Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:23])=[CH:6][C:7]([CH3:22])([CH3:21])[NH:8]2.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[C:3]([CH2:2][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:22])([CH3:21])[CH:6]=[C:5]2[CH3:23]
Reactant: COc1ccccc1-c1ccc2c(c1CCl)C(C)=CC(C)(C)N2
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1-c1ccc2c(c1CN1CCCC1)C(C)=CC(C)(C)N2
Temperature: 50 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A mixture of 5-chloromethyl-6-(2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 5-1, 41.2 mg, 0.126 mmol), pyrrolidine (52.6 μL, 0.630 mmol) and potassium carbonate (34.8 mg, 0.252 mmol) was suspended in anhydrous N,N-dimethylformamide mL), and the reaction mixture was stirred at 50° C. for 1 hour. After cooling down, it was diluted with ethyl acetate (50 mL). The whole was washed with water (50 mL) and saturated brine (50 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (36.1 mg) as a colorless solid: (Yield 79%)
Reaction SMILES: [NH2-:1].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4]>CN(C)C1C=CC=CC=1>[NH2:1][C:9]1[CH:8]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)c1ccncc1
Reactant: [NH2-]
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Product: CC(C)(C)c1ccnc(N)c1
Temperature: 150 °C
Reaction time: 6 h
Yield: 55.2 %

Procedure:
To 790 mg of sodium amide were added 20 mL of N,N-dimethylaniline and 2.74 g of 4-t-butyl pyridine at rt. The mixture was stirred at 150° C. for 6 h. During this period, 3 more portions of sodium amide (790 mg each) were added. The reaction was cooled down to rt. The mixture was partitioned between ethyl acetate and water. Aqueous layer was extracted with ethyl acetate (3×). The combined organic phase was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography with 50% ethyl acetate in hexanes followed by 100% ethyl acetate to give 1.68 g of the title compound as a solid:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([S:20](=[O:28])(=[O:27])[NH:21][C:22]3[S:26][N:25]=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)(C)(C)C>Cl.O1CCOCC1>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:21][C:22]3[S:26][N:25]=[CH:24][N:23]=3)(=[O:28])=[O:27])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(S(=O)(=O)Nc3ncns3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(c2ccc(S(=O)(=O)Nc3ncns3)cc2)CC1
Yield: 78.9 %

Procedure:
Prepared using general procedure 28, method B. Under N2 atmosphere, a solution of tert-butyl-1-(4-(N-1,2,4-thiadiazol-5-ylsulfamoyl)phenyl)piperidin-4-ylcarbamate (3 g, 7.02 mmol) in 4 M HCl/dioxane (100 mL) was stirred at RT for 16 h. The formed precipitate was filtered off and washed with dioxane (20 mL) to give 4-(4-aminopiperidin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (1.88 g, 81%). LC/MS (10%/99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=340; tR=1.28 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=3)[CH:19]=[C:18]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:17]=2[CH3:32])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[CH3:31][O:30][C:28](=[O:29])[CH2:27][C:18]1[C:17]([CH3:32])=[C:16]([C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=2)[CH:19]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)Cc1cc2ccc(F)cc2c(C(=O)N2CCNCC2)c1C
Reaction time: 4 h

Procedure:
A solution of 4-(7-fluoro-3-methoxycarbonylmethyl-2-methyl-naphthalene-1-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (410 mg, 0.92 mmol) in dichloromethane (10 mL) was treated with trifluoroacetic acid (2.5 mL) at room temperature, and stirred for 4 hours. The resulting mixture was concentrated in vacuo to afford [6-fluoro-3-methyl-4-(piperazine-1-carbonyl)-naphthalen-2-yl]-acetic acid methyl ester trifluoroacetate as a viscous oil which was used in the next step without further purification.
Reaction SMILES: CO[C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[OH-].[Na+].[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([C:31]2[C:35]([NH2:36])=[CH:34][NH:33][N:32]=2)=[O:30])=[CH:24][CH:23]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CS(C)=O.O>[F:21][C:22]1[CH:23]=[CH:24][C:25]([NH:28][C:29]([C:31]2[C:35]([NH:36][C:3](=[O:18])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[O:10][CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)=[CH:34][NH:33][N:32]=2)=[O:30])=[CH:26][CH:27]=1
Reactant: Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1
Reactant: COC(=O)c1ccccc1OCCN1CCCC1
Agent: On1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1c[nH]nc1C(=O)Nc1ccc(F)cc1)c1ccccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 13.7 %

