Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][N:13]1[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=[O:23].ClC1C=C(C(F)(F)F)C=CC=1NN.[O-]CC.[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[NH:13][C:14](=[O:23])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]1=[O:22]
Reactant: O=C1c2ccccc2C(=O)N1Nc1ccc(C(F)(F)F)cc1Cl
Agent: CC[O-]
Agent: NNc1ccc(C(F)(F)F)cc1Cl
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]n(-c2ccc(C(F)(F)F)cc2Cl)c(=O)c2ccccc12
Temperature: 85 °C
Reaction time: 2 h

Procedure:
1.74 g 2-(2-Chloro-4-trifluoromethyl-phenylamino)-isoindole-1,3-dione (prepared from 2-chloro-4-trifluoromethyl-phenylhydrazine analogously to method A) in 80 ml dry EtOH were treated with 347 mg sodium ethoxide and the mixture was stirred at 85° C. for 2 hrs. After cooling, the mixture was evaporated and dissolved in water. Precipitate was filtered off and washed several times with water. The combined filtrates was acidified by addition of conc. HCl whereupon the product precipitated. It was isolated by filtration and purified by chromatography on silica eluting with a gradient from heptane/EtOAc (50:50) to pure EtOAc. Yield 250 mg (40%)
Reaction SMILES: Cl[CH2:2][CH2:3][NH2:4].[CH3:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[N:15]=[C:16]=[S:17]>>[CH3:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[N:15]=[C:16]1[N:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:3][CH2:2][S:17]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: NCCCl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCN1c1ccccc1

Procedure:
N-(2-Hydroxyethyl)aniline was reacted with SOCl2 according to Method B7a to give N-2-chloroethyl)anilinium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to afford 2-(2-methyl -4-nitrophenylimino)-3-phenyl-1,3-thiazolidine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:29])[C:8](CC)=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=1)=[O:5])[CH3:2].Br[C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH:33]=[CH:34][NH:35]2>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:29])[CH:8]=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[CH:34][NH:35]3)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: Brc1cccc2[nH]ccc12
Reactant: CCOC(=O)c1c(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)c(C#N)c(CC)n1C
Product: CCOC(=O)c1c(-c2ccc(-c3cccc4[nH]ccc34)cc2)c(C#N)cn1C

Procedure:
Prepare the title compound in the manner analogous to the procedure set fourth in example E-222 using 4-cyano-5-ethyl-1-methyl-3-(4-trifluoromethanesulfonyloxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester (prepared in example E-97a or 97b) and 4-bromo-indole. Purify the material by silica gel chromatography eluting with eluting with hexanes/ethyl acetate 4:1 to provide the title compound which is triturated with methylene chloride and hexanes to provide the title compound as a white solid. Mass spectrum (m/e): 398.2 (M*+1).
Reaction SMILES: CC(C)=[CH:3][CH:4]=[O:5].[Cl-].[NH4+].[C:9]1([CH3:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[O:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:15]=[CH:3][CH2:4]1
Reactant: Cc1ccccc1
Reactant: CC(C)=CC=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Product: C1=Cc2ccccc2OC1

Procedure:
In 100 ml of toluene was dissolved 10 g (0.0328 mole) of a compound represented by the following formula: ##STR253## and 18.71 g (0.00820 mole) of titanium tetraethoxide was added to the solution at room temperature. Ethanol was removed by azeotropic distillation. Then, toluene was added to the residue to form 500 ml of a reaction liquid. Then, a solution of 4.14 g (0.0492 mole) of 3-methyl-2-butenal in 300 m of toluene was added to the reaction liquid and the mixture was refluxed for 8 hours. After the reaction, a saturated aqueous solution of ammonium chloride was added to the reaction liquid and the mixture was extracted with ether. The solvent was removed under reduced pressure and the remaining product was purified by the chromatography on silica gel to obtain 6 g of a chromene compound represented by the following formula: ##STR254##
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:32][CH3:33])[N:23]([CH2:24][C:25]3([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1.[N:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>ClCCl>[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:32][CH3:33])[N:23]([CH2:24][C:25]3([OH:31])[CH2:30][CH2:29][N:28]([C:40]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:41])[CH2:27][CH2:26]3)[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCc1nc2c(N)nc3cccnc3c2n1CC1(O)CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(N)nc3cccnc3c2n1CC1(O)CCN(C(=O)N2CCOCC2)CC1
Temperature: -5 °C
Reaction time: 48 h
Yield: 88.3 %

