Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.CN(C)CCN(C)C.C([Li])CCC.CCCCCC.[C:31](=[O:33])=[O:32]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:7]=1[C:31]([OH:33])=[O:32]
Reactant: FC(F)(F)c1ccc(Cl)cc1
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
The title compound was prepared according to the method described in Tetrahedron Lett., vol. 37, p. 2767 (1996). To a solution of 1-chloro-4-(trifluoromethyl)benzene (25.8 g, 143 mmol) and tetramethylethylene diamine (16.6 g, 143 mmol) in tetrahydrofuran (250 mL) cooled to −78° C., was added a solution of 1.6M butyllithium in hexane (89.4 mL, 143 mmol) was added dropwise under an argon atmosphere, and the mixture was stirred at the same temperature for 30 minutes. The solution was carefully poured onto crushed dry ice, and the resulting mixture was allowed to warm to room temperature. The solution was concentrated under reduced pressure, and the residue was poured into water. The solution was washed with diethylether, and subsequently made acidic by the addition of conc. hydrochloric acid, and organic matter was extracted with dichloromethane. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was crystallized from hexane to give the title compound (20.6 g, 64% yield). NMR (CDCl3) δ: 7.65. (1H, d, J=8.4 Hz), 7.75 (1H, dd, J=2.2 Hz. 8.4 Hz), 8.31 (1H, d, J=2.2 Hz), hidden (1H)
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1>[Ni]>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[CH2:2][NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: Nc1ccc(C(=O)O)cc1
Agent: [Ni]
Product: O=C(O)c1ccc(NCC(O)C(O)C(O)C(O)CO)cc1

Procedure:
As starting materials D-glucose and p-amino-benzoic acid were used. The reductive amination was carried out using Raney nickel as catalyst and heating for 2 hours to 50° C. and for 3 hours to 70° C. The product obtained had a melting point of 111° to 112° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.C([O:27][B:28](OC(C)C)[O:29]C(C)C)(C)C.Cl>O1CCCC1.CCCCCC>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([B:28]([OH:29])[OH:27])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCOc1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCOc1ccc(-c2ccc(B(O)O)cc2)cc1
Temperature: -30 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-bromo-4′-n-butyloxybiphenyl (3.05 g) in tetrahydrofuran (60 ml) was added 1.55 M n-butyllithium in n-hexane (7.74 ml) at −60° C. over a period of 10 minutes. The solution was stirred at −30° C. for 1.5 hours and cooled to −60° C. To the solution was added triisopropylborate (3.46 ml) over a period of 5 minutes, and the mixture was stirred for 1.5 hours without cooling. To the solution was added 1N hydrochloric acid (20 ml) and the solution was stirred for 30 minutes and extracted with ethyl acetate. The organic layer was separated and washed with water, brine and dried over magnesium sulfate. The solvents were removed under reduced pressure and the residue was triturated with n-hexane. The solid was collected by filtration and dried under reduced pressure to give 4-(4-n-Butyloxyphenyl)phenylboronic acid (2.31 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([C:13]2[C:21]([CH:22]=[CH:23][C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]3[CH2:32][CH3:33])=[O:25])=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[C:21]([CH:22]=[CH:23][C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]3[CH2:32][CH3:33])=[O:25])=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:4])=[O:3]
Reactant: CCC1CCCCN1C(=O)C=Cc1c(-c2cccc(N)c2)nn2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1CCCCN1C(=O)C=Cc1c(-c2cccc(NS(C)(=O)=O)c2)nn2ccccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 24.8 %

Procedure:
Methanesulfonyl chloride (0.59 g) was added dropwise to a stirred solution of 1-[3-{2-(3-amino-phenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine (trans isomer) (1.20 g) and triethylamine (0.52 g) in methylene chloride (7.2 ml) with ice-cooling. After being stirred at room temperature for 6 hours, the reaction mixture was washed twice with water and once with saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (22 g) with chloroform as an eluent. The fractions containing the objective compound were combined and evaporated in vacuo to give crystals of 1-[3-{2-(3-methanesulfonamidophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine (trans isomer) (0.36 g).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][C:10](=[O:12])[CH3:11])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:10]([NH:9][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])[N:4]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1nc(O)ncc1F
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(OS(=O)(=O)c2ccccc2)ncc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.6 %