Procedure:
2-(2-Pyrrolidin-1-yl-ethoxy)-benzoic acid methyl ester (0.104 g, 0.42 mmol) was treated with 2 M aqueous NaOH (20 ml) and water (20 ml). The reaction mixture was stirred at room temperature for 20 hours, then reduced in vacuo and azeotroped with toluene (3×5 ml). Water (50 ml) was added and the mixture taken to pH 5 using 1M aqueous HCl. The resulting solution was reduced in vacuo and azeotroped with toluene (3×5 ml) to give a white solid, which was combined with 4-amino-1H-pyrazole-3-carboxylic acid (4-fluoro-phenyl)-amide (Example 2B) (0.055 g, 0.25 mmol), EDC (0.058 g, 0.3 mmol) and HOBt (0.041 g, 0.3 mmol) and stirred at room temperature in DMSO (3 ml) for 20 hours. The reaction mixture was poured into water (30 ml) and the resultant solid was collected by filtration and dried in a vacuum oven to give the title compound as a grey solid (0.015 g, 14%). (LC/MS: Rt 2.18, [MH]+ 438.06).
Reaction SMILES: [O:1]1[CH2:6][C:5](=O)[CH2:4][C:3](=[O:8])[CH2:2]1.[I:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O.[NH2:19][C:20]1[N:24]([CH3:25])[NH:23][C:22](=[O:26])[CH:21]=1>>[F:18][C:17]1[CH:16]=[CH:15][C:12]([CH:13]2[C:21]3[C:22](=[O:26])[NH:23][N:24]([CH3:25])[C:20]=3[NH:19][C:5]3[CH2:6][O:1][CH2:2][C:3](=[O:8])[C:4]2=3)=[CH:11][C:10]=1[I:9]
Reactant: O=Cc1ccc(F)c(I)c1
Reactant: O=C1COCC(=O)C1
Reactant: Cn1[nH]c(=O)cc1N
Product: Cn1[nH]c(=O)c2c1NC1=C(C(=O)COC1)C2c1ccc(F)c(I)c1
Yield: 69.5 %

Procedure:
2H-Pyran-3,5(4H,6H)-dione (0.085 g, 0.75 mmol), 3-iodo-4-fluoro-benzaldehyde (0.182 g, 0.75 mmol) and 5-amino-1-methyl-1,2-dihydropyrazol-3-one (0.084 g, 0.75 mmol) were processed as described in Example 26C to provide 0.23 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 3.5 (s, 3H), 4.0 (s, 2H), 4.52 (q, 2H), 4.92 (s, 1H), 7.1 (t, 1H), 7.18 (m, 1H), 7.55 (dd, 1H), 9.62 (bs, 1H), 10.1 (s, 1H); MS (ESI−) m/z 440 (M−H)−; Anal. calcd for C16H13N3FIO3.C2H5OH: C, 44.37; H, 3.93; N, 8.62. Found: C, 44.38; H, 3.89; N, 8.74.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([OH:5])=O.[CH2:32]([NH:34][CH2:35][CH3:36])[CH3:33]>>[CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3]([N:34]([CH2:35][CH3:36])[CH2:32][CH3:33])=[O:5]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: CCNCC
Product: CCN(CC)C(=O)C(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=O

Procedure:
Starting materials: 2,6,10,14,18-pentamethyl-22-oxo-2,6,10,14,18-tricosapentaenoic acid and diethylamine
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[NH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].[CH:27]1(Br)[CH2:31][CH2:30][CH2:29][CH2:28]1.O>CN(C=O)C>[CH:27]1([N:13]2[C:14]3=[N:15][CH:16]=[N:17][C:18]([NH2:20])=[C:19]3[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[N:12]2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: BrC1CCCC1
Reactant: Nc1ncnc2[nH]nc(-c3ccc4ccccc4c3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccccc3c1)nn2C1CCCC1
Temperature: 60 °C

