Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]3[N:18]=[C:17]4[C:13]([NH:14][C:15](=[O:27])[N:16]4[C@H:19]4[CH2:24][CH2:23][C@@H:22]([O:25][CH3:26])[CH2:21][CH2:20]4)=[C:12]([C:28]([NH2:30])=[O:29])[N:11]=3)[CH:8]=2)[N:3]=[CH:2]1.N/C(/C#N)=C(\NC(N[C@H:40]1[CH2:45][CH2:44][C@@H:43]([O:46][CH3:47])CC1)=O)/C#N.O1CCCCC1N1C2C(=NC=C(C=O)C=2)N=C1.C(N(CC)CC)C>CO>[CH3:26][O:25][C@@H:22]1[CH2:21][CH2:20][C@H:19]([N:16]2[C:15](=[O:27])[NH:14][C:13]3[C:17]2=[N:18][C:10]([C:7]2[CH:8]=[C:9]4[N:1]([CH:43]5[CH2:44][CH2:45][CH2:40][CH2:47][O:46]5)[CH:2]=[N:3][C:4]4=[N:5][CH:6]=2)=[N:11][C:12]=3[C:28]([NH2:30])=[O:29])[CH2:24][CH2:23]1
Reactant: CO[C@H]1CC[C@@H](NC(=O)N/C(C#N)=C(\N)C#N)CC1
Reactant: CO[C@H]1CC[C@@H](n2c(=O)[nH]c3c(C(N)=O)nc(-c4cnc5nc[nH]c5c4)nc32)CC1
Agent: O=Cc1cnc2ncn(C3CCCCO3)c2c1
Solvent: CCN(CC)CC
Solvent: CO
Product: CO[C@H]1CC[C@@H](n2c(=O)[nH]c3c(C(N)=O)nc(-c4cnc5ncn(C6CCCCO6)c5c4)nc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1H-Imidazo[4,5-b]pyridin-6-yl)-9-(cis-4-methoxycyclohexyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxamide. 1-((Z)-2-Amino-1,2-dicyanovinyl)-3-(cis-4-methoxycyclohexyl)urea (See example 160.B) (375 mg, 1.42 mmol), 1-(tetrahydro-2H-pyran-2-yl)-1H-imidazo[4,5-b]pyridine-6-carbaldehyde (See example 130.C) (644 mg, 2.80 mmol), triethylamine (0.4 mL, 2.80 mmol) and methanol (20 mL) were reacted according to General Procedure B. The solution was allowed to stir at room temperature overnight and the resulting precipitate was collected by filtration to give 9-(cis-4-methoxycyclohexyl)-8-oxo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-imidazo[4,5-b]pyridin-6-yl)-8,9-dihydro-7H-purine-6-carboxamide. This THP-protected intermediate (235 mg, 0.48 mmol) was dissolved in dioxane (2 mL) and a 4.0 M HCl/dioxane solution (4.0 mL) and water (0.3 mL) were added. The resulting solution was stirred at room temperature overnight. The reaction was neutralized with saturated sodium bicarbonate, extracted with EtOAc (3×50 mL), and pooled organics were dried over sodium sulfate. The crude product was purified via reverse-phase semi-prepatory HPLC (20-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). The volatiles were removed under reduced pressure, treated with saturated sodium bicarbonate and extracted with ethyl acetate (3×75 mL). Organic layers were pooled, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was washed with diethyl ether and dried in a vacuum oven at 60° C. overnight to afford the title compound (15 mg, 0.036 mmol, 7.5%) as a white solid. 1H NMR (400 MHz, MeOD-d3) δ 9.56 (s, 1H), 8.50 (m, 1H), 7.80 (m, 1H), 4.31 (m, 1H), 3.51 (m, 1H), 3.39 (s, 3H), 2.77 (m, 2H), 2.07 (m, 4H), 1.53 (m, 4H); MS (ESI) m/z 409.0 [M+1]+; mp 360° C. dec.
