Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25](I)[CH2:26][CH3:27].[H-].[Na+].O>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]([CH:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)[CH2:25][CH2:26][CH3:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)CC1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(C(=O)OCc1ccccc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.8 %

Procedure:
To 110 mg (0.32 mmol) 4-benzyloxycarbonylamino-1-t-butoxycarbonylpiperidine from Step C and 0.16 mL (1.6 mmol) of n-propyl iodide in 2 mL of DMF under nitrogen was added 26 mg (0.65 mmol) of 60% sodium hydride in mineral oil. The reaction was stirred at rt for 16 h and was then poured into water and extracted twice with ether. The organic layers were each washed with a portion of brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC eluting with 20% ethyl acetate in hexanes to afford 90 mg of title compound.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:32][C:33]1[CH:38]=[C:37]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([C:11]([N:8]4[CH2:7][CH2:6][N:5]([CH:1]5[CH2:2][CH2:3][CH2:4]5)[CH2:10][CH2:9]4)=[O:12])=[CH:21][CH:20]=3)[CH:16]=[C:17]2[C:22]([N:24]2[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]2)=[O:23])[CH:36]=[CH:35][CH:34]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(Cl)c1)N1CCN(C2CCC2)CC1
Yield: 10 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless solid (10%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].Cl[CH2:21][CH2:22][O:23][CH2:24][CH2:25]Cl.C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][C:5]=1[O:11][Si:12]([C:15]([CH3:16])([CH3:18])[CH3:17])([CH3:13])[CH3:14]
Reactant: ClCCOCCCl
Reactant: COC(=O)c1cc(N)ccc1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(N2CCOCC2)ccc1O[Si](C)(C)C(C)(C)C
Yield: 17.8 %

Procedure:
A solution of 5-amino-2-(tert-butyl-dimethyl-silanyloxy)benzoic acid methyl ester (4.5 g, 16 mmol), 2-chloroethyl ether (1.9 mL, 16.2 mmol), and diisopropylethylamine (5.6 mL, 32.1 mmol) in DMF (50 mL) was stirred at 100° C. for 48 h. The reaction mixture was poured into 10% aqueous NaHCO3 (100 mL) and extracted with ether (200 mL). The organic layer was washed with water (5×100 mL) and brine (100 mL), dried over magnesium sulfate (MgSO4), and concentrated to a red syrup. The residue was purified by flash chromatography (silica gel, 4×15 cm, eluted with 9/1 hexanes/EtOAc) to yield 2-(tert-butyl-dimethyl-silanyloxy)-5-morpholin-4-yl-benzoic acid methyl ester (1.0 g, 18%).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@@H:6]1[C:13](=[O:14])[N:12]2[C@@H:7]1[S:8][CH2:9][C:10](/[CH:18]=[C:19]1/[C:20](=[O:43])[N:21]([CH2:24][C:25]3[CH:30]=[CH:29][N+:28]([CH2:31][C:32](=[O:42])[NH:33][C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([F:41])[CH:35]=4)=[CH:27][CH:26]=3)[CH2:22][CH2:23]/1)=[C:11]2[C:15]([O-:17])=[O:16])=[O:4].[CH3:44][N:45]1[CH:49]=[N:48][N:47]=[C:46]1[SH:50].C(N(CC)CC)C>CN(C)C=O>[F:41][C:36]1[CH:35]=[C:34]([NH:33][C:32]([CH2:31][N+:28]2[CH:27]=[CH:26][C:25]([CH2:24][N:21]3[CH2:22][CH2:23]/[C:19](=[CH:18]\[C:10]4[CH2:9][S:8][C@H:7]5[N:12]([C:13](=[O:14])[C@H:6]5[NH:5][C:3](=[O:4])[CH2:2][S:50][C:46]5[N:45]([CH3:44])[CH:49]=[N:48][N:47]=5)[C:11]=4[C:15]([O-:17])=[O:16])/[C:20]3=[O:43])=[CH:30][CH:29]=2)=[O:42])[CH:39]=[CH:38][C:37]=1[OH:40]
Reactant: Cn1cnnc1S
Reactant: O=C(C[n+]1ccc(CN2CC/C(=C\C3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)CBr)[C@H]4SC3)C2=O)cc1)Nc1ccc(O)c(F)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1cnnc1SCC(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(/C=C3\CCN(Cc4cc[n+](CC(=O)Nc5ccc(O)c(F)c5)cc4)C3=O)CS[C@H]12
Reaction time: 12 h