Procedure:
3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.42 mmol) was dissolved in DMF (3 mL) and K2CO3 (220 mg, 1.6 mmol) and cyclopentyl bromide (49.5 μL, 0.46 mmol) were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration. ESI-MS (M+H)+ m/z calcd 330.2, found 330.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:5]([NH2:20])=[CH:4][CH:3]=1.[C:21](=O)(O)[O-].[Na+]>C(O)=O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)[CH:21]=[N:20][C:5]2=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1NCc1ccc2ncccc2c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: Clc1ccc2ncn(Cc3ccc4ncccc4c3)c2n1
Temperature: 100 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
Intermediate 9 (0.200 g, 0.702 mmol) was dissolved in formic acid (1.0 ml) and heated to 100° C. and stirred for 12 h. The reaction mixture was poured into ice water and pH adjusted to 7-8 with sodium bicarbonate solution, extracted with ethyl acetate, washed with brine, dried over sodium sulphate and concentrated to afford the title compound as yellowish brown solid (0.200 g, 97% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.88 (dd, J=4.0, 1.3 Hz, 1H), 8.70 (s, 1H), 8.33 (d, J=8.2 Hz, 1H), 8.19 (d, J=8.3 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.81 (s, 1H), 7.73 (dd, J=8.7, 1.7 Hz, 1H), 7.52 (dd, J=8.3, 2.2 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 5.69 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)=S)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:27]>>[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)=[NH:27])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(NC(=S)Nc2ncccc2OCc2ccccc2)cc1
Reactant: N
Product: N#Cc1ccc(NC(=N)Nc2ncccc2OCc2ccccc2)cc1
Reaction time: 20 h

Procedure:
To a stirring suspension of N-(3-benzyloxy-2-pyridyl)-N'-(4-cyanophenyl)thiourea (2 g, 0.0055 mol) in ammonia-saturated methanol (40 ml) was added yellow mercuric oxide (3 g, 0.014 mol). Stirring was continued for 20 h, then the mixture filtered through celite, and the solid washed several times with chloroform. The filtrate was evaporated to a white solid, which was triturated with ether. Yield 1.12 g (59%), m.p. 173°-175 ° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][CH2:5][C:6]([OH:8])=O.[OH:10][PH:11]([OH:13])=[O:12].P(Cl)(Cl)Cl>O>[CH3:1][N:2]1[C:3]([P:11]([OH:13])(=[O:10])[OH:12])([P:11]([OH:13])(=[O:10])[OH:12])[CH2:4][CH2:5][C:6]1=[O:8]
Reactant: CNC(=O)CCC(=O)O
Reactant: O=[PH](O)O
Solvent: ClP(Cl)Cl
Solvent: O
Product: CN1C(=O)CCC1(P(=O)(O)O)P(=O)(O)O
Reaction time: 5 h

