Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F-].[K+]>>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][C:12]1[C:13]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:15]=[CH:16][CH:17]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccccc1-c1ccccc1
Agent: [F-]
Agent: [K+]
Product: O=[N+]([O-])c1ccccc1Nc1ccccc1-c1ccccc1
Temperature: 200 °C
Yield: 91.1 %

Procedure:
A mixture of 1-fluoro-2-nitrobenzene (13.06 g, 92.6 mmol), 2-aminobiphenyl (31.3 g, 185.2 mmol), and potassium fluoride (8.1 g, 138.9 mmol) was prepared in a 100 mL round bottom flask. The flask was evacuated and replaced with nitrogen. The mixture was heated to 200° C. overnight. The reaction mixture was cooled and ethyl acetate and water were added. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered, and evaporated. The residue was preabsorbed onto Celite and purified by column chromatography eluting with 0, 2, and 5% ethyl acetate/hexanes. 24.5 g (91%) of product was obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][O:11][CH3:12].[B:13](OC(C)C)([O:18]C(C)C)[O:14]C(C)C.C([Li])CCC>C1(C)C=CC=CC=1.C1COCC1>[CH3:12][O:11][CH2:10][CH2:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:13]([OH:18])[OH:14]
Reactant: COCCOc1ccccc1I
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COCCOc1ccccc1B(O)O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 49.4 %

Procedure:
To a solution of the compound of step 1 (2.20 g, 7.91 mmol) in toluene (20 ml) and THF (4 ml) was added triisopropyl borate (2.19 ml, 9.49 mmol), and the mixture was cooled to −78° C. n-Butyllithium (3.79 ml, 9.49 mmol, 2.5 M in hexane) was added dropwise and the reaction mixture was stirred at −78° C. for 1.5 h. The cooling bath was removed and the reaction mixture was allowed to warm to −20° C. Then 2 N hydrochloric acid (7 ml) was added. When the mixture had reached room temperature, water and EA were added. The organic layer was separated, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by silica gel chromatography (EA/HEP 1:4). 766 mg of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[N:11]1([CH:16]([CH3:20])[CH2:17][CH2:18][NH2:19])[CH:15]=[CH:14][N:13]=[CH:12]1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:19][CH2:18][CH2:17][CH:16]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH3:20])=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC(CCN)n1ccnc1
Product: CC(CCNC(=O)c1ccc(Cl)nc1)n1ccnc1

Procedure:
When 6-chloronicotinic acid was reacted with 3-(1H-imidazol-1-yl)butanamine by the procedure of Example 20 the desired compound was obtained, mp 137°-139° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:9]1([P:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(#N)C>[Br-:1].[OH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][P+:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: OCCCCCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: OCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Yield: 93.2 %

Procedure:
Into a 4 L, 3 neck round bottom flask fitted with nitrogen inlet, condenser, thermometer, mechanical stirring and nitrogen outlet is added 6-bromo-1-hexanol (500 g, 2.76 mol), triphenylphosphine (768 g, 2.9 mol) and acetonitrile (1800 ml) under nitrogen. The reaction mixture is heated to reflux for 72 hrs. The reaction mixture is cooled to room temperature and transferred into a 5 L beaker. The product is recrystallized from anhydrous ethyl ether (1.5 L) at 10° C. Vacuum filtration of the mixture followed by washing the white crystals with ethyl ether and drying in a vacuum oven at 50° C. for 2 hrs. gives 1140 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[C:12]1[C:13]2[C:14](=[N:19][N:20]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:21]=2)[N:15]=[C:16]([Cl:18])[N:17]=1.[C:27]([N:34](C)[CH2:35][CH2:36][NH2:37])(OC(C)(C)C)=O>C(O)C>[ClH:18].[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[C:12]1[C:13]2[C:14](=[N:19][N:20]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:21]=2)[N:15]=[C:16]([NH:37][CH2:36][CH2:35][NH:34][CH3:27])[N:17]=1
Reactant: O=C1Nc2ccc(Br)cc2C1c1nc(Cl)nc2nn(C3CCCC3)cc12
Reactant: CN(CCN)C(=O)OC(C)(C)C
Solvent: CCO
Product: CNCCNc1nc(C2C(=O)Nc3ccc(Br)cc32)c2cn(C3CCCC3)nc2n1
Product: Cl
Temperature: 130 °C
Yield: 61.8 %