Procedure:
Under a nitrogen atmosphere triethylamine (1.39 mL, 10.0 mmol) was added to a suspension of 4-[(4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]piperidin-4-ol dihydrochloride (1.00 g, 2.50 mmol) in dichloromethane (25 mL). The mixture was cooled to −5° C. 4-Morpholinecarbonyl chloride (292 μL, 2.50 mmol) was added and the reaction mixture was allowed to slowly warm to ambient temperature. The reaction mixture was stirred at ambient temperature for 2 days and then at 30° C. for 2 days. More 4-morpholinecarbonyl chloride (30 μL) was added and the reaction mixture was stirred at 30° C. for 5 days. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between chloroform (150 mL) and saturated aqueous sodium carbonate (30 mL). The organic was washed with saturated aqueous sodium carbonate (20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide an off white solid. This material was triturated with acetonitrile, recrystallized from chloroform/hexanes, isolated by filtration, washed with hexanes, and dried under high vacuum at 130° C. to provide 0.97 g of 4-[(4-amino-2-ethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)methyl]-1-(morpholin-4-ylcarbonyl)piperidin-4-ol as a white powder, mp>255.0° C. Anal. Calcd for C22H29N7O3-0.25H2O C, 59.51; H, 6.70; N, 22.08. Found: C, 59.32; H, 6.36; N, 22.00.
Reaction SMILES: CS([O:5][C@@:6]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:21]=1[NH2:22])([C:11]#[C:12][CH:13]1[CH2:15][CH2:14]1)[C:7]([F:10])([F:9])[F:8])(=O)=O.[OH-].[Na+].[C:31]([O-])([O-])=[O:32].[Na+].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(OCC)(=O)C>[CH:13]1([C:12]#[C:11][C@:6]2([C:7]([F:10])([F:9])[F:8])[C:16]3[CH:17]=[C:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:19]=[CH:20][C:21]=3[NH:22][C:31](=[O:32])[O:5]2)[CH2:15][CH2:14]1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)O[C@](C#CC1CC1)(c1cc(-c2ccccc2)ccc1N)C(F)(F)F
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(-c3ccccc3)cc2[C@](C#CC2CC2)(C(F)(F)F)O1
Temperature: 15 °C
Reaction time: 0.25 h

Procedure:
(R)-2-(4-Aminobiphenyl-3-yl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol methane-sulfonate (CN46630-MSA) of example 2 (14.7 g, 34.4 mmol) in ethyl acetate/heptanes (1:1 v/v, 27.9 g) was charged in a jacketed 150 mL-reactor with agitator and off-gas scrubber with caustic soda. After addition of aqueous Na2CO3 (12%-w/w, 32.3 g, 36.4 mmol, formation of gas during addition!) the mixture was stirred for 15 min at 15° C. The aqueous phase was separated and discarded. Aqueous Na2CO3 (12%-w/w, 41 g, 46 mol) and ethyl acetate (20 g) were charged to the organic phase. Triphosgene (4.41 g, 14.9 mmol) was added in portions over a period of 25 min at 10° C. The reaction mixture was stirred for 2 h at 8° C. The mixture was diluted with ethyl acetate (45 g) and the phases were separated. The aqueous phase was discarded. The organic phase was washed with water (12 mL), dried over MgSO4, filtered and concentrated and dried at 50° C. under reduced pressure to obtain (R)-4-(cyclopropylethynyl)-6-phenyl-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (CN46685, compound of formula I, wherein R1 is trifluoromethyl, R2 is cyclopropyl, R8 is 6-phenyl, R9 is hydrogen and R10 is hydrogen) (12.1 g, 33.9 mmol, 98%) as a yellowish solid (99.5% purity, according to Method C).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[CH2:18]1[O:28][C:27]2[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][C:20]=2[O:19]1>>[O:28]1[C:27]2[CH:26]=[CH:25][C:22]([CH2:23][N:12]3[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]3[CH:2]3[CH:3]4[CH2:4][CH:5]5[CH2:6][CH:7]([CH2:8][CH:1]3[CH2:10]5)[CH2:9]4)=[CH:21][C:20]=2[O:19][CH2:18]1
Reactant: BrCc1ccc2c(c1)OCO2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccc2c(c1)OCO2

