Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[O:28][C@H:27]([CH2:29][O:30]C(=O)C3C=CC(Cl)=CC=3)[C@@H:16]([O:17]C(=O)C3C=CC(Cl)=CC=3)[CH2:15]2)=[C:7]([NH:40][Si](C)(C)C)[N:6]=1>CO>[CH:10]1[N:11]([C@@H:14]2[O:28][C@H:27]([CH2:29][OH:30])[C@@H:16]([OH:17])[CH2:15]2)[C:12]2[C:8](=[C:7]([NH2:40])[N:6]=[C:5]([Cl:4])[N:13]=2)[N:9]=1
Reactant: C[Si](C)(C)Nc1nc(Cl)nc2c1ncn2[C@H]1C[C@H](OC(=O)c2ccc(Cl)cc2)[C@@H](COC(=O)c2ccc(Cl)cc2)O1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1nc(Cl)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a mixture of 25% sodium methoxide in MeOH (0.11 Kg, 0.5 mol, 0.1 eq.) and MeOH (14.8 Kg, 5 P) at about at 25° C. was added 2-chloro-6-trimethylsilylamino-9-[3,5-di-O-(4-chlorobenzoyl)-2-deoxy-β-D-ribofuranosyl]-purine (IVa) and non-silylated derivative 2-chloro-6-amino-9-[3,5-di-O-(4-chlorobenzoyl)-2′-deoxy-β-D-ribofuranosyl]-purine (IVb) (3.70 Kg, combined HPLC purity of >96.3%) and the mixture was agitated at about 25° C. for 2 hours. The solids were filtered, washed with MeOH (1.11 Kg, 0.4 P) and then dried in vacuo at 60° C. for 4 hours to give 1.43 Kg of a crude cladribine with 97.8% HPLC purity in ca. 87% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[N:18]([CH2:22][CH3:23])[N:19]=[CH:20][CH:21]=4)=[CH:15][N:14](COC(=O)C(C)(C)C)[C:11]3=[N:12][CH:13]=2)=[CH:4][C:3]=1[C:32](=[O:36])[N:33]([CH3:35])[CH3:34].[OH-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[N:18]([CH2:22][CH3:23])[N:19]=[CH:20][CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][C:3]=1[C:32]([N:33]([CH3:34])[CH3:35])=[O:36]
Reactant: CCn1nccc1-c1cn(COC(=O)C(C)(C)C)c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCn1nccc1-c1c[nH]c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,2-dimethyl-propionic acid 5-(4-amino-3-dimethylcarbamoyl-phenyl)-3-(2-ethyl-2H-pyrazol-3-yl)-pyrrolo[2,3-b]pyridin-1-ylmethyl ester was dissolved in tetrahydrofuran. 1 M sodium hydroxide in methanol was added to the mixture, and the reaction was stirred for 2 h at room temperature until complete conversion was confirmed by HPLC-MS. Saturated aqueous sodium bicarbonate solution was added and the mixture extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated. The crude material was purified by preparative HPLC to give 2-amino-5-[3-(2-ethyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide. 1H-NMR (250 MHz, d6-DMSO) δ 12.12 (s, 1H), 8.51 (d, J=2.0 Hz, 1H), 7.97 (d, J=2.3 Hz, 1H), 7.76 (d, J=2.3 Hz, 1H), 7.55 (s, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.35 (d, J=2.0 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.53 (s, 1H), 5.29 (s, 2H), 4.20 (quart., J=7.3 Hz, 2H), 2.96 (s, 6H), 1.32 (t, J=7.1 Hz, 3H); MS: m/z 375.1 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[OH:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[C:27](Cl)(=[O:34])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CN(C=O)C>[CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH:15]([O:16][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CCCCCCC(=O)Cl
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCN(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCC(=O)OC(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 0.6 %