Procedure:
A mixture of 5-Bromo-3-(6-chloro-2-cyclopentyl-2-H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,3-dihydro-indol-2-one (50 mg, 0.115 mmol) (Example 182), N′-BOC-N′-methylethylenediamine (200 mg, 1.15 mmol) and ethanol (2 mL) were heated to 130° C. in a microwave for 10 minutes. The reaction was concentrated, treated with ethyl ether and filtered to give 36 mg (55%) of the product. The product was dissolved in 4N HCl in dioxane (3 mL) and stirred at rt for 1 hr. The reaction was concentrated, treated with acetone and filtered. The solid was washed with acetone, ethyl ether and pumped dry to give 9 mg (28%) of Example 378. Example 378: 1H NMR (400 MHz, TFA-d) δ 8.9 (s, 1H), 8.1 (s, 1H), 7.7 (d, 1H), 7.4 (d, 1H), 5.1 (m, 1H), 4.3 (m, 2H), 4.0 (m, 4H), 3.1 (m, 3H), 2.1-2.8 (m, 8H); MS (m/e) 470 (M+1); HPLC (99%) purity, retention time 3.040 minutes—Method C; mp 201-204° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)=[C:6]([CH:9]=1)[CH:7]=[O:8].[BH4-].[Na+].O>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)=[C:6]([CH2:7][OH:8])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1OCc1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1cc(Br)ccc1OCc1cccc(Cl)c1
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-2-(3-chloro-benzyloxy)-benzaldehyde (6.0 g, 18.4 mmol) in MeOH (90 mL) at rt was added NaBH4 (1.07 g, 27.7 mmol) over 1 h. After 18 h at rt, H2O was added (5 mL) and the reaction concentrated to a residual mass, which was dissolved into EtOAc (150 mL). This EtOAc solution was washed with H2O (2×100 mL) and dried to yield the title compound as a light yellow (6.0 g, 100%). MS (ESI): mass calcd. for C14H12BrClO, 327.6; m/z found, 328.3 [M+H]+. 1H NMR (CDCl3) 7.48 (d, J=2.5 Hz, 1H), 7.42-7.20 (m, 5H), 6.76 (d, J=8.7 Hz, 1H), 5.07 (d, J=19.2 Hz, 2H), 4.69 (d, J=17.5 Hz, 2H), 2.15 (t, J=10.0 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([CH3:21])[C:9](=[N:16][NH:17][C:18]([NH2:20])=[S:19])[CH:10]1SCCCS1)([CH3:4])([CH3:3])[CH3:2].[C:23](=O)([O-])[O-].[Ca+2].IC>C(#N)C.O>[CH3:23][S:19][C:18]1[N:17]=[N:16][C:9]([CH:8]([NH:7][C:6](=[O:22])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:21])=[CH:10][N:20]=1
Reactant: CC(NC(=O)OC(C)(C)C)C(=NNC(N)=S)C1SCCCS1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC#N
Solvent: CI
Solvent: O
Product: CSc1ncc(C(C)NC(=O)OC(C)(C)C)nn1
Temperature: 40 °C
Yield: 17.1 %