Procedure:
N-(5-fluoro-2-hydroxypyrimidin-4-yl)-acetamide (200 mg, 1.17 mmol) was suspended in pyridine (5 mL) and stirred at ambient temperature. To the stirred suspension was added benzenesulfonyl chloride (226 mg, 1.29 mmol) and agitation was continued for 16 hours. The solvent was evaporated under a stream of nitrogen and the residue was suspended in dichloromethane (2-3 mL), placed directly onto a silica gel column, and eluted with ethyl acetate in petroleum ether (0-50% gradient) to isolate 180 mg, 0.58 mmol (49%) of the title compound as a white solid: mp 142-143° C.; 1H NMR (DMSO-d6) δ 10.96 (s, 1H), 8.67 (d, J=2.6 Hz, 1H), 8.12-8.06 (m, 2H), 7.86-7.79 (m, 1H), 7.73-7.65 (m, 2H), 2.98 (s, 3H); HPLC-MS (ESI) m/z 312 (M+H)+, 310 (M−H)−. *N-(5-fluoro-2-hydroxypyrimidin-4-yl)-acetamide can be prepared through known literature methods.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>CO.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:16][CH2:17]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN2CCC(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(Nc1ccc(Cl)c(Cl)c1)C1CCN(C[C@@H]2CCCNC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.8 %

Procedure:
To a solution of tert-butyl (3S)-3-[(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperidin-1-yl)methyl]piperidine-1-carboxylate (2.3 g) in methanol (50 mL) was added 4M HCl in dioxane (15 mL). The mixture was stirred at room temperature for 18 hours and then evaporated. The residue was then partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate. The layers were separated and the organic extract was evaporated. The residue was triturated with dichloromethane and filtered to give the title compound as a white solid (1.5 g, 83%)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][CH:24]=1)[CH2:15][CH:12]1[CH2:14][CH2:13]1)=[O:6]
Reactant: NCC(CC1CC1)c1cnc(C(F)(F)F)nc1
Reactant: O=C(O)c1c(Cl)cccc1Cl
Product: O=C(NCC(CC1CC1)c1cnc(C(F)(F)F)nc1)c1c(Cl)cccc1Cl

Procedure:
From 2,6-dichlorobenzoic acid and 3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propan-1-amine. LCMS (MH+): m/z=418.1, tR (minutes, Method G)=2.62
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:17][C:11]2[N:12]=[CH:13][NH:14][C:15](=O)[C:10]=2[C:9]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.P(Cl)(Cl)([Cl:28])=O.O.N>S1(CCCC1)(=O)=O>[Cl:28][C:15]1[C:10]2[C:9]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[O:17][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2c(-c3ccccc3F)oc3nc[nH]c(=O)c23)cc1
Agent: N
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: COc1ccc(-c2c(-c3ccccc3F)oc3ncnc(Cl)c23)cc1
Temperature: 25 °C

Procedure:
Stir a mixture of 20 g (0.06 mol) 6-(2-fluorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4(3H)-one in 78 ml sulpholane and 11 ml (18 g, 0.12 mol) phosphoryl chloride for 1 h at 120° C. After cooling to room temperature, add the reaction solution dropwise to a mixture of 1000 ml water and 100 ml 25% aqueous ammonia solution, stirring vigorously and cooling with ice. Filter off the solid that is precipitated at 10° C. and wash several times with water. Dissolve the solid in 700 ml ethyl acetate again and wash the solution twice with 500 ml water each time. Dry the organic phase over sodium sulphate, filter, and concentrate the filtrate by vacuum evaporation. Mix the residue with 60 ml diisopropyl ether, filter, and dry under vacuum. 18 g (81% of theor.) of the title compound is obtained.
Reaction SMILES: [CH:1]1([CH2:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[CH:1]1([CH2:7][NH:8][C:29]2[N:28]=[C:27]([C:20]3[C:21]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:18][CH:19]=3)[CH:32]=[CH:31][N:30]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: NCC1CCCCC1
Product: c1cnc2[nH]cc(-c3ccnc(NCC4CCCCC4)n3)c2c1
Yield: 50.7 %

