Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH:9]=[CH:10][C:11]([NH:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.OO.C(O)(=[O:21])C=C.CN>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:9]2[O:21][CH:10]2[C:11]([NH:13][CH3:14])=[O:12])=[O:15])=[CH:6][CH:7]=1
Reactant: CNC(=O)C=CC(=O)c1ccc(Cl)cc1
Reactant: C=CC(=O)O
Agent: CN
Agent: OO
Product: CNC(=O)C1OC1C(=O)c1ccc(Cl)cc1

Procedure:
3 was prepared as a white solid, m.p.: 160°-161° C, from 4-(4-chlorophenyl)-N-methyl-4-oxo-2-butenamide (3A) by hydrogen peroxide oxidation by the procedure described in Example 1, 3A having been prepared from the corresponding acrylic acid and monomethylamine by the procedure described in Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8](=[O:13])[N:7]([C@@H:14]([CH2:18][CH3:19])[C:15]([OH:17])=O)[CH:6]=[CH:5]2.ClC1C(Cl)=CC(C(O)=O)=C(C=O)C=1.[C:33]([O:37][C:38](=[O:56])[CH2:39][C@H:40]([NH2:55])[CH:41]([OH:54])[CH2:42][O:43][C:44]1[C:49]([F:50])=[C:48]([F:51])[CH:47]=[C:46]([F:52])[C:45]=1[F:53])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38](=[O:56])[CH2:39][C@H:40]([NH:55][C:15](=[O:17])[C@@H:14]([N:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=2)[C:8]1=[O:13])[CH2:18][CH3:19])[C:41](=[O:54])[CH2:42][O:43][C:44]1[C:49]([F:50])=[C:48]([F:51])[CH:47]=[C:46]([F:52])[C:45]=1[F:53])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC[C@@H](C(=O)O)n1ccc2cc(Cl)c(Cl)cc2c1=O
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(O)COc1c(F)c(F)cc(F)c1F
Agent: O=Cc1cc(Cl)c(Cl)cc1C(=O)O
Product: CC[C@@H](C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)COc1c(F)c(F)cc(F)c1F)n1ccc2cc(Cl)c(Cl)cc2c1=O

Procedure:
This compound was prepared using (S)-2-(6,7-dichloro-1-oxo-1H-isoquinolin-2-yl)-butyric acid (synthesized from 4,5-dichloro-2-formyl-benzoic acid [prepared as described in methods R-T] using procedures similar to those described in methods A-E) and (3S)-3-Amino-4-hydroxy-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid tert-butyl ester (prepared as described in methods H-J) using procedures similar to those described in methods F-G. The title compound was isolated as a white solid (94% last step); IR (solid) 1784.5, 1734.7, 1650.1, 1610.2, 1585.4, 1515.7, 1490.8, 1426.0, 1216.9, 1172.1, 1092.5, 933.1 cm−1; 1H NMR (400 MHz, d6-DMSO) δ 0.80 (3H, t), 1.90-1.98 (1H, m), 2.04-2.12 (1H, m), 2.55-2.79 (2H, m), 4.56-4.71 (1H, m), 5.08-5.41 (3H, m), 6.67 (1H, d), 7.56-7.59 (2H, m), 8.07 (1H, brs), 8.25 (1H, d), 8.85-8.95 (1H, 2×d), 12.73 (1H, brs); 19F NMR (376 MHz, d6-DMSO) (proton decoupled) δ −140.93, −140.95, −140.99, −141.01, −141.04, −141.07, −141.10, −156.76, −156.79, −156.82, −156.85, −156.89, −156.91; MS ES (+): 577.14 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:14]([C:18](Cl)=[O:19])=[CH:13][CH:12]=[CH:11]3)=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].[Cl:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30]>C(Cl)Cl.C(Cl)(Cl)Cl.O>[Cl:26][C:27]1[CH:28]=[C:29]([NH:30][C:18]([C:14]2[C:15]3[C:10](=[CH:9][C:8]([O:7][C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[CH:17][CH:16]=3)[CH:11]=[CH:12][CH:13]=2)=[O:19])[CH:31]=[CH:32][CH:33]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(Cl)c1cccc2cc(Oc3ccncc3)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(Nc1cccc(Cl)c1)c1cccc2cc(Oc3ccncc3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-(Pyridin-4-yloxy)-1-naphthoyl chloride (50 mg, 0.18 mmol) was suspended in CH2Cl2 and solid NaHCO3 (excess) was added. The mixture was blanketed with nitrogen and 3-chloroaniline (18.6 μL, 0.18 mmol) was added and the reaction mixture stirred at RT for 1 h. The reaction mixture was diluted with CHCl3 and water (using heat to dissolve the solids) and the organic layer further washed with brine, dried with Na2SO4, filtered and concentrated in-vacuo. The residue was crystallized from CH2Cl2/hexanes to give the title compound as a brown solid. MS (ESI pos. ion) m/z: 375.1 (M+H). Calc'd for C22H15ClN2O2−374.82.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([CH:10]([C:23]1[CH:27]=[C:26]([Si:28]([CH3:31])([CH3:30])[CH3:29])[O:25][CH:24]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[N+]=[N-]>O1CCCC1>[NH2:7][CH:10]([C:23]1[CH:27]=[C:26]([Si:28]([CH3:31])([CH3:30])[CH3:29])[O:25][CH:24]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCC(N=[N+]=[N-])c1coc([Si](C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(N)c1coc([Si](C)(C)C)c1
Reaction time: 1 h