Procedure:
To a solution of 230.0 mg (0.34 mmol) (E)-(6R,7R)-7-(2-Bromo-acetylamino)-3-(1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate in 5 ml N,N-dimethylformamide was added 40.0 mg (0.37 mmol) 4-methyl-4H-[1,2,4]triazole-3-thiol. After 1 h 47.0 μl (0.34 mmol) triethyl amine was added and stirring was continued for 12 h. The solution was poured on diethyl ether and the resulting solid was purified by column chromatography on MCI gel (75-150μ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (1:0, 4:1, 3:1, 2:1). The organic solvent was stripped off at a rotary evaporator and the aqueous phase was freeze-dried.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[O-]CC.[Na+].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[O:17]>C(O)C.C(O)C.C1(C)C=CC=CC=1>[C:3]([CH:2]([CH2:15][C:16](=[O:17])[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CC(=O)c1ccc(Cl)cc1Cl)C(C)=O
Reaction time: 0.25 h

Procedure:
To a solution of 3.26 ml of ethyl acetoacetate in ethanol (20 ml) is added dropwise 0.5 ml of a sodium ethoxide solution (21% in EtOH) at 0° C. The mixture is stirred for 15 minutes and 5.82 g de 2-bromo-1-(2,4-dichlorophenyl)ethanone predissolved in 30 ml of an ethanol/toluene mixture (2/1; v/v) is then added. The mixture is stirred for 4 hours at RT and then concentrated to dryness. The residue is purified by chromatography on silica gel to give 3.8 g of liquid corresponding to the expected product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[C-:31]#[N:32].[Na+].O>CS(C)=O>[C:31]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:10]=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)#[N:32]
Reactant: [C-]#N
Reactant: BrCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCCCCn1c(-c2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.3 %

Procedure:
1-(6-Bromohexyl)-2,4,5-triphenylimidazole (27.6 g) in dry dimethylsulphoxide (70 ml) was added over 10 minutes to a mixture of sodium cyanide (3.68 g) in dimethyl-sulphoxide (50 ml) and the reaction was stirred at room temperature for 20 h. The reaction mixture was poured into water (300 ml) and extracted with dichloromethane (3×150 ml). The extracts were combined, washed with water, dried over anhydrous magnesium sulphate and evaporated to dryness in vacuo. Recrystallisation from diethyl ether and hexane gave 1-(6-cyanohexyl)-2,4,5-triphenylimidazole (24.19 g, 99%) as a white solid, m.p. 104°-6°.
Reaction SMILES: [C:1](O)(=[O:5])[CH:2]([CH3:4])[OH:3].[NH2:7][CH2:8][C@@H:9]([C@H:11]([C@@H:13]([C@@H:15]([CH2:17][OH:18])[OH:16])[OH:14])[OH:12])[OH:10]>O>[C:1]([NH:7][CH2:8][C@@H:9]([C@H:11]([C@@H:13]([C@@H:15]([CH2:17][OH:18])[OH:16])[OH:14])[OH:12])[OH:10])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(O)C(=O)O
Solvent: O
Product: CC(O)C(=O)NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 120 °C

Procedure:
Equimolar quantities of lactic acid and glucamine were mixed together. This mixture was then heated at 120° C. for 2 hours and the resulting water of reaction was continuously removed. The final product was a viscous, amber colored liquid.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].Br[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=1>CN1CCCC1=O.O>[CH2:28]([O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:22][CH:23]=1)[CH3:29]
Reactant: CCOc1ccc(CCBr)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOc1ccc(CCn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 10 %