Procedure:
To a mechanically stirred solution of tert-butyl-2-[(aminocarbonothioyl)hydrazono]-2-(1,3-dithian-2-yl)-1-methylethylcarbamate (Intermediate 2) (600 g, 1.6 mol) in acetonitrile (11 L) and water (1.3 L) was added calcium carbonate (490 g, 4.9 mol) followed by slow addition of iodomethane (2.3 kg, 16 mol) using an addition funnel. After the addition was complete, the solution was heated to 40° C. for 24 hours. The solution was allowed to cool to room temperature and concentrated under reduced pressure until about 1.5 L remained. Water (1.0 L) was added to the solution and the product was extracted with ethyl acetate (6×1 L). The combined extracts were washed with water (4×1 L) and brine (1 L). The solution was dried with magnesium sulfate, filtered and concentrated until a red oil remained (190 g). The oil was dissolve in dichloromethane (250 mL) and 25 mL of this solution was loaded into a RediSep silica gel cartridge (330 g; ISCO) and subjected to a gradient elution using dichlormethane to dichloromethane:ethyl acetate (70:30). The separation was repeated in 25 mL portions until all of the solution was consumed. The appropriate (higher Rf) fractions were combined and concentrated under reduced pressure to give tert-butyl 1-[3-(methylthio)-1,2,4-triazin-6-yl]ethylcarbamate (74 g) as a yellow solid. 1H NMR (CDCl3): δ8.41 (s, 1H), 5.35 (br, 1H), 4.99 (br, 1H), 2.67 (s, 3H), 1.57 (d, J=6.9 Hz, 3H), 1.42 (s, 9H).). MS m/z 271 (M+1). Additionally, the appropriate (lower Rf) fractions were combined and concentrated under reduced pressure to give the isomer tert-butyl 1-[3-(methylthio)-1,2,4-triazin-5-yl]ethylcarbamate (11 g) as a gold oil. 1H NMR (CDCl3): δ8.94 (s, 1H), 5.23 (br, 1H), 4.80 (br, 1H), 2.67 (s, 3H), 1.47 (d, J=7.2 Hz, 3H), 1.43 (s, 9H). MS m/z 271 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12](SC)=[N:11][C:10]=2[CH:16]=1.[C:17]1(C)C=CC(S(OC)(=O)=O)=CC=1.[CH2:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:43])[CH2:40][O:41][CH3:42])=[CH:34][C:33]=1[N:44]=[C:45]1[N:49]([CH2:50][C:51]2[O:52][CH:53]=[CH:54][CH:55]=2)[C:48](=[O:56])[CH2:47][S:46]1)[CH3:30]>>[CH2:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:43])[CH2:40][O:41][CH3:42])=[CH:34][C:33]=1[N:44]=[C:45]1[N:49]([CH2:50][C:51]2[O:52][CH:53]=[CH:54][CH:55]=2)[C:48](=[O:56])[C:47](=[C:12]2[N:11]([CH3:17])[C:10]3[CH:16]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=[CH:8][C:9]=3[S:13]2)[S:46]1)[CH3:30]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CCNc1ccc(NC(=O)COC)cc1N=C1SCC(=O)N1Cc1ccco1
Reactant: COCCOc1ccc2sc(SC)nc2c1
Product: CCNc1ccc(NC(=O)COC)cc1N=C1SC(=C2Sc3ccc(OCCOC)cc3N2C)C(=O)N1Cc1ccco1

Procedure:
In a manner similar to Example 156, 5-(2-methoxyethoxy)-2-(methylthio)benzothiazole was alkylated with methyl p-toluenesulfonate and then condensed with intermediate N-[4-ethylamino-3-(3-furan-2-ylmethyl-4-oxothiazolidin-2-ylideneamino)phenyl]-2-methoxyacetamide. 1H-NMR (CDCl3): δ 8.09 (1H, s), 7.28-7.38 (3H, m), 7.15 (1H, dd), 6.76 (1H, dd), 6.64 (1H, d), 6.44 (1H, d), 6.33 (1H, m), 5.16 (2H, s), 4.14 (2H, m), 4.01 (2H, s), 3.77 (2H, m), 3.72 (3H, s), 3.51 (3H, s), 3.44 (3H, s), 3.15 (2H, q), 1.23 (3H, t); MS(ESI): 624 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[CH:10]=[N:11][N:12]3[CH:17]=[CH:16][CH:15]=[N:14][C:13]=23)[CH:3]=1.COC1C=C(OC)C=CC=1C[N:23]([C:36]1[S:40][N:39]=[CH:38][N:37]=1)[S:24]([C:27]1[CH:32]=[C:31]([F:33])[C:30](F)=[CH:29][C:28]=1[F:35])(=[O:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.ClCCl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:30]2[C:31]([F:33])=[CH:32][C:27]([S:24]([NH:23][C:36]3[S:40][N:39]=[CH:38][N:37]=3)(=[O:25])=[O:26])=[C:28]([F:35])[CH:29]=2)=[C:4]([C:9]2[CH:10]=[N:11][N:12]3[CH:17]=[CH:16][CH:15]=[N:14][C:13]=23)[CH:3]=1
Reactant: Oc1ccc(Cl)cc1-c1cnn2cccnc12
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(F)cc2F)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=S(=O)(Nc1ncns1)c1cc(F)c(Oc2ccc(Cl)cc2-c2cnn3cccnc23)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
To a solution of 4-chloro-2-(pyrazolo[1,5-a]pyrimidin-3-yl)phenol (0.150 g, 0.61 mmol) and N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (0.285 g, 0.64 mmol) in dimethylsulfoxide (5 mL) was added potassium carbonate (0.127 g, 0.92 mmol) and the mixture was stirred at ambient temperature for 4 h. The mixture was partitioned between ethyl acetate (100 mL) and water (20 mL). The organic phase was washed with brine (2×10 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue obtained was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (3 mL). The reaction mixture was stirred for 3 h at ambient temperature and concentrated in vacuo. The residue was suspended in a mixture of dichloromethane and methanol (1:1, 50 mL) and filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo and the residue that was triturated in ethyl acetate to afford 4-(4-chloro-2-(pyrazolo[1,5-a]pyrimidin-3-yl)phenoxy)-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide as a beige solid in 68% yield (0.233 g): 1H NMR (300 MHz, DMSO-d6) δ9.20 (d, J=6.6 Hz, 1H), 8.77-8.70 (m, 1H), 8.61-8.45 (m, 3H), 7.82 (dd, J=9.1, 6.3 Hz, 1H), 7.38 (dd, J=8.3, 2.1 Hz, 1H), 7.28 (d, J=8.7 Hz, 1H), 7.23-7.09 (m, 2H); MS (ES+) m/z 520.7 (M+1), 522.7 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=1)[C:6]2=[O:15].O.[OH-].[Li+]>C1COCC1>[Br:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)[C:6]2=[O:15]
Reactant: COC(=O)c1ccc(CN2Cc3c(cc(OC)c(OC)c3Br)C2=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(c(Br)c1OC)CN(Cc1ccc(C(=O)O)cc1)C2=O
Temperature: 25 °C
Yield: 78.6 %

