Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Br.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:18]=[O:19]>>[CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:18]([OH:19])[C:17]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:15]([O:14][CH3:13])[CH:16]=1
Reactant: COc1ccc(C=O)cc1OC
Reactant: COC(OC)c1ccccc1Br
Product: COc1ccc(C(O)c2ccccc2C(OC)OC)cc1OC
Yield: 89 %

Procedure:
2-bromobenzaldehyde dimethylacetal and 3,4-dimethoxybenzaldehyde are reacted in the same manner as described in Example 1-(1), whereby 2-(3,4-dimethoxy-α-hydroxybenzyl)benzaldehyde dimethylacetal is obtained as pale yellow syrup.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][C:9]2[N:10]=[CH:11][NH:12][C:13](=O)[C:8]=2[CH2:7]1)=[O:5])[CH3:2].C(OC(C1N(C(OC(C)(C)C)=O)CC2C(=O)NC=NC=2C1)=O)C.C(Cl)(Cl)(Cl)[Cl:48].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCCl>[CH2:1]([O:3][C:4]([CH:6]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][C:9]2[N:10]=[CH:11][N:12]=[C:13]([Cl:48])[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCOC(=O)C1Cc2c(nc[nH]c2=O)CN1C(=O)OC(C)(C)C
Agent: CCOC(=O)C1Cc2nc[nH]c(=O)c2CN1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: CCOC(=O)C1Cc2c(Cl)ncnc2CN1C(=O)OC(C)(C)C

Procedure:
To a solution of the mixture of 4-Oxo-4,5,6,8-tetrahydro-3H-pyrido[3,4-d]pyrimidine-6,7-dicarboxylic acid 7-tert-butyl ester 6-ethyl ester and 4-Oxo-3,5,7,8-tetrahydro-4H-pyrido[4,3-d]pyrimidine-6,7-dicarboxylic acid 6-tert-butyl ester 7-ethyl ester (1.5 g, 4.64 mmol) in DCE (25 mL), carbon tetrachloride (1.34 mL, 13.9 mmol) and triphenylphosphine (2.43 g, 9.28 mmol) are added. The reaction is heated at reflux and after completion of reaction as judged by LCMS. The solvents are removed and the products are isolated using FCC eluting with heptane:EtOAc 80:20. At this point the two products are separated. 4-Chloro-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-6,7-dicarboxylic acid 7-tert-butyl ester 6-ethyl ester MS (ESI) m/z 342.1 (M+1) and 4-chloro-7,8-dihydro-5H-pyrido[4,3-a]pyrimidine-6,7-dicarboxylic acid 6-tert-butyl ester 7-ethyl ester MS (ESI) m/z 342.1 (M+1) are isolated as an almost 4:1 ratio.
Reaction SMILES: S(=O)(=O)(O)O.C(N)=O.[C:9]1([N:15]2[C:19]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[C:18](=[O:25])[NH:17][CH2:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[C:9]1([N:15]2[C:19]3([CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)[C:18](=[O:25])[N:17]=[CH:16]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: O=S(=O)(O)O
Solvent: O
Solvent: NC=O
Product: O=C1N=CN(c2ccccc2)C12CCNCC2

Procedure:
As shown in Scheme 2, Compounds (I) wherein R is hydrogen can be prepared from a piperidine-4-one (V) through a compound (VI) according to known procedures as described in U.S. Pat. No. 3,238,216. First, the compound (V) can be reacted with a hydrochloric acid salt of an amino compound (VII) (i.e., XNH2) in the presence of a suitable cyanating agent such as potassium cyanide (KCN), to give the compound (VI). This reaction can be carried out in a suitable reaction inert solvent such as water at 0° to 50° C. for 30 min. to 7 days. Then, the compound (VI) may be treated with sulfuric acid at 0° to 100° C. for 30 min. to 10 hours, followed by reaction with formamide (HCONH2). The reaction with formamide may be carried out at 150° to 250° C. for 30 min. to 20 hours. If a mixture of 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one derivative and 1-phenyl-1,3,8-triazaspiro[4.5]dec-2-en-4-one derivative is obtained in this reaction condition, the mixture may be treated with a reducing reagent such as sodium borohydride (NaBH4) to give desired 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one derivative.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([NH:8][C:9](=O)[CH3:10])[C:5](=O)[CH3:6].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.FC(F)(F)C(O)=O>C(#N)CCC>[CH3:10][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([CH3:6])=[C:4]([C:3]([O:2][CH3:1])=[O:12])[N:8]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C(NC(C)=O)C(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCCC#N
Product: COC(=O)c1nc(C)n(-c2ccccc2)c1C
Yield: 46 %