Reaction SMILES: [Br:1][CH:2]([C:4]([CH2:9][OH:10])([CH2:7][OH:8])[CH2:5][OH:6])O.[CH2:11](OC(OCC)OCC)C.C(O)C>>[Br:1][CH2:2][C:4]12[CH2:9][O:10][CH:11]([O:8][CH2:7]1)[O:6][CH2:5]2
Reactant: OCC(CO)(CO)C(O)Br
Reactant: CCOC(OCC)OCC
Solvent: CCO
Product: BrCC12COC(OC1)OC2
Reaction time: 3 h

Procedure:
Monobromopentaerythritol from A (10 g, 0.05 mole) and 9 ml triethylorthoformate (0.05 mole) are mixed in a sublimation apparatus equipped with a side arm. The mixture is heated to about 100° C. with magnetic stirring, and 1,5 equivalents of ethanol are allowed to distill out. Then about 100 ml dioctyl phthalate and a trace of anhydrous p-toluenesulfonic acid are added. Under vacuum the mixture is heated to about 140°-150° C. Periodically the collected crystals are removed from the cold finger. After about 3 hours no more compound sublimes. The yield of 4-bromoethyl-2,6,7-trioxabicyclo[2.2.2]octane is 6.5 g (60%).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([OH:12])[CH3:11])[CH3:3].CN([P:16](N(C)C)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C>C1(C)C=CC=CC=1>[CH3:3][CH:2]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH:10]([CH3:11])[O:12][P:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:1]1
Reactant: CN(C)P(c1ccccc1)N(C)C
Reactant: CC(O)c1ccccc1C(C)O
Solvent: Cc1ccccc1
Product: CC1OP(c2ccccc2)OC(C)c2ccccc21

Procedure:
A solution of 1-[2-(1-Hydroxy-ethyl)-phenyl]-ethanol (1.0 g, 6.02 mmol) and bis-(dimethylamino)phenylphosphine (1.18 g, 6.02 mmol) in toluene (5 ml) was heated at reflux under a nitrogen atmosphere until all of the bis-(dimethylamino)phenylphosphine had been consumed (31P-NMR, 24 h). The solvent was then removed in vacuum to leave the product as a colourless oil in almost quantitative yield. 1H/13C-NMR (CDCl3, 300 MHz, HSQC/HMBC/NOE): δ/δ 1.59 (d, 3H, J=6.7 Hz)/21.77 (d, J=2.2 Hz) Ph anti-CH3; 1.90 (d, 3H, J=6.4 Hz)/23.51 (d, J=7.0 Hz) Ph syn-CH3; 5.41 (p, 1H, JP,H≈7 Hz)/70.72 (d, J=6.1 Hz) Ph syn-CHCH3); 5.63 (p, J=JP,H≈6.4 Hz)/74.72 (d, J=9.6 Hz) Ph anti-CHCH3); 7.19/126.65 ortho-CH); 7.30/126.65 ortho-CH); 7.21/127.35 meta-CH); 7.28/127.58 meta-CH); 7.41/128.33 (d, J=4.6 Hz) Ph meta-CH); 7.68/129.80 (d, J=20.1 Hz) Ph ortho-CH); 7.41/130.28 (d, J=0.6 Hz) Ph p-CH); 141.03 (d, J=0.9 Hz) ipso-C); 141.65 (d, J=32.6 Hz) Ph ipso-C); 142.54 (d, J=0.6 Hz) ipso-C). 31P-NMR: δ 154.2.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:45])([F:44])[O:10][C:11]1[CH:12]=[C:13]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[C:20](=[O:32])[C:19](NC3C=CC(C(F)(F)F)=CC=3)=[CH:18]2)[CH:14]=[CH:15][CH:16]=1.COC1CCC(OC)O1.[Cl:55][C:56]1[CH:64]=[CH:63][C:59]([C@H:60]([NH2:62])[CH3:61])=[CH:58][CH:57]=1.[OH-].[K+]>CO.O.C(O)(=O)C.C(O)C>[F:31][C:28]([F:29])([F:30])[C:25]1[CH:26]=[CH:27][C:22]([N:21]2[C@@H:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:9]([F:44])([F:45])[F:8])[CH:12]=3)[CH:18]=[C:19]([NH:62][C@@H:60]([C:59]3[CH:63]=[CH:64][C:56]([Cl:55])=[CH:57][CH:58]=3)[CH3:61])[C:20]2=[O:32])=[CH:23][CH:24]=1
