Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=CC=1.NC1C(C2C=CC=CC=2[F:35])=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C1(N)CCC1>C(O)(=O)C>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=4[F:35])[C:10]=3[N:9]=[CH:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Agent: NC1CCC1
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3F)c2ncn1C1CCC1
Yield: 91.7 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (100 mg, 0.40 mmol), triethyl orthoformate (1.0 ml), cyclobutylamine (0.065 ml, 0.76 mmol), and acetic acid (0.1 ml) were used to give 110.2 mg (0.37 mmol, 91.7% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]C)=[O:6].C([Si](Cl)(C)C)(C)(C)C.N1C=CN=C1>CN(C)C=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cccc(O)c1
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(O)c1
Reaction time: 10 h

Procedure:
Into a 250 mL round bottom flask was added 50 mL of dry dimethyl formamide. Ffifteen parts of the hydroxy benzoate (27) and seventeen parts of tert-butyldimethyl silyl chloride were added to the reaction flask with stirring. Seventeen parts of Imidazole was added in portions and stirring was continued for 10 hours. The reaction mixture was extracted with (3×300 mL) of hexane and the hexane layer was washed twice with 250 mL of water. The organic layer was dried on anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give an oil, yield 26 parts. This material was pure enough for the next step of the reaction. The material was prepared according to the following equation:
Reaction SMILES: [Cl:1][C:2]1[O:6][C:5]([C:7]([NH2:9])=[O:8])=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>>[Cl:1][C:2]1[O:6][C:5]([C:7]2[O:8][CH:14]=[C:12]([CH2:11][Cl:10])[N:9]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Cl)o1
Reactant: O=C(CCl)CCl
Product: ClCc1coc(-c2ccc(Cl)o2)n1
Yield: 24 %

Procedure:
In substantially the same manner as in Reference Example 47, 5-chloro-2-furancarboxamide was allowed to react with 1,3-dichloroacetone to give 2-(5-chloro-2-furyl)-4-chloromethyloxazole. The yield was 24%. Recrystallization from diethyl ether-hexane gave colorless prisms, mp 107-108° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23](O)[CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH3:29])=[CH:17][C:16]=2[F:31])=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].O1C(CCOCCC)C1.C(O)(=O)C(CC(O)=O)O.C(OC1C=NC(C2C=CC(O)=CC=2[F:71])=NC=1)CCCCCC.CCN(S(F)(F)F)CC>C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]([F:71])[CH2:24][CH2:25][O:26][CH2:27][CH2:28][CH3:29])=[CH:17][C:16]=2[F:31])=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1cnc(-c2ccc(O)cc2F)nc1
Reactant: CCCCCCCOc1cnc(-c2ccc(OCC(O)CCOCCC)cc2F)nc1
Agent: CCCOCCC1CO1
Agent: CCN(CC)S(F)(F)F
Agent: O=C(O)CC(O)C(=O)O
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CCCCCCCOc1cnc(-c2ccc(OCC(F)CCOCCC)cc2F)nc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 0.1 mol of 5-heptyloxy-2-(4-(2-hydroxy-5-oxaoctyloxy)-2-fluorophenyl)pyrimidine (prepared by heating optically active 1,2-epoxy-5-oxaoctane, obtainable from malic acid, with 5-heptyloxy-2-(4-hydroxy-2-fluorophenyl)pyrimidine in the presence of dry potassium carbonate and methyl ethyl ketone as solvent) in methylene chloride is cooled to -40° C. and 0.11 mol of DAST is added to it dropwise with moisture being excluded. The reaction mixture is then stirred for 12 hours while heating slowly to room temperature. Then hydrolysis is carried out with ice cooling and the reaction mixture is washed with dilute sodium hydroxide solution and several times with water. After drying over magnesium sulfate, the solvent is removed on a rotary evaporator and the crude product is purified chromatographically and by crystallization. Optically active 5-heptyloxy-2-(4-(2-fluoro-5-oxaoctyloxy)-2-fluorophenyl)pyrimidine is obtained.
Reaction SMILES: [Cl:1]([O:5][CH:6]([CH2:12][C:13](=[O:15])[O-:14])[CH2:7][N+:8]([CH3:11])([CH3:10])[CH3:9])(=[O:4])(=[O:3])=[O:2].[CH2:16]([O:18][CH2:19][CH2:20][C:21](Cl)=[O:22])[CH3:17].C(Cl)(Cl)Cl.CO.O.[NH4+].[OH-].C(OCC)C>CC#N.CC(C)=O>[Cl:1]([O:5][C:6]([C:21](=[O:22])[CH2:20][CH2:19][O:18][CH2:16][CH3:17])([CH2:12][C:13](=[O:14])[O-:15])[CH2:7][N+:8]([CH3:11])([CH3:9])[CH3:10])(=[O:2])(=[O:4])=[O:3]
Reactant: CCOCCC(=O)Cl
Reactant: C[N+](C)(C)CC(CC(=O)[O-])O[Cl+3]([O-])([O-])[O-]
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(C)=O
Solvent: O
Product: CCOCCC(=O)C(CC(=O)[O-])(C[N+](C)(C)C)O[Cl+3]([O-])([O-])[O-]
Temperature: 0 °C
Reaction time: 48 h