Procedure:
To an ice-cooled stirred solution of 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol (2.5 g, 7.78 mmol) in DMF (5 mL) was added sodium hydride (373 mg, 15.56 mmol). After stirring for 20 min, heptanoyl chloride (1.9 g, 13.23 mmol) was added into the reaction mixture, which was stirred at 0° C. for 30 min. The progress of reaction was monitored by LCMS and TLC. The reaction mixture was quenched with ice water (200 mL) and extracted with EtOAc (400 mL). The combined organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (6% MeOH-DCM), followed by reverse phase HPLC to yield heptanoic acid 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethyl ester (20 mg). 1H NMR (CD3OD, TFA salt) δ (ppm): 8.74 (s, 2H), 7.91 (s, 2H), 7.28 (m, 2H), 7.04 (t, 1H), 6.2 (m 1H), 4.7 (d 1H), 4.59 (m, 2H), 4.3 (m, 1H), 3.5 (t, 1H), 3.34 (m, 1H), 3.31 (m, 2H), 3.12 (s, 3H), 2.4 (s, 3H), 2.3 (m, 2H), 2.1 (m, 1H), 1.35 (m, 2H), 1.22 (m, 2H), 1.15 (m, 3H), 0.86 (t, 3H). Separation by chiral HPLC provides enantiomers 338a-b.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>O>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:12][NH:14][C:4]2=[O:5]
Reactant: NC=O
Reactant: Nc1ccc(I)cc1C(=O)O
Solvent: O
Product: O=c1[nH]cnc2ccc(I)cc12
Temperature: 25 °C
Yield: 81 %

Procedure:
A solution of 2-amino-5-iodobenzoic acid (14.2 g, 50 mmol) and formamide (100 mL) was refluxed for 10 hours. After cooling to room temperature, water (100 mL) was added. The solid product was collected by filtration, washed with water. Further drying in a vacuum provided 6-Iodo-4-quinazolinone (11 g, 81%) as a gray solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].FC(F)(F)C(O)=O.[C:17]1([C:23]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:23]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Fc1ccc(S)c(Cl)c1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
2-Chloro-4-fluoro-benzenethiol (250 g, 1.54 mol) was dissolved in dichloromethane (1.25 L) and trifluoroacetic acid (120 mL, 1.57 mol) followed by triphenylmethanol (400 g, 1.54 mol) were added at room temperature (ice bath cooling necessary during addition of triphenylmethanol). The mixture was stirred for 1.5 h at room temperature, concentrated and dried in vacuo to yield the title compound as a yellow solid (622 g, 99% purity by HPLC, 99%), that was used without further purification in the next step. 1H NMR (CDCl3, 400 MHz): δ 6.55 (ddd, J=2.9 Hz, 8.0 Hz, 8.9 Hz, 1H), 6.91 (dd, J=6.2 Hz, 8.9 Hz, 1H), 6.97 (dd, J=2.9 Hz, 8.6 Hz, 1H), 7.20-7.27 (m, 9H), 7.34-7.39 (m, 6H).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH:15]=[CH2:16])[C:9]=1[OH:17].[OH-].[K+]>CO>[C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=[CH:15][CH3:16])[C:9]=1[OH:17]
Reactant: C=CCc1cccc(Sc2ccccc2C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC=Cc1cccc(Sc2ccccc2C)c1O
Temperature: 110 °C
Yield: 101.3 %

