirred under ice-cooling for 1 hr. The crystals were collected by filtration and washed with 70% ethanol-water to give the title compound (6.58 g, 34%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][C:12]([CH:13]=O)=[C:11]([I:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][C:12]([CH:13]=[N:21][OH:22])=[C:11]([I:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: COc1cc(C=O)c(I)cc1OCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cc(C=NO)c(I)cc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 100.8 %

Procedure:
A mixture of 4-benzyloxy-2-iodo-5-methoxybenzaldehyde (reference example 1-1) (12.2 g), hydroxylamine hydrochloride (2.54 g), sodium acetate (6 g) and ethanol (170 mL) was stirred at 70° C. for 1.5 hours. The mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was stirred at room temperature for 30 minutes. The solid was collected by filtration to give the title compound (12.8 g).
Reaction SMILES: [CH:1]1([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:17][CH:18]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]=[C:34]=[O:35]>CCCCCC>[CH:18]1([N:17]([CH2:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][N:8]([CH:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:34]([NH:33][C:27]3[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=3[F:25])=[O:35])[CH:11]=2)[C:34]([NH:33][C:27]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=2[F:25])=[O:35])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: c1cc(CNC2CCCCCC2)cc(CNC2CCCCCC2)c1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: CCCCCC
Product: O=C(Nc1ccc(F)cc1F)N(Cc1cccc(CN(C(=O)Nc2ccc(F)cc2F)C2CCCCCC2)c1)C1CCCCCC1
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a solution of 1 g N,N'-dicycloheptyl-m-xylylenediamine in 50 ml n-hexane, was added dropwise with stirring 5 ml of a n-hexane solution containing 1 g 2,4-difluorophenyl isocyanate under ice cooling. Stirring was continued at room temperature for two hours, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography and then recrystallized from isopropanol, giving 1.6 g of 1,3-bis[[1-cycloheptyl-3-(2,4-difluorophenyl)ureido]methyl]benzene.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:14]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>C(#N)C>[CH3:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(OC)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (10 g, 0.05 mol) in acetonitrile (100 mL) were added K2CO3 (15.3 g, 0.11 mol) and dimethyl sulfate (8.4 g, 0.06 mol) under an inert atmosphere. The reaction mixture was stirred at 80° C. for 2 h and then extracted with EtOAc (2×300 mL), The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to afford ethyl 2-(4-methoxyphenyl)acetate (8 g, 74%) as a white solid.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:25])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[C:12]([C:10]1[N:11]=[C:6]([C:4]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:5])[C:7]([OH:25])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9]=12)#[N:13]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccccc2F)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccn(Cc3ccccc3F)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 7-cyano-1-(2-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 369 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]1[OH:13].[C:20]1([C:26](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@H:12]([OH:13])[C@H:14]([OH:15])[C@@H:16]([CH2:18][O:19][C:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:17]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O[C@@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O[C@H]1n1cnc2c(Cl)ncnc21
Temperature: 40 °C
Yield: 65.1 %

Procedure:
To a solution of 6-chloro-9-β-D-ribofuranosylpurine (5.00 g, 17.4 mmol) and triphenylmethyl chloride (9.72 g, 34.8 mmol) in DMF (60 mL) was added DIPEA (2.7 mL, 19.1 mmol) dropwise. The reaction was heated to 40° C. overnight, cooled to r.t. and filtered. The yellow filtrate was diluted with chloroform and washed with water, 0.5 N HCl, and water. The organic layer was dried (Na2SO4), filtered and concentrated. The yellow foam was purified by flash chromatography (0 to 4% MeOH/CHCl3) to yield the product as a pale yellow foam (5.99 g, 65%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]2[O:19][C:20]([CH2:23][CH3:24])=[CH:21][N:22]=2)[O:12]1.C(N(C(C)C)CC)(C)C.Cl.[NH2:35][CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C(O)(C)C>[CH2:23]([C:20]1[O:19][C:18]([C@@H:13]2[C@@H:14]([OH:17])[C@@H:15]([OH:16])[C@H:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[NH:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[O:12]2)=[N:22][CH:21]=1)[CH3:24]
Reactant: CCc1cnc([C@H]2O[C@@H](n3cnc4c(Cl)ncnc43)[C@H](O)[C@@H]2O)o1
Reactant: NC1CCOCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCc1cnc([C@H]2O[C@@H](n3cnc4c(NC5CCOCC5)ncnc43)[C@H](O)[C@@H]2O)o1
Yield: 355.6 %