Procedure:
3.9 g (0.015 moles) of carnitine perchlorate were dissolved in 50 cc of anhydrous CH3CN. To this solution 3-ethoxypropionyl chloride was added dropwise with a dropping funnel while cooling to about 0° C. with an ice bath. The reaction mixture was allowed to stand for 48 hours at room temperature (TLC chloroform-methanol-water-NH4OH 55:35:5:5). During this period of time a stream of nitrogen was blown into the reaction mixture at intervals of about 5 minutes, in order to remove the hydrochloric acid formed during the reaction. The reaction mixture was slowly poured into 300 cc of ethyl ether. A precipitate was thus obtained which was taken up with anhydrous acetone and the resulting solution was allowed to stand for some hours. The solution was filtered and ethyl ether was added thereto and a precipitate formed. The precipitate dried under vacuum presented the appearence of a transparent and viscous oil which consisted of 3-ethoxypropionyl carnitine perchlorate.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:32][CH2:31][N:30]3[C:23](=[CH:24][C:25]4[CH2:26][C:27]([CH3:34])([CH3:33])[CH2:28][C:29]=43)[C:22]2=[O:35])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH2:18])[C:15](=[O:19])[N:14]([CH3:20])[CH:13]=1)(=O)C.[Li+].[OH-]>CC(O)C.C1COCC1.O>[NH2:18][C:16]1[C:15](=[O:19])[N:14]([CH3:20])[CH:13]=[C:12]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([N:21]3[CH2:32][CH2:31][N:30]4[C:23](=[CH:24][C:25]5[CH2:26][C:27]([CH3:33])([CH3:34])[CH2:28][C:29]=54)[C:22]3=[O:35])[C:6]=2[CH2:5][OH:4])[CH:17]=1
Reactant: CC(=O)OCc1c(-c2cc(N)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2CO)cc(N)c1=O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
A mixture of 103c (1.1 g, 2.3 mmol) and LiOH (450 mg, 11.0 mmol) in iPrOH/THF (1:1, 10 mL) and H2O (2.5 mL) was stirred at 40° C. for 0.5 h. The mixture was evaporated in vacuo. The residue was partitioned between EtOAc and water. The combined EtOAc extract was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 10:1 dichloromethane/methanol to afford 103d (350 mg, 36%) as a pale yellow solid. MS-ESI: [M+H]+ 434.3. 1H NMR (500 MHz, CDCl3) δ 8.44 (d, J=5.0 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 7.21 (d, J=5.0 Hz, 1H), 6.83 (s, 1H), 6.82 (d, J=2.0 Hz, 1H), 5.04-5.03 (m, 1H), 4.63-4.62 (m, 1H), 4.50-4.48 (m, 1H), 4.30-4.28 (m, 1H), 4.16-4.10 (m, 3H), 3.87-3.85 (m, 1H), 3.65 (s, 3H), 2.57-2.56 (m, 2H), 2.50 (s, 2H), 1.26 (s, 6H).
Reaction SMILES: [CH2:1]([NH2:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:34])[C:15]2[O:21][C:20]3[C:22]([Cl:30])=[CH:23][C:24]([NH:26][CH2:27][CH2:28]Cl)=[CH:25][C:19]=3[CH2:18][S:17](=[O:32])(=[O:31])[C:16]=2[CH:33]=1)=[O:11]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:34])[C:15]2[O:21][C:20]3[C:22]([Cl:30])=[CH:23][C:24]([NH:26][CH2:27][CH2:28][NH:7][CH2:1][C:2]4[O:6][CH:5]=[CH:4][CH:3]=4)=[CH:25][C:19]=3[CH2:18][S:17](=[O:31])(=[O:32])[C:16]=2[CH:33]=1)=[O:11]
Reactant: NCc1ccco1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCNCc3ccco3)cc(Cl)c1O2
Temperature: 110 °C
Reaction time: 5 h

