Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](CCl)=[N:8][C:9]2[C:14]([C:15]=1C1C=CC(OC)=C(OC)C=1)=[CH:13][C:12](OC)=[C:11](OC)[CH:10]=2)=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=[O:40])C=1>CO>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N+:8]([O-:40])[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Solvent: CO
Product: CCOC(=O)c1cc2ccccc2[n+]([O-])c1
Reaction time: 2 h
Yield: 136.8 %

Procedure:
A mixture of 2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylic acid ethyl ester (3.0 g), m-chloroperbenzoic acid (85%, 2.3 g) and methanol (40 ml) was stirred under refluxing conditions for 2 hours. The reaction mixture was distilled under reduced pressure to remove the solvent. The residue was poured over chloroform. The chloroform layer was washed with water and dried (MgSO4), after which the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with chloroform-ethyl acetate (6:4, v/v) to yield 2-chloromethyl-6,7-dimethoxy-4-3,4-dimethoxyphenyl)quinoline-3-carboxylic acid ethyl ester 1-oxide (2.0 g, 65%), which was then recrystallized from acetone-isopropyl ether to yield a colorless prismatic crystal having a melting point of 193 to 194° C.
Reaction SMILES: CN1CCOCC1.CN(C1C=CC=CN=1)C.[C:17]([NH:21][C:22]([C:24]1[O:28][N:27]=[C:26]([CH:29]([CH3:31])[CH3:30])[C:25]=1[C:32]([OH:34])=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>ClCCl.C(OCC)(=O)C>[C:17]([N:21]1[C:22](=[O:23])[C:24]2[O:28][N:27]=[C:26]([CH:29]([CH3:31])[CH3:30])[C:25]=2[C:32]1=[O:34])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)c1noc(C(=O)NC(C)(C)C)c1C(=O)O
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)c1noc2c1C(=O)N(C(C)(C)C)C2=O
Yield: 86.8 %

Procedure:
7.5 g (74.1 mmol) of methylmorpholine, 2.4 g (20 mmol) of dimethylaminopyridine and 17.4 g of a 50% strength solution of propanephosphonic anhydride (27.3 mmol) in dichloromethane were added dropwise in succession to 5.1 g (20 mmol) of 5-tert-butylaminocarbonyl-3-isopropylisoxazole-4-carboxylic acid in 200 ml of dichloromethane at -5° C., and the mixture was then refluxed for 6 hours. The solvent was stripped off under reduced pressure, the residue was taken up in 300 ml of ethyl acetate and the solution was extracted twice with saturated sodium bicarbonate solution and once each with 5% strength citric acid solution, saturated sodium carbonate solution and saturated sodium chloride solution. The organic phase was dried and the solvent was stripped off under reduced pressure. 4.1 g (87%) of N-tert-butyl-3-isopropylisoxazole-4,5-dicarboximide were obtained as a solid of melting point 60°-62° C. (Example No. 1.003).
Reaction SMILES: O[CH2:2][N:3]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]1=[O:15].P(Cl)(Cl)[Cl:17]>CC(C)=O>[Cl:17][CH2:2][N:3]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]1=[O:15]
Reactant: O=C1C=C(c2ccccc2)C(=O)N1CO
Reactant: ClP(Cl)Cl
Solvent: CC(C)=O
Product: O=C1C=C(c2ccccc2)C(=O)N1CCl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 200 ml of acetone was suspended 20.3 g of N-hydroxymethyl-α-phenylmaleimide and then 4.6 ml of phosphorus trichloride was added in one portion at room temperature. After the mixture was stirred for 30 minutes, 5.0 ml of phosphorus trichloride was further added. After stirring for another one hour, the reaction solution was poured into ice-water and the crystals thus separated were collected by filtration. The crude crystal was dried under reduced pressure and then recrystallized from n-theptane/ethyl acetate to afford 12.1 g of N-chloromethyl-α-phenylmaleimide.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([O:10][C:11]2[CH:12]=[CH:13][CH:14]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:15]3[C:19]=2[N:18]=[C:17]2[CH2:20][CH2:21][CH2:22][CH:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=4)[C:16]=32)=[CH:8][CH:9]=1)=[O:4].C(C1C2C(=NC3C=2C(CCCCCCCC)C=CC=3OC2OC(C(O)=O)=CC=2)CCC1)CCCCCCC>>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([CH:23]2[C:16]3[C:17](=[N:18][C:19]4[C:15]=3[CH:14]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:13]=[CH:12][C:11]=4[O:10][C:7]3[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=3)[CH2:20][CH2:21][CH2:22]2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCCCCCCCC1C=CC(Oc2ccc(C(=O)OC)o2)=C2N=C3CCCC(c4cccc(OC)c4)C3=C21
Agent: CCCCCCCCC1C=CC(Oc2ccc(C(=O)O)o2)=C2N=C3CCCC(CCCCCCCC)C3=C21
Product: CCCCCCCCC1C=CC(Oc2ccc(C(=O)O)o2)=C2N=C3CCCC(c4cccc(OC)c4)C3=C21

