Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([NH:10][C@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH2:14])=[O:13])=[CH:5][C:4]=1F)#[N:2].Cl.[NH2:21][C:22]1[S:26][N:25]=[C:24]([CH3:27])[CH:23]=1.[H-].[Na+].CC(O)=O>CS(C)=O>[C:1]([C:3]1[C:4]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH3:27])[CH:23]=2)=[CH:5][C:6]([NH:10][C@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: Cc1cc(N)sn1
Reactant: CC(C)C[C@@H](Nc1cc(F)c(C#N)c(F)c1)C(N)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(N[C@H](CC(C)C)C(N)=O)cc(F)c2C#N)sn1
Reaction time: 1 h
Yield: 30.9 %

Procedure:
To a solution of (R)-2-(4-cyano-3,5-difluorophenylamino)-4-methylpentanamide (92 mg, 0.34 mmol) and 5-amino-3-methylisothiazole hydrochloride (70 mg, 0.46 mmol) in DMSO (2 mL), NaH (60% in mineral oil, 80 mg, 2.00 mmol) was added. H2 gas evolved. The mixture was stirred at 130 C for 1 h. After being acidified with HOAc (1.0 mL), the mixture was purified by HPLC to give (R)-2-(4-cyano-3-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-4-methylpentanamide (38 mg).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[C:12]([CH2:21][C:22]3[N:27]=[C:26]([C:28]([OH:30])=O)[CH:25]=[CH:24][CH:23]=3)=[C:11]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39].Cl.C(N=C=NCCCN(C)C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[C:12]([CH2:21][C:22]3[N:27]=[C:26]([C:28]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:30])[CH:25]=[CH:24][CH:23]=3)=[C:11]2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc2c(Cc3cccc(C(=O)O)n3)c(-c3ccccc3)n(S(=O)(=O)c3ccccc3)c2c1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2c(Cc3cccc(C(=O)NS(C)(=O)=O)n3)c(-c3ccccc3)n(S(=O)(=O)c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.2 %

Procedure:
To a solution of 6-(1-benzenesulfonyl-6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylic acid (867 mg) in dichloromethane (17.4 mL) were added methanesulfonamide (199 mg), 4-dimethylaminopyridine (510 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (800 mg) successively, and this mixture was stirred at room temperature for 24 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, followed by extraction with dichloromethane. The organic layer was washed with 1 mol/L hydrochloric acid, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: methanol-dichloromethane) to obtain the title compound (633 mg). 1H-NMR (DMSO-d6) δ ppm: 3.39 (3H, s), 3.86 (3H, s), 4.03 (2H, s), 6.85-6.98 (2H, m), 7.37 (1H, d, J=8.8 Hz), 7.39-7.53 (9H, m), 7.60-7.71 (2H, m), 7.77-7.88 (2H, m), 11.00-11.56 (1H, br). ESI-MS (m/z): 576 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:18]3[S:19][CH:20]=[C:21]([CH:23]([CH3:25])[CH3:24])[N:22]=3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38].[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]([CH2:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[C:18]3[S:19][CH:20]=[C:21]([CH:23]([CH3:24])[CH3:25])[N:22]=3)=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:35][CH2:36][C:37]([OH:39])=[O:38]
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(CN(CCc3ccc(F)cc3)c3nc(C(C)C)cs3)cc2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)c1csc(N(CCc2ccc(F)cc2)Cc2ccc(COc3ccc(CCC(=O)O)c(F)c3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
Ethyl 3-{2-fluoro-4-[(4-{[[2-(4-fluorophenyl)ethyl](4-isopropyl-1,3-thiazol-2-yl)amino]methyl}benzyl)oxy]phenyl}-propanoate (485 mg) was dissolved in ethanol (5 mL), 2N aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with water, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was dried using a Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.) and concentrated to give the title compound (354 mg, yield 75%) as colorless crystals.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([CH2:19][CH:20]=[CH2:21])[CH2:4][C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[H-].[Na+].[CH2:24](Br)[CH:25]=[CH2:26]>C1COCC1>[CH2:26]([O:1][CH2:2][C@H:3]([CH2:19][CH:20]=[CH2:21])[CH2:4][C@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:25]=[CH2:24]