Procedure:
Freshly distilled furfurylamine (0.58 g, 0.60 mmol) and tetrabutylammonium iodide (0.010 g, 0.027 mmol) were sequentially added with stirring to a solution of Example 56k (0.5 g, 1.20 mmol) in dry methanol (10 mL). The reaction mixture was stirred at 110° C. for 5 h in an atmosphere of nitrogen. It was concentrated, treated with methanolic HCl solution (15 mL), refluxed overnight, concentrated, treated with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.438 g, (84.88%); 1H NMR (DMSO-d6): δ 1.70 (s, 2H, CH2), 2.30 (m, 6H, 3CH2), 2.65 (s, 3H, CH3), 3.05 (q, 2H, CH2), 3.60 (t, 2H, CH2), 3.90 (s, 3H, OCH3), 5.10 (s, 2H, CH2), 6.25 (t, 1H, NH), 6.70 (s, 1H, Ar), 6.70 (s, 1H, Ar), 8.10 (s, 1H, Ar), 8.15 (s, 1H, Ar); MS (CI+): m/e (ES+) 490 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].C(N(CC)C(C)C)(C)C.[CH2:20]([SH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Pd+2].ClC1C=C[C-](P(C(C)(C)C)C(C)(C)C)C=1Cl.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[CH2:20]([S:27][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: SCc1ccccc1
Reactant: N#Cc1cc(Br)ccc1F
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(C)(C)P([c-]1ccc(Cl)c1Cl)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(SCc2ccccc2)ccc1F
Temperature: 60 °C
Yield: 50.8 %