Procedure:
Lithium aluminum hydride (a 1M solution in tetrahydrofuran; 1.1 ml, 1.1 mmol) was added dropwise to a solution of 3-(1-azidotridecyl)-5-trimethylsilylfuran (334 mg, 0.92 mmol) in tetrahydrofuran at room temperature. After one hour at room temperature, the excess hydride was destroyed by adding acetone slowly to the mixture with cooling. Sodium sulfate (ca. 0.5 g) was added and the mixture was extracted thoroughly with ethyl acetate. Evaporation of the dried (magnesium sulfate) extracts gave an oil, which was purified by flash chromatography on silica using 5% methanol/dichloromethane containing 0.2% triethylamine. Fractions with Rf of about 0.18 on evaporation gave the title amine as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:9](=[S:14])[NH:10][CH:11]1[CH2:13][CH2:12]1)=[C:6]([NH2:8])[CH3:7])[CH3:2].BrBr.C(OCC)C.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1[C:6]([CH3:7])=[N:8][S:14][C:9]=1[NH:10][CH:11]1[CH2:13][CH2:12]1)=[O:15])[CH3:2]
Reactant: CCOC(=O)C(C(=S)NC1CC1)=C(C)N
Agent: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(C)nsc1NC1CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 41.2 %

Procedure:
To a vigorously stirred solution of 1 g of 3-amino-2-cyclopropylthiocarbamoyl-but-2-enoic acid ethyl ester (4.4 mmol) in chloroform (16 ml) was added dropwise a solution of 1.4 g of bromine in chloroform (8 ml) at 0° C. After completion of the addition the reaction mixture was stirred at 0° C. for additional 5 min. Then diethyl ether and sat. NaHCO3-solution were added and the mixture was extracted with diethyl ether. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography (100% DCM) to give 5-cyclopropylamino-3-methyl-isothiazole-4-carboxylic acid ethyl ester (410 mg, 40%) as a brown liquid. 1HNMR (CDCl3, 300 MHz): δ 0.73 (m, 2H), 0.81 (m, 2H), 1.36 (t, J=7.2 Hz, 3H), 2.50 (s, 3H), 2.63 (m, 1H), 4.29 (q, J=7.2 Hz, 2H), 7.80 (br s, 1H).
Reaction SMILES: C([C:4]1C(=O)[N:6]([CH2:18][CH:19]([CH3:21])[CH3:20])[N:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([F:17])[CH:11]=2)[CH:9]=1)(O)=O.C(N(CC)CC)C.C(Cl)(=O)[O:31][CH2:32][CH3:33].[BH4-].[Na+].Cl.C1C[O:42]CC1>O>[F:17][C:12]1[CH:11]=[C:10]([C:8]2[C:9]([CH3:4])=[C:32]([OH:31])[C:33](=[O:42])[N:6]([CH2:18][CH:19]([CH3:20])[CH3:21])[N:7]=2)[CH:15]=[CH:14][C:13]=1[CH3:16]
Reactant: Cc1ccc(-c2cc(C(=O)O)c(=O)n(CC(C)C)n2)cc1F
Reactant: C1CCOC1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2nn(CC(C)C)c(=O)c(O)c2C)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To a solution of 4-carboxy-6-(3-fluoro-4-methyl-phenyl)-2-isobutyl-2H-pyridazin-3-one (4.53 g, 14.9 mmol) in THF (40 mL) was added triethylamine (1.66 g, 16.4 mmol). To the ice-cooled mixture was added dropwise a solution of ethyl chlorocarbonate (1.78 g, 16.4 mmol) in THF (5 mL), and the mixture was stirred for 30 minutes. Triethylamine hydrochloride was filtered off. A solution of sodium borohydride (564 mg, 14.9 mmol) in water (1 mL) was added to the filtrate, and then, the mixture was stirred at room temperature for 10 minutes. Thereafter, 2 mol/L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel [silica gel 300 g, chloroform/methanol (100/1→50/1)) to yield the title compound as a colorless crystalline powder (1.08 g, 25.0%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](Cl)=[N:7][CH:6]=1)[CH3:2].[CH3:16][NH2:17]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([NH:17][CH3:16])=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CN
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(NC)c([N+](=O)[O-])c1