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 0.001 mol) was dissolved in N-methyl 2-pyrolidone (3.0 mL). Powdered potassium hydroxide (0.448 g, 0.008 mol) was added and heated at 120° C. for 2 h. 1-(2-Bromo-ethyl)-4-ethoxy-benzene (0.228 g, 0.001 mol) was added at the same temperature and stir for 3 h. at RT (TLC showed incomplete reaction). Reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×100 mL). Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (4% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide the desired compound as light yellow oil (0.035 g, 10% yield). 5-[2-(4-Ethoxy-phenyl)-ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.035 g, 0.0001 mol) was dissolved in THF (0.5 mL), A solution of oxalic acid dihydrate (0.013 g, 0.0001 mol) in THF (0.5 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as off white solid (0.015 g, 34% yield).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:16])[CH:8]=[CH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[O:22]=[C:20]1[C:19]2[C:18](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17](=[O:27])[N:21]1[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:16])[CH:8]=[CH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(C=Cc1cccnc1)NCCCCO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: O=C(C=Cc1cccnc1)NCCCCN1C(=O)c2ccccc2C1=O

Procedure:
Batch size: 7.8 g (35.4 mmol) N-(4-hydroxybutyl)-3-pyridin-3-yl-acrylamide, 9.3 g (35.4 mmol) tripdhenylphosphine, 5.2 g (35.4 μmmol) phthalimide and 6.2 g (35.4 mmol) azodicarboxylic acid diethyl ester in 100 ml THF.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C:5]1[N:6]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]2[CH2:17][CH:18]([CH3:20])[CH3:19].S([O-])(O[O-])(=O)=[O:33].[K+].[K+].OOS([O-])=O.[K+]>CO.O>[OH:1][CH2:2][CH2:3][S:4]([C:5]1[N:6]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]2[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:33]
Reactant: O=S(=O)([O-])O[O-]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCO)n(Cc3cccc4ccccc34)cc21
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(S(=O)CCO)n(Cc3cccc4ccccc34)cc21
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-(2-hydroxyethyl)thio-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (100 mg) in methanol (20 ml) was added potassium peroxymonosulphate (commercially sold under the trade mark "OXONE") (300 mg) in water (10 ml). After stirring for 10 minutes the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were dried over magnesium sulphate and concentrated in vacuo. Chromatography on silica gel (ethyl acetate) gave the title compound (70 mg) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35]([OH:39])[CH:34]=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>C(Cl)Cl>[OH:39][C:35]1[CH:34]=[C:33]([NH:32][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])[CH:38]=[CH:37][N:36]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1ccnc(O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccnc(O)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.49 g, 1.1 mmol) was reacted with 4-amino-pyridin-2-ol (Molbridge) (0.14 g, 1.3 mmol), HATU (0.72 g, 1.9 mmol) and iPr2NEt (0.46 mL, 2.6 mmol) in CH2Cl2 at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-hydroxy-pyridin-4-yl)-amide as a off white solid (20 mg, 3.4%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[C:10]=2F)[C:5](=[S:8])[S:6][CH:7]=1.[CH3:18][NH2:19]>C(#N)C.CO>[CH3:18][N:19]1[C:10]2[C:9](=[CH:14][CH:13]=[C:12]([F:15])[C:11]=2[F:16])[N:4]2[C:5](=[S:8])[S:6][CH:7]=[C:3]2[CH2:2]1
Reactant: CN
Reactant: Fc1ccc(-n2c(CCl)csc2=S)c(F)c1F
Solvent: CO
Solvent: CC#N
Product: CN1Cc2csc(=S)n2-c2ccc(F)c(F)c21
Temperature: 50 °C
Reaction time: 16 h