Procedure:
A mixture of 2-(o-tolylthio)-6-allylphenol (24 g) and potassium hydroxide (32 g) in methanol (100 ml) was stirred at 110° C. Methanol was distilled off from the mixture under ordinal pressure, and the mixture was stirred at 100° C. for an hour. The reaction mixture was cooled, acidified with conc. hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried and evaporated under reduced pressure to give oily 2-(o-tolylthio)-6-(1-propenyl)phenol (24.3 g).
Reaction SMILES: CCN=C=NCCCN(C)C.[Cl:12][C:13]1[CH:21]=[N:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O.[NH2:22][C:23]1[CH:28]=[C:27]([C:29]([F:38])([C:34]([F:37])([F:36])[F:35])[C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:25][C:24]=1[OH:39]>N1C=CC=CC=1>[Cl:12][C:13]1[CH:21]=[N:20][CH:19]=[CH:18][C:14]=1[C:15]([NH:22][C:23]1[CH:28]=[C:27]([C:29]([F:38])([C:30]([F:31])([F:32])[F:33])[C:34]([F:35])([F:36])[F:37])[CH:26]=[CH:25][C:24]=1[OH:39])=[O:17]
Reactant: Nc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1O
Reactant: O=C(O)c1ccncc1Cl
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: O=C(Nc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1O)c1ccncc1Cl
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 79.8 %

Procedure:
To a mixture of 0.58 g of WSC and 5 ml of pyridine 5m1, 0.48 g of 3-chloroisonicotinic acid was added. The reaction mixture was stirred at room temperature for 25 minutes. To the reaction mixture, 0.75 g of 2-amino-4-(heptafluoroisopropyl)phenol was added and was stirred while heating at 60° C. for three hours. The reaction mixture was cooled to room temperature, the 0.24 g of 3-chloroisonicotinic acid and 0.29 g of WSC was added and stirred while heating at 60° C. for 1.5 hours and then at 80° C. for 1.3 hours. The mixture reaction was cooled to room temperature, and then concentrated under reduced pressure. Then, water was added to the residue, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.90 g of 3-chloro-N-[2-hydroxy-5-(heptafluoroisopropyl)phenyl]isonicotinamide.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][CH:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[C:5]([C:12]([NH2:14])=[O:13])=[N:6][C:7]=1[C:8](O)([CH3:10])[CH3:9].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH2:23][CH2:24][CH:25]([N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)[CH2:26][CH2:27]3)=[CH:20][CH:21]=2)[C:5]([C:12]([NH2:14])=[O:13])=[N:6][C:7]=1[CH:8]([CH3:10])[CH3:9]
Reactant: CN1CCN(C2CCN(c3ccc(Nc4nc(Cl)c(C(C)(C)O)nc4C(N)=O)cc3)CC2)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1Cl
Temperature: 25 °C
Yield: 84.9 %

Procedure:
To a mixture of 5-chloro-6-(2-hydroxypropan-2-yl)-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (11.2 g) and trifluoroacetic acid (110 mL) was added triethylsilane (18.2 mL) under ice-cooling, and followed by stirring under ice-cooling for 10 minutes and at room temperature for 14 hours. The reactant was concentrated, then diluted with chloroform, and washed with a saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-500:10:1) to obtain an orange solid. The obtained solid was heated and washed with ethyl acetate to obtain 5-chloro-6-isopropyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (9.2 g) as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[CH:15][CH2:14][N:13]2[C:30]([O:32]C(C)(C)C)=[O:31])(=[O:11])=[O:10])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH:18]=[CH:17][C:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[CH:15][CH2:14][N:13]2[C:30]([OH:32])=[O:31])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)C2=CCN(C(=O)OC(C)(C)C)N(S(=O)(=O)c3ccc(OC)cc3)C=C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)C2=CCN(C(=O)O)N(S(=O)(=O)c3ccc(OC)cc3)C=C2)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
The t-butyl 1,5-di-[(4-methoxyphenyl)sulfonyl]-diazepine-2-carboxylate (0.45 g, 0.8 mmol) is dissolved in methylene chloride (1.5 mL) and cooled down in an ice bath. Trifluoroacetic acid (1.5 mL, 19.0 mmol) is added and the resulting solution is stirred at 0° C. for 3 hours. The reaction mixture is warmed to room temperature and an additional 1 mL of trifluroacetic acid is added. The resulting solution is stirred for an additional hour and the mixture is concentrated under reduced pressure. The residue is carried forward without further purification. MS (ESI): 485 (M+H+), 502 (M+NH4+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12](O)=[O:13])=[N:8][NH:9]2)=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH4+].[Cl-]>C1COCC1.C(Cl)Cl.CCOCC.O=[Mn]=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]=[O:13])=[N:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C(=O)O)n[nH]c2c1
Agent: O=[Mn]=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2c(C=O)n[nH]c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 54.6 %

