Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:13]=[C:14]2[N:22]3[C:17](=[CH:18][C:19]([CH3:23])=[N:20][C:21]=13)[N:16]([CH:24]([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[C:15]2=[NH:31].[CH3:32]OS(OC)(=O)=O.[H-].[Na+].[OH-].[Na+]>O1CCCC1.O>[Br:2][C:3]1[CH:8]=[C:7]([CH:9]([CH3:10])[CH3:11])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:13]=[C:14]2[N:22]3[C:17](=[CH:18][C:19]([CH3:23])=[N:20][C:21]=13)[N:16]([CH:24]([CH2:25][CH2:26][CH3:27])[CH2:28][CH2:29][CH3:30])[C:15]2=[N:31][CH3:32]
Reactant: COS(=O)(=O)OC
Reactant: CCCC(CCC)n1c(=N)c2cc(-c3ccc(C(C)C)cc3Br)c3nc(C)cc1n32
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC(CCC)n1c(=NC)c2cc(-c3ccc(C(C)C)cc3Br)c3nc(C)cc1n32
Temperature: 65 °C
Yield: 40.4 %

Procedure:
To a mixture of 4-(2-bromo-4-isopropyl-phenyl)-6-methyl-1-(1-propyl-butyl)-1H-1,5,7b-triaza-cyclopenta[cd]inden-2-ylideneamine hydrochloride (350 mg) and dimethylsulfate (866 mg) in tetrahydrofuran (3.5 mL) was added NaH (60% in oil, 139 mg) and heated at 65° C. for 1 hour. After addition of water, the reaction mixture was poured into 2.5 M NaOH aqueous solution, extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: chloroform/ethyl acetate=10:1) to give [4-(2-bromo-4-isopropyl-phenyl)-6-methyl-1-(1-propyl-butyl)-1H-1,5,7b-triaza-cyclopenta[cd]inden-2-ylidene]-methyl-amine (135 mg)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[OH-].[Na+].C(=O)=[O:14]>>[NH:8]1[C:4]2[N:5]=[CH:6][CH:7]=[C:2]([OH:14])[C:3]=2[CH:10]=[CH:9]1
Reactant: O=C=O
Reactant: Clc1ccnc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Product: Oc1ccnc2[nH]ccc12
Temperature: 180 °C

Procedure:
4-Chloro-1H-pyrrolo-[2,3-b]pyridine [80 g, Reference Example 64] was treated with 10% aqueous sodium hydroxide solution (330 g) and heated to 180° C. for 8 hours in a parr bomb with magnetic stirring. The reaction mixture was cooled to room temperature and excess sodium hydroxide was neutralized with a large excess of solid carbon dioxide pellets. Undissolved starting material was removed by filtration and the filtrate was concentrated in vacuo. The residue was extracted with hot methanol (3×1000 mL). The combined methanol extracts were concentrated and the residue purified by flash column chromatography on silica gel eluting with a mixture of dichloromethane and methanol (9:1 v:v to 4:1 v:v) to afford the title compound as a solid (63 g). TLC: RF=0.32 (dichloromethane/methanol 4/1).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([OH:17])[C:11]([OH:18])=[N:10]2>S(=O)(=O)(O)O>[Cl:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[N+:1]([O-:4])=[O:2])[N:13]=[C:12]([OH:17])[C:11]([OH:18])=[N:10]2
Reactant: O=[N+]([O-])[O-]
Reactant: Oc1nc2ccc(Cl)cc2nc1O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2nc(O)c(O)nc2cc1Cl
Yield: 87.8 %