Reactant: C=CCBr
Reactant: C=CC[C@@H](CO)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOC[C@H](CC=C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
To a solution of (S)-tert-butyl 4-((R)-2-(hydroxymethyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (30 g, 100 mmol, 1 eq) in anhydrous THF (600 mL) was added NaH (60%, 16 g, 400 mmol, 4 eq) in portions at 0° C. The mixture was stirred for 10 min at 0° C., followed by the dropwise addition of allyl bromide (48 g, 400 mmol, 4 eq) over 15 min. After stirring for 30 min at 0° C., the mixture was allowed to warm to rt and stirred for 16 h. The reaction was quenched with aq. NH4Cl and the mixture was extracted with EA (3×). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under reduced pressure to afford the crude product. It was purified by column chromatography on silica gel (PE:EA=100:1→60:1) to give (S)-tert-butyl 4-((R)-2-(allyloxymethyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (26.15 g, 77.0%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH3:10]N(C=O)C.[H-].[Na+].CI>CCOC(C)=O>[CH3:10][N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: Cn1ccc2cccnc21
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridine (1.00 g, 8.46 mmol) and DMF (10 mL) is added 60% NaH (0.41 g, 10.16 mmol). After 30 min, MeI (0.63 mL, 10.16 mmol) is added and the solution stirred for 1 h. The solution is diluted with EtOAc (60 mL), washed with water (2×50 mL), brine (50 mL), dried aver MgSO4, filtered and concentrated to furnish the title compound (1.10 g, 0.83 mmol, 99%). 1H NMR (CDCl3), δ 3.90 (s, 3H), 6.45 (d, J=3.5 Hz, 1H), 7.05 (dd, J=8.1, 4.6 Hz, 1H), 7.17 (d, J=3.5 Hz, 1H), 7.90 (d, J=7.7, 1.8 Hz, 1H), 8.40 (dd, J=4.8, 1.3 Hz, 1H). LC/MS (m/z): calcd. for C8H8N2 (M+H)+: 133.2. found.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].P([O-])(OCC)([S:12][CH2:13][CH3:14])=S.Cl>CCOC(C)=O>[S:12]1[CH:13]=[CH:14][N:2]=[C:1]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9]
Reactant: N#Cc1ccccc1O
Reactant: CCOP([O-])(=S)SCC
Agent: Cl
Solvent: CCOC(C)=O
Product: Oc1ccccc1-c1nccs1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
The title compound was prepared according to the method in Z. Naturforsh. 376, 877-880 (1982) or Helv. Chim. Acta 36, 886-890 (1953). o-Cyanophenol (55 mmol, 6.55 g) in EtOAc (160 mL) was treated with diethyl dithiophosphate (9.15 mL, 55 mmol) and HCl(g) was bubbled into the stirred solution at a moderate rate for about 45 min. without external cooling. After stirring at about 20° C. under N2 (g) for about 16 h., excess HCl was removed by N2 (g) sparge and saturated aqueous Na2CO3 (100 mL) was added carefully with stirring. The organic phase was separated and washed (3×) with saturated Na2CO3 until no further orange color resulted in the aqueous phases. The organic phase was dried over Na2SO4 (s) and concentrated in vacuo. An orange crystalline impurity (~3.0 g; m.p. 215° C., El-MS m/z 255) precipitated upon addition of ether and was removed by filtration. The filtrate was concentrated in vacuo and recrystallized from Et2O/hexanes to afford 2.9 g (m.p. 117° C.; GC-MS m/z 153) of the desired thioamide. This material (2.0 g, 13 mmol) was dissolved in EtOH (5 mL) and α-bromoacetaldehyde dimethyl acetal (1.55 mL, 13 mmol) was added. The mixture was refluxed under N2 (g) atmosphere for 3.5 h. and Et2O (15 mL) was added to complete the precipitation of the 2-(thiazol-2-yl)phenol as its hydrobromide salt which was recrystallized from MeOH/CHCl3 /Et2O to produce 1.55 g of pure HBr salt (LSIMS m/z 178 (MH+)). This material could be alkylated directly if an extra equivalent of base was included to neutralize the HBr, or it could be free-based by extraction from saturated aqueous NaHCO3 with Et2O followed by drying over Na2SO4 (s) and concentration of etheral phases in vacuo.