Procedure:
Methyl 4-((4-bromo-5,6-dimethoxy-1-oxoisoindolin-2-yl)methyl)benzoate (500 mg, 1.19 mmol) in the step 2 and lithium hydroxide monohydrate (199 mg, 4.76 mmol, 4 equiv.) were dissolved in a mixture of THF and distilled water (mixture ratio=2:1 (v/v), 10 mL), and stirred at room temperature for 1 night. The reaction proceeded until no starting material is detectable by TLC. The resulting mixture thus obtained was distilled under a reduced pressure to remove THF. The resulting material was dissolved in distilled water and 1N HCl was added thereto to be pH 2. White precipitates thus obtained were filtered and dried under vacuum to obtain the title compound (380 mg, 78%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:10]=[C:9]1[CH2:23]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:25][CH2:26][CH3:27].[Na+]>C(O)C>[CH2:1]([N:8]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:10]=[C:9]1[CH2:23][O:25][CH2:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[O-]
Reactant: CCOC(=O)c1nc(CBr)n(Cc2ccccc2)c1C(=O)OCC
Agent: [Na+]
Solvent: CCO
Product: CCOCc1nc(C(=O)OCC)c(C(=O)OCC)n1Cc1ccccc1
Reaction time: 13 h

Procedure:
A solution of 1.80 g of diethyl 1-benzyl-2-bromomethylimidazole-4,5-dicarboxylate [prepared as described in Preparation42(ii)] in 50 ml of ethanol was added dropwise to a solution of sodium ethoxide in ethanol (prepared from 0.18 g of sodium and 50 ml of ethanol), and the resulting mixture was left at room temperature for 13 hours. At the end of this time, a procedure similar to that described in Preparation 42(iii) was repeated, and the residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.14 g of the title compound as a syrup.
Reaction SMILES: C(O[C@H]1[C@@H](OC(=O)C)[C@H](COC(=O)C)O[C@@H]1N1C=NC(C(OC)=O)=N1)(=O)C.O.[CH:29]1[N:33]([C@@H:34]2[O:38][C@H:37]([CH2:39][OH:40])[C@@H:36]([OH:41])[C@H:35]2[OH:42])[N:32]=[C:31]([C:43]([NH2:45])=[O:44])[N:30]=1>CO.N>[C@H:34]1([N:33]2[CH:29]=[N:30][C:31]([C:43]([NH2:45])=[O:44])=[N:32]2)[O:38][C@@H:37]([CH2:39][OH:40])[C@H:36]([OH:41])[C@@H:35]1[OH:42]
Reactant: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Agent: COC(=O)c1ncn([C@H]2O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Agent: N
Solvent: O
Solvent: CO
Product: NC(=O)c1ncn([C@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The substrate (20) (1.1 g) was dissolved in CH3OH/NH3 at 0° C. and placed in a steel bomb. The bomb was closed and stirred at room temperature for 18 h. The steel bomb was cooled, opened and evaporated to dryness. The residue was tried to crystallization with little ethanol. The product crystallized, but on filtration, the crystals re-absorbed water and became a paste. The crystallization repeated several times. Finally it crystallized from Methanol/Ethanol mixture. The colorless crystals was filtered, washed with methanol and dried in vacuo. The filtrate was evaporated again which on standing gave further crystals. Total yield 0.5 g (72%); mp: 177-179° C.; [a]D=+38.33 (c 3 mg/mL H2O); D form of Ribavirin [a]D=−36.0 (c 3.0 mg/mL H2O); 1H NMR (Me2SO-d6) δ3.46 (m, 1H, C5′H), 3.60 (m, 1H, C5′H), 3.92 (q, 1H, C4′H), 4.12 (q, 1H), 4.34 (q, 1H), 4.88 (t, 1H, C5′OH), 5.20 (d, 1H), 5.58 (d, 1H), 5.80 (d, 1H, C1′H), 7.60 (bs, 1H, NH), 7.82 (bs, 1H, NH), and 8.82 (s, 1H, C3H). Anal. Calc. for C8H12N4O5 (244.20): C, 39.34; H, 4.95; N, 22.94. Found: C, 39.23; H, 4.97; N, 22.91.
Reaction SMILES: [Cl:1][C:2]1[C:12]([C:13]([OH:15])=O)=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][S:9][C:4]=2[CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][C:22]([S:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1)=[CH:21]2>>[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][C:22]([S:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH:34]([NH:37][C:13]([C:12]3[C:2]([Cl:1])=[CH:3][C:4]4[S:9][CH2:8][C:7](=[O:10])[NH:6][C:5]=4[CH:11]=3)=[O:15])[CH2:33][CH2:32]1)=[CH:21]2
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)cc2c1
Reactant: O=C1CSc2cc(Cl)c(C(=O)O)cc2N1
Product: COc1ccc2ncc(SCCN3CCC(NC(=O)c4cc5c(cc4Cl)SCC(=O)N5)CC3)cc2c1

Procedure:
The title compound is prepared as a white solid (13 mg, 24% yield) following Scheme 3 and in analogy to Example 53 using 7-chloro-3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (22 mg, 0.09 mmol, 1.0 eq) and 1-[2-(6-methoxy-quinolin-3-ylsulfanyl)-ethyl]-piperidin-4-ylamine (30 mg, 0.09 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([OH:17])=[CH:4][CH:3]=1.COC1C2[C:32](=[O:34])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)SC=2C(OC)=CC=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)(=O)C1C=CC=CC=1>O.CC(=O)CC>[C:32]([O:17][C:5]1[C:6]2[S:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14](=[O:16])[C:15]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:34])[C:31]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=c1c2ccccc2sc2c(O)ccc(Cl)c12
Reactant: COc1ccc(OC)c2c(=O)c3ccccc3sc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(Cl)c1ccccc1
Solvent: O
Solvent: CCC(C)=O
Product: O=C(Oc1ccc(Cl)c2c(=O)c3ccccc3sc12)c1ccccc1
Yield: 74 %

Procedure:
1-Chloro-4-hydroxythioxanthone as prepared in Example 1 (6.6 g), potassium carbonate (4.1 g), 2-butanone (60 ml) and water (6 ml) were heated under reflux. Benzoyl chloride (5.3 g) was added over 20 minutes and the mixture heated under reflux for 3 hours. A solid precipitated from solution during the heating period. The mixture was cooled, quenched with water (120 ml), the solid filtered and recrystallised from 2-butanone with a charcoal treatment. The title compound (6.8 g; 74.0%) was obtained of mp 177°-78°. Analysis C20H11ClO3S=366.81 Requires C 65.48% H 3.02% Cl 9.67% S 8.74% Found C 65.46% H 3.13% Cl 9.77% S 8.70%
Reaction SMILES: [CH3:1][C:2]([CH3:10])([C:7](=O)[CH3:8])[CH2:3][CH2:4][C:5]#[N:6].[NH3:11]>[O-2].[O-2].[Ti+4].[H][H]>[CH3:1][C:2]([CH3:10])([CH:7]([NH2:11])[CH3:8])[CH2:3][CH2:4][CH2:5][NH2:6]
Reactant: [H][H]
Reactant: CC(=O)C(C)(C)CCC#N
Reactant: N
Agent: [Ti+4]
Agent: [O-2]
Product: CC(N)C(C)(C)CCCN
Yield: 88 %

Procedure:
21 g of 4,4-dimethyl-5-oxohexanenitrile (purity 97.2%) and 180 g of liquid ammonia were pumped hourly from bottom to top at 250 bar and 80° C. through a tubular reactor (diameter 0.16 mm, fill level 50 cm, oil-heated twin jacket) arranged before the hydrogenation reactor and filled with 63.5 g (100 ml) of titanium dioxide (anatase). in the form of 1.5 mm pellets. 100 l (s.t.p.)/h of hydrogen were subsequently passed in, and the product discharged from the upstream imination reactor was passed through the hydrogenation reactor from bottom to top at 250 bar and 110° C. The mixture was decompressed at atmospheric pressure, and the ammonia was removed by distillation. The discharge from 24 hours was separated by fractional distillation on a 30 cm packed column (3-mm glass rings). 445 g of 4,4-dimethyl-1,5-hexanediamine were obtained as a colorless liquid (b.p. 90° C./3 mbar), corresponding to a yield of 88%.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]([CH:11]([CH3:13])[CH3:12])[C:9]([C:14]2[C:19]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[CH:18][C:17]([Cl:34])=[CH:16][N:15]=2)=[N:8][N:7]=1)=O)C.[CH3:35][NH:36][CH3:37].[C-]#N.[K+]>C1COCC1>[CH3:35][N:36]([CH3:37])[C:4]([C:6]1[N:10]([CH:11]([CH3:13])[CH3:12])[C:9]([C:14]2[C:19]([NH:20][S:21]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([CH3:31])([CH3:32])[CH3:33])=[CH:28][CH:29]=3)(=[O:23])=[O:22])=[CH:18][C:17]([Cl:34])=[CH:16][N:15]=2)=[N:8][N:7]=1)=[O:3]
Reactant: CNC
Reactant: CCOC(=O)c1nnc(-c2ncc(Cl)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C(C)C
Agent: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)n1c(C(=O)N(C)C)nnc1-c1ncc(Cl)cc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A 25 mL scintillation vial was charged with 5-[3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-4-isopropyl-4H-[1,2,4]triazole-3-carboxylic acid ethyl ester (prepared according to general procedure B, 11 mg, 0.02 mmol), dimethylamine in THF (2 mL, 2.0 M), and KCN (1 mg, 0.01 mmol). The vial was sealed and stirred at 50° C. for 16 h. The volatiles were then evacuated in vacuo and the residue was purified via preparatory HPLC to afford 4-tert-butyl-N-[6-chloro-2-(4-ethyl-5-methyl-4H-[1,2,4]triazol-3-yl)-pyridin-3-yl]-enzenesulfonamide as a white powder: MS (ES) M+H expected 505.2. found 505.5.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1.[O:15]1[CH2:35][CH:16]1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:26]([CH3:34])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=2)=[CH:21][CH:20]=1.CO>CS(C)=O>[C:10]([C:9]1[CH:13]=[C:5]([CH:6]=[CH:7][C:8]=1[OH:14])[O:4][CH2:3][CH2:2][NH:1][CH2:35][CH:16]([OH:15])[CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:26]([CH3:34])[CH:27]=[C:28]([C:30]([F:32])([F:33])[F:31])[N:29]=2)=[CH:23][CH:24]=1)(=[O:11])[NH2:12]
Reactant: NCCOc1ccc(O)c(C(N)=O)c1
Reactant: Cn1cc(C(F)(F)F)nc1-c1ccc(OCC2CO2)cc1
Solvent: CO
Solvent: CS(C)=O
Product: Cn1cc(C(F)(F)F)nc1-c1ccc(OCC(O)CNCCOc2ccc(O)c(C(N)=O)c2)cc1
Reaction time: 1 h

Procedure:
A solution of 3.9 g of 5-(2-aminoethoxy)-salicylamide in 30 ml of dimethyl sulphoxide is heated to 70° and 7.2 g of 2-[4-(2,3-epoxypropoxy)-phenyl]-1-methyl-4-(trifluoromethyl)-1H-imidazole are added. The reaction mixture is stirred for 1 hour at 70° and worked up analogously to Example 12. 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-phenoxy]-2-propanol having a melting point of 195°-197° is obtained (from methanol).