Procedure:
Using the procedure of Example 137, 3.2 g of the methyl ester from Example 130 was saponified to 1.9 g (61%) of rac-5-[[1,2,3,4-tetrahydro-1,9-dioctyl-9H-dibenzo[b,d]pyrrol-6-yl]oxy]-2-furancarboxylic acid as a white foam.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:14])[NH:8]2)#N.C(O)=[O:16]>[Ni]>[CH3:13][C:10]1[C:9]2[NH:8][C:7](=[O:14])[CH2:6][CH2:5][C:4]=2[C:3]([CH:1]=[O:16])=[CH:12][CH:11]=1
Reactant: O=CO
Reactant: Cc1ccc(C#N)c2c1NC(=O)CC2
Agent: [Ni]
Product: Cc1ccc(C=O)c2c1NC(=O)CC2
Yield: 62 %

Procedure:
5-Cyano-8-methyl-3,4-dihydro-1H-quinolin-2-one (2.0 g) and Raney nickel (10 g) were suspended in formic acid (40 ml), and the suspension was heated under reflux for 6 hours. The reaction mixture was filtered to remove the insoluble matter, and the filtrate was concentrated. Ethyl acetate and water were added to the residue, and after stirring, the mixture was filtered through Celite. The filtrate was separated into layers, and the organic layer was washed with water and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was recrystallized from an ethyl acetate-diethyl ether mixed solvent to thereby obtain 1.29 g (yield: 62%) of 8-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxaldehyde as a light brown powder.
Reaction SMILES: [H][H].[Cl:3][C:4]1[CH:32]=[CH:31][C:7]([C:8]([C:10]2[C:11]([CH3:30])=[C:12]([CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:6][CH:5]=1>CO.[Ni]>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:10]2[C:11]([CH3:30])=[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:31][CH:32]=1
Reactant: Cc1c(C=CCCCCCCCCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Cc1c(CCCCCCCCCCCC(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Yield: 63.9 %