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3,4-(methylenedioxy)benzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)=[C:4]([CH2:16][Br:17])[CH:3]=1.[N+:18]([O-])([O-:20])=[O:19].[K+]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:11]([N+:18]([O-:20])=[O:19])=[C:10]2[C:5]([N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)=[C:4]([CH2:16][Br:17])[CH:3]=1
Reactant: COc1nc2cc(Br)cc(CBr)c2nc1OC
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1nc2c(CBr)cc(Br)c([N+](=O)[O-])c2nc1OC
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
20 ml of sulfuric acid are cooled to 0° C. and then 5 g (13.8 mmol) of 7-bromo-5-bromomethyl-2,3-dimethoxy-quinoxaline are added. After a further 15 minutes, 1.46 g (1.05 equiv.) of potassium nitrate are added and the mixture is stirred for 15 hours at 20° C. The mixture is poured onto ice, and the solid is filtered off and washed with water. The title compound is obtained in the form of a beige solid.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[CH2:8]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH:10]([C:21]([OH:23])=[O:22])[CH2:9]1>CO.C(O)(C(F)(F)F)=O>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C@H:13]2[CH2:8][CH2:9][C@H:10]([C:21]([O:23][CH3:1])=[O:22])[CH2:11][CH2:12]2)=[CH:19][CH:18]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)C1CCC(c2ccc(Cl)cc2)CC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1

Procedure:
Trimethylsilyldiazomethane (15.71 ml, 31.4 mmol) was slowly added into a solution of (e)-4-(4-chlorophenyl)cyclohexanecarboxylic acid (3 g, 12.57 mmol) in MeOH (75 mL) at room temperature. LCMS indicated complete conversion in 1 hr. Added a few drops of TFA to quench the reaction. Volatiles were removed under reduced pressure. The resulting pot residue was purified by flash chromatography (SiO2, Biotage 65i cartridge). The column was eluted by an EtOAc/hexanes mixture (0% to 20%). Related fractions were pooled and evaporated to afford a white solid as the titled compound. LCMS calc.=252.09. found=253.20 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[C:21]([F:22])=[CH:20][C:16]2[S:17][CH:18]=[CH:19][C:15]=2[C:14]=1[F:23].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C.O>[F:23][C:14]1[C:15]2[CH:19]=[CH:18][S:17][C:16]=2[CH:20]=[C:21]([F:22])[C:13]=1[CH:12]=[O:11]
Reactant: OCc1c(F)cc2sccc2c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=Cc1c(F)cc2sccc2c1F
Reaction time: 1 h

Procedure:
To a solution of 0.22 ml of oxalyl chloride in 10 ml of methylene chloride is added 0.35 ml of dimethyl sulfoxide at -78° C. Then, to the resulting solution is added dropwise a solution of 0.20 g of 5-hydroxymethyl-4,6-difluorobenzo[b]thiophene in 3 ml of methylene chloride. At the same temperature, the resulting mixture is stirred for one hour, and then, 0.70 ml of triethylamine is added thereto. The temperature of the resulting mixture is elevated to room temperature, and thereafter, 10 ml of water and 10 ml of ethyl acetate are added thereto, after which the resulting organic layer is separated, washed successively with water and a saturated saline solution and then dried over anhydrous magnesium sulfate. Then, the solvent is removed from the thus dried layer by distillation under reduced pressure. The residue obtained is purified by a column chromatography [eluent: hexane], to obtain 0.20 g of colorless, solid 4,6-difluorobenzo[b]thiophene-5-carbaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([NH2:17])[N:5]([CH3:18])[N:4]=1.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29](N)(=[O:31])=[O:30])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.C(O)C.[OH-].[Na+].Cl>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:17][C:6]2[N:5]([CH3:18])[N:4]=[C:3]([O:2][CH3:1])[C:7]=2[O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])(=[O:31])=[O:30])=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: COc1ccccc1Oc1c(OC)nn(C)c1N
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: COc1ccccc1Oc1c(OC)nn(C)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 33.6 %