Procedure:
6-Methylamino-5-nitro-nicotinic acid ethyl ester (911 mg) was prepared by following General Procedure A starting from 6-chloro-5-nitro-nicotinic acid ethyl ester (1.0 g) and methylamine (2 M in THF, 3.25 mL) in DMF.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[N:13]=[C:14]([NH:17][C:18](=[O:24])[C:19]([O:21]CC)=O)[CH:15]=[CH:16][C:10]3=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([NH2:27])[CH3:26]>C1COCC1>[CH2:25]([NH:27][C:19](=[O:21])[C:18]([NH:17][C:14]1[CH:15]=[CH:16][C:10]2[C:11]([N:13]=1)=[N:12][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:8][N:9]=2)=[O:24])[CH3:26]
Reactant: CCOC(=O)C(=O)Nc1ccc2ncc(-c3ccccc3)nc2n1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNC(=O)C(=O)Nc1ccc2ncc(-c3ccccc3)nc2n1

Procedure:
23 mg (0.07 mmol) of ethyl N-(3-phenylpyrido[2,3-b]pyrazin-6-yl)oxalamidate were dissolved in 5ml of dry THF and admixed with 0-15 ml (0.38 mmol) of a 2.0 M ethylamine solution in THF.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:31]=[C:32]([Cl:37])[C:33]=1[O:34][CH2:35][CH3:36])[NH2:30].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:26][C:27]1[CH:28]=[C:29]([NH:30][C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][N:9]=2)=[O:13])[CH:31]=[C:32]([Cl:37])[C:33]=1[O:34][CH2:35][CH3:36]
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: CCOc1c(Cl)cc(N)cc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1c(Cl)cc(NC(=O)c2ccc(C(=O)OC)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
5-(Methoxycarbonyl)-2-pyridine carboxylic acid (50 mg, 276 μmol) was dissolved in DMF (2 mL) and treated with CDI (60 mg, 370 μmol). The reaction mixture was stirred at RT for 2 h. 3,5-Dichloro-4-ethoxyaniline (2) (57 mg, 276 μmol) and DIPEA (96 μL, 552 μmol) were added sequentially and the reaction mixture was stirred at RT overnight, then at 70° C. for 19 h. The reaction mixture was partitioned between EtOAc and aqueous HCl (1 M). The organic layer was washed successively with water and brine, and then dried over MgSO4, filtered and concentrated in vacuo. The residue was crystallised from methanol to afford methyl 6-(3,5-dichloro-4-ethoxyphenylcarbamoyl)nicotinate (3) (46 mg, 45%) as a white solid: m/z 369 [M+H]+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 11.12 (1H, s), 9.18 (1H, dd), 8.55 (1H, dd), 8.29 (1H, dd), 8.13 (2H, s), 4.06 (2H, q), 3.94 (3H, s), 1.37 (3H, t).
Reaction SMILES: O=[C:2]1[C:6]2=[C:7]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[NH:8][C:9](=[O:10])[C:5]2=[C:4]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[NH:3]1.[C:21]([O-:24])([O-])=O.[K+].[K+].[CH2:27]([CH:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:36]Br)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].O>CN(C)C=O>[CH2:27]([CH:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:2][N:3]1[C:4]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[C:5]2[C:6](=[C:7]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[N:8]([CH2:36][CH:35]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[C:9]2=[O:10])[C:21]1=[O:24])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: O=C1NC(c2cccs2)=C2C(=O)NC(c3cccs3)=C12
Reactant: O=C([O-])[O-]
Reactant: CCCCCCCCCCC(CBr)CCCCCCCC
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCC(CCCCCCCC)CN1C(=O)C2=C(c3cccs3)N(CC(CCCCCCCC)CCCCCCCCCC)C(=O)C2=C1c1cccs1
Temperature: 120 °C
Yield: 54 %