Reactant: O=C1C(Nc2ccc(C(F)(F)F)cc2)=CC(c2cccc(OC(F)(F)F)c2)N1c1ccc(C(F)(F)F)cc1
Reactant: C[C@@H](N)c1ccc(Cl)cc1
Agent: COC1CCC(OC)O1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC1=C[C@H](c2cccc(OC(F)(F)F)c2)N(c2ccc(C(F)(F)F)cc2)C1=O)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 41.4 %

Procedure:
Mix ethanol (120 mL), glacial acetic acid (15 mL), water (3.0 mL, 164.7 mmol), trifluoroacetic acid (6.2 mL, 82.4 mmol), (±)-5-(3-trifluoromethoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-3-(4-trifluoromethyl-phenylamino)-1,5-dihydro-pyrrol-2-one (30.0 g, 54.9 mmol), and 2,5-dimethoxy-tetrahydrofuran (10.7 mL, 82.4 mmol). Warm the solution to 50° C. and stir the reaction mixture for about 18 hours. Discontinue heating the solution, add water (35 mL), and cool the reaction mixture to −19° C. Filter the slurry and wash the solid with a 1:4 mixture of water-methanol (20 mL). Transfer the filtrate to a separatory funnel and wash with 6% brine (280 mL), add 6% brine (100 mL), methanol (40 mL), diethyl ether (100 mL), and saturated sodium bicarbonate solution (43 mL) to the organic phase. Separate the layers, add methanol (60 mL) to the organic phase, and concentrate the solution to approximately 1 volume containing (±)-5-(3-trifluoromethoxy-phenyl)-1-(4-trifluoromethyl-phenyl)-pyrrolidine-2,3-dione. Add methanol (60 mL) and (R)-4-chloro-alpha-methylbenzylamine (7.8 mL, 55.0 mmol) and stir at room temperature for 24 hours. Monitor the reaction by HPLC for completion (Method 4), then cool the solution to −7° C. and continue stirring at this temperature for 72 hours. Add a pre-mixed solution of potassium hydroxide (0.69 g, 10.5 mmol) in methanol (11 mL) to the reaction mixture, warm the solution to 10° C., and stir for an additional 4 hours. Cool the solution to −7° C., filter the slurry, and rinse the resultant product with methanol (5 mL×3). Dry the solid under vacuum to obtain 1-(4-trifluoromethyl-phenyl)-3-[1(R)-(4-chloro-phenyl)-ethylamino]-5 (R)-(3-trifluoromethoxy-phenyl)-1,5-dihydro-pyrrol-2-one (12.3 g, 47.7%) as a white solid: LC-MS ESI m/z: 539.0 (M−H)−, Tr=4.3 min., method 4. 1H NMR (500 MHz, DMSO-d6) δ 7.76 (d, 2H, J=8.5 Hz), 7.62 (d, 2H, J=9.0 Hz), 7.38-7.36 (m, 2H), 7.30-7.27 (m, 3H), 7.10 (dd, 1H, J=8.5, 1.0 Hz), 7.05 (d, 1H, J=7.5 Hz), 6.95 (s, 1H), 6.06 (d, 1H, J=8.0 Hz), 5.96 (d, 1H, J=3.0 Hz), 5.22 (d, 1H, J=3.0 Hz), 4.35-4.32 (m, 1H), 1.43 (d, 3H, J=6.5 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][N:10]=[C:9]2[CH2:13]Cl)=[C:4]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:16])[CH:3]=1.[CH3:23][NH:24][CH3:25]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][N:10]=[C:9]2[CH2:13][N:24]([CH3:25])[CH3:23])=[C:4]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:16])[CH:3]=1
Reactant: O=C(c1ccccn1)c1cc(Br)ccc1-n1cnnc1CCl
Reactant: CNC
Solvent: CCO
Product: CN(C)Cc1nncn1-c1ccc(Br)cc1C(=O)c1ccccn1

Procedure:
