Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:17]=[C:16]2[C:7]([O:8][C:9]3[C:10]([F:34])=[CH:11][C:12]([O:32][CH3:33])=[CH:13][C:14]=3[C:15]32[CH2:22][CH2:21][S:20][C:19]([NH:23]C(=O)C2C=CC=CC=2)=[N:18]3)=[CH:6][CH:5]=1>CO.O>[Br:3][C:4]1[CH:17]=[C:16]2[C:7]([O:8][C:9]3[C:10]([F:34])=[CH:11][C:12]([O:32][CH3:33])=[CH:13][C:14]=3[C:15]32[CH2:22][CH2:21][S:20][C:19]([NH2:23])=[N:18]3)=[CH:6][CH:5]=1
Reactant: COc1cc(F)c2c(c1)C1(CCSC(NC(=O)c3ccccc3)=N1)c1cc(Br)ccc1O2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(F)c2c(c1)C1(CCSC(N)=N1)c1cc(Br)ccc1O2
Temperature: 65 °C

Procedure:
A 2 N solution of lithium hydroxide (22.50 ml, 45.0 mmol) was added to a solution of N-(7′-bromo-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-yl)benzamide (7.7 g, 15.00 mmol) in MeOH (250 ml). The reaction mixture was heated to 65° C. for 3 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure. The residue was purified via column chromatography [0-70% 90/10/1 (DCM/MeOH/ammonia) in DCM] to afford 7′-bromo-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-amine as a racemic mixture (2 g, 2.443 mmol, 32% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C@@H:5]([CH2:7][CH2:8]OS(C)(=O)=O)[C:4]([CH3:15])([CH3:14])[O:3]1.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C)C=O>[N:17]([CH2:8][CH2:7][C@@H:5]1[O:6][C:2]([CH3:16])([CH3:1])[O:3][C:4]1([CH3:15])[CH3:14])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)O[C@@H](CCOS(C)(=O)=O)C(C)(C)O1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)O[C@@H](CCN=[N+]=[N-])C(C)(C)O1
Temperature: 95 °C
Yield: 81.1 %

Procedure:
Step H To a solution of methanesulfonic acid 2-((S)-2,2,5,5-tetramethyl-[1,3]dioxolan-4-yl)-ethyl ester (2.5 g, 9.9 mmol) in N,N-dimethylformamide (50 mL) was added NaN3 (6 g, 70 mmol). The reaction mixture was heated at 95° C. for 4 h. Then the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine several times, dried over MgSO4, concentrated to give (S)-5-(2-azido-ethyl)-2,2,4,4-tetramethyl-[1,3]dioxolane as a yellow oil (1.6 g, 80%).
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[CH:5]=1)([O-:3])=[O:2].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.FC(F)(F)C(O)=O>CC#N>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[N:8]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:7]1
Reactant: C1=COCCC1
Reactant: COC(=O)c1cc([N+](=O)[O-])[nH]n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)c1cc([N+](=O)[O-])n(C2CCCCO2)n1
Yield: 0 %

Procedure:
A mixture of methyl 5-nitro-1H-pyrazole-3-carboxylate (7.5 g, 43.8 mmol), 3,4-dihydro-2H-pyran (8 mL, 87.7 mmol) and trifluoroacetic acid (65 μL, 0.9 mmol) in anhydrous MeCN (100 mL) was refluxed for 16 hrs. The solvent was evaporated and the residue was resuspended in CH2Cl2 (50 mL) and washed with H2O and brine. After drying with Na2SO4, solvent evaporation and silica gel column chromatography (PE-EtOAc, 9:1) methyl 1-(tetrahydro-2H-pyran-2-yl)-5-nitro-1H-pyrazole-3-carboxylate (3.71 mg, 33%) was obtained.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:36]2[C:37]([C:42]3[CH:47]=CC=C(F)C=3)=[N:38][O:39][C:40]=2C)=NC=1.NC1CCOCC1>>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:38][CH:37]2[CH2:42][CH2:47][O:39][CH2:40][CH2:36]2)=[O:24])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccnc3)noc2C)nc1
Agent: NC1CCOCC1
Product: Cc1onc(-c2cccnc2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 83 %