Procedure:
In a three-neck, oven dried, 250 ml round bottom flask, 2,5-dihydro-1,4-dioxo-3,6-dithienylpyrrolo[3,4-c]-pyrrole (2), (7.0 g. 23.30 mmol) and anhydrous K2CO3 (8.95 g, 69.91 mmol) were dissolved in 250 ml of anhydrous N,N-dimethylformamide (DMF), and heated to 120° C. under argon for 1 h. 2-octyl-1-dodecylbromide (25.27 g, 69.91 mmol) was then added dropwise, and the reaction mixture was further stirred and heated overnight at 130° C. The reaction mixture was cooled to room temperature and then poured into water and stirred for 30 minutes. The product was extracted with chloroform, then successively washed with water, and dried over MgSO4. Removal of the solvent afforded the crude product which was then purified using column chromatography on silica gel using a mixture of hexane and chloroform as eluent, giving a purple solid (11.0 g, 54%). 1H NMR (CDCl3): (0.87 (t, 12H), 1.13-1.45 (m, 64H), 1.89 (s, 2H), 4.00 (d, 4H), 7.26 (d, 2H), 7.52 (d, 2H), 8.87 (d, 2H). MS (MALDI-TOF) m/z 860.63 (M). calcd. for C54H88N2O2S2=860.25.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[CH3:13][C:14]1([CH3:19])[CH2:17][CH:16]([NH2:18])[CH2:15]1>C(O)C>[CH3:13][C:14]1([CH3:19])[CH2:17][CH:16]([NH:18][CH2:12][C@@H:10]([C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[N:2][N:1]=3)[CH:9]=2)[OH:11])[CH2:15]1
Reactant: CC1(C)CC(N)C1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Solvent: CCO
Product: CC1(C)CC(NC[C@H](O)c2ccc3nnnn3c2)C1
Yield: 104 %

Procedure:
A solution of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane (375 mg, 2.31 mmol) and (3,3-dimethylcyclobutyl)amine (1.14 g, 11.5 mmol) in 0.8 ml of absolute ethanol was heated at 70° C. in a sealed reaction vessel for 3 hours. The reaction mixture was concentrated and the residue was purified by preparative Tlc on silica gel (90:10:1 methylene chloride:methanol:NH4OH) to give 628 mg of product; Analysis: Calc'd. for C13H19N5O:
Reaction SMILES: [CH2:1]1[C:5]2[C:6]3[CH2:12][CH2:11][CH2:10][CH2:9][C:7]=3[S:8][C:4]=2[C:3](=[N:13]O)[CH2:2]1.[OH2:15]>>[C:3]1(=[O:15])[C:4]2[S:8][C:7]3[CH2:9][CH2:10][CH2:11][CH2:12][C:6]=3[C:5]=2[CH2:1][CH2:2][NH:13]1
Reactant: O
Reactant: ON=C1CCc2c1sc1c2CCCC1
Product: O=C1NCCc2c1sc1c2CCCC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 105d (285 mg, 1.38 mmol) and polyphosphoric acid (15 g). After stirring at 80° C. for 16 h, the reaction mixture was cooled to room temperature, and water (30 mL) was added. The resulting mixture was stirred for 30 min and filtered. The filter cake was washed with water (20 mL) and dried in a vacuum oven at 45° C. to afford a 75% yield (215 mg) of 105e as an off-white solid: mp 203° C. dec; 1H NMR (500 MHz, CDCl3) δ 5.62 (s, 1H), 3.59 (t, 2H, J=7.0 Hz), 2.81 (t, 2H, J=6.0 Hz), 2.72 (t, 2H, J=7.0 Hz), 2.48 (t, 2H, J=6.0 Hz), 1.84 (m, 4H). MS (APCI+) m/z 208.3 (M+H)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:9][CH2:8][C:7]3([CH2:11][CH2:10]3)[CH2:6][N:5]2[C:12](=[O:14])[CH:13]=1.[C:15](=O)([O-])[O-].[Cs+].[Cs+].O.[C:22]([O:25][CH2:26][CH3:27])(=O)[CH3:23]>CC#N>[Cl:1][C:2]1[N:3]=[C:4]2[N:9]([CH2:27][CH2:26][O:25][CH:22]([CH3:23])[CH3:15])[CH2:8][C:7]3([CH2:10][CH2:11]3)[CH2:6][N:5]2[C:12](=[O:14])[CH:13]=1
Reactant: CCOC(C)=O
Reactant: O=C([O-])[O-]
Reactant: O=c1cc(Cl)nc2n1CC1(CC1)CN2
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CC(C)OCCN1CC2(CC2)Cn2c1nc(Cl)cc2=O
Temperature: 65 °C
Yield: 71 %