Procedure:
28.5 gm of succinic acid monomethylamide (0.216 mol) were melted with 35.4 gm of H3PO3 (0.432 mol) at 70° C. and then slowly mixed with 37.8 ml of PCl3 (0.432 mol). After an additional 5 hours at 70° C., the product was hydrolyzed with 300 ml of H2O. Filtration with activated carbon at the boiling point yielded a clear solution from which the N-methyl-pyrrolidone-5,5-diphosphonic acid was precipitated with ethanol and acetone. Crude yield 4.2 gm (7% of the theory).
Reaction SMILES: OC1SC2C=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(C(C)C)CC)(C)C.N1CCCC1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:33]=[N:34][C:35]([N:38]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([C:47]([OH:49])=O)[CH:45]=3)[C:40]([S:50]([CH3:52])=[O:51])=[CH:39]2)=[N:36][CH:37]=1>ClCCl>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:37]=[N:36][C:35]([N:38]2[C:46]3[C:41](=[CH:42][CH:43]=[C:44]([C:47]([N:6]4[CH2:5][CH2:7][CH2:8][CH2:9]4)=[O:49])[CH:45]=3)[C:40]([S:50]([CH3:52])=[O:51])=[CH:39]2)=[N:34][CH:33]=1
Reactant: Oc1nc2ccccc2s1
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)O)ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCNC1
Product: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CCCC3)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
EDCxHCl (115 mg, 0.60 mmol), hydroxybenzothiazol (82 mg, 0.60 mmol), diisopropylethylamine (0.35 ml, 2.02 mmol) and pyrrolidine (0.05 mL, 0.60 mmol) were added to an ice-cooled suspension of 51e) (200 mg, 0.50 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature for 16 h and then diluted with dichloromethane (40 mL). The organic phase was successively washed with saturated ammonium chloride solution (2×50 mL), saturated sodium hydrogen carbonate solution (2×30 mL), water (30 mL), and brine (30 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography [100-200 mesh silica; 2% methanol in dichloromethane]. White solid. Yield: 65 mg (28% of theory). HPLC-MS (method 5): Rt=3.13 min; m/z [M+H]+=449.1
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:11][CH3:12])(=O)=O.C(#N)C.[O:19]1[C@@:36]2([CH3:37])[C@@H:20]1[CH2:21][C@@H:22]1[C:27]([C:28]([OH:30])=[O:29])=[CH:26][O:25][C@@H:24]([O:31][C:32](=[O:35])[NH:33][CH3:34])[C@H:23]12>CCCCCC.C(OCC)(=O)C>[CH2:11]([O:29][C:28]([C:27]1[C@H:22]2[CH2:21][C@@H:20]3[O:19][C@:36]3([CH3:37])[C@@H:23]2[C@H:24]([O:31][C:32](=[O:35])[NH:33][CH3:34])[O:25][CH:26]=1)=[O:30])[CH3:12]
Reactant: CNC(=O)O[C@@H]1OC=C(C(=O)O)[C@H]2C[C@@H]3O[C@]3(C)[C@H]12
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C1=CO[C@@H](OC(=O)NC)[C@@H]2[C@@H]1C[C@@H]1O[C@]21C
Temperature: 70 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
130 mg of potassium carbonate and 121 μl of diethyl sulfate were added to an acetonitrile solution containing 210 mg of (1S, 4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy) cyclopenta [c]-pyrane-4-carboxylic acid described in Example 1 followed by heating and stirring for 1 hour at 70° C. The reaction mixture was then extracted with ethyl acetate. After washing the organic phase with dilute hydrochloric acid, saturated aqueous sodium bicarbonate and brine, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless oil from the hexane-ethyl acetate eluate in the form of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1, 4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy) cyclopenta [c]-pyrane-4-carboxylic acid ethylester (204 mg, yield: 88%). The physicochemical properties of this compound are described in Table 1, Compound No. 4.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: OB(O)c1ccccc1Br
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccccc2Br)cn1
Yield: 11 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (68.2 mg, 0.3 mmol) was converted, using 2-bromophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (12 mg, 11%) which was obtained as an off-white solid. MS: m/e=381.5[M+H]+.
Reaction SMILES: CC1(C)[O:7][C:6](=[O:8])[C:5]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[C:4](=[O:29])[O:3]1.C1COCC1.[Li+].[OH-]>O>[N+:16]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:5]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)([C:4]([OH:29])=[O:3])[C:6]([OH:8])=[O:7])=[CH:15][CH:14]=1)([O-:18])=[O:17]
Reactant: CC1(C)OC(=O)C(Cc2ccc([N+](=O)[O-])cc2)(Cc2ccc([N+](=O)[O-])cc2)C(=O)O1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(Cc1ccc([N+](=O)[O-])cc1)(Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reaction time: 17 h
Yield: 87.2 %

Procedure:
An adaptation of the procedure described by Tiefenbacher and Rebek (2012) was followed. To a suspension of 5.33 g (12.9 mmol) of 2,2-dimethyl-5,5-di(4-nitrobenzyl)-1,3-dioxane-4,6-dione in 60 mL of a 9:1 mixture of THF to water was added 1.11 g (46.3 mmol) LiOH. This suspension was stirred for ˜17 h. After stirring, 100 mL of water was added to the suspension. The aqueous solution was washed twice with 50 mL of diethyl ether. The aqueous solution was then acidified to pH=1. The product was extracted with ethyl acetate. The ethyl acetate solution was washed once with 100 ml of water and once with 100 mL of brine. The ethyl acetate solution was dried with MgSO4 and the solvent was removed in vacuo to yield 4.21 g (87%) of the desired material. IR, 1HNMR, 13CNMR in addition to TLC were used to confirm identity of the product.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]([CH3:18])[CH3:17])[C:5]2[N:6]=[C:7]([S:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>C(Cl)Cl>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]([CH3:18])[CH3:17])[C:5]2[N:6]=[C:7]([S:11]([CH3:12])=[O:27])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1
Reactant: CSc1nc(C)c2cc(Br)c(=O)n(C(C)C)c2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1nc(S(C)=O)nc2c1cc(Br)c(=O)n2C(C)C
Yield: 47.6 %

