Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14](O)[CH3:15]>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:14][CH3:15])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CCO
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Product: CCOC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reaction time: 20 h

Procedure:
To 500 ml of ethanol containing 4-hydroxy-3-nitrobenzoic acid (50.0 g) was added concentrated sulftuic acid (33.0 ml) and the resulting mixture was refluxed with stirring for 20 hours. After this reaction mixture was concentrated under a vacuum, the residue was diluted with water and then the crystal was collected by filtration. This crystal was suspended in water and neutralized in saturated aqueous sodium hydrogencarbonate solution. Thereafter, the crystal was collected by filtration, washed with water, and dried under a vacuum, thereby yielding 54.0 g of ethyl 4-hydroxy-3-nitrobenzoate. As in the case of Reference Example 4, this compound (46.6 g) was benzylated with 4-fluorobenzyl bromide (50.0 g) folowed by hydrolysis with potassium hydroxide, thereby yielding 58.0 g of 4-(4-fluorobenzyloxy)-3-nitrobenzoic acid. To 180 ml of a chloroform solution containing this compound (16.0 g), triethylamine (15.3 ml) and diphenylphosphinic chloride (10.5 ml) were added. After the resulting mixture was stirred for 1 hour, 1-isobutylpiperazine dihydrochloride (11.8 g) and triethylamine (15.3 ml) were added and the mixture was stirred for 13 hours at room temperature. The reaction mixture was successively washed with water, saturated aqueous sodium hydrogencarbonate solution, and saturated brine, dried over magnesium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2 to 1:1), thereby yielding 19.8 g of 1-[4-(4-fluorobenzyloxy)-3-nitrobenzoyl]-4-isobutylpiperazine as a crystal. To 20 ml of ethyl acetate solution containing this compound (1.38 g), 1N hydrogen chloride ether solution (3.4 ml) was added. After the mixture was stirred for 15 minutes at room temperature, the resulting crystals were collected by filtration, thereby yielding 1.48 g of the aimed compound.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[C:24]([O:28][C:29]([NH:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25].[OH-].[Na+]>CN(C=O)C.CO>[C:24]([O:28][C:29]([NH:31][C:32]1[CH:33]=[CH:34][C:35]([NH:36]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:37][CH:38]=1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-tert.butoxycarbonylamino-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [CH2:1]([N:3]([CH2:42][CH3:43])[C:4](=[O:41])[CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:40])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N+:37]([O-])=O)=[CH:25][CH:24]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7])[CH3:2].C(OCC)(=O)C>C(O)C.[Pd]>[NH2:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:30]([NH:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH:5]([C:6]([NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)(=[O:11])=[O:10])=[O:7])[C:4]([N:3]([CH2:42][CH3:43])[CH2:1][CH3:2])=[O:41])=[CH:28][CH:27]=1)=[O:40]
Reactant: CCN(CC)C(=O)C(Cc1ccc(NC(=O)c2ccccc2[N+](=O)[O-])cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)C(Cc1ccc(NC(=O)c2ccccc2N)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 11 h
Yield: 89.2 %

Procedure:
To a mixture of the compound (538 mg) obtained in Example 42 in ethanol (10 mL)/ethyl acetate (10 mL) was added 10% palladium/carbon (100 mg), and the mixture was stirred under hydrogen atmosphere at room temperature for 11 hr. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (456 mg) as a brown powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH:23]([O:36][C:37]([NH:39][C:40]1[N:48]=[CH:47][N:46]=[C:45]2[C:41]=1[N:42]=[CH:43][N:44]2[CH2:49][C:50](O)=[O:51])=[O:38])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:50](=[O:51])[CH2:49][N:44]1[CH:43]=[N:42][C:41]2[C:45]1=[N:46][CH:47]=[N:48][C:40]=2[NH:39][C:37]([O:36][CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:38])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Reactant: O=C(O)Cn1cnc2c(NC(=O)OC(c3ccccc3)c3ccccc3)ncnc21
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cnc2c(NC(=O)OC(c3ccccc3)c3ccccc3)ncnc21
Yield: 79.9 %