Procedure:
0.1 g of 8′-chloro-1′,2′-dihydro-6′H-spiro[cyclopropane-1,3′-pyrimido[1,2-a]-pyrimidin]-6′-one are suspended in 10 mL of CH3CN, 0.2 g of cesium carbonate and 0.17 g of 2,2-isopropoxyethyl methanesulfonate are added. The mixture is heated to 65° C. for 72 h. Water, ethyl acetate are added and then after decantation, the organic phase is dried with magnesium sulfate and then evaporated. The crude is purified by flash chromatography on silica gel SiO2 (CH2Cl2/MeOH, 99/1). 0.1 g (yield=71%) of 8′-chloro-1′-(2-isopropoxyethyl)-1′,2′-dihydro-6′H-spiro[cyclopropane-1,3′-pyrimido[1,2-a]pyrimidin]-6′-one are obtained as a white powder including the following characteristics:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][C:19]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([NH2:38])[N:33]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:48](Cl)(=[O:50])[CH3:49]>C1COCC1.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[NH:18][C:19]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([NH:38][C:48](=[O:50])[CH3:49])[N:33]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=3)[N:21]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nccc(-c2[nH]c(C3CCN(C(=O)OCc4ccccc4)CC3)nc2-c2cccc(C(F)(F)F)c2)n1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nccc(-c2[nH]c(C3CCN(C(=O)OCc4ccccc4)CC3)nc2-c2cccc(C(F)(F)F)c2)n1
Temperature: 20 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
To a stirred solution of 4-[5-(2-aminopyrimidin-4-yl)-4-(3-trifluoromethylphenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid benzyl ester (Example 12) (0.220 g, 0.421 mmole) in THF (4 mL) under argon at 0° C. was added diisopropylethylamine (0.22 mL, 1.26 mmole) followed by acetyl chloride (0.036 mL, 0.50 mmole). The reaction was stirred at 20° C. for 1 hour, diluted with water (10 mL) and product extracted with ethyl acetate (2×50 mL). The ethyl acetate extracts were dried over anhydrous sodium sulfate, filtered, concentrated and chromatographed on silica using 5% methanol/methylene chloride to give the product (0.170 g) as an oil.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:39])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][CH2:23][O:24][CH3:25])[CH:17]=[C:16]([C:26]([OH:28])=[O:27])[C:15]3=[O:29])=[C:8]([C:30]2[S:31][CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[N:34]=2)[CH:7]=1)[CH3:2].C1COCC1.[OH-].[Na+:46]>CO>[CH2:1]([NH:3][C:4](=[O:39])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][CH2:23][O:24][CH3:25])[CH:17]=[C:16]([C:26]([O-:28])=[O:27])[C:15]3=[O:29])=[C:8]([C:30]2[S:31][CH:32]=[C:33]([C:35]([F:37])([F:38])[F:36])[N:34]=2)[CH:7]=1)[CH3:2].[Na+:46]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3CCOC)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)[O-])cn3CCOC)cn1
Yield: 85.7 %