Procedure:
To a degassed solution of 5-bromo-2-fluorobenzonitrile (10 g, 50 mmol) in toluene (250 mL) was added N,N-diisopropylethylamine (26 mL, 150 mmol), benzyl mercaptan (5.87 mL, 52 mmol) and dichloro[1,1′ bis(di-tert-butylphosphino)]ferrocene palladium (II) (500 mg, 1 mmol). The reaction mixture was heated at 60° C. for 16 hours. The reaction mixture was diluted to 500 mL volume with ethyl acetate and washed with dilute brine (300 mL), then 2N HCl (2×300 mL) and finally dilute brine (300 mL). The combined organic layers were dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified using silica gel column chromatography eluting with 10% ethyl acetate in heptane to afford the title compound as light brown solid (6.18 g, 51%)
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[O:5][C:4](=[O:13])[CH:3]=1.[H-].[Na+].[CH3:16]I>CN(C)C=O.C(OCC)(=O)C.[NH4+].[Cl-]>[CH3:16][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[O:5][C:4](=[O:13])[CH:3]=1
Reactant: CI
Reactant: Cc1ccc2oc(=O)cc(O)c2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(=O)oc2ccc(C)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
To a solution of 4-hydroxy-6-methylcoumarin (300 mg, 1.70 mmol) in 3.4 mL of dry N,N-dimethylformamide was added sodium hydride (89 mg, 55%, 2.0 mmol) under nitrogen at 0° C. After the reaction mixture was stirred at room temperature for 30 min, methyl iodide (0.16 mL, 2.6 mmol) was added with additional stirring for 30 min. The reaction mixture was diluted with 10 mL of ethyl acetate and 10 mL of saturated NH4Cl aqueous solution at 0° C., successively, and the solution was extracted with 100 mL of ethyl acetate. The extract was washed with saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the solution was concentrated in vacuo to obtain crude 4-methoxy-6-methylcoumarin (140 mg, 43%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][S:23][CH2:22][CH2:21]2)=[C:12]([NH2:26])[CH:11]=1)=[O:5].[C:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=O)=[CH:32][CH:31]=1)#[N:29]>C(O)(=O)C>[C:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34]2[N:16]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][S:23][CH2:22][CH2:21]3)[C:13]3[CH:14]=[CH:15][C:10]([C:9]([NH:8][CH2:7][CH2:6][C:4]([O:3][CH3:2])=[O:5])=[O:27])=[CH:11][C:12]=3[N:26]=2)=[CH:32][CH:31]=1)#[N:29]
Reactant: COC(=O)CCNC(=O)c1ccc(NCCCN2CCSCC2)c(N)c1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C#N)cc1)n2CCCN1CCSCC1
Temperature: 120 °C

Procedure:
48.6 g of 3-amino-4-(3-thiomorpholino-propylamino)-benzoic acid-[N-(2-methoxycarbonyl-ethyl)-amide]-hydrochloride are dissolved in 500 ml of glacial acetic acid with heating, 19.5 g of 4-cyano-benzoylchloride are added, the mixture is heated for one hour over a steam bath and a further 2 hours at a bath temperature of 120° C. The mixture is evaporated down in vacuo and the residue is purified by chromatography on silica gel (eluant:methylene chloride/methanol/conc. ammonia=9:1:0 to 8:2:0.2). Yield: 33.7 g (58% of theory), Rf value: 0.84 (silica gel; methylene chloride/methanol/conc. ammonia=19:1:0.1, after developing three times)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[O:24][CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:25][C:26](=O)[CH2:27][CH3:28].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1COCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@H:19]3[O:24][CH2:23][CH2:22][N:21]([C@H:26]([CH3:25])[CH2:27][CH3:28])[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(Nc1ccc(F)c(Cl)c1)N1CCN(C[C@H]2CNCCO2)CC1
Reactant: CCC(C)=O
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC[C@@H](C)N1CCO[C@H](CN2CCN(C(=O)Nc3ccc(F)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 13.1 %

Procedure:
To a stirred solution of N-(3-chloro-4-fluorophenyl)-4-[(2R)-morpholin-2-ylmethyl]piperazine-1-carboxamide (300 mg, 0.84 mmol) and 2-butanone (0.16 ml, 1.12 mmol) in THF:DCM, 1:1 (8 ml), was added titanium tetraisopropoxide (1.99 ml, 6.72 mmol) and the reaction stirred at ambient temperature for 3 hours. Sodium tris-acetoxyborohydride (356 mg, 1.68 mmol) was added and the reaction stirred overnight. 2M NaOH was then added and the cloudy mixture filtered through celite. The filtrate was then extracted with EtOAc (×2), organics dried (Na2SO4), filtered and evaporated to a yellow oil. This was then purified by reverse phase HPLC using basic modifier to give the product as a yellow gum (42 mg, 0.11 mmol, 13% yield).
Reaction SMILES: C(ON)C.[CH2:5]([O:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1F)[CH3:6].[S-2:18].[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:5]([O:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[SH:18])[CH3:6]
Reactant: [S-2]
Reactant: CCOC(=O)c1cccc(F)c1F
Agent: CCON
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(F)c1S
Reaction time: 10 h