Procedure:
The title compound (2.91 g, 80%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol) and [6-N-(benzhydryloxycarbonyl)-adenin-9-yl]-acetic acid (2.02 g, 5 mmol) as per the procedure of Example 20. 1H NMR (500 MHz; DMSO-d6) δ 10.93 (s, 1H), 9.00 (s, 0.6H), 8.60 (s, 0.4H), 8.59 (s, 0.4H), 8.54 (s, 0.6H), 8.33(d, 1H), 8.28 (m, 1H), 8.19 (d, 1H), 7.69 (m, 2H), 7.52-7.29 (m, 10H), 6.83 (s, 1H), 5.47 (s, 1.2H), 5.37 (s, 0.8H), 4.47 (s, 0.8H), 4.18 (q, 0.8H), 4.08 (s, 1.2H), 4.03 (q, 1.2H), 3.71 (t, 1.2H), 3.61 (q, 1.2H) 3.49 (t, 0.8H) 3.42 (q, 0.8H), 1.24 (t, 1.2H), 1.13 (t, 1.8H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[CH3:11].[NH:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@H:13]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:12]1([C:6]([C:5]2[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([CH3:11])[CH:4]=2)=[O:8])[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[CH2:24][C@H:13]12
Reactant: Cc1cc(C(=O)O)ccc1O
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1cc(C(=O)N2CCC[C@@H]3c4ccccc4C[C@@H]32)ccc1O
Yield: 35 %

Procedure:
The title compound is prepared from 4-hydroxy-3-methyl-benzoic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 35% of theory; LC (method 4): tR=1.92 min; Mass spectrum (ESI+): m/z=313 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=[O:43])[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>CN(C)C1C=CN=CC=1.ClCCl>[C:37]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])(=[O:43])[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reactant: CCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCC(=O)OC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 116 mg (1 mmole) of n-hexanoic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 150 mg (Yield: 39%) of the title compound having the following structure as a red precipitate.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:8]([N+:13]([O-])=O)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16]Br>C(O)(=O)C.[Zn]>[Br:16][C:11]1[CH:12]=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH2:13])=[N:9][CH:10]=1
Reactant: BrBr
Reactant: O=[N+]([O-])c1ncccc1OC1CCCC1
Agent: [Zn]
Solvent: CC(=O)O
Product: Nc1ncc(Br)cc1OC1CCCC1
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
3-(cyclopentyloxy)-2-nitropyridine (8.2 g, 39.3 mmol) in acetic acid (90 mL) was cooled in a water bath. Zn dust (10 microns) (12.9 g, 197 mmol) was slowly added in portions over 15 minutes and the reaction stirred for an additional 30 minutes. The solution was filtered over celite and the solids were rinsed with DCM. The filtrate was concentrated to about 90 mL of acetic acid. To this solution was added bromine (2.0 mL, 39.3 mmol) in dropwise manner. After 15 minutes, the material was concentrated and neutralized with saturated NaHCO3 solution. The material was extracted with dichloromethane and the organic layer was dried, and concentrated. Flash chromatography gave 5-bromo-3-(cyclopentyloxy)pyridin-2-amine (5.26 g, 52% yield) as a yellow solid.
Reaction SMILES: [CH2:1]([SH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][SH:11].C(=O)([O-])[O-].[K+].[K+].Cl[C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:36])[C:27]([CH3:35])([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH3:28])=[CH:22][CH:21]=1>CC(N(C)C)=O>[SH:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11][C:20]1[CH:21]=[CH:22][C:23]([C:26](=[O:36])[C:27]([CH3:28])([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[CH3:35])=[CH:24][CH:25]=1
Reactant: CC(C)(C(=O)c1ccc(Cl)cc1)N1CCOCC1
Reactant: SCCCCCCCCCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C(=O)c1ccc(SCCCCCCCCCCS)cc1)N1CCOCC1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
51.7 g (0.25 mol) of 1,10-decanedithiol are added to a suspension of 13.9 g (0.10 mol) of potassium carbonate in 50 ml of dimethylacetamide. The suspension is heated to 85° C., and a solution of 13.4 g (0.05 mol) of 1-(4-chlorophenyl)-2-methyl-2-morpholin-4-yl-propan-1-one in 25 ml of dimethylacetamide is added dropwise over 5 h. After stirring for 18 h, the solid is filtered off, the filtrate is poured into 30 ml of 2N HCl solution. The formed white precipitate is collected by filtration and then dissolved in methylene chloride and neutralized with 30 ml of 2N NaOH solution. After methylene chloride is distilled off, the residual crystals are further purified by recrystallization from chloroform-ethanol (20:80). The obtained product has a melting point of 87-90° C. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 1.28-1.39 (m, 9H), 1.45 (m, 2H),1.31 (s, 6H), 1.64 (q, 4H), 1.69 (m, 2H), 2.52 (q, 2H), 2.56 (m, 4H), 2.99 (m, 2H), 3.71 (m, 4H), 7.26 (d, 2H), 8.49 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([C:8]#[N:9])[S:5][C:6]=1Br.C(O)(=O)C>[Zn].O>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([C:8]#[N:9])[S:5][CH:6]=1
Reactant: Cc1c(C#N)sc(Br)c1Br
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(Br)csc1C#N
Temperature: 102.5 °C
Yield: 96.2 %