Procedure:
Hydrogen was passed through a solution of 2.07 g of the acid of Step A in 60 ml of methanol in the presence of 3 g of Raney nickel for 2 hours and the mixture was then filtered. The filtrate was evaporated to dryness and the residue was crystallized from isopropyl ether to obtain 1.328 g of 12-[3'-(4-chlorobenzoyl)-2'-methyl-phenyl]-dodecanoic acid melting at 79° C.
Reaction SMILES: N[C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:12]3[CH2:15][CH2:14][CH2:13]3)[CH:7]=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.N([O-])=O.[Na+].O.[ClH:23]>>[Cl:23][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH:12]3[CH2:15][CH2:14][CH2:13]3)[CH:7]=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1
Reactant: Cl
Reactant: Nc1ccc2c(c1)S(=O)(=O)N=CN2C1CCC1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=S1(=O)N=CN(C2CCC2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 7-amino-4-cyclobutyl-4H-1,2,4-benzothiadiazine 1,1-dioxide prepared in the Step above (3.48 g) in 6N HCl (40 mL) is cooled on an ice bath and then an aqueous solution of NaNO2 (2 g in 15 mL) is added dropwise. The solution obtained is added gradually to a solution of the Cu2Cl2 in concentrated HCl (30 mL). After stirring for 30 minutes at ambient temperature, water (150 mL) is added to the reaction mixture and the precipitate obtained is collected by filtration, washed with water and dried.
Reaction SMILES: [C:1]([NH:4][NH:5][C@@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1[OH:20])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:27](Cl)(=[O:29])[CH3:28]>C(Cl)(Cl)Cl>[C:27]([N:5]([C@@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1[OH:20])[NH:4][C:1](=[O:3])[CH3:2])(=[O:29])[CH3:28]
Reactant: CC(=O)NN[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)NN(C(C)=O)[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Temperature: 20 °C

Procedure:
Trans-4-(2-acetylhydrazino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol, 320 mg, was dissolved in 6 ml of chloroform and to this was added 0.5 ml of pyridine. While stirring under water cooling (20° C.), 0.23 ml of acetyl chloride was added and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under a reduced pressure, and to the residue was added ice water to scrape and crush it. After filtration and drying, it was recrystallized from ethyl acetate - hexane (1:1) to give 260 mg of trans-4-(1,2-diacetylhydrazino)-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol as white crystals, m.p. 230°-233° C.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[Cl:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[C:19]([CH2:26][OH:27])=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1.Br[CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>O>[Cl:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[N:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[C:19]([CH2:26][O:27][CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: OCc1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Reactant: BrCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1nc(Nc2cccc(Cl)c2)ncc1COCC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 60% sodium hydride (26 mg) and N,N-dimethylformamide (4 mL) was added {2-[(3-chlorophenyl)amino]-4-(trifluoromethyl)pyrimidin-5-yl}methanol (200 mg), followed by stirring at room temperature for 30 minutes. Thereafter, bromomethyl cyclohexane (139 μL) was added thereto, followed by stirring at room temperature for 2 hours. 60% Sodium hydride (26 mg) and bromomethyl cyclohexane (139 μL) were added thereto again, followed by stirring at room temperature overnight. To the reaction mixture was added water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, then dried over anhydrous magnesium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain N-(3-chlorophenyl)-5-[(cyclohexylmethoxy)methyl]-4-(trifluoromethyl)pyrimidin-2-amine (100 mg) as a white solid.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12]2[C:11]([O:13][CH3:14])=[CH:10][CH:9]=[C:8]([C:15]([OH:17])=O)[C:7]=2[CH:6]=[CH:5]1)[CH3:3].[NH2:18][CH2:19][C:20]1[C:21](=[O:30])[NH:22][C:23]([CH3:29])=[CH:24][C:25]=1[CH2:26][CH2:27][CH3:28].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>O.CS(C)=O>[CH3:3][CH:2]([N:4]1[C:12]2[C:11]([O:13][CH3:14])=[CH:10][CH:9]=[C:8]([C:15]([NH:18][CH2:19][C:20]3[C:21](=[O:30])[NH:22][C:23]([CH3:29])=[CH:24][C:25]=3[CH2:26][CH2:27][CH3:28])=[O:17])[C:7]=2[CH:6]=[CH:5]1)[CH3:1]
Reactant: COc1ccc(C(=O)O)c2ccn(C(C)C)c12
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1ccc(OC)c2c1ccn2C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.8 %