Reaction SMILES: CS([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH3:12])[C:7]1=[O:13])(=O)=O.[C:14]([O-])(=[S:16])[CH3:15].[K+]>CC(C)=O>[C:14]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH3:12])[C:7]1=[O:13])(=[S:16])[CH3:15]
Reactant: CC([O-])=S
Reactant: CN1CCCC(OS(C)(=O)=O)C1=O
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=S)OC1CCCN(C)C1=O
Yield: 40.1 %

Procedure:
A mixture of 1-methyl-2-oxo-3-piperidinyl methanesulfonate (1.7 g., 0.008 mole) and potassium thioacetate (1.39 g., 0.012 mole) in 80 ml. acetone was refluxed under nitrogen for 20 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in 50 ml. ethyl acetate and 50 ml. water. The ethyl acetate layer was washed with 50 ml. water and 50 ml saturated aqueous sodium chloride solution, dried over anhydrous sodium acetate and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate to yield 600 mg (40% yield) of the title compound. NMR (CDCl3): 1.7-2.5 (c) and 2.38 (s) (total 7H); 3.0 (s, 3H); 3.36 (m, 2H); and 4.2 (m, 1H)ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Na+].[CH3:24][O:25][C:26](=[O:40])[C@H:27](OS(C)(=O)=O)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.C(OCC)(=O)C>[CH3:24][O:25][C:26](=[O:40])[C@@H:27]([N:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([NH:9][C:10](=[O:21])[C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=2)[C:5]1=[O:8])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)OS(C)(=O)=O
Reactant: O=C(Nc1cc(Br)cnc1O)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccccc1)n1cc(Br)cc(NC(=O)c2ccc(C(F)(F)F)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
To a solution of N-(5-bromo-2-hydroxypyridin-3-yl)-4-trifluoromethyl-benzamide from Step D (760 mg, 2.1 mmol) in tetrahydrofuran (10 mL) was added 95% sodium hydride (80 mg, 3.15 mmol) at room temperature. After the reaction mixture was stirred at room temperature for 30 min, (R)-2-methanesulfonyloxy-3-phenylpropionic acid methyl ester from Step B (820 mg, 3.15 mmol) was added and the reaction was stirred and heated at 50° C. for 20 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL) and washed with saturated ammonium chloride solution and brine. The organic layer was separated, dried with sodium sulfate, filtered and concentrated in vacuo. Purification by medium pressure liquid chromatography on silica gel (1:6 ethyl acetate/hexanes) gave 770 mg (70%) of the title compound as a semisolid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[Cl:10])=O.[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[NH:17])=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[NH:17][C:3]([C:5]3[S:6][CH:7]=[CH:8][C:9]=3[Cl:10])=[CH:2][N:18]=2)=[CH:14][CH:13]=1
Reactant: O=C(CBr)c1sccc1Cl
Reactant: N=C(N)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: Clc1ccc(-c2ncc(-c3sccc3Cl)[nH]2)cc1

Procedure:
Compounds of this invention with Formula IV may be prepared as illustrated by the exemplary reaction in Scheme 3. Reaction of 2-bromo-1-(3-chloro-thiophen-2-yl)-ethanone with 4-chloro-benzamidine in chloroform produces the product 2-(4-chloro-phenyl)-5-(3-chloro-thiophen-2-yl)-1H-imidazole.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[C:22]1([N:28]=[C:29]=[S:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C.O>[C:1]([NH:4][NH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:29]([NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[S:30])=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(CNc2ccc(NNC(C)=O)cc2)cc1
Reactant: S=C=Nc1ccccc1
Solvent: O
Solvent: CCO
Product: COc1ccc(CN(C(=S)Nc2ccccc2)c2ccc(NNC(C)=O)cc2)cc1

Procedure:
1-Acetyl-2-[4-(4-methoxybenzyl)aminophenyl]hydrazine (3.1 g, 0.011 mole) and phenylisothiocyanate (1.35 g, 0.01 mole) were mixed in ethanol (25 ml) and the resulting mixture was refluxed for 10 minutes. The mixture was chilled in ice and diluted with water. The product oiled out of solution, but upon standing and scratching the substance solidified. The solid material was filtered off, washed with water and allowed to dry. The material was stirred twice in a large volume of ether, then was filtered and washed with fresh ether. The product was a white powder. Yield 2.75 g (66%), m.p. 126°-128° C.