Procedure:
As described for example 89, 6-(5-methyl-3-pyridin-3-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (130 mg, 0.4 mmol), instead of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, was converted to the title compound (117 mg, 83%) which was obtained as an off white solid. MS: m/e=395.1 [M+H]+.
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([N:11](CC4C=CC(OC)=CC=4)[C:12](=[O:19])[N:13]([CH3:18])[C:14]3=[O:17])=[N:9]2)=[CH:3][CH:2]=1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C1COCC1.O>[C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([NH:11][C:12](=[O:19])[N:13]([CH3:18])[C:14]3=[O:17])=[N:9]2)=[CH:5][CH:6]=1
Reactant: COc1ccc(Cn2c(=O)n(C)c(=O)c3cn(Cc4ccc(-c5ccccc5)cc4)nc32)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)[nH]c2nn(Cc3ccc(-c4ccccc4)cc3)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(biphenyl-4-ylmethyl)-7-(4-methoxybenzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (300 mg, 0.663 mmol) in THF (9 mL), a solution of ammonium cerium (IV) nitrate (1.82 g, 3.32 mmol) in water (3 mL) is added. The resulting orange solution is stirred at room temperature overnight. Another batch of CAN (1.82 g, 3.32 mmol) is added and the mixture is stirred for 6 hours, and then the third batch of CAN (1.82 g) is added, and the mixture is stirred at r.t. overnight. The reaction mixture is evaporated to dryness. The residue is treated with brine, and extracted with methylene chloride five times. The organic phase is combined and concentrated. The residue is purified by chromatography to give product as white solids with a high yield. 1H NMR (400 MHz, DMDO-d6) 153.16 (s, 3H), 5.37 (s, 2H), 7.38 (m, 3H), 7.46 (m, 2H), 7.65 (m, 4H), 8.59 (s, 1H), 11.6 (s, 1H). MS (FAB) m/z 333.3 [M+H]+.
Reaction SMILES: C([N:8]([CH2:12][CH2:13][CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15]1=[O:23])[CH2:9][CH2:10][OH:11])C1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].C(=O)([O-])O.[K+].O>ClCCl>[CH2:28]([O:27][C:25]([N:8]([CH2:12][CH2:13][CH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][C:15]1=[O:23])[CH2:9][CH2:10][OH:11])=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1Nc2ccccc2C1CCN(CCO)Cc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C1Nc2ccccc2C1CCN(CCO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52 %

Procedure:
3-[2-[N-Benzyl-N-(2-hydroxyethyl)amino]ethyl]-2,3-dihydro-1H-indol-2-one (463 mg) was dissolved in dichloromethane (9.2 ml), added with benzyl chloroformate (0.51 ml) and potassium hydrogencarbonate (358 mg) and stirred at room temperature for 24 hours. The reaction mixture was added with water (10 ml) and extracted twice with dichloromethane (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (10 ml), added with 1 N aqueous sodium hydroxide (2.2 ml) and stirred for 30 minutes. The reaction mixture was added with water (50 ml) and extracted twice with dichloromethane (40 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 272 mg of the title compound. Yield: 52%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15].[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][CH:11]1[C:10](=[O:15])[CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:14][CH2:13][CH2:12]1
Reactant: O=C1CCCCC1c1cc(F)ccc1F
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C1C(Br)CCCC1c1cc(F)ccc1F
Temperature: 25 °C
Yield: 105.2 %

Procedure:
2-(2,5-Difluoro-phenyl)-cyclohexanone (51 mg, 0.24 mmol) was dissolved in chloroform (1 mL). To this solution bromine (40.7 mg, 0.26 mmol) in chloroform (0.5 mL) was added drop wise at room temperature. The reaction was stirred for 1½ hours at room temperature. The solvent was removed under reduced pressure to yield the cude title compound (73 mg) which was used directly in the next step without further purification.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[C:14]([NH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:12][C:11]=1[OH:25])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:27]([CH3:31])[C:28](=O)[CH3:29].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:17]([NH:16][C:14]1[CH:15]=[C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:11]2[O:25][C:27]([CH3:31])=[C:28]([CH3:29])[C:12]=2[CH:13]=1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(Nc1ccc(O)c(NC(=O)c2ccccc2)c1)c1ccccc1
Reactant: CC(=O)C(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1oc2c(NC(=O)c3ccccc3)cc(NC(=O)c3ccccc3)cc2c1C
Temperature: 70 °C
Reaction time: 3 h
Yield: 53.3 %