Procedure:
Added 1-(1-methylethyl)-7-(methyloxy)-1H-indole-4-carboxylic acid (160 mg, 0.686 mmol), 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (186 mg, 0.857 mmol), 1-hydroxy-7-azabenzotriazole (187 mg, 1.372 mmol), EDC (263 mg, 1.372 mmol) and N-methylmorpholine (0.302 mL, 2.74 mmol) to DMSO (10 mL) and stirred mixture at RT for 16 h. Added 25 ml of water and stirred for 10 minutes. Filtered off solids and dried in vacuo. The solids were purified by column chromatography (Biotage; 0% to 15% gradient MeOH:DCM; 10 g-HP-silica gel column) to give 165 mg of 1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-7-(methyloxy)-1H-indole-4-carboxamide.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([OH:15])=[O:14])[N:10]([C:16](=[O:39])[C@@H:17]([NH:19][C@H:20]([C:29]([O:31]CC2C=CC=CC=2)=[O:30])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:18])[C:9]1=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[H][H].[Pd]>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([OH:15])=[O:14])[N:10]([C:16](=[O:39])[C@@H:17]([NH:19][C@H:20]([C:29]([OH:31])=[O:30])[CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH3:18])[C:9]1=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](N[C@@H](CCc1ccccc1)C(=O)OCc1ccccc1)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1C(=O)N(Cc2ccccc2)C[C@H]1C(=O)O
Yield: 83.9 %

Procedure:
1.0 g of (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-benzyloxycarbonyl-3-phenylpropyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylic acid is dissolved in 20 ml of methanol, and 50 mg of palladium black are added thereto. The mixture is shaken at room temperature in hydrogen gas atmosphere for two hours under an atmospheric pressure. Insoluble materials are filtered off, and the filtrate is concentrated under reduced pressure to remove solvent. The residue is triturated with ether, whereby 0.7 g of (4S)-1-benzyl-3-{(2S)-2-[N-((1S)-1-carboxy-3-phenylpropyl)amino]propionyl}-2-oxo-imidazolidine-4-carboxylic acid is obtained as colorless crystals. Yield: 83.9% The physico-chemical properties of this product are identical with those of the sample obtained in Example 8-(2).
Reaction SMILES: [CH:1]([N:4]1[N:13]=[C:12]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[C:11]2[C:6](=[CH:7][C:8]([O:21][CH2:22][CH2:23][S:24][CH3:25])=[CH:9][CH:10]=2)[C:5]1=[O:26])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:32]>C(Cl)Cl>[CH:1]([N:4]1[N:13]=[C:12]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[C:11]2[C:6](=[CH:7][C:8]([O:21][CH2:22][CH2:23][S:24]([CH3:25])=[O:32])=[CH:9][CH:10]=2)[C:5]1=[O:26])([CH3:2])[CH3:3]
Reactant: CSCCOc1ccc2c(Nc3cc(C)[nH]n3)nn(C(C)C)c(=O)c2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(Nc2nn(C(C)C)c(=O)c3cc(OCCS(C)=O)ccc23)n[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
To a solution of 2-isopropyl-4-(5-methyl-1H-pyrazol-3-ylamino)-7-(2-methylsulfanyl-ethoxy)-2H-phthalazin-1-one (0.077 g, 0.23 mmol) in DCM (2 ml), was added m-chloro-peroxybenzoic acid (0.040 g, 0.23 mmol) portion wise. The solution was stirred at RT for 1 hour. After this time LC-MS indicated complete consumption of starting material and the solvent was removed under vacuum. Preparative thin layer chromatography (elution: 50% EtOAc, 50% EtOH) afforded the title compound (0.015 g, 14% yield) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[CH:37][C:6]([CH2:7][N:8]([C:32]2[S:33][CH:34]=[CH:35][N:36]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27]COC)[CH2:19][CH2:18][O:17][C:16]=3[CH:31]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl>C(Cl)Cl.O1CCOCC1>[OH:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[N:20]1[CH2:19][CH2:18][O:17][C:16]2[CH:31]=[C:12]([S:9]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:38][CH:37]=3)[C:32]3[S:33][CH:34]=[CH:35][N:36]=3)(=[O:10])=[O:11])[CH:13]=[CH:14][C:15]1=2
Reactant: COCOc1ccccc1N1CCOc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.8 %