Procedure:
Finely powdered potassium nitrate (1.01 g, 10 mmol) was added during 5 min. to a stirred solution of 6-chloro-2,3-dihydroxyquinoxaline (1.97 g, 10 mmol) in 50 ml of conc. sulfuric acid at 0° C. (icebath). After 1 h the icebath was removed and stirring was continued for 21/2 h at room temperature. The mixture was poured into 200 ml of ice/water and the precipitate was isolated, washed with water, ethanol, and ether. The product was dissolved in 70 ml of hot 2N sodium hydroxide, filtered while hot, and reprecipitated with conc. hypochloric acid to give 2.12 g (88%) of pure title compound; m.p. >300° C.;
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([C:29]5([CH2:35][OH:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1.CCN(C(C)C)C(C)C.[CH:46]([S:48]([CH:51]=C)(=[O:50])=[O:49])=[CH2:47]>>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([C:29]5([CH2:35][OH:36])[CH2:30][CH2:31][N:32]([CH2:47][CH2:46][S:48]([CH3:51])(=[O:50])=[O:49])[CH2:33][CH2:34]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1
Reactant: C=CS(=O)(=O)C=C
Reactant: OCC1(c2ccc3c(c2)-c2nn(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CCN1CCC(CO)(c2ccc3c(c2)-c2nn(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1
Yield: 57.5 %

Procedure:
To a stirring mixture of (4-{2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulen-9-yl}-piperidin-4-yl)-methanol hydrochloride 75 (97 mg, 0.1873 mmol) in IMS (3 mL) was added DIPEA (165 L, 0.94 mmol) followed by vinyl sulfone (18 ul, 0.206 mmol) at RT, as illustrated in FIG. 16. After 3 h the solvent was removed in vacuo and the residue was subjected to HPLC (Gemini C6-Phenyl column, gradient 10 to 60%, 20 min ramp) to afford 188 (63 mg, 53%). 1H NMR δ ppm (DMSO-d6): 8.42-8.39 (1H, m), 8.23 (1H, s), 8.19 (1H, s), 7.80 (1H, td, J=8.77, 5.87 Hz), 7.53 (1H, ddd, J=10.34, 8.85, 2.77 Hz), 7.36 (1H, d, J=2.40 Hz), 7.33-7.27 (1H, m), 7.12 (1H, dd, J=8.59, 2.48 Hz), 6.85 (1H, dd, J=8.55, 4.83 Hz), 4.17 (2H, t, J=5.04 Hz), 3.22-3.14 (6H, m), 3.02 (2H, t, J=5.09 Hz), 2.98 (3H, s), 2.02 (2H, s), 1.72 (4H, s). 2 Protons obscured by water peak. LCMS: RT=6.57 min, M+H+=585
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[CH:4][C:3]=1[C:11](=O)[CH3:12].Cl.[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([CH2:22][O:23][NH2:24])=[CH:20][CH:19]=1)([O-:17])=[O:16].N1C=CN=C1.C(OCC)(=O)C.CCCCCC>CCO>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([CH2:22][O:23]/[N:24]=[C:11](/[C:3]2[CH:4]=[C:5]([OH:10])[C:6]([O:8][CH3:9])=[CH:7][C:2]=2[Br:1])\[CH3:12])=[CH:25][CH:26]=1)([O-:17])=[O:16]
Reactant: COc1cc(Br)c(C(C)=O)cc1O
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(Br)c(/C(C)=N/OCc2ccc([N+](=O)[O-])cc2)cc1O

Procedure:
A magnetically stirred solution of ketone 39 (162 mg, 0.661 mmol) in EtOH (2.0 mL) was treated with compound 19 (271 mg, 1.32 mmol) and imidazole (68 mg, 0.999 mmol) then the resulting mixture stirred at reflux for 2 h before being cooled and concentrated under reduced pressure. The ensuing residue was partitioned between CH2Cl2 (10 mL) and H2O (10 mL) and the separated aqueous fraction extracted with CH2Cl2 (1×10 ml). The combined organic fractions were then dried (MgSO4), filtered and concentrated under reduced pressure. The resulting mixture was subjected to flash chromatography (15:85 v/v ethyl acetate/hexane) to afford a ca. 3:1 mixture of the E- and Z-isomeric foams of the title compound CP302108 (229 mg, 88%) as a pale-yellow solid, Rf 0.5 in 1:1 v/v ethyl acetate/hexane. Recrystallisation of this material (twice from isopropanol) afforded the major isomer, CP302108-major, as a pale-yellow solid, m.p. 136.8-138.4° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[CH3:27][C:28]1([CH3:42])[CH2:37][C:36](=[O:38])[C:35]2[C:30](=[CH:31][CH:32]=[C:33](B(O)O)[CH:34]=2)[O:29]1.N1C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:27][C:28]1([CH3:42])[CH2:37][C:36](=[O:38])[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([N:3]3[C:4](=[O:26])[C:5]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([C:18]5[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=5)=[CH:14][CH:13]=4)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=[C:2]3[CH3:1])[CH:34]=2)[O:29]1
Reactant: CC1(C)CC(=O)c2cc(B(O)O)ccc2O1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc3c(c2)C(=O)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 72 h
Yield: 46.4 %