Procedure:
A solution of 3-methoxy-4-(2-methoxyphenoxy)-1-methyl-1H-pyrazol-5-amine (Preparation 68) (45 mg), (4-tert-butyl)benzenesulfonamide (42 mg) and 4-dimethylaminopyridine (22 mg) in dry pyridine (2 ml) was stirred at room temperature for 16 hours. A further aliquot of (4-tert-butyl)benzenesulfonamide (42 mg) was added to the reaction mixture and stirring at room temperature was continued for a further 24 hours. The reaction mixture was diluted with ethanol (2 ml) and 1.0M aqueous sodium hydroxide solution (4 ml) and was then stirred at room temperature for 4 hours. The mixture was diluted with aqueous 1.0M hydrochloric acid (20 ml) and then extracted with ethyl acetate (3×15 ml). The combined organic extracts were washed with aqueous 1.0M hydrochloric acid (20 ml), dried (magnesium sulfate) and then concentrated under vacuum. The residue was purified by chromatography on silica (5 g) using 40% ethyl acetate/pentane as eluant to give the title compound as an off-white solid (27 mg), Rf 0.85 (ethyl acetate), m.p. 187.6° C.
Reaction SMILES: [H-].[Li+].[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[F:14])[NH:10][C:9](=[O:15])[CH:8]=[N:7]2.Br[CH2:17][CH2:18][CH:19]1[O:23][CH2:22][CH2:21][O:20]1.O>CN(C)C=O>[O:20]1[CH2:21][CH2:22][O:23][CH:19]1[CH2:18][CH2:17][N:10]1[C:11]2[C:6](=[CH:5][C:4]([F:3])=[C:13]([F:14])[CH:12]=2)[N:7]=[CH:8][C:9]1=[O:15]
Reactant: O=c1cnc2cc(F)c(F)cc2[nH]1
Reactant: BrCCC1OCCO1
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cnc2cc(F)c(F)cc2n1CCC1OCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
Lithium hydride (52 mg, 6.5 mmol) was added to a solution of 6,7-difluoroquinoxalin-2(1H)one (1 g, 5.4 mmol) in N,N-dimethylformamide (10 ml) under cooling on ice and the reaction mixture was stirred at room temperature for 30 minutes. The mixture was cooled on ice again, a solution of 2-(2-bromoethyl)-1,3-dioxolane (0.8 ml, 6.5 mmol) in N,N-dimethylformamide (2 ml) was gradually added thereto and the obtained mixture was stirred for 4 hours. Water was gradually added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 0.6 g (39%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([CH3:26])=[C:9]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:10]([CH3:17])=[N:11]2.CO.[OH-].[Na+].Cl>O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:27])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH3:17])[C:9]([O:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)=[C:8]2[CH3:26]
Reactant: COC(=O)COc1ccc(Cl)c2nc(C)c(Oc3ccc(Cl)cc3)c(C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc2c(Cl)ccc(OCC(=O)O)c2c(C)c1Oc1ccc(Cl)cc1

Procedure:
A solution of [8-chloro-3-(4-chlorophenoxy)-2,4-dimethylquinolin-5-yloxy]acetic acid methyl ester (0.20 g), methanol (5.0 mL), water (1.0 mL) and 5.0 M aqueous sodium hydroxide solution (1.0 mL) was stirred at room temperature for 3 hours. The pH of the solution was adjusted to 1 by the addition of 1.0 M hydrochloric acid and the methanol removed under reduced pressure. The residue was purified by preparative reverse-phase HPLC using a gradient over 30 minutes of acetonitrile in water (40% to 98% of organic modifier) to afford title compound as a yellow-green solid, 0.025 g.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=1)=[O:5])C.O[Li].O.Cl>CO.O>[C:19]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:8]1[C:9]2[C:14](=[N:13][CH:12]=[CH:11][CH:10]=2)[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7]1
Reactant: CCOC(=O)c1cn(Cc2ccccc2-c2ccccc2)c2cccnc2c1=O
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)c1cn(Cc2ccccc2-c2ccccc2)c2cccnc2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.3 %