Procedure:
To a solution of N-(4-methoxybenzyl)-4-(2-(methoxymethoxy)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (600 mg, 2.169 mmol) in DCM (20 mL) was added 20% HCl in 1,4-Dioxane (2.0 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h. After completion, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with DCM (2×20 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain 4-(2-hydroxyphenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as a yellow solid (550 mg, 99%) which was used for next step without purification.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]([OH:9])[C:6]2[O:10][CH:11]=[CH:12][C:5]=2[CH2:4]1)[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16](F)[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([O:9][CH:7]2[CH2:8][N:3]([CH2:1][CH3:2])[CH2:4][C:5]3[CH:12]=[CH:11][O:10][C:6]2=3)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: CCN1Cc2ccoc2C(O)C1
Product: CCN1Cc2ccoc2C(Oc2ccc(Cl)c(Cl)c2)C1

Procedure:
The same method as in Example 1 was conducted using 5-ethyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridin-7-ol (Reference Example 34) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:28][CH2:27][O:26][C:25]2=[O:29])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)=[O:9].C(N(CC)CC)C.O1CCCC1.Cl[CH2:43][CH2:44][CH2:45][S:46](Cl)(=[O:48])=[O:47]>O>[CH3:22][C:21]1[C:16]([N:13]2[CH2:12][CH2:11][N:10]([C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:24]4[CH2:28][CH2:27][O:26][C:25]4=[O:29])=[CH:3][C:2]=3[N:1]3[CH2:43][CH2:44][CH2:45][S:46]3(=[O:48])=[O:47])=[O:9])[CH2:15][CH2:14]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3N)CC2)c(C)c1
Reactant: O=S(=O)(Cl)CCCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3N3CCCS3(=O)=O)CC2)c(C)c1
Reaction time: 8 h

Procedure:
To a mixture of 3-{3-amino-4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}oxazolidin-2-one (93.1 mg) described in Example 133, triethylamine (63 μL) and tetrahydrofuran (1 mL) was added 3-chloropropanesulfonyl chloride (38 μL), and the mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. To the residue were added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (42 μL) and DMF (1 mL), and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. To the residue was added a mixed solvent of isopropyl ether and ethyl acetate, and the precipitated crystals were collected by filtration to give the title compound (62.1 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22]C)=[O:21]>C(#N)C>[Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([O:10][CH2:19][C:20]([OH:22])=[O:21])=[C:4]([F:11])[CH:3]=1
Reactant: O=Cc1cc(Br)cc(F)c1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1cc(Br)cc(F)c1OCC(=O)O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of 5-bromo-3-fluoro-2-hydroxybenzaldehyde (4.57 mmol) in acetonitrile (30 mL) was treated with potassium carbonate (12.66 mmol). The reaction mixture was stirred for 30 min and was then treated with methyl bromoacetate (5.48 mmol). The resulting mixture was stirred at room temperature overnight. Analysis by LCMS indicated the formation of the desired intermediate ester, and the reaction mixture was concentrated to dryness in vacuo. The crude material was dissolved in a 3:1 methanol:water mixture (20 mL) and was heated to 50° C. with stirring for 2 h. The reaction was then cooled to room temperature and was acidified to pH˜3 using 1N aq HCl. The methanol was removed in vacuo and the resulting aqueous suspension was diluted with water (100 mL) and was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated in vacuo to give the crude title product. The beige solid was used without further purification (1.05 g, 83% yield). MS(ES)+ m/e 276.9, 278.9 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[C:6]#[N:7])[CH3:2].F[C:13]1[N:18]=[CH:17][C:16]([N:19]2[C:23](=[O:24])[C:22]([CH3:26])([CH3:25])[NH:21][C:20]2=[O:27])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>CN(C)C=O.O>[CH3:25][C:22]1([CH3:26])[C:23](=[O:24])[N:19]([C:16]2[CH:15]=[CH:14][C:13]([O:11][C:10]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=3[CH2:1][CH3:2])=[N:18][CH:17]=2)[C:20](=[O:27])[NH:21]1
Reactant: CC1(C)NC(=O)N(c2ccc(F)nc2)C1=O
Reactant: CCc1cc(C#N)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCc1cc(C#N)ccc1Oc1ccc(N2C(=O)NC(C)(C)C2=O)cn1
Temperature: 120 °C
Reaction time: 96 h
Yield: 33.7 %