Procedure:
A mixture of 0.400 g (1.42 mmol) of 4,5-dibromo-3-methyl-2-thiophenecarbonitrile, 0.186 g (2.85 mmol) of zinc dust, 4 mL of acetic acid and 1 mL of water was heated at 100-105° C. for 45 minutes. After cooling, the solvents were removed under reduced pressure and the residue was dissolved in 10 mL of ether and washed with water (2×5 mL) and dilute, aqueous sodium carbonate solution (1×5 mL). After drying (sodium sulfate), the ether was removed on the rotovap to afford 0.276 g (96%) of an off-white solid: mp 54-58° C.; 1H NMR (CDCl3) 7.47 (s, 1H, ring-H) and 2.42 (s, 3H, CH3); GC-MS (EI) 201/203 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH:5]=O.[N+:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([O-:19])=[O:18].C(N)CCC>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4](/[CH:5]=[C:20](/[N+:17]([O-:19])=[O:18])\[CH2:21][CH2:22][CH2:23][CH3:24])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=Cc1ccc(OC2CCCCC2)c(Br)c1
Reactant: CCCCC[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCCCN
Product: CCCC/C(=C\c1ccc(OC2CCCCC2)c(Br)c1)[N+](=O)[O-]
Yield: 70.4 %

Procedure:
3-bromo-4-cyclohexyloxy-benzaldehyde (13 mmol, 3.7 g), 1-nitro-pentane (19.6 mmol, 2.3 g) and n-butyl amine (2.6 mmol, 0.19 g) were dissolved in toluene (5 mL) and refluxed for 48 h. The reaction mixture was cooled, filtered and evaporated the solvent and purified by column chromatography using 2% ethyl acetate in hexane as an eluents to provide 2-bromo-1-cyclohexyloxy-4-((E)-2-nitro-hex-1-enyl)-benzene (3.5 g).
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[C:12]([NH2:14])[N:11]=[C:10]([C:15]3[N:19]=[C:18](C(Cl)(Cl)Cl)[O:17][N:16]=3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.Cl.[F:34][C:35]([F:46])([F:45])[CH2:36][O:37][CH2:38][CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>CN(C=O)C>[C:1]1([NH:7][C:8]2[N:13]=[C:12]([NH2:14])[N:11]=[C:10]([C:15]3[N:19]=[C:18]([N:42]4[CH2:41][CH2:40][CH:39]([CH2:38][O:37][CH2:36][C:35]([F:34])([F:45])[F:46])[CH2:44][CH2:43]4)[O:17][N:16]=3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)COCC1CCNCC1
Reactant: Nc1nc(Nc2ccccc2)nc(-c2noc(C(Cl)(Cl)Cl)n2)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Nc2ccccc2)nc(-c2noc(N3CCC(COCC(F)(F)F)CC3)n2)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 8.9 %