Procedure:
To a solution of (2R,3R,4S,5S)-2-(6-chloro-purin-9-yl)-5-(5-ethyl-oxazol-2-yl)-tetrahydro-furan-3,4-diol (0.19 g), in isopropanol (15 ml) was added diisopropylethylamine (0.3 ml) and 4-aminotetrahydropyran hydrochloride (0.135 g). After stirring at reflux for 16 h, further diisopropylethylamine (0.2 ml) and 4-aminotetrahydropyran hydrochloride (60 mg) were added. Stirring was continued at reflux for a further 20 h before the mixture was cooled and concentrated in vacuo to give a yellow gum (0.8 g). Purification by chromatography on silica gel (Merck 7734) with dichloromethane:ethanol:ammonia (250:8:1)-(100:8:1), gave the title compound, as a white foam (0.182 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Br)=[CH:6][CH:7]=1.[CH3:9][S:10]C.[Na]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([S:10][CH3:9])=[CH:6][CH:7]=1
Reactant: CSC
Reactant: Brc1ccc(Br)nc1
Agent: [Na]
Solvent: O
Solvent: CS(C)=O
Product: CSc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3,6-dibromopyridine (1.0 eq.) in DMSO (0.3M) was added sodium methylsulfide (1.1 eq.). The mixture was stirred for 2 d at rt then poured in water. The resulting precipitate was filtered to afford the title compound as white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[N:13]#[C:14]Br.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]1[O:5][C:14]([NH2:13])=[N:7][N:6]=1
Reactant: N#CBr
Reactant: Cc1ccc(C(=O)NN)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2nnc(N)o2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a solution of 2,4-dimethylbenzohydrazide (example 16b) (2 g) in dry dioxane (12 mL) was added cyanic bromide (1.28 g, 12.2 mmol) followed by a solution of NaHCO3 (1.02 g, 12.2 mmol) in water (12 mL). The resulting mixture was stirred 2 hours at rt. The solution was concentrated to ½ volume on vacuum and diluted with water (20 mL). The resulting solid was collected and dried on vacuum to give 5-(2,4-Dimethylphenyl)-1,3,4-oxadiazol-2-amine (1.88 g, 82%) as a white solid. 1H NMR (300 MHz, dMSO): δ 2.29 (s, 3H), 2.52 (d, 3H), 7.13 (d, 1H), 7.16 (s, 3H), 7.54-7.56 (d, 1H); MS (M+H, 190).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:33]([OH:34])[C@@H:32]([CH3:35])[C@@H:31]([OH:36])[C@@H:30]([CH3:37])[C@H:29]([O:38][C:39]([CH3:41])=[O:40])[C@H:28]([CH3:42])[C@@H:27]([O:43][CH3:44])[CH:26]=[CH:25][O:24][C@:21]2([CH3:45])[C:22](=[O:23])[C:14]3=[C:15]([O:20]2)[C:16]([CH3:19])=[C:17]([OH:18])[C:12]2=[C:13]3[C:46]([OH:50])=[C:47]([CH:48]=O)[C:10](=[C:11]2[OH:51])[NH:9][C:7](=[O:8])[C:6]([CH3:52])=[CH:5][CH:4]=[CH:3]1.[NH2:53][N:54]1[CH2:59][CH2:58][N:57]([CH:60]2[CH2:64][CH2:63][CH2:62][CH2:61]2)[CH2:56][CH2:55]1>O1CCCC1>[CH3:1][C@@H:2]1[C@H:33]([OH:34])[C@@H:32]([CH3:35])[C@@H:31]([OH:36])[C@@H:30]([CH3:37])[C@H:29]([O:38][C:39]([CH3:41])=[O:40])[C@H:28]([CH3:42])[C@@H:27]([O:43][CH3:44])[CH:26]=[CH:25][O:24][C@@:21]2([CH3:45])[O:20][C:15]3[C:14]([C:22]2=[O:23])=[C:13]2[C:46](/[C:47](=[CH:48]/[NH:53][N:54]4[CH2:55][CH2:56][N:57]([CH:60]5[CH2:64][CH2:63][CH2:62][CH2:61]5)[CH2:58][CH2:59]4)/[C:10](=[C:11]([OH:51])[C:12]2=[C:17]([OH:18])[C:16]=3[CH3:19])[NH:9][C:7](=[O:8])[C:6]([CH3:52])=[CH:5][CH:4]=[CH:3]1)=[O:50]
Reactant: NN1CCN(C2CCCC2)CC1
Reactant: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c(C=O)c(O)c4c3C2=O)NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(O)c(c(C=O)c(O)c4c3C2=O)NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Agent: CO[C@H]1/C=C/O[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)/C(=C/NN2CCN(C3CCCC3)CC2)C(=C4O)NC(=O)/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Solvent: C1CCOC1
Product: CO[C@H]1C=CO[C@@]2(C)Oc3c(C)c(O)c4c(c3C2=O)C(=O)/C(=C/NN2CCN(C3CCCC3)CC2)C(=C4O)NC(=O)C(C)=CC=C[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C
Reaction time: 0.5 h