Procedure:
To a stirred and cooled (−20° C.) solution of 6-bromo-8-isopropyl-4-methyl-2-(methylthio)-pyrido[2,3-d]pyrimidin-7(8H)-one (380 mg, 1.16 mmol) in CH2Cl2 (25 mL) was added MCPBA (340 mg, 77%, 1.52 mmol). After stirring for 30 min (−20° C. to 0° C.), the mixture was quenched with saturated aqueous NaHCO3, extracted with EtOAc, dried and evaporated. The crude product was washed with EtOAc/Hexane to give the title compound (190 mg, 48%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH2:14]([N:21]=[C:22]=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[CH2:14]([NH:21][C:22](=[O:23])[NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: O=C=NCc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)NCc2ccccc2)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 4.7 g of ethyl 2-aminothiazol-4-ylglyoxylate, 4.5 g of benzyl isocyanate and 30 ml of dimethylformamide. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[CH:5]=[CH:4][C:3]=1[NH:13][C:14]1[N:19]=[C:18]([NH:20][CH3:21])[C:17]([C:22]([F:25])([F:24])[F:23])=[CH:16][N:15]=1.[C:26]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[N:11][N:10]([CH3:26])[N:9]=2)[CH:5]=[CH:4][C:3]=1[NH:13][C:14]1[N:19]=[C:18]([NH:20][CH3:21])[C:17]([C:22]([F:24])([F:25])[F:23])=[CH:16][N:15]=1
Reactant: CNc1nc(Nc2ccc(-c3nn[nH]n3)cc2Cl)ncc1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CNc1nc(Nc2ccc(-c3nnn(C)n3)cc2Cl)ncc1C(F)(F)F
Temperature: 40 °C
Yield: 68.5 %

Procedure:
A mixture of N2-(2-chloro-4-(2H-tetrazol-5-yl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (80 mg, 0.22 mmol), K2CO3 (45 mg, 0.32 mmol) and methyl iodide (15 uL, 0.24 mmol) in acetone (2 mL) was heated at 40° C. for 1 h. The mixture was cooled and filtered. The filtrate was concentrated under reduced pressure and the crude residue purified via silica gel column chromatography (0-100% ethyl acetate/isohexane) to give N2-(2-chloro-4-(2-methyl-2H-tetrazol-5-yl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine (58 mg, 70%). LCMS (10 cm_ESCI_Formic_MeCN): [MH+]=385 at 4.31 min. 1H NMR (400 MHz, CDCl3): δ 8.76 (d, J=8.7, 1H); 8.23-8.19 (m, 2H); 8.05 (dd, J=8.7, 2.0, 1H); 7.72 (s, 1H); 5.29 (s, 1H); 4.40 (s, 3H); 3.12 (d, J=4.7, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:7][CH2:6][C:5]([N+:16]([O-:18])=[O:17])([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][O:3]1.[C:20](Cl)(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH3:1][C:2]1([CH3:19])[O:3][CH2:4][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:12][CH:11]=2)([N+:16]([O-:18])=[O:17])[CH2:6][O:7]1
Reactant: CCCCCCCC(=O)Cl
Reactant: CC1(C)OCC(CCc2ccccc2)([N+](=O)[O-])CO1
Product: CCCCCCCC(=O)c1ccc(CCC2([N+](=O)[O-])COC(C)(C)OC2)cc1

Procedure:
The title compound was prepared from 2-dimethyl-5-nitro-5-phenethyl-1,3-dioxane (20) and octanoyl chloride, according to example 2, affording compound (21) with 68% yield, which was used at the next step without additional purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:20])=[C:4]([CH:14]2[CH2:18][O:17][C:16](=[O:19])[NH:15]2)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:8](O)[CH3:9])[CH:7]=1.CN(C)C=O.S(Cl)([Cl:28])=O>ClCCl>[Cl:1][C:2]1[C:3]([F:20])=[C:4]([CH:14]2[CH2:18][O:17][C:16](=[O:19])[NH:15]2)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH2:8][CH2:9][Cl:28])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CCOc1c(C(C)O)cc(Cl)c(F)c1C1COC(=O)N1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1c(CCCl)cc(Cl)c(F)c1C1COC(=O)N1

Procedure:
4-[3-chloro-6-ethoxy-2-fluoro-5-(1-hydroxyethyl)phenyl]-1,3-oxazolidin-2-one (150 mg, 0.49 mmol) (from Step 10) was stirred in dichloromethane (4 mL) with N,N-dimethylformamide (96 μL) and thionyl chloride (110 μL, 1.5 mmol) was added. The mixture was evaporated. Water was added and the mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give the desired compound, 159 mg, 100%.