Procedure:
To 2-N-phenyl-6-[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]-1,3,5-triazine-2,4-diamine (Intermediate 134, 0.100 g, 0.268 mmol) in DMF (2 mL) was added DIPEA (93.6 μL, 0.537 mmol) at the mixture was stirred at room temperature for 5 min. 4-[(2,2,2-trifluoroethoxy)methyl]piperidine hydrochloride (Intermediate 179, 0.063 g, 0.268 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was then heated to 50 C for 18 h and to 70 C for 36 h. The reaction mixture was concentrated under reduced pressure, dissolved in EtOAc and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by preparative HPLC, Method C, to afford the title compound (10.8 mg, 8.9%).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:7]=1[CH:16]=[CH2:17])(=[O:4])=[O:3].C(=O)([O-])O.[Na+].[Cl:23][CH2:24][C:25](=[O:30])[C:26](Cl)=[N:27][OH:28]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[C:10]([C:12]([F:13])([F:14])[F:15])[CH:9]=[CH:8][C:7]=1[CH:16]1[O:28][N:27]=[C:26]([C:25](=[O:30])[CH2:24][Cl:23])[CH2:17]1)(=[O:4])=[O:3]
Reactant: C=Cc1ccc(C(F)(F)F)cc1OS(C)(=O)=O
Reactant: O=C(CCl)C(Cl)=NO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CS(=O)(=O)Oc1cc(C(F)(F)F)ccc1C1CC(C(=O)CCl)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a solution of 5-(trifluoromethyl)-2-vinylphenyl methanesulphonate (1.05 g) in acetonitrile (10 ml) were added sodium hydrogencarbonate (2.55 g) and 3-chloro-N-hydroxy-2-oxopropanimidoyl chloride (0.60 g) at room temperature under argon. The reaction mixture was stirred at room temperature for one hour. The solids were filtered off with suction and the filtrate was concentrated under reduced pressure. The residue was stirred with heptane to obtain 2-[3-(chloroacetyl)-4,5-dihydro-1,2-oxazol-5-yl]-5-(trifluoromethyl)phenyl methanesulphonate (1.33 g, 86% pure, 75%).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([NH:26][NH2:27])=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=2)[N:4]=1)[CH3:2].[CH3:36]OC(OC)OC>>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]4[O:25][CH:36]=[N:27][N:26]=4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=2)[N:4]=1)[CH3:2]
Reactant: COC(OC)OC
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)NN)ccn34)c12
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(-c5nnco5)ccn34)c12
Temperature: 110 °C
Yield: 32.7 %

Procedure:
To N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(hydrazinecarbonyl)imidazo[1,2-a]pyridine-3-carboxamide (15 mg, 0.0320 mmol) was added trimethoxymethane (340 mg, 3.20 mmol). The reaction mixture was sealed and heated to 110° C. for 30 minutes. The mixture was cooled to ambient temperature and concentrated under reduced pressure. Silica gel chromatography (DCM/MeOH 10:1) gave the final product (5 mg). MS (ES+APCI) m/z=479 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3[O:14][CH:8]3[C:7]=2[CH:15]=1)#[N:2].[CH3:16][O:17][C:18](=[O:21])[NH:19][NH2:20]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([NH:20][NH:19][C:18]([O:17][CH3:16])=[O:21])[C:7]=2[CH:15]=1)#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: COC(=O)NN
Product: COC(=O)NN[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O