Procedure:
A mixture of 2,4-bis(benzoylamino)phenol (6.0 g), 3-chlorobutan-2-one (2.3 g) and potassium carbonate (5.0 g) in N,N-dimethylformamide (30 ml) was stirred at 70° C. for 3 hours. The reaction mixture was cooled and poured into water. The separated oil was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. To the residue was added conc. sulfuric acid (30 ml) and the mixture was stirred at 40° C. for 7 hours. The reaction mixture was cooled and poured into a mixture of ice and water. The separated oil was extracted with ethyl acetate and the extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from diethyl ether to give 5,7-bis(benzoylamino)-2,3-dimethylbenzo[b]furan (3.7 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:19][C:18]2[C:17]([NH:20][NH2:21])=[N:16][C:15](=[O:22])[N:14]([CH2:23][CH2:24][CH3:25])[C:13]=2[N:12]=1)[CH2:2][CH3:3].[C:26](OCC)(OCC)(OCC)[CH3:27]>>[CH3:26][C:27]1[N:16]2[C:17]([C:18]3[NH:19][C:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:1][CH2:2][CH3:3])=[N:12][C:13]=3[N:14]([CH2:23][CH2:24][CH3:25])[C:15]2=[O:22])=[N:20][N:21]=1
Reactant: CCCOc1ccccc1-c1nc2c([nH]1)c(NN)nc(=O)n2CCC
Reactant: CCOC(C)(OCC)OCC
Product: CCCOc1ccccc1-c1nc2c([nH]1)c1nnc(C)n1c(=O)n2CCC
Yield: 77 %

Procedure:
A mixture of 8-(2-propoxyphenyl)-3-propyl-6-hydrazino-3,7-dihydropurin-2-one (1.0 g, 2.9 mmol, see Preparation 9) and triethyl orthoacetate (10 mL) was heated under reflux for 2 h. The resulting mixture was cooled and the precipitate collected by filtration and washed with water and ethanol, then dried under vacuum to yield the title compound (0.82 g, 77%) as an off-white solid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-Boc-4-hydroxypiperidine (32.2 g, 0.160 mol) in DCM (400 mL) were added triethylamine (26.8 mL, 0.192 mol), methanesulfonyl chloride (13.6 mL, 0.176 mol) and 4-dimethylaminopyridine (0.20 g, 0.0016 mol) at 0° C. undernitrogen atmosphere. The resulting mixture was slowly warmed to rt and stirred at rt overnight. The mixture was washed with sat. aq. NaHCO3 (3×80 mL), brine (2×80 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated to give the title compound as a white solid. It was used in the next step without further purification. 1H NMR (CDCl3): δ=1.47 (s, 9H), 1.80-1.85 (m, 2H), 1.95-1.99 (m, 2H), 3.05 (s, 3H), 3.28-3.34 (m, 2H), 3.68-3.74 (m, 2H), 4.89 (mc, 1H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)[CH2:2][CH:3]=[CH2:4].Br[C:15]1[C:28]2[C:19](=[C:20]3[C:25](=[CH:26][CH:27]=2)[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:23][CH:22]=[N:21]3)[N:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+].CO>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[C:28]3[C:19](=[C:20]4[C:25](=[CH:26][CH:27]=3)[C:24]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:23][CH:22]=[N:21]4)[N:18]=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: Brc1ccnc2c1ccc1c(-c3ccccc3)ccnc12
Reactant: C=CCCc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: C=CCCc1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Temperature: 100 °C