Procedure:
A mixture of 6-methoxy-1H-indazole-3-carboxylic acid (0.200 g, 1.04 mmol) in THF (15 mL) was stirred for 10 min at 0° C. under N2. LAH was added and the mixture was stirred overnight at room temperature under N2. Then, an aqueous NH4Cl solution (5 mL) was added and the reaction mixture was concentrated to half its volume and extracted with EtOAc. The organic layer was washed with brine and water, dried over anhydrous MgSO4, and the solvent removed in vacuo to give a residue. MnO2 (0.680 g, 7.8 mmol) was added to the residue in anhydrous CH2Cl2 (15 mL) at 0° C. with stirring. After the addition, the mixture was stirred at room temperature for 8 h. The mixture was diluted with anhydrous ether (50 mL) and filtered through a pad of Celite. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography to give 6-methoxy-1H-indazole-3-carbaldehyde (0.100 g, 56%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]1[N:14]=[CH:15][NH:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:21]([O:20][C:18]([C:17]1[N:16]=[CH:15][N:14]([C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[C:13]=1[CH3:12])=[O:19])[CH3:22]
Reactant: CCOC(=O)c1[nH]cnc1C
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ncn(-c2cc(F)ccc2[N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 96 h
Yield: 45.2 %

Procedure:
A mixture of 2,4-difluoronitrobenzene (36.6 g, 230 mmol), ethyl 4-methyl-5-imidazolecarboxylate (35.6 g, 231 mmol), potassium carbonate (36.5 g, 264.4 mmol) and acetonitrile (250 ml) was stirred at 25° C. for 96 h. The reaction mixture was filtered and the solvent removed under reduced pressure. The residue was submitted to flash chromatography on silica gel 60 eluting with toluene graduated to toluene/ethyl acetate (1:1) to give 30.5 g (65%) of 4-ethoxycarbonyl-5-methyl-1-(2-nitro-5-fluorophenyl)-1H-imidazole.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH3:12].[C:17]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][C:2]2[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=2[CH2:4][CH2:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][N:7]2[CH3:12])=[O:26])=[CH:23][CH:22]=1)(=[O:19])[CH3:18]
Reactant: CN1CCCCC1CCc1ccccc1N
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C(=O)Nc2ccccc2CCC2CCCCN2C)cc1

Procedure:
Reaction of 2-(o-aminophenethyl)-1-methylpiperidine with p-acetoxybenzoyl chloride in pyridine according to Example 1 provides 4-acetoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide. Analytically pure product is obtained by crystallization from isopropyl ether, m.p. 88°-108°C. (corr.). The broad melting point of the analytically pure material is due to the polymorphism.
Reaction SMILES: [IH:1].[O:2]=[C:3]1[N:8]([CH2:9][C:10]#[CH:11])[N:7]=[N:6][C:5]2=[C:12]([C:15](SC)=[NH:16])[N:13]=[CH:14][N:4]12.Cl.[NH2:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>>[IH:1].[O:2]=[C:3]1[N:8]([CH2:9][C:10]#[CH:11])[N:7]=[N:6][C:5]2=[C:12]([C:15](=[NH:16])[NH:20][CH2:21][C:22](=[O:23])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:13]=[CH:14][N:4]12
Reactant: NCC(=O)c1ccccc1
Reactant: C#CCn1nnc2c(C(=N)SC)ncn2c1=O
Agent: Cl
Agent: I
Product: C#CCn1nnc2c(C(=N)NCC(=O)c3ccccc3)ncn2c1=O
Yield: 29 %