A mixture of 0.25 g of 4-[4-bromo-2-(2-pyridinecarbonyl)phenyl]-3-chloromethyl-4H-1,2,4-triazole, 10 ml. of ethanol and 0.5 ml. of dimethylamine is refluxed for 1.5 hours. After evaporation of the solvent, the residue is diluted with water and then extracted with chloroform. The chloroform layer is washed with water, dried over sodium sulfate and then the solvent is evaporated. The residue is subjected to chromatography through a column of silica gel (15 g) using a mixture of chloroform-methanol-ethyl acetate (85 : 10 : 5) as an eluent to give 4-[4-bromo-2-(2-pyridinecarbonyl)phenyl]-3-dimethylaminomethyl-4H-1,2,4-triazole as crystals. Recrystallization from a mixture of acetone and n-hexane gives colorless prisms, melting at 145° to 146° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:30])([F:29])[F:28])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:40])[C:18](=[O:39])[N:19](COCC[Si](C)(C)C)[N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:29])([F:28])[F:30])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:40])[C:18](=[O:39])[NH:19][N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(CC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1C(=O)NN=C2COc3cc(C(F)(F)F)c(CC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 80 °C
Yield: 52.3 %

Procedure:
To a solution of 3-[4-methyl-3-oxo-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylmethyl]-azetidine-1-carboxylic acid tert-butyl ester (0.052 g, 0.08 mmol) in THF (1 mL) was added TBAF (1M in THF, 1 mL) and the solution was heated to 80° C. for 14 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was partioned between EtOAc (5 mL) and water (5 mL). The aqueous phase was extracted with EtOAc (3×10 mL). The combined organic portion was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (eluting with 50% EtOAc in petroleum ether) to give 3-(4-methyl-3-oxo-7-trifluoromethyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylmethyl)-azetidine-1-carboxylic acid tert-butyl ester (0.019 g, 44%). LC/MS (Table 1, Method 2) Rt=1.230 min.; MS m/z: 477 [M+23]+.
Reaction SMILES: C(#N)C.[Na].[CH2:5]([C:12]1[O:13][C:14](=O)[C:15](=[CH:17][OH:18])[N:16]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[C:21]([NH2:29])(=[NH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[C:22]1([C:21]2[NH:29][C:17](=[O:18])[C:15]([NH:16][C:12](=[O:13])[CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:14][N:28]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1OC(Cc2ccccc2)=NC1=CO
Reactant: N=C(N)c1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CC#N
Solvent: O
Product: O=C(Cc1ccccc1)Nc1cnc(-c2ccccc2)[nH]c1=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
Acetonitrile (6 ml) was added to 2-benzyl-4-hydroxymethylene-5-oxazolone sodium salt (0.50 g, 2.22 mmol) and benzamidine hydrochloride (0.35 g, 2.22 mmol), and the mixture was stirred overnight at 80° C. Water (3 ml) was added, and the mixture was stirred. The precipitate was collected by filtration, and the obtained crystals were washed with water and vacuum dried to give 2-phenyl-6-oxo-5-phenylacetylamino-1,6-dihydropyrimidine (0.51 g, 1.67 mmol).