Procedure:
A mixture of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (10 g), (2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromen-6-yl)boronic acid (6.6 g), copper(II) acetate (5.5 g), pyridine (12 mL), triethylamine (21 mL), molecular sieves 4 A (20 g) and dichloromethane (100 mL) was stirred for 3 days. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (7.0 g, 45%) as a colorless solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[C:16]([Br:18])=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnc2c1ncn2Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Nc1ncnc2c1nc(Br)n2Cc1ccccc1

Procedure:
To a stirred solution of 9-benzylpurine (6) (15.0 g, 66.5 mmol) in chloroform (750 mL) was added N-bromosuccinimide (59.26 g, 332.9 mmol) and the reaction mixture was stirred under an atmosphere of nitrogen at reflux temperature for 3 h. The reaction mixture was then transferred to a separatory funnel and washed with saturated aqueous sodium sulfite (2×250 mL) followed by brine solution (2×250 mL). The chloroform fraction was dried over anhydrous sodium sulfate and concentrated to give a reddish oil, which was purified by flash chromatography on silica gel using EtOAc/hexane (4:6) for elution. Yield 9.72 g. (48%). Mp 199-201° C. 1H NMR (CDCl3) δ 5.39 (s, 2H, benzylic CH2), 7.29-7.33 (m, 5H, Ar—H), 8.29 (s, 1H, purine C2—H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[CH2:12][CH2:13]Cl.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(O)C>[CH2:15]([N:22]1[C:2]2[N:7]3[N:8]=[CH:9][N:10]=[C:6]3[N:5]=[C:4]([CH3:11])[C:3]=2[CH2:12][CH2:13]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1nc2ncnn2c(Cl)c1CCCl
Reactant: NCc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc2ncnn2c2c1CCN2Cc1ccccc1

Procedure:
A mixture of 2g of 7-chloro-6-(2-chloroethyl)-5-methyl-s-triazolo[1,5-a]pyrimidine, 0.94g of benzylamine, 3 ml of triethylamine and 20 ml of ethanol was stirred under reflux for 1 hour. The reaction mixture was then concentrated under reduced pressure and the residue was washed with water. The crystals thus obtained were recrystallized from ethanol to give 1.4g of colorless prisms of m.p. 170.5° - 172° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[Mg+2].[Cl-].[Cl-].[CH2:22]=[O:23].Cl>C(#N)C>[C:1]([C:5]1[C:6]([OH:11])=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH:22]=[O:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1O
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cccc(C=O)c1O