Procedure:
Using the procedure of example 1, C-cyclohexyl-methylamine (92 mg) was reacted with compound 1f (100 mg) to provide compound 16 (42 mg, 51%). 1H NMR (400 MHz, CD3OD) δ 8.96 (d, J=7.8 Hz, 1H), 8.28 (d, J=4.8 Hz, 1H), 8.20 (s, 1H), 8.12 (d, J=5.6 Hz, 1H), 7.25 (dd, J=7.8 Hz, 4.8 Hz, 1H), 7.02 (d, J=5.6 Hz, 1H), 3.37 (d, J=4.8 Hz, 2H), 1.94-1.90 (m, 5H), 1.34-1.04 (m, 6H). MS (ESI) m/z: 308 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:16]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=3)[C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:25]=1.B(Br)(Br)Br.N1C=CN=C1.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]>ClCCl.CN(C)C=O>[CH3:39][C:38]([Si:35]([CH3:37])([CH3:36])[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:16]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=3)[C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:25]=1)([CH3:41])[CH3:40]
Reactant: COc1ccc2c(c1)C=Cc1oc(C)nc1C2c1c[nH]c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: BrB(Br)Br
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc2c(o1)C=Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of the product from step (vii) (1.5 g) in dichloromethane (20 ml) was added a solution of boron tribromide (1M in dichloromethane) (6 ml). The mixture was stirred at room temperature for 2 hours. A further 10 ml of boron tribromide solution was added and the mixture was stirred for 2 hours before quenching with water. The pH was adjusted to 7 with sodium bicarbonate solution and the aqueous solution extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated under reduced pressure to give a brown solid. The solid was dissolved in N,N-dimethylformamide (20 ml) and treated with imidazole (0.68 g) followed by tert-butyldimethylsilyl chloride (0.68 g). The mixture was stirred overnight then partitioned between water and ethyl acetate. The organic phase was dried (MgSO4) and evaporated under reduced pressure. Purification was by precipitation with methanol/dichloromethane/isohexane.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[F:12][CH:13]([F:38])[O:14][C:15]1[C:35]([CH3:36])=[CH:34][C:18]2[NH:19][C:20]([S:22][CH2:23][C:24]3[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[CH:26][N:25]=3)=[N:21][C:17]=2[C:16]=1[CH3:37].C(=O)([O-])[O-].[Na+].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[F:38][CH:13]([F:12])[O:14][C:15]1[C:35]([CH3:36])=[CH:34][C:18]2[NH:19][C:20]([S:22]([CH2:23][C:24]3[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[CH:26][N:25]=3)=[O:6])=[N:21][C:17]=2[C:16]=1[CH3:37]
Reactant: COc1ccnc(CSc2nc3c(C)c(OC(F)F)c(C)cc3[nH]2)c1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccnc(CS(=O)c2nc3c(C)c(OC(F)F)c(C)cc3[nH]2)c1OC
Reaction time: 0.25 h

Procedure:
5 ml of a 0.2N solution of m-chloroperoxybenzoic acid in methylene chloride are added dropwise at -40° C. to a solution of 0.39 g (1 mmol) of 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridyl)methylthio]-4,6-dimethyl-1H-benzimidazole in 20 ml of methylene chloride, and the mixture is stirred for 15 minutes. 0.5 ml of triethylamine are then added and the reaction mixture is poured into 20 ml of a 1:1 mixture of 5% sodium carbonate solution and 5% sodium thiosulphate solution. After phase separation, the aqueous phase is extracted twice more with 30 ml of methylene chloride each time, and the combined organic phases are washed with sodium carbonate solution, dried over magnesium sulphate, filtered and concentrated to 2 ml. After crystallisation from diisopropyl ether, the crystals are filtered off and dried to constant weight. This gives 0.3 g (74% of theory) of the title compound as a colourless solid of m.p. 163°-164° C. (decomposition).
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][Cl:15])=[CH:8][CH:7]=1>C(O)C>[Cl:15][CH2:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:1]#[N:2])=[CH:7][CH:8]=1
Reactant: [C-]#N
Reactant: ClCCCc1ccc(CCl)cc1
Agent: [Na+]
Solvent: CCO
Product: N#CCc1ccc(CCCCl)cc1
Temperature: 25 °C