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([C:18]([O:20]C)=[O:19])=[C:8]2[N:3]1[CH:4]=[CH:5][C:6]1[CH:24]=[CH:23][S:22][C:7]=12.[OH-].[K+].Cl>O.CO>[O:1]=[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([C:18]([OH:20])=[O:19])=[C:8]2[N:3]1[CH:4]=[CH:5][C:6]1[CH:24]=[CH:23][S:22][C:7]=12
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2ccc3ccsc3c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2)c(=O)n2ccc3ccsc3c12

Procedure:
(aa) 1.34 g of methyl 7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylate were heated under reflux and under argon with 0.45 g of potassium hydroxide in 25 ml of water/methanol. After the reaction was completed, the mixture was acidified with 2N hydrochloric acid and the yellow crystals were removed by filtration. After washing with water, the acid was dried in vacuo for several hours. There was obtained 7-oxo-8-phenyl-7H-thieno[2,3-a]quinolizine-10-carboxylic acid of m.p. 185°-186° (dec.).
Reaction SMILES: CCN(CC)CC.[Si:8]([O:15]S(C(F)(F)F)(=O)=O)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[CH3:23][C:24]1[C:25]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][C:28]=2[C:34](=O)[CH3:35]>C(Cl)Cl>[Si:8]([O:15][C:34]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:27]=1[N:26]=[C:25]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:24]([CH3:23])=[CH:33]2)=[CH2:35])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(=O)c1cccc2cc(C)c(Oc3ccccc3)nc12
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(O[Si](C)(C)C(C)(C)C)c1cccc2cc(C)c(Oc3ccccc3)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
Et3N (0.105 mL, 0.751 mmol) and TBSOTf (0.146 mL, 0.635 mmol) were sequentially added (TBSOTf: dropwise, over 2 min) to a solution of 1-(3-methyl-2-phenoxyquinolin-8-yl)ethanone (160.1 mg, 0.577 mmol) in DCM (3.0 mL) at 0° C., and the resulting was stirred at 0° C. for 30 min. The mixture was partitioned between DCM (50 mL) and saturated aq. NaHCO3 (20 mL). The organic layer was separated, and the aq. layer was extracted with DCM (2×20 mL). The combined organic extracts were then dried over Na2SO4, filtered, and concentrated in vacuo to provide 8-(1-((tert-butyldimethylsilyl)oxy)vinyl)-3-methyl-2-phenoxy quinoline (214.0 mg, 0.547 mmol, 95% yield) as a colorless oil. This material was taken up in THF (3.0 mL), water (0.166 mL, 9.24 mmol) and NBS (103 mg, 0.577 mmol) were sequentially added at 25° C., and the resulting solution was stirred at 25° C. for 15 min. The mixture was partitioned between Et2O (50 mL) and water (30 mL). The organic layer was separated, sequentially washed with saturated aq. NaHCO3 (20 mL), water (20 mL), and brine (20 mL), and then dried over MgSO4, filtered, and concentrated in vacuo to provide 2-bromo-1-(3-methyl-2-phenoxyquinolin-8-yl)ethanone (240 mg) as a light-yellow oil: m/z (ESI, +ve) 356.0 (M+H)+. NH4OAc (178 mg, 2.309 mmol) and piperidine-2,4-dione (78 mg, 0.693 mmol) were added to the resulting oil, and the mixture was taken up in EtOH (3.0 mL) and stirred at 25° C. for 5 min. The reaction vial was sealed under argon and heated at 50° C. for 14.5 h. The mixture was cooled to 25° C. and concentrated in vacuo. The residue was partitioned between DCM (50 mL) and saturated aq. NaHCO3 (30 mL). The aq. layer was extracted with DCM (3×30 mL), and the combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-10% MeOH/DCM) furnished 2-(3-methyl-2-phenoxyquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (53.4 mg, 0.145 mmol, 25% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 11.28 (1H, br. s.), 7.92-8.00 (2H, m), 7.50-7.58 (3H, m), 7.34-7.43 (2H, m), 7.29 (2H, d, J=7.8 Hz), 7.08 (1H, d, J=1.8 Hz), 5.36 (1H, br. s.), 3.50 (2H, t, J=6.7 Hz), 2.56 (3H, s), 2.42 (2H, t, J=6.9 Hz). m/z (ESI, +ve) 370.1 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.[C:32](O)(=[O:36])[CH:33]([CH3:35])[CH3:34]>CN(C=O)C>[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][N:29]([C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:14])=[CH:5][CH:4]=1
Reactant: CC(C)C(=O)O
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CCNCC3)c2)c2ccc(F)cc21
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)C(=O)N1CCC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Yield: 94.9 %

Procedure:
Following the general method as outlined in Example 83, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole hydrochloride (Intermediate 17; 271 mg; 0.59 mmol) and isobutyric acid (104 mg; 1.18 mmol) in DMF (15 mL), 277 mg (90%) of the title compound was obtained as a yellow oil after purification by a silica gel chromatography (DCM/MeOH=20/1).