Reaction SMILES: [F:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[F:66][C:67]([F:71])([F:70])[CH2:68][NH2:69]>CN(C=O)C>[F:66][C:67]([F:71])([F:70])[CH2:68][NH:69][C:6]([CH:4]1[CH2:5][C:2]([F:1])([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:22])([F:23])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:3]1)=[O:8]
Reactant: NCC(F)(F)F
Reactant: O=C(O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(F)(F)F)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.9 %

Procedure:
To a stirred solution of 3-fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid (Preparation 7, 0.1 g, 0.200 mmol) in DMF (3 mL) was added HOBt (0.026 g, 0.200 mmol), DIPEA (0.050 g, 0.392 mmol) followed by addition of EDCl.HCl (0.056 g, 0.294 mmol, 1.5 eq.) and 2,2,2-trifluoro-ethylamine hydrochloride (0.026 g, 0.200 mmol) at room temperature. Resulting reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3×20 mL). Combined organic layer was washed with water (5×30 mL), brine (50 mL), saturated NaHCO3 (50 mL), dried over sodium sulphate and evaporated in vacuo to get crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 1% methanol in DCM to afford sticky mass, which was crystallized with pentane to afford white solid (0.065 g, 56%). 1H-NMR (400 MHz, CDCl3) δ: 2.77-2.83 (m, 3H), 2.96-3.08 (m, 2H), 3.68 (d, 1H, J=17.2 Hz), 3.92-4.00 (m, 2H), 4.08 (d, 1H, J=17.2 Hz), 5.70 (t, 1H, J=6.3 Hz), 7.52 (d, 2H, J=8.2 Hz), 7.64 (s, 2H), 7.70 (d, 2H, J=8.12 Hz); LC-MS (m/z): [M−H] 588.60.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][N:6]([CH2:17][C:18]([O:20]CC)=[O:19])[C:7]1[CH:12]=[C:11]([C:13]([NH2:15])=O)[CH:10]=[CH:9][C:8]=1[CH3:16])C.[OH-].[Na+]>CO.O1CCCC1>[C:13]([C:11]1[CH:10]=[CH:9][C:8]([CH3:16])=[C:7]([N:6]([CH2:17][C:18]([OH:20])=[O:19])[CH2:5][C:4]([OH:23])=[O:3])[CH:12]=1)#[N:15]
Reactant: CCOC(=O)CN(CC(=O)OCC)c1cc(C(N)=O)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C#N)cc1N(CC(=O)O)CC(=O)O
Temperature: 25 °C
Yield: 86.7 %

Procedure:
The compound (6.02 g, 19.8 mmol) obtained in step F was dissolved in a methanol-tetrahydrofuran=1:1 mixed solvent (100 ml). 1N sodium hydroxide (100 ml) was added with stirring at room temperature, and the mixture was stirred at the same temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid (110 ml) was added, and the aqueous layer was extracted 4 times with chloroform. The organic layer was mixed, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure, and the obtained solid was washed with diethyl ether-hexane mixed solvent, and dried under reduced pressure to give the title compound (4.26 g, yield 87%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][CH:18]([N:22]1[C:30]2[C:25](=[CH:26][C:27](/[C:31](/[CH3:36])=[CH:32]/[C:33](O)=[O:34])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1)[CH2:19][CH2:20][CH3:21]>>[CH3:17][CH:18]([N:22]1[C:30]2[C:25](=[CH:26][C:27](/[C:31](/[CH3:36])=[CH:32]/[C:33]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:34])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: CCCC(C)n1ccc2cc(/C(C)=C/C(=O)O)ccc21
Product: CCCC(C)n1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
1.20 g of compound 16 was obtained in a similar manner to those described in the Examples 1 and 2 using 2.63 g of ethyl 4-(2-aminophenoxy)butyrate and 1.60 g of 3-[1-(1-methylbutyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:11]=1[C:12]#[N:13].C(O)(C(F)(F)F)=O>>[Br:8][C:15]1[C:14]([CH3:18])=[C:11]([C:10]([F:9])=[CH:17][CH:16]=1)[C:12]#[N:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(F)c1C#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Br)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NBS (265 g, 1490 mmol) was added portion wise to a stirred, cooled room temperature mixture of 2-Fluoro-6-methylbenzonitrile (191.8 g, 1419 mmol) in TFA (553 mL, 8500 mmol) and then the mixture was heated at reflux for 48 hours. The reaction was poured into 1 L of ice, diluted with 700 mL 30% EtOAc/Hexanes, and agitated. The aqueous layer was cut, and the organic layers were washed with 1N NaOH twice and with water. The organic layers were dried over Na2SO4, concentrated, and then stored in a −10° C. freezer overnight. The resulting crystals were filtered and washed with 5% EtOAc/Hexanes to yield the title product.