Procedure:
Part C: To a magnetically stirred solution of 2-acetylamino-3-oxo-butyric acid methyl ester (5 gram, 28.9 mmol) in butyronitrile was added aniline (3.42 ml) and trifluoroacetic acid (2.89 ml) and the resulting mixture was heated at reflux for 45 minutes. The butyronitrile was removed in vacuo at room temperature and the resulting residues was taken up dichloromethane and washed twice with an aqueous potassium carbonate solution. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (diethyl ether/acetone=4/1 (v/v)) to give methyl 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylate (3.0 gram, 46% yield). 1H-NMR (400 MHz, CDCl3): 2.22 (s, 3H), 2.33 (s, 3H), 3.91 (s, 3H), 7.18-7.22 (m, 2H), 7.51-7.59 (m, 3H).
Reaction SMILES: [N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]([OH:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1>>[OH:31][CH:29]([C:25]1[CH:24]=[C:23]([NH:22][C:16](=[O:18])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([S:10]([N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)(=[O:12])=[O:11])[CH:14]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:30]
Reactant: CC(O)c1cccc(N)c1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCc3ccccc32)c1
Product: CC(O)c1cccc(NC(=O)c2cccc(S(=O)(=O)N3CCc4ccccc43)c2)c1

Procedure:
3-(indolin-1-ylsulfonyl)benzoic acid (3) (200 mg, 0.66 mmol) and 1-(3-aminophenyl)ethanol (75 mg, 0.55 mmol) using method C. The residue was purified using flash chromatography eluting with 0-50% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give N-(3-(1-hydroxyethyl)phenyl)-3-(indolin-1-ylsulfonyl)benzamide as an off-white solid. Yield: 93 mg (40%). 1H-NMR: 10.46 (s, 1H), 8.37 (s, 1H), 8.25 (d, J=8.0 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.74-7.69 (m, 2H), 7.64 (d, J=8.5 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.29 (t, J=8.0 Hz, 1H), 7.21 (t, J=8.0 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 6.99 (dt, J=7.5, 7.5, 1.0 Hz, 1H), 5.19 (d, J=4.0 Hz, 1H), 4.75-4.68 (m, 1H), 3.98 (t, J=8.5 Hz, 2H), 2.93 (t, J=8.5 Hz, 2H), 1.32 (d, J=6.0 Hz, 3H).
Reaction SMILES: Br[CH:2]([C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7])[CH2:3][CH2:4][Cl:5].[F-:15].[K+].C1OCCOCCOCCOCCOCCOC1.C1C=CC=CC=1>O>[F:15][CH:2]([C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7])[CH2:3][CH2:4][Cl:5]
Reactant: [F-]
Reactant: O=C(c1ccc(Cl)cc1)C(Br)CCCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: O=C(c1ccc(Cl)cc1)C(F)CCCl
Yield: 52.8 %