Procedure:
Using the general procedure, the title compound was synthesized from methyl 4-oxo-3-(prop-2-ynyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbimidothioate hydroiodide and aminoacetophenone hydrochloride, using a reaction time of 5 hours and 30 minutes for the amidine formation. Yield 29%. δH (DMSO-d6): 9.74 (2H, m), 9.54 (1H, bs), 9.25 (1H, s), 8.07-8.05 (2H, m), 7.78-7.73 (1H, m), 7.65-7.61 (2H, m), 5.27-5.24 (4H, m), 3.62 (1H, t, J=2.5).
Reaction SMILES: CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:30]([N:37]([S:42]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=1)(=[O:44])=[O:43])[CH2:38][C:39](O)=[O:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[NH2:53][C:54]1[S:55][S:56][C:57](=[S:59])[N:58]=1.Cl>CN(C)C=O>[CH2:30]([N:37]([S:42]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=1)(=[O:44])=[O:43])[CH2:38][C:39]([NH:53][C:54]1[S:55][S:56][C:57](=[S:59])[N:58]=1)=[O:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1ccc(S(=O)(=O)N(CC(=O)O)Cc2ccccc2)cc1
Reactant: Nc1nc(=S)ss1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(CC(=O)Nc2nc(=S)ss2)Cc2ccccc2)cc1
Reaction time: 1 h
Yield: 31.7 %

Procedure:
N-methylmorpholine (0.79 ml, 7.15 mmol), N-hydroxybenzotriazole (1.10 g, 7.15 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (1.37 g, 7.15 mmol) are added to a solution of 2-{benzyl[(4-methoxyphenyl)sulfonyl]amino}acetic acid (2.00 g, 5.96 mmol) in N,N-dimethylformamide (20 ml) while being cooled with ice, and stirred for 1 hour. Then, the mixture, with 3-amino-1,2,4-dithiazole-5-thione (1.08 g, 7.15 mmol) added thereto, was stirred for 5 hours at room temperature. The reaction, with 1N hydrochloric acid added thereto, was extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate water and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (3% methanol/chloroform), to give aimed 2-{benzyl[(4-methoxyphenyl)sulfonyl]amino}-N-(3-thioxo-3H-1,2,4-dithiazol-5-yl)acetoamide (Compound 1) (0.883 g, 32%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[CH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:11]=1.CO>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:31])[CH:4]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)C(=Cc1ccc(OCc2ccccc2)nc1)NC(=O)OCc1ccccc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C(Cc1ccc(OCc2ccccc2)nc1)NC(=O)OCc1ccccc1
Temperature: 35 °C
Reaction time: 96 h