Procedure:
6-(6-(3-Ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.032 g, 0.06 mmol, Example 1) was suspended in MeOH (1.0 mL)/THF (1.0 mL). 1N NaOH (0.057 mL, 0.06 mmol) was added. Once in solution, the reaction mixture was concentrated under reduced pressure and dried for several hours to yield a white solid (0.030 g).
Reaction SMILES: [CH3:1][C:2](=[O:4])[CH3:3].C(O)C.[F:8][C:9]([F:13])([F:12])[S:10]Cl>ClCCl>[F:8][C:9]([F:13])([F:12])[S:10][CH2:1][C:2](=[O:4])[CH3:3]
Reactant: FC(F)(F)SCl
Reactant: CC(C)=O
Solvent: CCO
Solvent: ClCCl
Product: CC(=O)CSC(F)(F)F
Temperature: 25 °C
Reaction time: 120 h
Yield: 69 %

Procedure:
A mixture of 2-propanone (0.25 mole), ethanol (0.49) and dichloromethane (75 ml) was introduced into a sealed and pressure tested vessel having a volume of about 500 ml under reduced pressure. Trifluoromethanesulfenyl chloride (0.22 mole) was then added to the cooled, evacuated vessel. The vessel was warmed to about 25°C and then rocked for five days. The vessel was vented through a cold gas trap (-78°C) to trap any unreacted trifluoromethylsulfenyl chloride gas and then through a scrubbing system to remove the vented hydrogen chloride gas. Residual liquid was transferred to a flask and distilled to give about 24 g of 1-trifluoromethylthio-2-propanone. The structure of the purified product (b.p. 51°-52°C/22 mm Hg) was confirmed by spectral and elemental analyses.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[C:14]([CH2:16][O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:15][C:11]=2[C:10](I)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([Si:30]([CH3:52])([CH3:51])[O:31][C:32]1[CH:40]=[C:39]2[C:35]([CH:36]=[C:37](B(O)O)[N:38]2[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[CH:34][CH:33]=1)([CH3:29])([CH3:28])[CH3:27].C([Si](C)(C)OC1C=C2C(=CC=1)N(C(OC(C)(C)C)=O)C(B(O)O)=C2)(C)(C)C>>[C:44]([O:43][C:41]([N:38]1[C:39]2[C:35](=[CH:34][CH:33]=[C:32]([O:31][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:51])[CH3:52])[CH:40]=2)[CH:36]=[C:37]1[C:10]1[C:11]2[S:15][C:14]([CH2:16][O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][C:12]=2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[N:9]=1)=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)OC(=O)n1nc(I)c2sc(COCc3ccccc3)cc21
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(O[Si](C)(C)C(C)(C)C)cc21
Agent: CC(C)(C)OC(=O)n1c(B(O)O)cc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Product: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(O[Si](C)(C)C(C)(C)C)cc3n2C(=O)OC(C)(C)C)c2sc(COCc3ccccc3)cc21

Procedure:
2-(5-Benzyloxymethyl-1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-(tert-butyl-dimethyl-silanyloxy)-indole-1-carboxylic acid tert-butyl ester [Intermediate (92)] was prepared in 39% yield using procedures similar to those of Example 5C, substituting 5-benzyloxymethyl-3-iodo-thieno[3,2-c]pyrazole-1-carboxylic acid tert-butyl ester [Intermediate (91)] for 3-iodo-thieno[3,2c]pyrazole-1-carboxylic acid tert-butyl ester and 6-(tert-butyl-dimethyl-silanoxy)-1-(tert-butoxycarbonyl)-1H-indole-2-boronic acid [Intermediate (74), prepared by the application of method described in Example 4-6 of International Patent Application Publication No. WO 02/32861] for 5-(tert-butyl-dimethyl-silanoxy)-1-(tert-butoxycarbonyl)-1H-indole-2-boronic acid.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[Cl:15][CH2:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[Cl-:15].[CH3:19][C:18]([CH3:21])([CH3:20])[C:17](=[O:22])[CH2:16][N+:11]1[CH:12]=[CH:13][N:9]([C:2]2[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=2[CH3:14])[CH:10]=1
Reactant: CC(C)(C)C(=O)CCl
Reactant: Cc1cc(C)c(-n2ccnc2)c(C)c1
Solvent: C1CCOC1
Product: Cc1cc(C)c(-n2cc[n+](CC(=O)C(C)(C)C)c2)c(C)c1
Product: [Cl-]

Procedure:
According to the general synthesis procedure, 5.4 mmol (1.00 g) 1-mesitylimidazole and 6.4 mmol (0.870 g, 0.85 ml) 1-chloro-3,3-dimethyl-2-butanone are dissolved in 5 ml THF and heated for 45 min to 90° C.