Procedure:
Example 37(a) was prepared in a similar manner to that described for Example 35(a) except that the starting material described below was employed and that ethoxyamine was used instead of propylamine: 1H NMR (300 MHz, CDCl3) δ 8.59 (m, 1H), 8.08 (d, 1H), 7.88 (d, 1H, J=16.4 Hz), 7.79 (t, 1H), 7.65 (d, 1H), 7.60 (m, 1H), 7.50 (d, 1H, J=16.4 Hz), 7.40 (t, 1H), 7.36 (d, 1H), 7.28 (s, 1H), 7.23 (m, 1H), 7.10 (d, 1H), 3.90 (q, 2H), 1.19 (t, 3H). LCMS (100% area) Rt=4.85 min, (pos) [M+H]/z Calc'd 435.1, found 435.1, (neg) [M−H]/z Calc'd 433.1, found 433.1. Analyzed with 0.35H2O, 0.07 EtOAc Calc'd, C (62.56), H (4.57), N (12.54), S (7.17). Found: C (62.61), H (4.55), N (12.49), S (7.11). Starting material was prepared as follows: A solution of ethyl-2,3 difluorobenzoate (1.07 g, 5.75 mmol) in DMF (10 mL) was treated with sodium sulfide (896 mg, 11.5 mmol, 2.0 equiv) at 23° C. The mixture was stirred under argon for 10 h. The solution was diluted with ethyl acetate (50 mL) and water (50 mL) and 10% citric acid (5 mL). The organic layer was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, decanted and concentrated under reduced pressure to give 3-Fluoro-2-mercapto-benzoic acid ethyl ester. 1H NMR (300 MHz, CDCl3)57.71 (t, 1H), 7.38 (m, H), 7.12 (m, 1H), 4.41 (q, 2H), 1.40 (t, 3H); LCMS (100% area) Rt=4.53 min, (pos) [M+H]/z Calc'd 201.0, found 200.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:14](=O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:7]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1>>[CH3:1][O:2][C:3]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH2:7]1
Reactant: COc1ccc(CN2C(=O)c3cccc(OCCCN4CCOCC4)c3C2=O)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN2Cc3cccc(OCCCN4CCOCC4)c3C2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
2-(2,4-Dimethoxy-benzyl)-4-(3-morpholin-4-yl-propoxy)-isoindole-1,3-dione (298 mg, 0.68 mmol) was treated with a 1M solution of lithium aluminium hydride in THF (5 mL, 5 mmol) and maintained at r.t. for 21 hours. The mixture was heated to 75° C. for 1 hour then cooled in ice and quenched by the dropwise addition of water (0.2 mL), 2N sodium hydroxide solution (0.4 mL) and water (0.4 mL). Magnesium sulfate was added, followed by ethyl acetate and then the mixture was stirred at r.t. for 1 hour. The solids were removed by filtration, being well washed with ethyl acetate. Concentration of the filtrate gave a crude product which was purified by flash chromatography on silica, eluting with 5% methanol in DCM. This afforded the title compound (233 mg, 83%) as a red oil. 1H NMR (methanol-d4) 7.24 (1H, d), 7.15 (1H, t), 6.80 (1H, d), 6.78 (1H, d), 6.56 (1H, d), 6.52 (1H, dd), 4.05 (2H, t), 3.94 (2H, s), 3.88 (2H, s), 3.87 (2H, s), 3.83 (3H, s), 3.80 (3H, s), 3.70-3.68 (4H, m), 2.54-2.50 (2H, m), 2.49-2.47 (4H, m), 2.00-1.93 (2H, m). MS: [M+H]+ 413.
Reaction SMILES: C(Br)C.[Mg].Cl[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:8][CH:7]=1.Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].[Cl-].[NH4+]>[Ni](Cl)Cl.C1COCC1>[CH3:14][C:13]([CH3:15])=[CH:12][C:9]1[CH:10]=[CH:11][C:6]([CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7][CH:8]=1
Reactant: CC(C)=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)Br
Agent: Cl[Ni]Cl
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Product: CCOC(=O)C(C)c1ccc(C=C(C)C)cc1
Temperature: 115 °C
Reaction time: 1 h
Yield: 36.6 %