Procedure:
4-(3-Butenyl)phenylboronic acid is made by the method of Nakashima and Irie (Nakashima, H.; Irie, M. Macromol. Chem. Phys. 200, 683-692). 4-(3-butenyl)phenylboronic acid (0.44 g) and a solution of Pd(Ph3)4 (58 mg) in 5 mL of degassed toluene is placed in a 50 mL Schlenk tube. The mixture is purged with nitrogen, after which a solution of 4-bromo-7-phenyl-1,10-phenanthroline (0.670 g) and Na2CO3 (428 mg, 4 mmol) in 5 mL of degassed 4:1H2O/CH3OH is added. The mixture is heated under nitrogen at 100° C. with rapid stirring until TLC monitoring shows the reaction to be complete (ca 24 hrs). The reaction mixture is then added to a separatory funnel and washed with ether (3×50 mL). The combined organic fractions are dried over MgSO4 and concentrated by roto-evaporation. The desired product is purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane.
Reaction SMILES: [C:1](OC(=O)C)(=O)[CH3:2].[NH2:8][C:9]1[N:10]=[C:11]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[S:12][C:13]=1[C:14]([NH2:16])=[O:15].[OH-].[Na+].Cl>C(O)C.C(O)(=O)C>[CH3:1][C:2]1[NH:8][C:9]2[N:10]=[C:11]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[S:12][C:13]=2[C:14](=[O:15])[N:16]=1
Reactant: NC(=O)c1sc(N2CCOCC2)nc1N
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nc(=O)c2sc(N3CCOCC3)nc2[nH]1
Temperature: 60 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
A mixture of acetic anhydride (4 ml, 42.4 mmol), Acetic Acid (2.00 ml) and 4-amino-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (200 mg, 0.876 mmol) was stirred at 60° C. for 3 h, then quenched with methanol and concentrated under reduced pressure. A mixture of the residue, Ethanol (2.000 ml) and 6N NaOH (2 ml, 12.00 mmol) was irradiated (uwave) at 120° C. for 30 min, then acidified with 6N HCl to pH ˜5. The precipitate was collected, rinsed with water, and dried under vacuum to furnish 5-methyl-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (175 mg, 79%). LC/MS: MS(ES+) m/e 253 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.31 (s, 3H) 3.54-3.59 (m, 4H) 3.69-3.75 (m, 4H) 12.34 (br. s., 1H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([N:12]2[CH:16]=[C:15]([C:17]3[CH:38]=[CH:37][C:20]4[C:21]5[N:22]=[C:23]([C:29]6[N:30]([CH:34]([CH3:36])[CH3:35])[N:31]=[CH:32][N:33]=6)[S:24][C:25]=5[CH2:26][CH2:27][O:28][C:19]=4[CH:18]=3)[CH:14]=[N:13]2)[CH2:9]1)=[O:7])(C)(C)C.F[C:40](F)(F)[C:41](O)=[O:42].CCN(C(C)C)C(C)C.C(O)(=O)C(C)O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:42][CH:41]([CH3:40])[C:6]([N:8]1[CH2:9][CH:10]([N:12]2[CH:16]=[C:15]([C:17]3[CH:38]=[CH:37][C:20]4[C:21]5[N:22]=[C:23]([C:29]6[N:30]([CH:34]([CH3:36])[CH3:35])[N:31]=[CH:32][N:33]=6)[S:24][C:25]=5[CH2:26][CH2:27][O:28][C:19]=4[CH:18]=3)[CH:14]=[N:13]2)[CH2:11]1)=[O:7]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cnn(C4CN(C(=O)OC(C)(C)C)C4)c3)ccc1-2
Agent: CC(O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)C(=O)N1CC(n2cc(-c3ccc4c(c3)OCCc3sc(-c5ncnn5C(C)C)nc3-4)cn2)C1
Reaction time: 2 h
Yield: 16 %

Procedure:
3-{4-[2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-pyrazol-1-yl}-azetidine-1-carboxylic acid tert-butyl ester (2.2 mmol) was dissolved in 5 mL of methylene chloride and treated with 2 mL of trifluoroacetic acid. After 2 h, aqueous workup and concentration of the organics gave the crude deprotected azetidine as a colorless solid that was used in the next step without purification. Crude 8-(1-Azetidin-3-yl-1H-pyrazol-4-yl)-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (190 mg) was dissolved in 3 mL of THF and treated sequentially with DIPEA (0.23 mL, 1.3 mmol), lactic acid (0.10 L, 1.3 mmol) and HATU (333 mg, 0.88 mmol). After 2 h at room temperature, aqueous workup and extraction with ethylacetate gave a crude solid that was purified by reverse phase HPLC to give 345 as a colorless solid (35 mg, 16%). LCMS: 506.2. 1H NMR (400 MHz, DMSO) δ 8.47 (d, J=2.3 Hz, 1H), 8.33 (d, J=8.3 Hz, 1H), 8.11 (s, 2H), 7.48 (dd, J=8.3, 1.7 Hz, 1H), 7.36 (d, J=1.7 Hz, 1H), 5.84 (m, 1H), 5.28 (m, 1H), 5.23-5.17 (m, 1H), 4.80-4.69 (m, 1H), 4.60-4.50 (m, 1H), 4.39 (t, J=5.0 Hz, 2H), 4.34 (m, 1H), 4.22-4.12 (m, 2H), 3.45 (t, J=5.0 Hz, 2H), 1.56 (d, J=6.6 Hz, 6H), 1.23 (d, J=6.7 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].F[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26]>CS(C)=O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]([NH:1][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:25]([O-:27])=[O:26])[S:6][C:5]=2[CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)c1c(N)sc2cc(OC)ccc12
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2ccccc2[N+](=O)[O-])sc2cc(OC)ccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-amino-6-methoxybenzo[b]thiophene-3-carboxylate, 2-fluoronitrobenzene and dimethyl sulfoxide, ethyl 6-methoxy-2-(2-nitroanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][CH:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:35]([CH:33]([CH3:34])[CH3:32])(=[O:37])=[O:36])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)C(C)C)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and propane-2-sulfonyl chloride. Purity (ELSD, based on MW=527.6)=84%.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([S:19][C:16]2[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 95.5 %