Procedure:
In a 100 ml of round bottomed two-necked flask 4.4 g of NaCN, 18.2 g of 1-(4-chloromethylphenyl)3-chloropropane and 44.8 ml of 90% ethanol are added and boiled at reflux for 5 hours. The feedstock is cooled to room temperature and the precipitate is filtered by suction. The filtrate is concentrated by evaporation. The residue is absorbed in 700 ml of diethyl ether, washed to neutrality with 2×250 ml of distilled water and dried with sodium sulfate. The solution is evaporated to dryness in a rotary evaporator.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[CH3:19][C:20]1[O:21][C:22]([CH3:28])=[C:23]([C:25](O)=[O:26])[N:24]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[CH3:28])=[O:26])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: Cc1nc(C(=O)O)c(C)o1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: Cc1nc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OCC3(F)F)c2)c(C)o1

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 2,5-dimethyl-oxazole-4-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=383.2 [M+H]+.
Reaction SMILES: Br[CH:2]1[C:6]([CH3:8])([CH3:7])[O:5][C:4]([CH3:10])([CH3:9])[C:3]1=O.[NH2:12][C:13]([NH2:15])=[S:14].C(N(CC)CC)C>C(O)C>[CH3:7][C:6]1([CH3:8])[C:2]2[N:12]=[C:13]([NH2:15])[S:14][C:3]=2[C:4]([CH3:10])([CH3:9])[O:5]1
Reactant: NC(N)=S
Reactant: CC1(C)OC(C)(C)C(Br)C1=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(C)OC(C)(C)c2sc(N)nc21

Procedure:
To a solution of Example 248A (10.0 g, 0.045 mol) in ethanol (100 mL) were added thiourea (3.8 g, 0.05 mol) and triethylamine (6.3 mL, 0.045 mol). The reaction mixture was heated at reflux overnight, then cooled, and concentrated under reduced pressure. The residue was diluted with water (25 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (SiO2, 0-5% methanol in CH2Cl2) to afford the title compound MS (ESI+) m/z 199 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:22]=1.[CH3:23][NH:24][C:25](=[O:41])[C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[CH3:23][NH:24][C:25]([C:26]1[N:27]=[CH:28][C:29]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([CH:10]4[CH2:15][CH2:14][N:13]([C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]4)=[N:7][C:6]=3[CH:22]=2)=[CH:30][CH:31]=1)=[O:41]
Reactant: CC(C)OC(=O)N1CCC(c2nc3cc(Br)ccc3o2)CC1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CNC(=O)c1ccc(-c2ccc3oc(C4CCN(C(=O)OC(C)C)CC4)nc3c2)cn1
Yield: 5.8 %

Procedure:
Following the General Procedure-1, the titled compound (20 mg) was prepared from Intermediate 13 (300 mg, 0.82 mmol) and N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide (256 mg, 0.98 mmol) as a brown solid. M.P.: 158-161° C. MS (m/z): 423.5 [M+H]+.
Reaction SMILES: [Na].[Na].[Cl:3][C:4]1[CH:5]=[C:6]([N:11]2[C:15](=[O:16])[NH:14][NH:13][C:12]2=[O:17])[CH:7]=[C:8]([Cl:10])[CH:9]=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:26][CH:27]([CH2:30]Cl)[CH2:28]Br)=[CH:21][CH:20]=1>CN(C=O)C>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][O:26][CH:27]2[CH2:30][N:13]3[C:12](=[O:17])[N:11]([C:6]4[CH:5]=[C:4]([Cl:3])[CH:9]=[C:8]([Cl:10])[CH:7]=4)[C:15](=[O:16])[N:14]3[CH2:28]2)=[CH:23][CH:24]=1
Reactant: ClCC(CBr)OCc1ccc(Br)cc1
Reactant: O=c1[nH][nH]c(=O)n1-c1cc(Cl)cc(Cl)c1
Agent: [Na]
Solvent: CN(C)C=O
Product: O=c1n(-c2cc(Cl)cc(Cl)c2)c(=O)n2n1CC(OCc1ccc(Br)cc1)C2
Yield: 15 %