Procedure:
A flask was charged with 2-benzyloxycarbonylamino-3-(6-benzyloxy-pyridin-3-yl)-acrylic acid methyl ester (0.50 g, 1.2 mmol), Wilkinson's catalyst (200 mg, 0.2 equiv), methanol (5 mL), and toluene (3 mL). The flask was flushed with nitrogen, then hydrogen, heated to 35° C., and allowed to stir under an atmosphere of hydrogen for 4 days. The reaction was flushed with nitrogen, diluted with methanol, filtered, and concentrated to afford the crude product which was purified by column chromatography to give 145 mg (29%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([CH2:15][OH:16])[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1.P(Br)(Br)Br.Cl[C:25]1C=C(C=CC=1)NC1C2C=C(CBr)NC=2N=CN=1.C[O-].[Na+]>C(OCC)C.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([CH2:15][O:16][CH3:25])[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: OCc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reactant: Clc1cccc(Nc2ncnc3[nH]c(CBr)cc23)c1
Agent: BrP(Br)Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: COCc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cooled suspension of 82.5 mg (0.30 mmol) of 4-(3-chloro-anilino)-6-hydroxymethyl-7H-pyrrolo[2,3-d]pyrimidin (cf. Example 49) in 5 ml of diethyl ether are added under argon 14 μl (0.15 mmol) of phosphorus tribromide. After stirring for 18 h at 0° C. and 18 h at RT (→4-(3-chloro-anilino)-6-bromomethyl-7H-pyrrolo[2,3-d]pyrimidin), 2 ml of methanol are added. The mixture is stirred for 2 h and then 1 ml of sodium methanolate (5.4 M in methanol) is added dropwise. After 18 h, the mixture is concentrated in vacuo; the residue is redissolved in methanol, silica gel is added and the mixture is evaporated to a dry powder. This powder is put on top of a chromatography column (SiO2 ; CH2Cl2 /ethanol [2:1]). Eluation with CH2Cl2 /ethanol [2:1], concentration and washing with ethyl acetate/diethyl ether/hexane affords the title compound; m.p. 226-230° C.; TLC-Rf =0.59 (CH2Cl2 /methanol [10:1]); HPLC: tRet (Grad20)=9.7.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5]12[O:11][CH:10]1[CH2:9][O:8][CH2:7][CH2:6]2.[Cl-].[NH4+]>CO.O>[N:1]([C@@H:5]1[CH2:6][CH2:7][O:8][CH2:9][C@H:10]1[OH:11])=[N+:2]=[N-:3]
Reactant: C1CC2OC2CO1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=N[C@@H]1CCOC[C@H]1O
Temperature: 65 °C
Yield: 40.6 %

Procedure:
Sodium azide (50.4 g, 775 mmol) is added to a stirring solution of 4,7-dioxabicyclo[4.1.0]heptane (9.7 g, 96.9 mmol) and ammonium chloride (23.0 g, 426 mmol) in methanol (484 mL) and water (97 mL), and heated to 65° C. under nitrogen for 18 h. The mixture is cooled to room temperature and water (200 mL) is added. The methanol is removed in vacuo and the remaining aqueous layer is extracted with EtOAc (3×). The organic portions are combined, dried over sodium sulfate, filtered, and concentrated in vacuo to yield the title compound as a tan oil (5.63 g, 41%). 1H NMR (400 MHz, DMSO-d6) δ 5.40-5.33 (m, 1H), 3.78-3.74 (m, 2H), 3.40-3.32 (m, 3H), 2.97-2.90 (m, 1H), 1.82-1.77 (m, 1H), 1.46-1.41 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:25]=[C:26]([NH2:31])[C:27]([NH2:30])=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>[N+](C1C=CC=CC=1)([O-])=O>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[N:4][C:3]=1[C:10]1[CH:17]=[CH:16][C:13]([C:14]2[NH:31][C:26]3[CH:25]=[C:24]([N:21]4[CH2:22][CH2:23][O:18][CH2:19][CH2:20]4)[CH:29]=[CH:28][C:27]=3[N:30]=2)=[CH:12][CH:11]=1
Reactant: Nc1ccc(N2CCOCC2)cc1N
Reactant: O=Cc1ccc(-c2ncc(CO)cc2Cl)cc1
Solvent: O=[N+]([O-])c1ccccc1
Product: OCc1cnc(-c2ccc(-c3nc4ccc(N5CCOCC5)cc4[nH]3)cc2)c(Cl)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
0.50 g of 4-(3-chloro-5-(hydroxymethyl)pyridin-2-yl)benzaldehyde (3) (2.02 mmol) prepared in Example 1 and 0.39 g of 4-morpholinobenzene-1,2-diamine (18) (2.02 mmol) prepared in Example 12 were dissolved in nitrobenzene (5.5 mL), and refluxed under heating for 2 hours. The mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=10/1) to obtain 0.68 g of {5-chloro-6-[4-(6-morpholin-4-yl-1H-benzoimidazol-2-yl)-phenyl]-pyridin-3-yl}-methanol (yield 80%).