Procedure:
Under an atmosphere of nitrogen, 0.1 g of ethyl bromide was added to a solution composed of 0.27 g of magnesium turnings for Grignard reaction, 1.67 g of p-chloro-(2-methyl-1-propenyl)benzene and 1 ml of THF. After the starting of the reaction, the mixture was heated to 115° C. THF was added little by little so as to maintain the temperature in the range of 110° to 120° C., and the mixture was maintained at this temperature for 4 hours. After cooling, 5 ml of THF was added. The resulting Grignard reagent solution was added dropwise to a solution composed of 1.81 g of ethyl α-bromopropionate, 0.013 g of nickel chloride and 4 ml of THF. After the addition, the mixture was stirred for 1 hour, and an aqueous solution of ammonium chloride was added. The mixture was extracted with diethyl ether. The ethereal extract was washed with an aqueous solution of sodium chloride, dried, and concentrated. The concentrate was purified by silica gel column chromatography to give 0.85 g (yield 36.6%) of ethyl α-[p-(2-methyl-1-propenyl)phenyl]propionate having the following NMR spectrum.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][C@@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:21]=2[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]3[NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([Cl:32])[C:26]=2[F:33])[CH2:7][C@@H:6]1[C:34]([O:36]C)=[O:35])(=[O:4])[CH:2]=[CH2:3].O.[OH-].[Li+]>O1CCCC1.CO>[C:1]([N:5]1[CH2:10][CH2:9][C@@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:21]=2[O:22][CH3:23])[N:18]=[CH:17][N:16]=[C:15]3[NH:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([Cl:32])[C:26]=2[F:33])[CH2:7][C@@H:6]1[C:34]([OH:36])=[O:35])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)N1CC[C@@H](Oc2cc3c(Nc4ccc(F)c(Cl)c4F)ncnc3cc2OC)C[C@@H]1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=CC(=O)N1CC[C@@H](Oc2cc3c(Nc4ccc(F)c(Cl)c4F)ncnc3cc2OC)C[C@@H]1C(=O)O
Reaction time: 1 h
Yield: 68.5 %

Procedure:
15 mg of the compound obtained in Example 133 was dissolved in 0.2 ml of a mixed solvent of tetrahydrofuran and methanol (1:1), and 1.4 mg of lithium hydroxide monohydrate was added thereto at 0° C. The resulting mixture was incubated at room temperature for one hour. After the reaction terminated, the resulting solution was acidified to pH 4 with a 3N HCl and extracted twice with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure. The resulting residue was purified by column chromatography (methylene chloride:ethyl acetate:methanol=1:1:1) to obtain the title compound (10 mg, 69%).
Reaction SMILES: N[C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.[N+]([O-])([O-])=O.[Na+].[ClH:20]>O>[Cl:20][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: Cl
Reactant: Nc1ccc(C(=O)O)c2c1OCCO2
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(Cl)c2c1OCCO2
Temperature: 40 °C
Yield: 62 %

Procedure:
29.3 g of 8-amino-1,4-benzodioxane-5-carboxylic acid, 120 ml of water and 30 ml of hydrochloric acid were introduced into a balloon flask provided with an agitator and a thermometer. The mixture was heated to 40° C. and then cooled to 5° C. and a solution of 10.5 g of sodium nitrate in 20 ml of water was added in portions with the temperature being maintained at from 5°-10° C. The mixture was agitated and then poured into a solution of 12 g of cuprous chloride in 45 ml of hydrochloric acid (d=1.18) with the temperature being maintained below 30° C. The precipitate was dried off, washed in 300 ml of water and 25 g of sodium bicarbonate. The solution was filtered and treated with hydrochloric acid. The precipitate was dried off, washed with water and dried. 20 g of 8-chloro-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 195° C.; yield 62%).