Procedure:
A mixture of 4-(3,5-dichlorophenyl)-[1,2,4]triazolidine-3,5-dione disodium salt (1.5 g, 5.17 mmol) (Preparation 4) and 1-Bromo-4-(2-bromo-1-chloromethyl-ethoxymethyl)-benzene (1.95 g, 5.69 mmol) (Preparation 1) in DMF (25 ml) was heated under reflux for 2 h 30 min. The solvent was removed under vacuum, and water was added to the resulting material. The precipitate was washed with diethyl ether and chromatographed over silica gel (CH2Cl2) to yield the above compound as a white solid (366 mg, mp=142° C.). 1H NMR (CDCl3):7.44 (2H, d, J=8.3 Hz), 7.3-7.4 (3H, m), 7.09 (2H, d, J=8.3 Hz), 4.43 (2H, s), 4.15-4.35 (3H, m), 3.49 (2H, dd, J1=12.2 Hz, J2=2.2 Hz).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([CH:13]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:3]=1.C(N(CC)CC)C>CO.[C].[Pd]>[F:28][C:25]1[CH:24]=[CH:23][C:22]([CH:13]([C:4]2[CH:3]=[CH:2][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[OH:12])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:27][CH:26]=1
Reactant: O=C(O)CCCCCC(c1ccc(F)cc1)c1cc(Br)c2ccccc2c1O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)CCCCCC(c1ccc(F)cc1)c1ccc2ccccc2c1O
Reaction time: 1.5 h
Yield: 66.5 %

Procedure:
To a solution of 7-(4-bromo-1-hydroxy-2-naphthyl)-7-(4-fluorophenyl)heptanoic acid (1.70 g) in methanol (10 ml) were added 5% palladium-carbon (200 mg) and triethylamine (0.53 ml) and hydrogenation was carried out at room temperature for 1.5 hours. The catalyst was filtered off and the filtrate was distilled off at reduced pressure. The residue was extracted by addition of ethyl acetate and water. The ethyl acetate layer was washed with saturated saline and dried with anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by subjecting it to silica gel chromatography and eluting with ethyl acetate/hexane (1:2) to obtain 7-(4-fluorophenyl)-7-(1-hydroxy-2-naphthyl)heptanoic acid (930 mg) (Compound B-3). The physical properties and NMR spectrum data thereof are shown in Table 2.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH3:17])[CH:3]=1.C([Li])CCC.C[O:24]B(OC)OC.Cl>O1CCCC1>[CH2:10]([O:9][C:5]1[C:4]([CH3:17])=[CH:3][C:2]([OH:24])=[CH:7][C:6]=1[Cl:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(Br)cc(Cl)c1OCc1ccccc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(O)cc(Cl)c1OCc1ccccc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
Then, 40 g of 4-bromo-6-chloro-2-methyl-1-benzyloxybenzene was dissolved in 400 ml of tetrahydrofuran, followed by stirring at -70° C., to which 76 ml of n-butyl lithium solution (in hexane, 1.69 mol/liter) was added dropwise, followed by further stirring at -70° C. for 2 hours. To this reaction mixture was added dropwise a solution of 13.3 g of trimethoxyborane dissolved in 50 ml of tetrahydrofuran. Then, the reaction mixture was stirred for 1 hours, while warming to room temperature, and 100 ml of 10% aqueous hydrochloric acid solution was added in small portions, followed by stirring for 20 minutes. The tetrahydrofuran layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated. The residue was mixed with 200 ml of toluene, and heated at 70° C. under stirring, to which 36 ml of 30% aqueous hydrogen peroxide solution was added dropwise. After heating under reflux for 1 hour, the reaction mixture was washed once with water, twice with 10% ferrous sulfate and then ammonium water, and once with water, followed by phase separation. The toluene layer was dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 29 g of 4-benzyloxy-3-chloro-5-methylphenol (91% yield).