Procedure:
To a stirred solution of 1-Biphenyl-2-ylmethyl-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid ethyl ester (6) (850 mg, 2.4 mmol) in MeOH (8 mL) was added LiOH—H2O (100.2 mg, 4.8 mmol) and stirred at RT for 16 h. After completion of the reaction, distilled-off the solvent from the reaction and diluted with water. The aqueous part was acidified with 2 N HCl, extracted with EtOAC and organic layer was washed with brine. It was dried over Na2SO4, concentrated and the residue was purified by Prep-HPLC to get 1-Biphenyl-2-ylmethyl-4-oxo-1,4-dihydro-[1,5]naphthyridine-3-carboxylic acid (7) (88 mg, 11%) as off white solid.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH:18]=[CH:19][C:15]=2[CH:14]=1.[B:22](OC)([O:25]C)[O:23]C>O1CCCC1.O>[O:17]1[CH:18]=[CH:19][C:15]2[CH:14]=[C:13]([B:22]([OH:25])[OH:23])[CH:21]=[CH:20][C:16]1=2
Reactant: Brc1ccc2occc2c1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: OB(O)c1ccc2occc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A solution of n-butyl lithium in hexane (1.5M; 3.72 ml, 5.6 mmol) was added dropwise to a solution of 5-bromobenzo[b]furan (1.0 g, 5.0 mmol) in tetrahydrofuran (10 ml) under argon atmosphere at −60° C. and the mixture was stirred at the same temperature for 30 min. To the mixture was added trimethyl borate (0.69 ml, 6.0 mmol) and temperature of the mixture was raised to room temperature in 4 hrs. Water (5 ml) was added to the reaction mixture at 5° C. and tetrahydrofuran was distilled off under reduced pressure. To the residue was added 1N hydrochloric acid (pH 1) and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried. The solvent was distilled off and the residue was triturated with a mixture of n-hexane/diethyl ether, filtered and dried to give 5-benzo[b]furan boronic acid (551 mg) as a pale brown solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.CS(O[CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH2:35][CH3:36])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:34]([O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1)[CH2:35][CH3:36]
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: CCCOc1ccccc1CCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOc1ccccc1CCCOc1ccc2c(c1)C=C(C(=O)OC)CCS2(=O)=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 125.5 %

Procedure:
Methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (400 mg), 3-(2-propoxyphenyl)propyl methanesulfonate (1.06 g) and potassium carbonate (309 mg) were suspended in DMF (15 ml), and the resulting suspension was stirred at 60° C. for 3 hours. The reaction mixture was diluted with ethyl acetate and was washed respectively with water and an aqueous saturated solution of sodium chloride, and the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure to remove the solvent, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain methyl 7-[3-(2-propoxyphenyl)propoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (832 mg) as a yellow oil.
Reaction SMILES: [CH2:1]([N:10]=[C:11]=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]=[C:8]=[O:9].[NH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1>C1(C)C=CC=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([NH:13][C:8](=[O:9])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][NH:10][C:11]([NH:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:12])[CH:15]=1
Reactant: Nc1cccnc1
Reactant: O=C=NCCCCCCN=C=O
Solvent: Cc1ccccc1
Product: O=C(NCCCCCCNC(=O)Nc1cccnc1)Nc1cccnc1

Procedure:
A solution of hexamethylene di-isocyanate (1.68g.) in toluene (10ml.) was added to a solution of 3-aminopyridine (1.88g.) in toluene (18ml.) and the mixture was heated on a steam-bath for 10 minutes. The mixture was cooled, and the product was filtered off, washed with toluene and dried, to give 1,6-bis[3-(pyrid-3-yl)ureido]hexane, m.p. 197°-199°C., the starting material for compound 67.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[O:15][C:14]([CH3:28])([CH3:27])[CH2:13][C:12]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>O1CCCC1.O.[Pd](Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[O:15][C:14]([CH3:28])([CH3:27])[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(=O)c2cc(OCc3ccccc3)c(OCc3ccccc3)cc2O1
Agent: Cl[Pd]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C=Cc2cc(OCc3ccccc3)c(OCc3ccccc3)cc2O1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
7.8 g (20 millimoles) of 6,7-dibenzyloxy-2,2-dimethyl-4-chromanone are dissolved in 100 ml of a 1:1 mixture of tetrahydrofurane and water, whereupon 5.3 g (30 millimole) of palladium chloride and 8.31 g (220 millimoles) of sodium tetrahydroborate are added. The reaction mixture is stirred at 0° C. for 3 hours, filtered, and the filtrate is extracted three times with 100 ml of ether each. The ether extracts are evaporated, the residue is dissolved in 300 ml of dichloro methane and allowed to stand at 35° C. in the presence of 15 ml of pyridine and 2 g of phosphorous oxychloride for an hour. The reaction mixture is poured into 100 ml of water washed with 5% hydrochloric acid and water. The organic phase is dried and evaporated. The residue is crystallized from methanol. Thus 6 g of the desired compound are obtained, yield 81%. Mp.: 50°-51° C.