Reaction SMILES: [C:1](N1C2C(=NC=CC=2)N=N1)(=[O:3])[CH3:2].[CH2:13]([OH:24])[CH2:14][C:15]1[CH:23]=[CH:22][C:20]([OH:21])=[C:17]([O:18][CH3:19])[CH:16]=1.[OH-].[Na+]>C1COCC1.Cl>[C:1]([O:21][C:20]1[CH:22]=[CH:23][C:15]([CH2:14][CH2:13][OH:24])=[CH:16][C:17]=1[O:18][CH3:19])(=[O:3])[CH3:2]
Reactant: CC(=O)n1nnc2ncccc21
Reactant: COc1cc(CCO)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(CCO)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-acetyl-1H-1,2,3-triazolo[4,5-b]pyridine (0.964 g, 5.95 mmol) in dry THF (24 mL) was added to a solution of homovanillyl alcohol (1.00 g, 5.95 mmol) in 1N aq. NaOH (5.95 mL, 5.95 mmol) at 25° C. The reaction was stirred at 25° C. for 60 min. The reaction was diluted with 1N HCl (40 mL) and extracted with Et2O (3×50 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 144 mL, gradient to 50% EtOAc in hexanes over 360 mL, gradient to 100% EtOAc over 1944 mL) to afford 4-(2-hydroxyethyl)-2-methoxyphenyl acetate, as a colorless oil. Rf=0.71 (EtOAc). LCMS calc.=233.1; found=233.1 (M+Na)+. 1H NMR (500 MHz, CDCl3): δ 6.95 (d, J=8.0 Hz, 1 H); 6.83 (d, J=1.8 Hz, 1 H); 6.79 (dd, J=1.8, 8.0 Hz, 1 H); 3.88 (t, J=6.6 Hz, 2 H), 3.84 (s, 3 H); 2.82 (t, J=6.5 Hz, 2 H); 2.30 (s, 3 H); 1.76 (s, 1 H).
Reaction SMILES: [C:1]([CH:3]1[C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]([C:14]([O:16]CC2C=CC=CC=2)=[O:15])[C:6](=[O:24])[NH:5][C:4]1=[O:25])#[N:2].C(OCC)(=O)C>[Pd].CO>[C:1]([CH:3]1[C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]([C:14]([OH:16])=[O:15])[C:6](=[O:24])[NH:5][C:4]1=[O:25])#[N:2]
Reactant: N#CC1C(=O)NC(=O)C(C(=O)OCc2ccccc2)C12CCCCC2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: N#CC1C(=O)NC(=O)C(C(=O)O)C12CCCCC2
Temperature: 12 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
1.8 g of benzyl 5-cyano-2,4-dioxo-3-azaspiro[5,5]undecane-1-carboxylate, 25 ml of ethyl acetate and 0.09 g of 5% Pd/C are placed in a 100 ml flask equipped with a magnetic stirrer, thermometer and condenser. The mixture is stirred for 4 hours at 12° C. under a hydrogen atmosphere. 10 ml methanol are added and the mixture is filtered through celite. The solvent is evaporated at 20° C. under reduced pressure to obtain 1.32 g of 5-cyano-2,4-dioxo-3-azaspiro[5,5]undecane-1-carboxylic acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][C:11]3[CH:15]=[C:16]([S:19](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:21])=[O:20])[CH:17]=[CH:18][C:10]2=3)=[C:5]([O:34][CH3:35])[CH:4]=1)#[N:2].[NH2:36][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][N:38]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][C:11]3[CH:15]=[C:16]([S:19]([NH:36][C:37]4[CH:42]=[CH:41][N:40]=[CH:39][N:38]=4)(=[O:20])=[O:21])[CH:17]=[CH:18][C:10]2=3)=[C:5]([O:34][CH3:35])[CH:4]=1)#[N:2]
Reactant: COc1cc(C#N)ccc1N1CCOc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Reactant: Nc1ccncn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C#N)ccc1N1CCOc2cc(S(=O)(=O)Nc3ccncn3)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 8.7 %

Procedure:
To a solution of perfluorophenyl 4-(4-cyano-2-methoxyphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (180 mg, 0.351 mmol) and 4-amino pyrimidine (50 mg, 0.527 mmol) in THF (5 mL) was added LiHMDS (1M in THF, 0.7 mL, 0.703 mmol) at −78° C. The reaction mixture was stirred at same temperature for 5 minutes and at 0° C. for 1 h. After completion, reaction mixture was quenched with 2-3 drops of acetic acid and concentrated under reduced pressure. The crude mass was purified by prep purification to obtain 4-(4-cyano-2-methoxyphenyl)-N-(pyrimidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (13 mg, 11.3%) as a white solid. m/z (ESI) 423.0 (M+H)+. 1H NMR (400 MHz, DMSO) δ 11.88 (s, 1H), 8.64 (s, 1H), 8.36 (d, J=5.8 Hz, 1H), 7.65 (s, 1H), 7.55-7.43 (m, 2H), 7.35-7.15 (m, 2H), 7.00 (d, J=5.9 Hz, 1H), 6.34 (d, J=8.6 Hz, 1H), 4.30 (t, J=4.0 Hz, 2H), 3.81 (s, 3H), 3.67-3.65 (m, 2H).