Reaction SMILES: Br[C:2](=[N:12][OH:13])[CH:3]([C:8](=[O:11])[NH:9][CH3:10])[C:4]([CH3:7])([CH3:6])[CH3:5].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>CCOCC>[CH3:5][C:4]([CH3:7])([CH3:6])[CH:3]([C:8](=[O:11])[NH:9][CH3:10])[C:2](=[N:12][OH:13])[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: CNC(=O)C(C(Br)=NO)C(C)(C)C
Solvent: CCOCC
Product: CNC(=O)C(C(=NO)N1CCCC1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a solution of 12.6 g of 1-bromo-3,3-dimethyl-2-methylcarbamyloximinobutane in 100 ml of anhydrous ether is added, dropwise, 7.8 g (0.11 mol) of pyrrolidine. The mixture is stirred at room temperature for 1 hour and at reflux for 0.5 hour, then cooled and washed with water. The ether solution is separated, dried, and stripped of solvent to give 11.8 g of amber oil which solidifies on standing to an amber solid, m. 43°-46° C. Properties of this and analogous compounds prepared by substantially the same procedure are shown in Table 3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([C:19](=[O:21])[CH3:20])[CH:13]=[CH:14][C:15]=1[N+:16]([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:16][C:15]1[CH:14]=[CH:13][C:12]([C:19](=[O:21])[CH3:20])=[CH:11][C:10]=1[S:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: CC(=O)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(=O)c1ccc(N)c(Sc2ccc(F)cc2F)c1
Yield: 96.3 %

Procedure:
A mixture of 3'-(2,4-difluorophenylthio)-4'-nitroacetophenone (2.3 g), iron powder (2 g), and ammonium chloride (0.2 g) in ethanol (20 ml) and water (10 ml) was refluxed with stirring for an hour. The insoluble was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, and concentrated to give crystals of 4'-amino-3'-(2,4-difluorophenylthio)acetophenone (2.0 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:47][CH3:48])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([NH:39][CH2:40][CH2:41][N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])=[C:14]3[C:15](=[O:38])[C:16]4[C:21]([C:8]([C:9]=23)=[N:7]1)=[C:20]([O:22]CC1C=CC=CC=1)[CH:19]=[CH:18][C:17]=4[O:30]CC1C=CC=CC=1)[CH3:2].ClCCl.B(Cl)(Cl)Cl>CO>[OH:30][C:17]1[CH:18]=[CH:19][C:20]([OH:22])=[C:21]2[C:16]=1[C:15](=[O:38])[C:14]1[C:9]3[C:8]2=[N:7][N:6]([CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:47][CH3:48])[C:10]=3[CH:11]=[CH:12][C:13]=1[NH:39][CH2:40][CH2:41][N:42]([CH2:43][CH3:44])[CH2:45][CH3:46]
Reactant: CCN(CC)CCNc1ccc2c3c(nn2CCN(CC)CC)-c2c(OCc4ccccc4)ccc(OCc4ccccc4)c2C(=O)c13
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCNc1ccc2c3c(nn2CCN(CC)CC)-c2c(O)ccc(O)c2C(=O)c13
Temperature: 25 °C
Yield: 87.1 %

Procedure:
0.100 g (0.148 mmol) 2-[2-(diethylamino)-ethyl]-5-[[2-(diethylamino)ethyl]amino]-7,10-bis(phenylmethoxy)-anthra[1,9-cd]pyrazol- 6(2H)-one is dissolved in cold, dry dichloromethane (4 ml) and boron trichloride (4 ml, 1M solution in dichloromethane) is added dropwise over 30 minutes under argon. The reaction mixture is maintained at 0°-5° C. for 1 hour and then treated dropwise with cold methanol under argon. The mixture is then maintained at room temperature for 2 hours and then evaporated to dryness in vacuo. The resulting crude hydrochloride salt is dissolved in a minimum volume of methanol and then chromatographed on a column of silica gel (60A) using an eluting solvent of dichloromethane:methanol (80:20 v/v) and then dichloromethane:methanol:triethylamine (80:20:1 v/v). The major red band is collected and evaporated in vacuo to yield 0.060 g of the title compound as an orange-red solid, m.p. 152° C.; λmax (methanol) (E/cm/M) 520 nm (22000).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][C:28]([O:31]C)=[C:27]([O:33]C)[CH:26]=3)[S:11][C:12]=2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([OH:33])[CH:26]=3)[S:11][C:12]=2[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Nc2nc(-c3ccc(F)cc3)c(Cc3ccc([N+](=O)[O-])cc3)s2)cc1OC
Agent: BrB(Br)Br
Product: O=C(Nc1nc(-c2ccc(F)cc2)c(Cc2ccc([N+](=O)[O-])cc2)s1)c1ccc(O)c(O)c1
Yield: 63.3 %

Procedure:
A procedure similar to that in Example 7 was used. N-[4-(4-fluoro-phenyl)-5-(4-nitro-benzyl)-thiazol-2-yl]-3,4-dimethoxy-benzamide prepared in Example 20 and boron tribromide were used as starting materials. The obtained crude product was recrystallized with acetone to give a product as a pale yellow solid in a yield of 63.3%, mp: 276-278 └(Dec). 1H-NMR (DMSO-d6, 400 MHz) δ: 4.41 (2H, s, CH2), 6.81 (1H, d, J=8.12 Hz, ArH), 7.29 (2H, t, 3JFH=3JHH=8.96 Hz, ArH), 7.47˜7.54 (4H, m, ArH), 7.67 (2H, dd, 3JHH=8.68 Hz, 4JFH=5.60 Hz, ArH), 8.20 (2H, d, J=8.40 Hz, ArH), 9.32 (1H, br, OH), 9.81 (1H, br, OH), 12.38 (1H, br, CONH); EI-MS m/e (%): 465.0 (M+, 28), 329.0 (100); HREI-MS Calcd. for C23H16FN3O5S: 465.0795. found: 465.0798.
Reaction SMILES: [NH:1]1[C:9](=[O:10])[C:8]2[NH:7][CH:6]=[N:5][C:4]=2[N:3]=[CH:2]1.C(N(CC)CC)C.[Cl:18][CH2:19][CH2:20][N:21]=[C:22]=[O:23]>CN(C)C=O>[Cl:18][CH2:19][CH2:20][NH:21][C:22]([O:10][C:9]1[N:1]=[CH:2][N:3]=[C:4]2[C:8]=1[NH:7][CH:6]=[N:5]2)=[O:23]
Reactant: O=c1[nH]cnc2nc[nH]c12
Reactant: O=C=NCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCCl)Oc1ncnc2nc[nH]c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of hypoxanthine (6.8 g, 50 mmoles) in dimethylformamide (200 ml) there is added triethylamine (5.05 g, 50 mmoles) and then at 15° to 20° C., 2-chloroethylisocyanate (5.8 g, 55 mmoles is dripped in. The reaction mixture is stirred at this temperature until dissolution of the solid (approx. for 2 hours), thereafter poured into an ice-water mixture (750 ml), the precipitate of the title product is separated by suction, washed with acetone and dried at room temperature. The yield is 8.2 g (67.8%) of compound Ib, m.p. 320°-240° C. (with decomposition), UV absorption spectrum (in dimethylsulfoxide), λ max 275 nm (log ⃝3.76).