Procedure:
A mixture of 2-(tert-butyl)phenol (15 g, 0.1 mol), Et3N (37 g, 374 mmol), MgCl2 (14.3 g, 0.15 mol) and paraformaldehyde (20.2 g, 674 mmol) in ACN (200 mL) was heated at reflux for 5 h, cooled, poured into aq. HCl (2N, 200 mL) and extracted with Et2O. The organic layer was concentrated and purified by CC (PE/EA=8/1) to give compound P7a (13 g, 74%) as a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([NH:9][C:10]1[C:14]([C:15]([O:17]C)=O)=[CH:13][S:12][CH:11]=1)=[O:8].Cl.[F:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])=[CH:23][CH:22]=1.C(=O)(O)[O-].[Na+].[I-].[Na+].NC1C(C(OC)=O)=CSC=1.BrCCCCN=C=O>C(O)(C)C.C1(C)C=CC=CC=1>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:15](=[O:17])[C:14]4=[CH:13][S:12][CH:11]=[C:10]4[NH:9][C:7]3=[O:8])[CH2:29][CH2:28]2)=[O:26])=[CH:33][CH:34]=1
Reactant: COC(=O)c1cscc1NC(=O)NCCCCBr
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: COC(=O)c1cscc1N
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: O=C(c1ccc(F)cc1)C1CCN(CCCCn2c(=O)[nH]c3cscc3c2=O)CC1

Procedure:
The title compound was prepared by dissolving N-(4-bromobutyl)-N'-(4-carbomethoxythien-3-yl)urea (6.92g, 21 mmol) in isopropanol (100 ml) and then successively treating the solution with 4-(4-fluorobenzoyl)piperidine hydrochloride (10.16 g, 42 mmol), sodium bicarbonate (3.7 g, 44 mmol) and sodium iodide (1.90 g, 12 mmol) to form a mixture. The urea was prepared by reacting methyl 4-aminothiophene-3-carboxylate with 4-bromobutylisocyanate in toluene at room temperature for 12 hours to produce the urea as a tan solid, mp 85°-86° C. The mixture was then heated to reflux under a nitrogen atmosphere for 12 hours. The reaction mixture was reduced to half volume, diluted with water, and concentrated to remove the remainder of the alcohol solvent. The residue was extracted with methylene chloride and the combined organic extracts were dried with saturated brine and magnesium sulfate. After concentration of the extracts, the residue was purified on silica gel using methylene chloride/ethanol/ammonium hydroxide (96:3.5:0.5) as eluant. There was obtained 3.62 g (40.8% yield) of the title compound as a brown solid. This material was recrystallized from CH2Cl2 /ether, mp 190°-192° C.
Reaction SMILES: [OH-].[K+].C(O)C.C([O:8][C:9](=[O:32])[C:10]([N:16]([CH3:31])[C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)=[O:18])([CH3:15])[C:11]([NH:13][CH3:14])=[O:12])C.S([O-])(O)(=O)=O.[K+]>O.C1COCC1>[C:9]([C:10]([N:16]([CH3:31])[C:17]([C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)=[O:18])([CH3:15])[C:11]([NH:13][CH3:14])=[O:12])([OH:32])=[O:8]
Reactant: CCOC(=O)C(C)(C(=O)NC)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CNC(=O)C(C)(C(=O)O)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 104.6 %

Procedure:
A 0.84 mol/L potassium hydroxide aqueous solution (3.0 mL) was added to an ethanol (3.0 mL)-THF (3.0 mL) solution of 4-{[1-ethoxy-2-methyl-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl (0.30 g) as obtained in Example 12-(1), and the mixture was stirred for 4.5 hours at room temperature. Under ice cooling, water and a 2.0 mol/L potassium hydrogen sulfate aqueous solution were added to adjust the mixture to pH 7, followed by extracting the mixture with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then the desiccant was filtered out. The solvent was distilled off under reduced pressure to obtain 4-{[2-carboxy-1-(methylamino)-1-oxopropan-2-yl](methyl)carbamoyl}biphenyl (orange solid) (0.29 g, 82%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[S:9][CH:10]=1.C(OCC)(=O)C>C(O)(C(F)(F)F)=O.ClCCl>[Br:5][C:6]1[C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[S:9][C:10]=1[N+:1]([O-:4])=[O:2]
Reactant: Brc1csc2ccccc12
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1sc2ccccc2c1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Add dropwise fuming nitric acid (90%, 8.6 mL, 183 mmol) to a mixture of 3-bromo benzo[b]thiophene (39 g, 183 mmol) in TFA (100 mL) and dichloromethane (400 mL) at 0° C. The reaction turn greenish, then yellow precipitates. To this reaction mixture, add dichloromethane (200 mL) and the reaction stir at 0° C. for 30 min. Then pour the reaction into ice-water (2L). Extract with dichloromethane (3×500 mL) and the organic layer dry over MgSO4. Evaporation give a yellow solid. The resulting yellow solid triturate with diethyl ether to give a yellow solid. (Total: 34.8 g, 73%). Mass spectrum (m/e): 259(M+1); 1HNMR(300 MHz, DMSO-d6) δ ppm: 7.70(tt, 2H), 8.04(d, 1H), 8.17(d, 1H). 13CNMR(75 MHz, DMSO-d6) δ ppm: 112.5, 124.8, 126.9, 127.9, 131.3, 137.0, 137.2, 166.1.
Reaction SMILES: [CH:1]([N:4]([C:18]([C:20]1[C:21]([C:43]([F:46])([F:45])[F:44])=[CH:22][C:23]2[O:28][C:27]([CH3:34])([CH2:29][O:30]C#CC)[C:26](=[O:35])[N:25]([CH2:36][CH2:37][NH:38][C:39]#[C:40][CH3:41])[C:24]=2[CH:42]=1)=[O:19])[C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CO>[OH:30][CH2:29][C:27]1([CH3:34])[C:26](=[O:35])[N:25]([CH2:36][CH2:37][NH:38][C:39]#[C:40][CH3:41])[C:24]2[CH:42]=[C:20]([C:18]([N:4]([CH:1]([CH3:2])[CH3:3])[C@@H:5]3[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]3)=[O:19])[C:21]([C:43]([F:46])([F:44])[F:45])=[CH:22][C:23]=2[O:28]1
Reactant: CC#CNCCN1C(=O)C(C)(COC#CC)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: CC#CNCCN1C(=O)C(C)(CO)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
tert-Butyl (3R)-3-(isopropyl{[2-methyl-3-oxo-4-[2-(propynylamino)ethyl]-2-[(propynyl-oxy)methyl]-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}amino)piperidine-1-carboxylate (24.9 g) was dissolved in methanol (100 mL), and thereto was added potassium carbonate (553 mg), and the mixture was stirred at 0° C. for one hour. After the reaction was complete, a saturated aqueous ammonium chloride solution was added thereto, and methanol was removed by evaporation under reduced pressure. The residue was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by column chromatography to give the title compound (4.92 g).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1)(=[O:4])=[O:3].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CO.C(Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)NCc1ccc(CO)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CS(=O)(=O)NCc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-[(methanesulfonamido)methyl]benzyl alcohol (1.0 g, 4.6 mmol) in CH2Cl2 (25 mL) was added pyridinium chlorochromate (1.5 g, 7.0 mmol). The reaction mixture was stirred for 1 h at rt and poured through a pad of silica gel eluting with 2% MeOH/CHCl3. The title compound was isolated as a tan solid (1.0 g, 100%): 1H NMR (CDCl3): δ10.03 (s,1H); 7.88 (d, 2H); 7.57 (d, 2H); 4.79 (br s, 1H); 4.43 (d, 2H); 2.93 (s, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[C:13]([F:19])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:20]C)[CH:3]=1.[CH2:22]([Sn](CCCC)(CCCC)CCCC)[CH:23]=[CH2:24]>>[CH2:24]([C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([F:19])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([OH:20])[CH:3]=1)[CH:23]=[CH2:22]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cc(Br)c2oc(-c3ccc(OC)c(F)c3)nc2c1
Product: C=CCc1cc(O)cc2nc(-c3ccc(O)c(F)c3)oc12

Procedure:
The title compound was prepared in substantially the same manner as described in Example 24, Route c, step b, from 7-bromo-2-(3-fluoro-4-methoxyphenyl)-5-methoxy-1,3-benzoxazole, allyltributyltin and dichlorobis(trio-tolylphosphine)palladium, followed by demethylation according to Example 20, step e. The desired product was obtained as a light pink solid, m.p. 169-171° C.; MS m/e 284 (M−H)+.
Reaction SMILES: C(O)(=O)C.O.[NH2:6]N.C[N:9]([CH:11]=[C:12]1[C:17](=O)[CH2:16][C:15]([CH3:20])([CH3:19])[CH2:14][C:13]1=[O:21])C>C(O)CCC>[CH3:19][C:15]1([CH3:20])[CH2:16][C:17]2[NH:6][N:9]=[CH:11][C:12]=2[C:13](=[O:21])[CH2:14]1
Reactant: CN(C)C=C1C(=O)CC(C)(C)CC1=O
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Solvent: CCCCO
Product: CC1(C)CC(=O)c2cn[nH]c2C1
Yield: 38.9 %

Procedure:
According to Scheme 2 Step 2: At 0° C., acetic acid (8.55 mL) followed by hydrazine monohydrate (197 mmol, 11.3 mL), were added slowly to a solution of 2-((dimethylamino)methylene)-5,5-dimethylcyclohexane-1,3-dione (197 mmol, 38.5 g) in butanol (400 mL). The reaction mixture was stirred under reflux for 16 hours. After evaporation of the filtrate, the crude residue was purified by flash chromatography over silica gel cyclohexane/AcOEt (100:0 to 50:50) and then over C18 gel using water/MeOH (100:0 to 50:50) as eluent to yield 6,6-dimethyl-6,7-dihydro-1H-indazol-4(5H)-one (76.7 mmol, 12.6 g, 39%) as a pale yellow solid.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([OH:22])[N:11]=[C:10]([CH2:23][C:24]2([C:29]3[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=3[Cl:36])[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:9]=1)=[O:7])(C)(C)C.O.C(OCC)(=O)C>O1CCCC1.O.CCCCCC>[CH2:15]([O:14][C:13]1[C:8]([C:6]([OH:7])=[O:5])=[N:9][C:10]([CH2:23][C:24]2([C:29]3[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=3[Cl:36])[CH2:25][CH2:26][CH2:27][CH2:28]2)=[N:11][C:12]=1[OH:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(c3cc(Cl)ccc3Cl)CCCC2)nc(O)c1OCc1ccccc1
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1nc(CC2(c3cc(Cl)ccc3Cl)CCCC2)nc(O)c1OCc1ccccc1
Yield: 72.5 %

Procedure:
To a stirred solution of 5-benzyloxy-2-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (204) (2.0 g, 3.788 mmol) in tetrahydrofuran-H2O (2:1) (30 mL) Li(OH).H2O (1.591 g, 37.88 mmol) was added, then the reaction mixture was stirred under reflux for 16 h. Silica thin layer chromatography was performed (40% ethyl acetate in hexane, Rf=0.1). After completion of the reaction, volatiles were removed, the reaction mixture was diluted with water, the pH was adjusted to pH ˜7 with 1N HCl, then the reaction mixture was extracted with ethyl acetate. The organic part was dried with Na2SO4, then concentrated to get pure 5-benzyloxy-2-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (205) (1.3 g, 72.5%) as a white solid.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([NH:9][C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[O:12]1[C@@H:14]([CH2:15][CH3:16])[CH2:13]1>CN(C=O)C.O>[OH:12][C@@H:14]([CH2:15][CH3:16])[CH2:13][N:9]1[C:7](=[O:8])[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:10]1=[O:11]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC[C@H]1CO1
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@H](O)CN1C(=O)c2ccccc2C1=O
Temperature: 60 °C

Procedure:
To 1,2-Benzenedicarboximide (4.29 g) in DMF (10 ml), (S)-(−)-1,2-epoxybutane (2.1 g) was added followed by K2 CO3 (4.03 g) and heated at 60° C. for 48 h. The reaction was diluted with water, extracted with EtOAc, dried and solvent removed to give the subtitle compound as a white solid, 1.8 g.