Procedure:
A mixture of 68 g of 4-chlorophenyl 1-bromo-3-chloropropyl ketone, 27.5 g of dry potassium fluoride, 11 g of 18-crown-6 and 200 ml of dry benzene is heated under reflux for 8 hours. Thereafter, 200 ml of water are added, and the organic phase is separated off, washed several times with water, dried over sodium sulphate and evaporated down in vacuo. The residue is stirred with light benzine, with the addition of a small amount of toluene. After the resulting solid has been filtered off under suction and drying has been carried out, 28.5 g (53% of theory) of 4-chlorophenyl 1-fluoro-3-chloropropyl ketone of melting point 53° C. are obtained. ##STR216##
Reaction SMILES: [CH2:1]([C:9]1[C:10]2[CH:17]=[CH:16][NH:15][C:11]=2[N:12]=[CH:13][N:14]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[I:18]N1C(=O)CCC1=O>C(C#N)(C)=O>[I:18][C:17]1[C:10]2[C:9]([CH2:1][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[N:14][CH:13]=[N:12][C:11]=2[NH:15][CH:16]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1ccc(CCc2ncnc3[nH]ccc23)cc1
Agent: CC(=O)C#N
Product: Ic1c[nH]c2ncnc(CCc3ccccc3)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
To a solution of 4-phenethyl-7H-pyrrolo[2,3-d]pyrimidine (3.15 g, 14.1 mmol) in AcCN was added N-iodosuccinimide and the mixture was stirred at r.t. for 12 hr. The precipitate was collected and recrystallized from MeOH to give the title compound (4.06 g, 83%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[F:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cn1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(-c2cccc(F)c2)cn1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To a reaction flask was added tert-butyl 5-bromopicolinate 33-4 (516 mg, 2.00 mmol), 3-fluorophenylboronic acid 6-6 (280 mg, 2.00 mmol), Pd(PPh3)4 (140 mg, 0.20 mmol), toluene (10 mL), ethanol (2 mL) and 2M Na2CO3 (3 mL). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 90° C. for 10 hours with the flask sealed. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated NaHCO3 aqueous solution, H2O and brine. The organic phase was dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography, and eluted with 30% hexanes in ethyl acetate to give tert-butyl 5-(3-fluorophenyl)picolinate 33-5 as a white solid. MS m/z 274.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[S:18][CH:19]2[CH2:24][CH2:23][N:22]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.ClC1C=C(C(OO)=[O:43])C=CC=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[S:18]([CH:19]2[CH2:24][CH2:23][N:22]([S:25]([C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)(=[O:27])=[O:26])[CH2:21][CH2:20]2)=[O:43])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(Sc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCC(S(=O)c3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Reaction time: 2 h
Yield: 9 %

Procedure:
To a stirred and cooled (0° C.) mixture of 7.2 parts of 4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]thio]-1-[(4-methylphenyl)sulfonyl]piperidine and 95 parts of dichloromethane was added dropwise a solution of 2.6 parts of 3-chlorobenzenecarboperoxoic acid in dichloromethane. Upon completion, stirring was continued for 2 hours at room temperature. The reaction mixture was washed with a sodium carbonate solution and with water. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 0.7 parts (9%) of 4-[[1-[(4-fluorophenyl)methyl]1H-benzimidazol-2-yl]sulfinyl]-1-[(4-methylphenyl)sulfonyl]piperidine; mp. 166.2° C. (30).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:27])[N:7]([CH2:20][C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:22])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:28][N:29]([CH3:46])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[CH3:28][N:29]([CH2:30][C:31]1[CH:32]=[C:33]([C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:27])[N:7]([CH2:20][C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:22])[C:8]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=4)=[N:9]3)=[CH:4][CH:3]=2)[CH:34]=[CH:35][CH:36]=1)[CH3:46]
Reactant: CN(C)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: COc1cccc(-c2nc3cc(Cl)ccc3c(=O)n2CC(=O)NC(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(-c2nc3cc(-c4cccc(CN(C)C)c4)ccc3c(=O)n2CC(=O)NC(C)C)c1
Temperature: 80 °C

