Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH:17]1([C:20]([NH:1][C:2]2[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=2)=[O:21])[CH2:19][CH2:18]1
Reactant: COC(=O)c1ccc(N)o1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)C2CC2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of methyl 5-aminofuran-2-carboxylate (1.0 g) and pyridine (1.2 mL) in methylene chloride (6.0 mL) is added dropwise cyclopropanecarbonyl chloride (0.78 mL) under ice-cooling and the mixture is stirred at room temperature for 2 hours. To the reaction mixture is added a saturated sodium hydrogencarbonate solution and the mixture is extracted with chloroform. The extract is dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel (Solvent; n-hexane:ethyl acetate=3:1) to give methyl 5-[(cyclopropylcarbonyl)amino]furan-2-carboxylate (0.82 g, yield; 56%) as colorless crystals. MS (APCI) m/z: 210 [M+H]+
Reaction SMILES: N[C:2]1[C:6]([C:7]#[N:8])=[C:5]([S:9][CH3:10])[S:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[I:16]CI.N(OCCC(C)C)=O>C(#N)C.CCCCCC>[C:7]([C:6]1[C:2]([I:16])=[C:3]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:4][C:5]=1[S:9][CH3:10])#[N:8]
Reactant: ICI
Reactant: CCOC(=O)c1sc(SC)c(C#N)c1N
Agent: CC(C)CCON=O
Solvent: CC#N
Solvent: CCCCCC
Product: CCOC(=O)c1sc(SC)c(C#N)c1I
Temperature: 40 °C
Reaction time: 2 h
Yield: 47.3 %

Procedure:
Ethyl 3-amino-4-cyano-5-(methylsulfanyl)thiophene-2-carboxylate (10 g, 41.3 mmol) was dissolved in acetonitrile (50 mL) under an atmosphere of argon. Diiodomethane (11.6 mL, 0.144 mol) was added and the mixture was heated at 40° C. Isoamyl nitrite (12.1 g, 0.103 mol) was added and the reaction was allowed to cool to room temperature and stirred for 2 hours. The mixture was cooled down to 0° C., diluted with hexane (50 mL) and the precipitate was filtered off, washed with 10:1 hexane-acetonitrile mixture (10 mL), 3:1 hexane-ether (10 mL) and hexane (10 mL). The precipitate was dried to afford ethyl 4-cyano-3-iodo-5-(methylsulfanyl)thiophene-2-carboxylate (6.90 g, 45%). LCMS: (FA) ES+ 354. 1H NMR (400 MHz, CDCl3) δ: 4.38 (q, 2H), 2.70 (s, 3H), 1.40 (t, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:13]([CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[N:5]2[N:4]=1)[CH3:2].CC1C=C(C)C=C(C)N=1.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46]([NH:48][NH2:49])=[O:47])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(OC(C)=O)(C)C.CCCCCCC.O.CN(C=O)C>[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46]([NH:48][NH:49][C:19](=[O:20])[C:18]2[CH:17]=[CH:16][C:15]([CH2:14][C:13]3[C:3]([CH2:1][CH3:2])=[N:4][N:5]4[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[N:7][C:6]=34)=[CH:23][CH:22]=2)=[O:47])[CH2:42][CH2:41]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: CC(=O)OC(C)C
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(C(=O)NNC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
A 500 ml four-necked flask equipped with an overhead stirrer and a thermocouple was charged with acid 27 (10.0 g, 32.3 mmol, 1.0 eq), 120 ml of DMF and 2,4,6 trimethylpyridine (11.75 g, 96.9 mmol) under nitrogen purge. After stirring the reaction mixture for 30 min at 23° C., 4-hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (9.4 g, 38.7 mmol, 1.2 eq), EDC (12.3 g, 64.3 mmol), HOBT (1.48 g, 9.6 mmol) were added. The reaction mixture was stirred for 12 h at 23° C. After completion of the reaction, it was diluted with i-PrOAc/heptane (100 mL, 1:1) and followed by water (250 ml) at 23° C. The suspension was stirred for 1 h at 23° C. The solid was collected by filtration and washed with 50 ml of water. The wet product was dried at 40° C. for 12 h to obtain a white solid.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([O:8][C:9]2[CH:23]=[CH:22][C:12]3[CH2:13][CH2:14][N:15]([CH:18]4[CH2:21][CH2:20][CH2:19]4)[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1.[O:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29]>>[CH:18]1([N:15]2[CH2:14][CH2:13][C:12]3[CH:22]=[CH:23][C:9]([O:8][C:5]4[N:6]=[CH:7][C:2]([N:26]5[CH2:27][CH2:28][O:24][C:25]5=[O:29])=[N:3][CH:4]=4)=[CH:10][C:11]=3[CH2:17][CH2:16]2)[CH2:21][CH2:20][CH2:19]1
Reactant: O=C1NCCO1
Reactant: Brc1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Product: O=C1OCCN1c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1

Procedure:
The title compound was prepared from 7-[(5-bromo-2-pyrazinyl)oxy]-3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepine (E259) and oxazolidinone using the method of Example 258 (E258); MS (ES+) m/e 381 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:10]([CH3:11])[CH:9]=[C:8](I)[C:6]=2[N:7]=1.[CH3:13][S:14]([NH:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)(=[O:16])=[O:15].C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:10]([CH3:11])[CH:9]=[C:8]([C:22]3[CH:23]=[C:18]([NH:17][S:14]([CH3:13])(=[O:15])=[O:16])[CH:19]=[CH:20][CH:21]=3)[C:6]=2[N:7]=1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: Cn1cc(I)c2nc(Cl)ncc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cccc(NS(C)(=O)=O)c2)c2nc(Cl)ncc21
Temperature: 100 °C
Yield: 68 %

Procedure:
To a solution of 2-chloro-7-iodo-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (0.140 g, 0.48 mmol, 1.0 eq.) in DMF (6 ml) was added 3-methanesulfonylaminophenylboronic acid (0.124 g, 0.576 mmol, 1.2 eq.) followed by aqueous Na2CO3 (2M, 0.7 ml, 1.44 mmol, 3.0 eq.). A flow of nitrogen was bubbled through the mixture during 15 to 20 min before adding Pd[PPh3]4 (0.055 g, 0.048 mmol, 0.1 eq.). The mixture was then heated up to 100° C. overnight. After cooling down the reaction mixture to room temperature a large amount of water (around 60 ml) was added and the mixture extracted with ethyl acetate (3 times). After evaporation the residue was purified by column chromatography using petroleum spirit/ethyl acetate (1:4) as eluent. The product was obtained as a pale yellow solid (110 mg, 68%). LRMS (EI): m/z calcd for [M+H]+ 337.05 found 337.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:9]([N:12]=[C:13]=[O:14])[CH2:10][CH3:11]>C1(C)C=CC=CC=1>[CH3:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:13]([NH:12][CH2:9][CH2:10][CH3:11])=[O:14]
Reactant: CCCN=C=O
Reactant: Cc1ccccc1N
Solvent: Cc1ccccc1
Product: CCCNC(=O)Nc1ccccc1C
Reaction time: 6 h
Yield: 64.1 %

Procedure:
2-Toluidine (32.1 g) was dissolved in toluene (500 ml) and propyl isocyanate (25.2 g) was added in one portion with stirring. The mixture was stirred for 1 h and then allowed to stand at room temperature for 6 h. The solid was collected by filtration and washed with toluene to provide the title compound (36.5 g).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[OH-].[Na+].O>CO>[I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(I)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)ccc1I
Temperature: 65 °C

Procedure:
A mixture of methyl 4-iodo-3-(methyloxy)benzoate (3.25 g, 0.011 mol), sodium hydroxide (0.48 g, 0.012 mol) and water (30 mL) in methanol (30 mL) was heated in an oil bath at 65° C. for 3 hr. The mixture was concentrated in vacuo to remove the methanol and the aqueous residue was chilled in an ice bath. Concentrated aqueous hydrogen chloride was added until the pH was acidic and the mixture was stirred at ice bath temperature. The resulting solid was filtered, washed with water and dried to give 4-iodo-3-(methyloxy)benzoic acid as a white solid, used without further purification. LC/MS (method A) tR 2.35 min; m/z 279 (M+H).
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[N:14]([CH:17]1[CH2:23][CH2:22][O:21][CH:20]([C:24]2[N:25]([CH3:32])[N:26]=[CH:27][C:28]=2[N+:29]([O-:31])=[O:30])[CH2:19][CH:18]1O)=[N+:15]=[N-:16].C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:14]([CH:17]1[CH2:23][CH2:22][O:21][CH:20]([C:24]2[N:25]([CH3:32])[N:26]=[CH:27][C:28]=2[N+:29]([O-:31])=[O:30])[CH2:19][CH:18]1[F:11])=[N+:15]=[N-:16]
Reactant: Cn1ncc([N+](=O)[O-])c1C1CC(O)C(N=[N+]=[N-])CCO1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1ncc([N+](=O)[O-])c1C1CC(F)C(N=[N+]=[N-])CCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of deoxo-Fluor (50% in THF, 0.576 mL, 1.56 mmol) was added dropwise to an ice-cooled solution of 5-azido-2-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-ol (353 mg, 1.25 mmol, intermediate 27) in DCM (6 mL). The mixture was allowed to warm to room temperature whilst stirring for 16 hr before being cooled in an ice bath and saturated aqueous NaHCO3 (10 mL) slowly added. The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel chromatography (0-50% EtOAc/isohexane) gave 5-(5-azido-4-fluorooxepan-2-yl)-1-methyl-4-nitro-1H-pyrazole as a clear gum. To a solution of this gum (145 mg, 0.51 mmol) in THF (5 mL) and water (1 mL) was added triphenylphosphine (147 mg, 0.56 mmol) and the mixture heated at 60° C. for 2 hr. The mixture was diluted with EtOAc (10 mL) and washed with brine (2×5 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. The residue was dissolved in DCM (2 mL) and DIPEA (0.178 mL, 1.02 mmol) and di-tert-butyl dicarbonate (134 mg, 0.61 mmol) were added. The mixture was stirred at room temperature for 2 hr. Water (2 mL) was added and the mixture extracted with DCM (3×2 mL). The combined organic layers were passed though a phase separation cartridge, concentrated under reduced pressure and the residue purified via silica gel chromatography (0-50% EtOAc/isohexane) to give tert-butyl N-[5-fluoro-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-yl]carbamate as a clear gum (180 mg, 39% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 5.54 (dd, J=10.5, 4.2 Hz, 1H), 5.10-4.92 (m, 2H), 4.21-4.09 (m, 2H), 4.05 (s, 3H), 3.74-3.62 (m, 1H), 2.57-2.38 (m, 1H), 2.35-2.15 (m, 2H), 1.91-1.81 (m, 1H), 1.46 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)CC(c2ccc(Br)cc2)c2ccc(Cl)cc2F)cn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CC(c1ccc(Br)cc1)c1ccc(Cl)cc1F)c1ccc(=O)[nH]c1

Procedure:
In analogy to example 162, step 2, 3-(4-bromo-phenyl)-3-(4-chloro-2-fluoro-phenyl)-1-(6-methoxy-pyridin-3-yl)-propan-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as an off-white powder, MS (ESI+): m/z=435.8 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:8][CH:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)=[N:4][CH:5]=[N:6][CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[C:29]1[S:30][CH:31]=[C:32]([C:34](O)=[O:35])[N:33]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[C:29]1[S:30][CH:31]=[C:32]([C:34]([NH:1][C:2]2[C:3]([O:8][CH:9]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]3)=[N:4][CH:5]=[N:6][CH:7]=2)=[O:35])[N:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncncc2N)C1
Reactant: O=C(O)c1csc(-c2c(F)cccc2F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncncc2NC(=O)c2csc(-c3c(F)cccc3F)n2)C1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Compound (1D3) (47 mg, 0.169 mmol), 2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (1E) (40 mg, 0.169 mmol, HATU (77 mg, 0.203 mmol) and DIEA (93 μL, 0.507 mmol) are mixed in DMF (5 mL) and stirred at 50° C. for 1 hour. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (50 mL), washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified with flash column (eluent: 10-30% ethyl acetate/petroleum ether) to obtain the product 1A (30 mg, 0.0596 mmol)
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.[CH3:23][CH:24]([CH3:33])[C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].[Na].C(O)C>C(Cl)Cl>[Cl:22][C:16]1[N:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([N:3]3[CH:2]([CH:26]([C:25](=[O:32])[CH:24]([CH3:33])[CH3:23])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:10]4[C:5](=[N:6][CH:7]=[CH:8][N:9]=4)[C:4]3=[O:11])=[N:13]2)=[CH:18][CH:17]=1
Reactant: O=C1c2nccnc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: [Na]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)C(C)C)C1c2nccnc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 43.9 %

Procedure:
Ethyl 2-{6-(7-chloro-1,8-naphthyridin-2-yl)-6, 7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin-5-yl}-4-methyl-3oxopentanoate may be obtained as in Example 29, but starting with 5-chloro-6-(7-chloro-1,8-naphthyridin-2-yl)-6, 7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazine (13 g), ethyl 4-methyl-3-oxopentanoate (8.7 g), sodium (1.1 g), ethanol (400 cc) and methylene chloride (200 cc). After recrystallization in methanol, ethyl 2-{6-(7-chloro-1, 8-naphthyridin-2-yl)-6,7-dihydro-7-oxo-5H-pyrrolo[3, 4-b]pyrazin-5yl}-4-methyl-3-oxopentanoate (7.8 g), m.p. 214° C., is thereby obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=3)=[O:22])=[C:7]([CH:18]([CH3:20])[CH3:19])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[O:33]1[CH2:37][CH2:36][C:35](=O)[CH2:34]1.[BH3-]C#N.[Na+]>CO.CC(O)=O.CCOC(C)=O>[CH2:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][CH:35]3[CH2:36][CH2:37][O:33][CH2:34]3)[CH:10]=2)[C:6]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)=[O:22])=[C:7]1[CH:18]([CH3:19])[CH3:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(N)cc2n1Cc1ccccc1
Reactant: O=C1CCOC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(NC3CCOC3)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
General Procedure T. To a solution of 6-amino-1-benzyl-N-(3,4-difluorobenzyl)-2-isopropyl-1H-indole-3-carboxamide (Compound 125, 15 mg, 0.035 mmol) in MeOH (1 ml) was added dihydrofuran-3(2H)-one (Compound 129, 6.0 mg, 0.069 mmol), NaBH3CN (2.2 mg, 0.035 mmol), and HOAc (1 drop). The reaction was stirred at room temperature for 3 h, diluted with EtOAc, washed with aqueous Na2CO3 and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:46][CH2:47][N:48]2[CH:52]=[CH:51][N:50]=[N:49]2)(=O)=O)=CC=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:46][CH2:47][N:48]4[CH:52]=[CH:51][N:50]=[N:49]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)OCCn2ccnn2)cc1
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(O)c(OC)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCn4ccnn4)c(OC)cc23)cc1Cl
Temperature: 120 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
A starting compound (N-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinolyl)oxy]phenyl}-N′-propylurea, 80 mg), potassium carbonate (138 mg), and 2-(1H-1,2,3-triazol-1-yl)ethyl 4-methyl-1-benzenesulfonate (59 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at 120° C. for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform-methanol to give 92 mg (yield 92%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH2:17][CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[C:5](=[N:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][N:10]=2)[S:6][CH:7]=1.NCCCN1C(CO[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=CSC1=NC1C=CC(OC(F)(F)F)=CC=1.Cl>>[NH2:20][CH2:19][CH2:18][CH2:17][N:4]1[C:3]([CH2:2][O:1][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:7][S:6][C:5]1=[N:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][N:10]=1
Reactant: NCCCn1c(COCc2ccccc2)csc1=Nc1ccc(OC(F)(F)F)cc1
Reactant: COc1ccc(N=c2scc(CO)n2CCCNC(=O)OC(C)(C)C)nc1
Agent: Cl
Product: COc1ccc(N=c2scc(COCc3ccccc3)n2CCCN)nc1

Procedure:
The compound (283 mg) obtained in the above (1) was treated in a similar manner to in Example 208 (3), (4) to give the title compound (128 mg) as hydrochloride.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C.[CH2:54]([O:56][CH2:57][CH2:58][NH2:59])[CH3:55]>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:59][CH2:58][CH2:57][O:56][CH2:54][CH3:55])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOCCN
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3)c2O)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Combined 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (100 mg, 0.327 mmol), EDCI (94.0 mg, 0.490 mmol), and HOBT (66.2 mg, 0.490 mmol) in DMF (2.5 mL) and added N,N-diisopropyl ethylamine (227 μL, 1.306 mmol). Then 2-ethoxyethanamine (43.7 mg, 0.490 mmol) was added and the reaction allowed to stir at room temperature for 16 hours. The reaction mixture was then diluted with water (3.5 mL) and acidified to an approximate pH=4 to give a solid which was collected by filtration, washed with water, MeOH, and diethyl ether to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 1.04 (t, J=6.95 Hz, 3 H) 3.33-3.41 (m, 4 H) 3.41-3.48 (m, 2 H) 7.70 (d, J=8.34 Hz, 2 H) 8.06 (d, J=7.07 Hz, 2 H) 8.26-8.49 (m, 2 H) 8.58 (br. s., 1 H) 8.71 (t, J=5.18 Hz, 1 H) 8.77-8.93 (m, 1 H) 12.95-13.90 (m, 1 H). MS m/z [M+H]+ 378.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][S@@](C(C)(C)C)=O)([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.CO>Cl.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)([NH2:30])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1
Reactant: CC(C)(C)[S@@](=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Yield: 89.9 %