Procedure:
3-ethyl-4-hydroxybenzonitrile (Intermediate 115, 70 mg) was dissolved in 2 mL of dimethylformamide. 3-(6-fluoro-3-pyridinyl)-5,5-dimethyl-2,4-imidazolidinedione (Intermediate 106, 102 mg) and potassium carbonate (126 mg, 0.915 mmol) were added. The reaction mixture was stirred at 120° C. during 96 hours. Some diethyl ether (4 mL) and water (4 mL) were added. The aqueous layer was extracted 4 times with diethyl ether. The gathered organic layers were dried over sodium sulphate and evaporated giving a residue which was purified by flash chromatography on silica gel (companion system, 12 g Si cartridge) using as eluent a gradient cyclohexane/ethyl acetate 100/0, then from 100/0 to 55/45. Evaporation afforded the title compound (54 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](B(O)O)[CH2:11][CH2:12][CH2:13][CH3:14]>>[CH2:10]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCB(O)O
Reactant: O=Cc1ccc(Br)cc1
Product: CCCCCc1ccc(C=O)cc1
Yield: 67.7 %

Procedure:
The compound was synthesized as in Example 3.1 using 4-bromobenzaldehyde (250 mg, 1.35 mmol) in place of 5-bromo-2-formylfuran and pentylboronic acid (259 mg, 2.23 mmol) in place of hexylboronic acid to give 4-pentylbenzaldehyde (161 mg, 68%). Used without further characterization.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:8][C:7]([CH2:13][C:14]#[CH:15])([C:9]([F:12])([F:11])[F:10])[O:6][CH:5]([O:16]CCCO)[C:4]2[CH:21]=[CH:22][CH:23]=[CH:24][C:3]1=2.Cl>C1COCC1>[CH3:1][C:2]1([CH3:25])[CH2:8][C:7]([CH2:13][C:14]#[CH:15])([C:9]([F:10])([F:11])[F:12])[O:6][CH:5]([OH:16])[C:4]2[CH:21]=[CH:22][CH:23]=[CH:24][C:3]1=2
Reactant: C#CCC1(C(F)(F)F)CC(C)(C)c2ccccc2C(OCCCO)O1
Agent: Cl
Solvent: C1CCOC1
Product: C#CCC1(C(F)(F)F)CC(C)(C)c2ccccc2C(O)O1
Temperature: 40 °C
Yield: 45.8 %

Procedure:
A solution of 3-(5,5-dimethyl-3-prop-2-ynyl-3-trifluoromethyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-yloxy)propan-1-ol (15.0 g) in THF (150 mL) was treated with 1M aqueous HCl (75 mL) and heated at 40° C. for 16 hours. The volatiles were then removed in vacuo and the aqueous layer extracted with ethyl acetate (300 mL), washed with two 100 mL portions of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude was purified by flash chromatography (300 g SiO2, hexanes to 4:1 hexanes:EtOAc) to give 5,5-dimethyl-3-prop-2-ynyl-3-trifluoromethyl-1,3,4,5-tetrahydrobenzo[c]oxepin-1-ol (5.75 g, 46%) as a 1:1 mixture of lactol and aldehyde by NMR. The mixture was used without further purification in the next transformation.