Procedure:
4-Chloromethyl-3-(2,3,4-trifluorophenyl)-2(3H)-thiazolethione (2.5 g) is dissolved in acetonitrile (25 ml) and thereto is added 40% solution of methylamine in methanol (3.3 g), and the mixture is stirred at 50° C. for 16 hours. The reaction mixture is evaporated to dryness under reduced pressure, and water is added to the residue and the mixture is extracted with chloroform. The extract is washed with saline solution, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue is recrystallized from cyclohexane-ethyl acetate to give the title compound (2.0 g) as yellow crystals.
Reaction SMILES: [CH2:1]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([NH:12][NH2:13])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[CH2:23]([S:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29])[CH3:24]>C(Cl)Cl>[CH2:23]([S:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:13][NH:12][C:10](=[O:11])[C:9]1[CH:8]=[CH:7][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:15][CH:14]=1)=[O:29])[CH3:24]
Reactant: CCCCCc1ccc(C(=O)NN)cc1
Reactant: CCSc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCc1ccc(C(=O)NNC(=O)c2ccccc2SCC)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of 4-pentylbenzohydrazide (1-C) (206 mg, 1.0 mmol) and triethylamine (153 μL, 1.1 mmol) in methylene chloride (5 mL) was added a solution of 2-(ethylthio)benzoyl chloride (1-B) (210 mg, 1.0 mmol) in methylene chloride (2.0 mL). After stirring at room temperature for 18 h, the mixture was diluted with methylene chloride and washed with water, 10% NaHCO3, brine, dried (MgSO4) and evaporated in vacuo to give 2-(ethylthio)-N′-(4-pentylbenzoyl)benzohydrazide (1-D). MS m/z 371 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16]([O:18][CH2:19][CH2:20]Br)[CH3:17].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH2:16][O:18][CH2:19][CH3:20])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1O
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCOc1ccc(Br)cc1C
Temperature: 70 °C
Reaction time: 4.5 h
Yield: 82.3 %

Procedure:
To a solution of 4-bromo-2-methylphenol (9.3 g) in DMF (50 ml) was added potassium carbonate (9.62 g) and then was added dropwise 2.-bromoethyl ethyl ether (7.99 g), and the mixture was stirred at 70° C. for 3 days. To the mixture was added dropwise 2-bromoethyl ethyl ether (1.52 g), and the mixture was stirred at 70° C. for 4.5 hours and cooled. To the mixture was added water, and the mixture was extracted with ether. The organic layer was washed with 1N sodium hydroxide solution and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was distilled under reduced pressure (3 mmHg, 170° C.) to give colorless oil of 4-bromo-2-methyl-(2-ethoxyethoxy)benzene (10.6 g).
Reaction SMILES: [C:1]([O:10]C)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].ClCC1C=CC(CCl)=CC=1.[OH-].[Na+].O>C1(C)C=CC=CC=1>[C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: COC(=O)c1ccccc1O
Agent: ClCc1ccc(CCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1ccccc1O
Temperature: 105 °C
Reaction time: 2 h