Procedure:
A similar procedure to Reference Example 5 was performed by using 6-cyano-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran and methylcarbazate, and as a result, trans-6-cyano-3,4-dihydro-2,2-dimethyl-4-(2-methoxycarbonylhydrazino)-2H-1-benzopyran-3-ol was obtained, m.p. 174°-175° C. (recrystallized from hexane-ethyl acetate).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH2:19][CH2:18][CH2:17][CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>O.CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH2:19][CH2:18][CH2:17][CH:16]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](CC1=CCCC1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC1=CCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(cyclopent-1-en-1-yl)propanoate (62 g, 0.23 mol) in water/methanol (900 mL, 2:1) was added lithium hydroxide hydrate (19.3 g, 0.460 mol). The reaction mixture was stirred at ambient temperature overnight and then concentrated to remove most of the methanol. The residue was washed with DCM (400 mL) and the aqueous phase was acidified with dilute HCl to pH=3-4. The resulting mixture was extracted with DCM (3×300 mL). The organic layers were combined and concentrated to afford (S)-2-((tert-butoxycarbonyl)amino)-3-(cyclopent-1-en-1-yl)propanoic acid (56 g, 95% yield) as viscous oil, which was used in the next step without further purification.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.CCCCC.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C@:23]12[CH2:32][O:31][C@@H:30]([CH2:33]O)[CH2:29][C@H:28]1[C@@H:27]([CH3:35])[S:26][C:25]([NH:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[N:24]2>ClCCl>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C@:23]12[CH2:32][O:31][C@@H:30]([CH2:33][F:7])[CH2:29][C@H:28]1[C@@H:27]([CH3:35])[S:26][C:25]([NH:36][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[N:24]2
Reactant: CCN(CC)S(F)(F)F
Reactant: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CO)C[C@@H]12
Solvent: ClCCl
Solvent: CCCCC
Product: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CF)C[C@@H]12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(Diethylamino)sulfur trifluoride (126 μL, 0.954 mmol) was added to a 0° C. solution of pentane (8 mL) and dichloromethane (5 mL). To this mixture was added N-[(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(hydroxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P2) (275 mg, 0.636 mmol) drop-wise over 10 minutes. The ice bath was removed, and the reaction mixture was allowed to warm to room temperature. After 6 hours, it was diluted with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with dichloromethane (3×35 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) afforded the product as a white solid. Yield: 154 mg, 0.354 mmol, 56%. 1H NMR (400 MHz, CD3OD) δ 8.08-8.16 (m, 2H), 7.51-7.58 (m, 1H), 7.40-7.50 (m, 3H), 7.01-7.11 (m, 2H), 4.34-4.55 (m, 2H), 4.17 (br d, J=12 Hz, 1H), 3.92 (d, J=11.9 Hz, 1H), 3.9-4.02 (m, 1H), 3.18-3.28 (br m, 1H), 2.98-3.08 (br m, 1H), 1.73-1.81 (m, 1H), 1.55-1.67 (m, 1H), 1.26 (d, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3](=O)[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=1)=O.[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>>[F:1][C:2]([F:18])([F:17])[C:3]1[N:24]([C:23]2[CH:25]=[CH:26][C:20]([F:19])=[CH:21][CH:22]=2)[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CSc1ccc(C(=O)CCC(=O)C(F)(F)F)cc1
Reactant: Nc1ccc(F)cc1
Product: CSc1ccc(-c2ccc(C(F)(F)F)n2-c2ccc(F)cc2)cc1
Yield: 42 %

Procedure:
Following a procedure similar to that described in Example 43(iii), but using 5,5,5-trifluoro-1-(4-methylthiophenyl)pentane-1,4-dione [prepared as described in step (ii) above] and 4-fluoroaniline as starting materials, the title compound was obtained as a pale brown oily substance (yield 42%).
Reaction SMILES: Br[C:2]1[CH:16]=[C:15]([CH2:17][N:18]([CH3:30])[S:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=2)(=[O:21])=[O:20])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[C:36]([O:38][CH3:39])[CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[F:31][C:32]1[CH:33]=[C:34]([C:2]2[CH:16]=[C:15]([CH2:17][N:18]([CH3:30])[S:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=3)(=[O:21])=[O:20])[CH:14]=[CH:13][C:3]=2[O:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH:35]=[C:36]([O:38][CH3:39])[CH:37]=1
Reactant: CN(Cc1ccc(OCC(=O)OC(C)(C)C)c(Br)c1)S(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: COc1cc(F)cc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(F)cc(-c2cc(CN(C)S(=O)(=O)c3ccc(F)c(Cl)c3)ccc2OCC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Yield: 45.6 %

Procedure:
To a mixture of tert-butyl 2-(2-bromo-4-((3-chloro-4-fluoro-N-methylphenylsulfonamido)methyl)phenoxy)acetate (10) (140 g, 0.27 mol, 1 eq), 3-fluoro-5-methoxyphenylboronic acid (45.7 g, 0.27 mol, 1 eq, Combi-Blocks Inc., San Diego, Calif., USA) and potassium carbonate (111 g, 0.81 mol, 3 eq) in dioxane/water (3:1, 800 mL) was added tetrakis(triphenylphoshine)palladium (3.08 g, 2.7 mmol, 0.01 eq). The mixture was heated at 60° C. for 3 h under N2. Solvent was evaporated, and the solid was dissolved in DCM and filtered. The DCM was evaporated and the crude product was recrystallized from ethanol to yield tert-butyl 2-(3-fluoro-5-methoxyphenyl)-4-((3-chloro-4-fluoro-N-methylphenylsulfonamido)methyl)phenoxyacetate (11) (70 g, 41%).