Procedure:
A solution of 4-chloro-3-nitro aniline (1.0 g, 5.79 mmol), 4-hydroxythiophenol (0.75 g, 6.00 mmol), cesium carbonate (3.9 g, 12 mmol) in dimethylsulfoxide (10 ml) was heated at 100° C. for 16 hours. Afterwards ice water (50 mL) was added to the solution and the resultant slurry was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate. The drying agent was filtered and solvent was removed under vacuum leaving a red solid as the title compound, (1.45 g, 92%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].N1C=CC=CC=1.[OH:11][CH2:12][C:13]#[C:14][C:15]([C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=1)=[O:16].P([O-])([O-])([O-])=O>C(Cl)Cl>[C:1]([O:11][CH2:12][C:13]#[C:14][C:15](=[O:16])[C:17]1[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COc1cc(C(=O)C#CCO)cc(OC)c1OC
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(C(=O)C#CCOC(C)=O)cc(OC)c1OC
Reaction time: 1 h

Procedure:
0.815 g of acetyl chloride and 0.827 g of pyridine were added simultaneously to a solution of 2.0 g (7.99 mmol) of 4-hydroxy-1-(3,4,5-trimethoxyphenyl)-2-butyn-1-one in 20 ml of methylene chloride. The reaction mixture was stirred at 0° for 1 hour, whereupon it was treated with 30 ml of phosphate buffer (pH 6) and the aqueous phase was extracted twice with methylene chloride. The combined organic phases were dried over magnesium sulphate and evaporated. The residue was recrystallized from ethyl acetate/hexane and there was obtained 3-(3,4,5-trimethoxy-benzoyl)-2-propynyl acetate of melting point 104°-105°.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[Cl:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[CH:12][N:11]=1>CN(C=O)C.O>[Cl:9][C:10]1[N:15]=[C:14]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])[CH:13]=[CH:12][N:11]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)COc1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a suspension of sodium hydride/60 percent oil dispersion (286 mg, 7.1 mmol) in DMF (10 mL) was added 2,2,2-trifluoroethanol (675 mg, 6.7 mmol). The reaction mixture was stirred for 30 minutes, then it was then added dropwise over 30 minutes to a solution of 2,4-dichloropyrimidine (1.0 g, 6.7 mmol). The solution was then allowed to stir overnight while warming to room temperature. The solution was diluted with H2O and extracted thrice with Et2O. The organics were combined, washed with brine, dried (Na2SO4) and filtered through silica gel, eluting with ether. The product was isolated as a semi-solid, 1.1 g, 5.2 mmol, 78 percent yield.
Reaction SMILES: [N:1]1([CH2:6][C:7]23[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:15][C:9]([SH:17])([CH2:10]4)[CH2:8]2)[CH2:14]3)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:18][O-].[Na+].IC>CO>[CH3:18][S:17][C:9]12[CH2:10][CH:11]3[CH2:12][CH:13]([CH2:14][C:7]([CH2:6][N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)([CH2:16]3)[CH2:8]1)[CH2:15]2
Reactant: SC12CC3CC(C1)CC(Cn1cccn1)(C3)C2
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CSC12CC3CC(CC(Cn4cccn4)(C3)C1)C2
Temperature: 25 °C

Procedure:
To a solution of EXAMPLE 81A (300 mg) in methanol (2 mL) was added sodium methoxide (4 mL, 0.5 M in methanol). Iodomethane (0.5 mL) was added, and the reaction heated to reflux for 3 hours. The reaction was cooled to room temperature and concentrated to dryness. The residue war purified by reverse phase HPLC, eluting with a gradient of 30% to 100% acetonitrile in water containing 0.1% v/v trifluoroacetic acid, to give the title product.