Procedure:
In a reactor equipped with a thermometer and a stirrer, 913 parts of methyl salicylate were charged, followed by heating to 100-110° C. At the same temperature, 525 parts of α,α'-dichloro-p-xylene were charged in portions over 5 hours. The resulting mixture was subjected to aging at 150° C. for 2 hours. The pressure of the reactor was reduced to 10 mmHg by a pump and unreacted methyl salicylate was separated for reuse at 150-180° C. After allowed to cool down to 100° C., 350 ml of toluene were added to the residue, whereby a toluene solution of a salicylic acid ester resin was obtained. In a reactor equipped with a thermometer and a stirrer, 160 parts of caustic soda and 907 parts of water were charged, followed by the dropwise addition of the above-obtained toluene solution at 85-90° C. over 4 hours. The temperature was raised to 100° C. so that the toluene was distilled off. After removal of insoluble matter, the residue was neutralized with 2,250 parts of an 8% aqueous solution of hydrochloric acid. The solid so precipitated was collected by filtration, washed with water and dried, whereby a salicylic acid resin was obtained in a yield of 705 parts. In a reactor equipped with a thermometer and a stirrer, 100 parts of the salicylic acid resin obtained above [composition (area %) according to a GPC analysis: 51.1% l=0, 22.3% l=1, 20.3% l=2, 4.3% l≥3, 1.0% others; number-average molecular weight: 543], 33.5 parts of benzyl chloride, 400 parts of 1,1,2-trichloroethane and 0.4 part of zinc chloride were charged, followed by reaction at 110° C. for 3 hours. After completion of the reaction, 1,000 parts of water were added and the 1,1,2-trichloroethane was azeotropically distilled off. The solid so precipitated was collected by filtration and dried, whereby 121 parts of an aralkylated salicylic acid resin were obtained. The resin was found to have a number-average molecular weight of 641 and a carboxylic acid equivalent of 251 g/eq.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([N:18]=2)[C:16]2[CH:19]=[C:20]([C:23](O)=[O:24])[CH:21]=[CH:22][C:15]=2[O:14][CH2:13][CH2:12]3)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH2:69][CH2:70][C:71]([CH3:74])([OH:73])[CH3:72]>CN(C=O)C>[OH:73][C:71]([CH3:74])([CH3:72])[CH2:70][NH:69][C:23]([C:20]1[CH:21]=[CH:22][C:15]2[O:14][CH2:13][CH2:12][C:11]3[N:17]([N:18]=[C:9]([C:8]4[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6][N:7]=4)[CH:10]=3)[C:16]=2[CH:19]=1)=[O:24]
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)O)ccc1OCC2
Reactant: CC(C)(O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)NCC(C)(C)O)ccc1OCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.3 %

Procedure:
2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylic acid (0.2 g, 0.59 mmol) was suspended in DMF (5 mL) and DIPEA (0.21 mL, 1.2 mmol) added. The resultant solution was treated with HATU (0.23 g, 0.6 mmol) and HOBT (81 mg, 0.6 mmol) before the addition of 1-amino-2-methyl-propan-2-ol (52.5 mg, 0.59 mmol) then stirred for 18 h at RT. The reaction mixture was concentrated in vacuo and the resultant residue partitioned between DCM and water. The aqueous layer was extracted three times with DCM and the combined organic extracts washed with water, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in ethyl acetate) and recrystallistion from ethyl acetate to give 116 (163 mg, 67%). 1H NMR (CDCl3, 400 MHz): δ 8.46 (d, J=2.2 Hz, 1H); 7.94 (s, 1H); 7.72 (dd, J=8.4, 2.2 Hz, 1H); 7.22 (d, J=8.4 Hz, 1H); 6.86 (s, 1H); 6.66 (s, 1H); 5.74-5.61 (m, 1H); 4.57 (t, J=5.7 Hz, 2H); 3.50 (d, J=5.9 Hz, 2H); 3.22 (t, J=5.7 Hz, 2H); 2.18 (s, 1H); 1.59 (d, J=6.6 Hz, 6H); 1.31 (s, 6H). LCMS: RT=9.53 min, M+H+=411
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[N:15]=[C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:17][C:18]=1[CH3:19])[CH:5]=[CH:6][CH:7]=O.[O:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][CH2:7][CH:30]2[O:26][C:27](=[O:32])[NH:28][C:29]2=[O:31])[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[N:15]=[C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:17][C:18]=1[CH3:19]
Reactant: O=C1COC(=O)N1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(C=CC=O)cc1F
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCCC2OC(=O)NC2=O)cc1F

Procedure:
In substantially the same manner as in Working Example 11, 3-fluoro-4-(5-methyl-2-phenyl-4-oxazolyl methoxy)cinnamaldehyde was condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic reduction to yield 5-[3-[3-fluoro-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-2,4-oxazolidinedione, which was recrystallized from dichloromethane-methanol to give colorless prisms, m.p.180-181° C.