Procedure:
An oven dried flask was charged with 2-[7-chloro-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (INTERMEDIATE IV.11) (38.5 mg, 0.10 mmol), dimethyl-[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]amine (INTERMEDIATE XI.1) (40 mg, 0.15 mmol) and K3PO4(69 mg, 0.33 mmol) followed by mixture of DMF: H2O (4:1, 5 mL) and purged with argon for a minimum of 10 minutes. CombiPhos™-Pd catalyst (CombiPhos Catalysts Inc., Princeton, N.J.) (1 mole %) was added and the mixture was heated at 80° C. for 18 h. The solvent was removed under vacuum and the residue was dissolved in methanol, filtered and purified by preparative HPLC to give 2-[7-(3-dimethylaminomethylphenyl)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (EXAMPLE 8a) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9](=[O:17])[NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1)#[N:2].Cl.[CH2:29]([OH:31])[CH3:30]>>[CH2:29]([O:31][N:2]=[CH:1][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:9](=[O:17])[NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:26][CH:27]=1)[CH3:30]
Reactant: CCO
Reactant: CCOC(=O)CNC(=O)N(Cc1ccc(C#N)cc1)OCc1ccccc1
Agent: Cl
Product: CCON=Cc1ccc(CN(OCc2ccccc2)C(=O)NCC(=O)OCC)cc1
Temperature: -30 °C
Reaction time: 24 h

Procedure:
2.99 g (8.14 mmol) of ethyl (3-(4-cyanobenzyl)-3-benzyloxyureido)acetate are dissolved in 250 ml of ethanol and cooled to -30° C. Dry HCl gas is introduced into the solution. After 24 h, excess HCl gas is driven out by nitrogen and the solvent is removed in vacuo. The residue crystallizes from ethyl acetate/ether.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18](F)[CH:17]=2)=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:7]=1.CS(C)=O.[C@H:28]1([NH2:35])[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1>C(OCC)(=O)C>[NH2:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([NH:35][C:18]2[CH:17]=[C:16]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[C:5]([NH:8][CH2:9][CH:10]4[CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)[N:4]=3)[C:21]([Cl:22])=[CH:20][N:19]=2)[CH2:29][CH2:30]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Fc1cc(-c2nc(NCC3CCOCC3)ccc2Cl)c(Cl)cn1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Cl)c(Cl)cn2)CC1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
To 3,5′-dichloro-2′-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine (Intermediate G) (250 mg, 0.702 mmol) was added DMSO (3 ml) and trans-cyclohexane-1,4-diamine (952 mg, 6.32 mmol). The reaction mixture was stirred at 100° C. for 20 hours and the reaction progress was followed by LCMS. The reaction mixture was cooled, diluted with 250 ml ethyl acetate, washed with saturated sodium bicarbonate (1×), water (3×) and concentrated to constant mass, giving 320 mg of product as a free base, which was used without further purification. A portion of the title compound, 25 mg was purified by prep LC and lyapholized to give 17.6 mg of the title compound as a TFA salt. LCMS (m/z): 450.2 (MH+), retention time=0.58 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.16-1.76 (m, 8H) 1.76-1.98 (m, 1H) 2.04-2.27 (m, 4H) 3.06-3.16 (m, 1H) 3.19 (d, J=6.74 Hz, 2H) 3.37 (t, J=11.87 Hz, 2H) 3.62-3.77 (m, 1H) 3.92 (dd, J=11.28, 3.08 Hz, 2H) 6.61 (d, J=8.79 Hz, 1H) 6.73 (s, 1H) 7.50 (d, J=9.08 Hz, 1H) 8.04 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH:35]=O)=[N:27]1.N1CCCCC1>CO>[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28](/[CH:35]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[N:27]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
The synthesis was performed with reference to the known literature (Tetrahedron, Vol. 29, p. 359, 1973). A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) in methanol (1.2 mL) was added with 1H-indazole-3-carboxaldehyde (0.0419 g, 0.287 mmol), and piperidine (0.00244 g, 0.0287 mmol) at room temperature, and the mixture was stirred at 60° C. for 3 hours. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.125 g, 91%).
Reaction SMILES: [N+]([O-])([O-])=[O:2].[NH4+].[Ce].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[C:15]1[S:16][C:17]2[C:18](=[C:20](N)[C:21]([O:26][CH3:27])=[CH:22][C:23]=2[O:24]C)[N:19]=1>O.C(OCC)(=O)C>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[C:15]1[S:16][C:17]2[C:23](=[O:24])[CH:22]=[C:21]([O:26][CH3:27])[C:20](=[O:2])[C:18]=2[N:19]=1
Reactant: O=[N+]([O-])[O-]
Reactant: COc1cc(OC)c2sc(-c3c(F)cccc3F)nc2c1N
Agent: [Ce]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC1=CC(=O)c2sc(-c3c(F)cccc3F)nc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A solution of 1.22 g of cerium ammonium nitrate (2.23 mmol, 2.1 equivalents) in 8 ml of water is added to 343 mg (1.06 mmol) of 2-(2,6-difluorophenyl)-5,7-dimethoxy-1,3-benzothiazol-4-amine in solution in 25 ml of ethyl acetate. The reaction mixture is maintained under vigorous stirring at ambient temperature for 1 hour 30 minutes then the organic phase is separated and washed with 3 times 20 ml of water, then dried over magnesium sulphate, filtered and the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on a silica column (eluent: ethyl acetate/heptane: 3/7) and 280 mg (yield=86%) of 2-(2,6-difluorophenyl)-5-methoxy-1,3-benzothiazole-4,7-dione is obtained in the form of yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH3:16])[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[O:6]1)=[O:4].[H-].[Na+].[CH3:19]I>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C@:5]1([CH3:16])[C:10](=[O:11])[N:9]([CH3:19])[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[O:6]1)=[O:4]
Reactant: CI
Reactant: COC(=O)C1(C)Oc2ccccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)[C@@]1(C)Oc2ccccc2N(C)C1=O
Yield: 70.5 %