Procedure:
(R)—N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (234 mg, 0.442 mmol) was stirred in 4N HCl in dioxane (1.5 mL) and MeOH (1.5 mL) at room temperature under Ar for 10 min. The reaction mixture was concentrated, and then purified by flash chromatography (silica gel, hexanes/EtOAc) to give (R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine (169 mg, 90%). LC-MS (ESI) 409.16 (M-NH3+H), retention time=3.26 minutes (0-100% MeOH in H2O with 0.1% TFA in 4-min run); Analytical HPLC: 2.52 minutes (0-100% CH3CN in H2O with 0.1% TFA in 4-min run); 1H NMR (400 MHz, CD3OD) δ ppm 7.29-7.50 (m, 2H), 6.87-7.22 (m, 8H), 6.77 (d, J=6.15 Hz, 2H), 6.04-6.48 (m, 1H), 3.57 (s, 2H).
Reaction SMILES: [CH2:1]([OH:13])[C@H:2]([OH:12])[C@@H:3](O)[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6].Cl.O>[Cl-].C[N+](C)(C)CCCCCCCCCCCCCCCC.C1(C)C=CC=CC=1.COCCOC>[O:8]=[C:7]1[O:9][C@H:3]([C@H:2]([CH2:1][OH:13])[OH:12])[C:4]([OH:10])=[C:5]1[OH:6]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: COCCOC
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 2-keto-L-gulonic acid (250 g, 1.15 mol, content: 89.6%, water: 8.6%) and trimethylcetylammonium chloride (0.275 g) was stirred in toluene (960 ml), and 36% conc. hydrochloric acid (30.0 g) was added. At this time, the amount of water in the reaction system was calculated as 2.0 mol per mol of 2-keto-L-gulonic acid. This mixture was stirred at 60° C. for 1 hour, a solution of hydrogen chloride gas (30.0 g) in ethylene glycol dimethyl ether (130 g) was added, and the mixture was stirred at the same temperature for 5 hours. Then, about 1200 g of the solvent was distilled away under reduced pressure while continuously introducing toluene (850 ml). The residue was filtered to give crude crystals of L-ascorbic acid. The crude crystals were dissolved in water. Quantitative analysis of the solution by high performance liquid chromatography (HPLC) showed that the solution contained L-ascorbic acid (191.1 g, yield: 94.1%) and 2-keto-L-gulonic acid (2.7 g, residual ratio: 1.2%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:35]=[CH:34][C:6]([O:7][C:8]2[CH:13]=[C:12]([N:14]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:11]3[N:31]=[CH:32][CH:33]=[C:10]3[N:9]=2)=[CH:5][CH:4]=1.C1C(=O)N([I:43])C(=O)C1>C(#N)C>[I:43][C:33]1[CH:32]=[N:31][N:11]2[C:12]([N:14]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:21])[CH3:22])[CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])=[CH:13][C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:35][CH:34]=3)=[N:9][C:10]=12
Reactant: O=C1CCC(=O)N1I
Reactant: CSc1ccc(Oc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)cc1
Solvent: CC#N
Product: CSc1ccc(Oc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
5-(4-(methylthio)phenoxy)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (490 mg, 0.81 m) was dissolved in ACN (15 mL) and NIS (200 mg, 0.88 mmol) was added. The resulting mixture was stirred at room temperature for 2 h and then the solvent was removed under reduced pressure. The residue was purified with column (silica gel, 10% EtOAc/Hexane) gave the product, 3-iodo-5-(4-(methylthio)phenoxy)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (541 mg) as yellowish oil. HPLC-MS tR=3.18 min (UV254 nm); mass calculated for formula C25H39IN4O3SSi2 658.1, observed LCMS m/z 659.2 (M+H).