Procedure:
0.01 Mole of 3-formylrifamycin SV is dissolved in tetrahydrofuran and to the obtained solution 0.011 mole of 1-amino-4-cyclopentylpiperazine is added to the reaction mixture at room temperature. After 30 minutes, the reaction is completed since thin layer chromatography of the mixture shows disappearance of the starting 3-formylrifamycin SV. The solvent is then evaporated off and the residue is crystallized from ethyl acetate. The title product, which melts at 179°-80° C, is obtained in a 55% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:4].[C:25]([Cu])#[N:26]>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:4]
Reactant: N#C[Cu]
Reactant: COC(=O)c1nc(Br)c2cccc(Oc3ccc(F)cc3)c2c1O
Product: COC(=O)c1nc(C#N)c2cccc(Oc3ccc(F)cc3)c2c1O

Procedure:
The title compound was synthesized from 1-bromo-5-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester and CuCN in analogy to example 3a; MS-(−)-ion: M−1=337.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][N:29]([CH2:30][CH3:31])[CH2:27][CH3:28])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCNCC
Reactant: CS(=O)(=O)OCCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Product: CCN(CC)CCCC#Cc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
According to the method in example 18, Methanesulfonic acid 5-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl ester and Diethylamine were converted to yield {5-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-ynyl}-diethyl-amine, MS: 383 (MH+).
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6]CC)=O.[CH3:13][N:14]1[C:19]2[N:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17](=O)[O:16]C1=O.Cl>O.C(O)C>[OH:16][C:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[N:14]([CH3:13])[C:4](=[O:6])[C:3]=1[C:2]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cn1c(=O)oc(=O)c2cccnc21
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(O)c2cccnc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 0.345 g. (0.15 g. atom) of sodium in 30 ml. of ethanol was added 4.8 g. of diethyl malonate. The mixture was stirred at room temperature for 5 minutes and then was evaporated in a rotary evaporator. The residue was dissolved in 30 ml. of N,N-dimethylformamide and 2.67 g. (0.015 mole) of 1-methyl-1H-4H-pyrido[2,3-d][1,3]-oxazine-2,4-dione was added. The mixture was heated under reflux for 10 minutes and the thick mixture was dissolved in 100 ml. of water. The solution was acidified with conc. hydrochloric acid and the precipitate which formed was collected, air dried, and a small amount of this 1.7 g. was recrystallized from ethanol to give the analytical sample of 4-hydroxy-1,2-dihydro-1-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester, m.p. 158°-160° C.