Procedure:
To a solution of (+)-methyl-3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazine-2-carboxylate (0.9 g, 4.1 mmoles) in anhydrous toluene (20 ml), NaH (0.12 g, 5.1 mmoles) and methyl iodide (0.87 g, 6.1 mmoles) were added with stirring and the mixture was heated at reflux temperature for 2 hours. After the completion of the reaction, the toluene solution was washed with water (2×20 ml), 0.1M HCl (2×20 ml) and saturated NaCl solution (20 ml). The solution was dried over MgSO4 and the solvent was evaporated. Thus there were obtained 0.68 g of the title product, which was recrystallized from a mixture of hexane and diethyl ether. The title product was in the form of white crystals, m.p. 76°-78° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][CH2:15][CH2:14][S:13]1.[C:17](Cl)(=[O:20])[CH2:18][CH3:19].CCN(CC)CC>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([C:17](=[O:20])[CH2:18][CH3:19])[CH2:15][CH2:14][S:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NCCS1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)N1CCSC1=Nc1ccc([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a solution of 2-(2-methyl-4-nitrophenylimino)-1,3-thiazolidine (prepared in a manner analogous to that described in Method C1a; 0.084 g, 0.35 mmol) in CH2Cl2 (5 mL) was added propionyl chloride (0.033 g, 0.35 mmol) and Et3N (0.049 mL, 0.35 mmol). The mixture was allowed to stir at room temp for 1 h, then was diluted with CH2Cl2 (40 mL). The resulting solution was sequentially washed with H2O (10 mL) and a saturated NaCl solution (10 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by preparative TLC (40% EtOAc/hex) to give 2-(2-methyl-4-nitrophenylimino)-3-propanoyl-1,3-thiazolidine (0.036 g, 35%): FAB-MS m/z 294 ((M+H)+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.Cl.[CH3:14][O:15][C:16](=[O:22])[C@H:17]([CH:19]([CH3:21])[CH3:20])[NH2:18]>>[CH3:14][O:15][C:16](=[O:22])[CH:17]([NH:18][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH:19]([CH3:21])[CH3:20]
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Product: COC(=O)C(NC(=O)CCc1ccc(O)cc1)C(C)C
Yield: 89.5 %

Procedure:
Following the same procedure of Example 4 except that 3-(4-hydroxyphenyl)propionic acid (1.0 g, 6.0 mmol) and valine methyl ester hydrochloride (1.1 g, 6.6 mmol) were used, 1.5 g of the title compound was obtained. The compound was finally purified by silica gel column chromatography (column size: 25 mm×150 mm, silica gel 70-230 mesh, eluent: hexane/EtOAc (1/1)). The results of analyses of the compound are as follows: