Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1.C(OCC)(=O)C.B(F)(F)F>CCOCC>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][O:18]3)[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2nc[nH]c2-c2ccccc2)cc1
Reactant: C1=COCCC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: c1ccc(-c2ncn(C3CCCCO3)c2-c2ccccc2)cc1

Procedure:
A mixture of 27 g (0.122 mole) 4,5-diphenylimidazole, 21 g (0.25 mole) dihydropyran, 250 ml ethyl acetate and 4.0 g BF3. Et2O was refluxed for five days. The nearly clear solution was diluted with ether and filtered to remove 0.6 g insoluble starting material. The ether filtrate was washed several times with 10% NaHCO3 then dried and evaporated. TLC showed starting material still present, so the crude product was chromatographed on 2 lb SilicAR CC-7, eluting with toluene containing 20 to 40% ethyl acetate. The pure 4,5-diphenyl-1-(2-tetrahydropyranyl)imidazole thus obtained weighed 30.3 g (82%) and had m.p. 170°-171°.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32](Cl)=[O:33].O>O1CCCC1.C(OCC)(=O)C>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32]([N:9]1[C:8](=[O:13])[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:11][C:10]1=[O:12])=[O:33]
Reactant: O=C1NC(=O)C(c2ccccc2)(c2ccccc2)N1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1C(=O)c1ccc2ccccc2c1
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
0.5 g of 5,5-diphenylimidazolidine-2,4-dione was dissolved in tetrahydrofuran (5 mL), and sodium hydride (60%, in oil) (87 mg) was added at 0° C. under ice-cooling. After stirred for 30 minutes, 2-naphthoyl chloride (415 mg) was added at 0° C., followed by stirring at room temperature for 2.5 hours. After water was carefully added, ethyl acetate (200 mL) was added, and the layers were separated. The resulting organic layer was washed with a saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further purification by silica gel chromatography (hexane:ethyl acetate=3:1) afforded white crystals. The resulting fraction was recrystallized from isopropyl ether (IPE) to obtain 441 mg of white crystals.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C@@:5]1([OH:13])[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH:23]=[C:24]([N:31]=[C:32]=S)[N:25]=[CH:26]2.C(N=C=NC(C)C)(C)C>CN(C)C=O>[Br:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH:23]=[C:24]([NH:31][C:32]1[O:13][C@:5]3([CH2:4][N:3]=1)[CH:10]1[CH2:9][CH2:8][N:7]([CH2:12][CH2:11]1)[CH2:6]3)[N:25]=[CH:26]2
Reactant: S=C=Nc1cc2c(Br)cccc2cn1
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Brc1cccc2cnc(NC3=NC[C@@]4(CN5CCC4CC5)O3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.207 g, 0.905 mmol) in N,N-dimethylformamide (20 mL) was added Cs2CO3 (0.737 g, 2.263 mmol) and 5-bromo-3-isothiocyanatoisoquinoline (0.24 g, 0.905 mmol). The suspension was stirred at room temperature for 30 minutes. N,N′-Diisopropylcarbodiimide (0.423 mL, 2.72 mmol) was then added and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated and purified by silica gel chromatography (5-15% [9.5:0.5 methanol:ammonium hydroxide]-ethyl acetate). The desired fractions were concentrated and further purified using 5-15% [9.5:0.5 methanol:ammonium hydroxide] in ethyl acetate to afford (R)—N-(5-bromoisoquinolin-3-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.248 g, 0.634 mmol, 70% yield) as a yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 8.99 (1H, s), 7.91 (2H, dd), 7.55 (1H, br. s.), 7.28 (1H, t), 3.96 (1H, d), 3.65 (1H, d), 3.17-3.26 (1H, m), 3.03-3.13 (1H, m), 2.70-2.99 (4H, m), 2.03-2.30 (2H, m), 1.47-1.87 (3H, m). LCMS: R.T.=1.69; [M+2]+=389.21.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[C:5]([CH3:14])([CH3:13])[CH2:4][CH:3]1[CH3:15].[C:17](Cl)(=[O:19])[CH3:18].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC(Cl)C>[C:17]([C:9]1[CH:10]=[C:11]2[C:6]([C:5]([CH3:14])([CH3:13])[CH2:4][CH:3]([CH3:15])[C:2]2([CH3:16])[CH3:1])=[CH:7][C:8]=1[CH3:12])(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: Cc1ccc2c(c1)C(C)(C)CC(C)C2(C)C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CC(=O)c1cc2c(cc1C)C(C)(C)CC(C)C2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a solution 1,1,2,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (21.0 g; 0.097 mol) and acetyl chloride (8.0 g; 0.102 mol) in dichloroethane (60 g), anhydrous aluminum chloride (14.9 g; 0.112 mol) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was treated with dilute hydrochloric acid. The organic layer was separated, washed with dilute hydrochloric acid, saturated sodium carbonate solution and saturated sodium chloride solution, dried and concentrated to give 7-acetyl-1,1,2,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (19.3 g; 0.075 mol; 77%). B.P., 109° C./0.2 mmHg. M.P., 61.5°-62.5° C.
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:20](Br)[CH:21]=[CH2:22]>C1COCC1>[C:8]([CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:22][CH:21]=[CH2:20])#[N:9]
Reactant: N#CCc1ccccc1
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(C#N)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution (−78° C.) of benzyl cyanide (5.00 g, 42.7 mmol) in anhydrous THF was added LiHMDS (1M in THF, 46.9 mL, 46.9 mmol) dropwise. After 0.5 hour, allyl bromide (5.16 g, 42.6 mmol) was added dropwise to the reaction mixture. The reaction mixture was warmed to room temperature, and the solvent was removed under vacuum. The residual material was purified using silica gel column chromatography eluting with 100% hexanes. The appropriate fractions were combined and concentrated to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.44 (m, 5H), 5.81 (m, 1H), 5.12 (m, 2H), 4.35 (t, J=6.9 Hz, 1H), 2.61 (m, 2H) ppm. ES MS M+1=158.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[S:16][CH:17]=1)[CH:6]=[O:7].C(O)C.[BH4-].[Na+].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[S:16][CH:17]=1
Reactant: COc1cc(C=O)ccc1OCc1csc(N2CCOCC2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CO)ccc1OCc1csc(N2CCOCC2)n1
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a solution of 3-methoxy-4-[(2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]benzaldehyde (1.20 g) in tetrahydrofuran (10 mL)-ethanol (10 mL) was gradually added sodium borohydride (0.14 g) at room temperature. After stirring the reaction mixture for 2 hrs, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give {3-methoxy-4-[(2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]phenyl}methanol as colorless crystals (1.03 g, yield 85%). melting point: 94-95° C.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]=1[Br:11].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:12]1([S:18]([N:1]([C:2]2[O:6][N:5]=[C:4]([C:7]([CH3:8])([CH3:10])[CH3:9])[C:3]=2[Br:11])[S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:20])=[O:19])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)c1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)c1noc(N(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)c1Br
Temperature: 500 °C
Reaction time: 16 h
Yield: 60.1 %

Procedure:
5-Amino-4-bromo-3-tert-butylisoxazole (440 mg, 2.0 mmol) was dissolved in dry pyridine (2 ml). Benzenesulfonyl chloride (344 mg, 2.0 mmol) and 4-dimethylamino-pyridine (5 mg) was added and the reaction was stirred at 500° C. for 16 h. The reaction mixture was diluted with ethyl acetate (20 ml), washed with 1N HCl (2×10 ml) and the organic phase was dried over magnesium sulfate. The solvent was removed under reduced pressure to yield a crude product, which was recrystallized from ethyl acetate/hexanes to give 300 mg (60% yield) of N-benzenesulfonyl-N-(4-bromo- 3-tert-butyl-5-isoxazolyl) benzenesulfonamide.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:12])=[CH:7][CH:8]=2)[N:3]=1.[NH3:13].CO>>[Cl:12][C:6]1[CH:5]=[C:4]2[C:9]([N:10]=[CH:11][C:2]([NH2:13])=[N:3]2)=[CH:8][CH:7]=1
Reactant: N
Reactant: Clc1ccc2ncc(Cl)nc2c1
Solvent: CO
Product: Nc1cnc2ccc(Cl)cc2n1
Yield: 98 %

Procedure:
At T=120° C., 30.0 g (60.0 mmol) of 2,7-dichloroquinoxaline are stirred in 400 ml of NH3/MeOH (w=22%) for 16 hours. The mixture is then evaporated to dryness under reduced pressure, and the residue is taken up in 250 ml of dichloromethane and 250 ml of water. After phase separation, the organic phase is then washed with 250 ml of water and dried over sodium sulphate, and the solvent is removed under membrane pump vacuum. The residue obtained is purified by column chromatography on silica gel (ethyl acetate/petroleum ether=1:5; silica gel: 200-300 mesh), which gives 10.5 g of 7-chloroquinoxalin-2-ylamine (yield 98%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][C:8]([C:11](=[O:15])[CH2:12][O:13][CH3:14])=[CH:9][N:10]=1.O1CCCC1.C(O)C.[BH4-].[Na+]>O>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[S:7][C:8]([CH:11]([OH:15])[CH2:12][O:13][CH3:14])=[CH:9][N:10]=1
Reactant: COCC(=O)c1cnc(C2OCCO2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COCC(O)c1cnc(C2OCCO2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
To a solution of 1-[2-(1,3-dioxolan-2-yl)-1,3-thiazol-5-yl]-2-methoxyethanone (2.00 g) in a mixed solvent of tetrahydrofuran (10 mL) and ethanol (10 mL) was slowly added sodium borohydride (0.18 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, the title compound (1.84 g, yield 91%) was obtained as a colorless oil from a fraction eluted with ethyl acetate. MS: 232 (MH+).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:31])[CH:6]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[NH:30])[NH2:29])=[CH:24][CH:23]=1)[C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[C:10]([O:16][CH2:17][CH2:18][OH:19])=[CH:9][C:8]=1[F:20])[CH3:3].Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34].C(N(CC)CC)C.C(Cl)Cl.CC(C)=O>CN(C=O)C>[CH2:2]([O:4][C:5](=[O:31])[CH:6]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([NH2:29])=[N:30][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:24][CH:23]=1)[C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[C:10]([O:16][CH2:17][CH2:18][OH:19])=[CH:9][C:8]=1[F:20])[CH3:3]
Reactant: CCOC(=O)C(Nc1ccc(C(=N)N)cc1)c1cc(OCC)c(OCCO)cc1F
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCOC(=O)N=C(N)c1ccc(NC(C(=O)OCC)c2cc(OCC)c(OCCO)cc2F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
The (RS)-(4-carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester hydrochloride (100 mg) described in example 1.6 was dissolved in DMF (1 ml). At 0° C., ethyl chloroformate (24 mg) and triethylamine (67 mg) were added. The mixture was stirred for 1 h at 0° C. The product was isolated by extraction and column chromatography (CH2Cl2/acetone) to give 106 mg of (RS)-[4-(amino-ethoxycarbonylimino-methyl)-phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester as a colorless foam. MS: 492 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][O:19][NH:20][CH3:21].O.N1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[N:20]([O:19][CH3:18])[CH3:21])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq, 21.8 mmol) was dissolved under inert conditions in 35 ml dry N,N-dimethylformamide. O,N-dimethyl-hydroxylamine hydrochloride (1.03 eq, 22.5 mmol), benzotriazol-1-ol monohydrate (1.03 eq, 22.5 mmol) and triethylamine (1.5 eq, 32.7 mmol) were added. The reaction mixture was cooled to 0° C., N-(3-Dimethylaminopropyl)-N-ethylcarbodiimid hydrochloride (1.0 eq, 21.8 mmol) was added over a period of 10 minutes and the mixture was stirred vigorously at 0° C. for 1 h and at r.t. for 18 h.
Reaction SMILES: [SH:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[F:16][C:17]([F:22])([F:21])[CH2:18][CH2:19]I>CCO>[F:16][C:17]([F:22])([F:21])[CH2:18][CH2:19][S:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(S)nc1
Reactant: FC(F)(F)CCI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1ccc(SCCC(F)(F)F)nc1
Yield: 56.7 %

Procedure:
To a stirred solution of 6-sulfanylpyridine-3-carboxylic acid (0.5 g, 3.22 mmol) in EtOH (50 mL) at 0 C was added sodium acetate (0.26 g, 3.22 mmol) and 1,1,1-trifluoro-3-iodopropane (0.72 g, 3.22 mmol) and the mixture was heated at 80 C for 24 h. The mixture was concentrated under vacuum, water was added and the mixture was acidified to pH 4 using acetic acid. The resultant yellow precipitate was collected by filtration and purified by FCC, eluting with 2% MeOH in DCM to afford the title compound (0.459 g, 57%). Method B HPLC-MS: MH+ requires m/z=252 Found: m/z=252, Rt=1.84 min (91%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[CH2:19][NH:18][C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[S:15]2)=[O:13])=[CH:7][C:6]=1[OH:24])([CH3:4])([CH3:3])[CH3:2].[OH:25]O>C(O)(=O)C.CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([CH:14]2[S:15](=[O:25])[C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[NH:18][CH2:19]2)=[O:13])=[CH:7][C:6]=1[OH:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: OO
Reactant: CC(C)(C)c1ccc(NC(=O)C2CNc3ccccc3S2)cc1O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(NC(=O)C2CNc3ccccc3S2=O)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.5 %

Procedure:
A solution of N-(4-tert-butyl-3-hydroxy-phenyl)-3,4-dihydro-2H-1,4-benzothiazine-2-carboxamide (20 mg, 0.058 mmol) in acetic acid (500 μL) was treated with hydrogen peroxide (12 μL of aq. 30% w/w, 0.12 mmol) and stirred at room temperature for 2 h. The reaction was diluted with DMF and purified by HPLC (10-99% CH3CN/5 mM HCl) to provide N-(4-tert-butyl-3-hydroxy-phenyl)-1-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-2-carboxamide (8 mg, 38% yield). LC/MS m/z 359.2 [M+H]+.
Reaction SMILES: [CH2:1]([CH:5]([CH2:8][OH:9])[CH2:6][OH:7])[CH2:2][CH2:3][CH3:4].C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([CH:5]1[CH2:8][O:9][CH:13]([CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[O:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC1COC(C(C(=O)OCC)C(=O)OCC)OC1
Yield: 89.4 %

Procedure:
A mixture of 17.45 g of 2-butyl-1,3-propanediol, 26.4 g of diethyl (ethoxymethylidene)-malonate, 250 ml of toluene and 0.285 g of p-toluenesulfonic acid monohydrate was heated to boiling for 1 hour, with moist toluene being distilled off and replaced by the addition of fresh toluene. The reaction mixture was neutralized with triethylamine and, after cooling, washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product (42.35 g) was chromatographed on 520 g of silica gel with hexane/ethyl acetate (4:1). 33.0 g of oily diethyl (5-butyl-1,3-dioxan-2-yl)-malonate were obtained.
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1.[C:13](=[O:15])=[O:14]>Cl.C1COCC1>[F:12][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([F:11])[CH:8]=1)[C:13]([OH:15])=[O:14]
Reactant: Fc1cc(F)cc(Br)c1
Reactant: O=C=O
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C(O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 54 %

Procedure:
In a reactor under an N2-atmosphere, 22.7 g (933 mmol) of magnesium flakes were added and stirred at room temperature for 3 days. Then, 80 ml of THF and an iodine flake were added, a 100 ml THF solution of 150 g (777 mmol) of 1-bromo-3,5-difluorobenzene was slowly added at room temperature, and then the mixture was refluxed for 1 hour. Next, the mixture was cooled to 10° C., slowly added with 75 g (1710 mmol) of dry ice and stirred at room temperature for 1 hour. The reaction solution was poured in 500 ml of 1N HCl(aq) and then subjected to extraction with ethyl acetate. The organic layer was collected, washed with water, dried over anhydrous magnesium sulfate, filtered to remove insoluble substance, and concentrated under a reduced pressure. The residue was washed using n-heptane to obtain 66.3 g of 3,5-difluorobenzoic acid as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:11]([S:12]([N:15]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:16]2[S:17][CH:18]=[CH:19][N:20]=2)(=[O:14])=[O:13])=[CH:10][C:5]2[O:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.Br[C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=1[O:41][CH3:42].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[C:11]([S:12]([N:15]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:16]2[S:17][CH:18]=[CH:19][N:20]=2)(=[O:14])=[O:13])=[CH:10][C:5]2[O:6][CH2:7][CH2:8][N:9]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=3[O:41][CH3:42])[C:4]=2[CH:3]=1
Reactant: COc1cc(C(F)(F)F)ccc1Br
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2cc3c(cc2Br)NCCO3)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2cc3c(cc2Br)N(c2ccc(C(F)(F)F)cc2OC)CCO3)cc1
Temperature: 25 °C
Yield: 46.3 %

Procedure:
A vial was charged with 6-bromo-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (107.43 mg, 0.216 mmol), 1-bromo-2-methoxy-4-(trifluoromethyl)benzene (Sigma-Aldrich, St. Louis, Mo., 193 mg, 0.757 mmol), Xantphos (25.04 mg, 0.043 mmol), Pd2(dba)3 (19.82 mg, 0.022 mmol), and cesium carbonate (212 mg, 0.649 mmol). The vessel was flushed with Ar (g), then 1,4-dioxane (2164 μl) was added. The vessel was sealed and placed in a 100° C. heating bath for 20 h. The mixture was cooled to room temperature, diluted with EtOAc, and filtered through celite. The filtrate was concentrated, and the residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-50% EtOAc/Heptane) to give 6-bromo-4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (67 mg, 0.100 mmol, 46.2% yield) as a yellow foam: m/z (ESI) 670.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[CH:15]2[O:16][CH2:17][CH:18]([O:19][CH2:20][CH2:21][OH:22])[CH:14]2[O:13][CH2:12]1.C(N(CC)CC)C>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[CH:15]3[O:16][CH2:17][CH:18]([O:19][CH2:20][CH2:21][OH:22])[CH:14]3[O:13][CH2:12]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: NC1COC2C(OCCO)COC12
Solvent: CCO
Solvent: CCN(CC)CC
Product: OCCOC1COC2C(Nc3nc(Cl)ncc3Cl)COC12
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
To a suspension of 2,4,5-trichloropyrimidine (0.71 g, 3.88 mmol) in EtOH (20 mL) were added 2-((6-aminohexahydrofuro[3,2-b]furan-3-yl)oxy)ethanol (crude product) and N,N-diethylethanamine (1.10 mL, 7.89 mmol). The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by silica chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as brown liquid (0.21 g, 16%, for three steps).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:11]1[CH:16]=[C:15]([O:17][C:18]2[S:19][CH:20]=[C:21]([C:23](OCC)=[O:24])[N:22]=2)[CH:14]=[C:13]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:12]=1[OH:32])([CH3:10])([CH3:9])[CH3:8].O.S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)C.O1CCCC1>[C:28]([C:13]1[CH:14]=[C:15]([O:17][C:18]2[S:19][CH:20]=[C:21]([CH2:23][OH:24])[N:22]=2)[CH:16]=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:12]=1[OH:32])([CH3:31])([CH3:30])[CH3:29]
Reactant: CCOC(=O)c1csc(Oc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(Oc2nc(CO)cs2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Yield: 42.2 %

Procedure:
Lithium aluminum hydride (0.40 g) was suspended in 100 ml of diethyl ether, a solution (30 ml) of 0.80 g of 2,6-di-tert-butyl-4-[(4-ethoxycarbonyl-2-thiazolyl)oxy]phenol (produced in Example 40) in tetrahydrofuran was added to the suspension with stirring at room temperature, and the resultant mixture was stirred for further 4 hours. Water and then magnesium sulfate were added to the reaction mixture with cooling in an ice bath, and the resultant mixture was stirred for 15 minutes. The insoluble matter was filtered off, and the filtrate was concentrated. The crude product obtained was recrystallized from diethyl ether-hexane to give 0.30 g of the desired product as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:9]=[O:10])[C:7]=1[OH:8].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)C(C)C)C>ClCCl>[CH3:15][O:14][C:12](=[O:13])[CH2:11][C:4]1[CH:5]=[C:6]([CH:9]=[O:10])[C:7]([O:8][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:2]([Br:1])[CH:3]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1cc(Br)c(O)c(C=O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Cc1cc(Br)c(OCc2ccccc2)c(C=O)c1
Temperature: 25 °C

Procedure:
To a 250 mL round-bottomed flask with a teflon stir bar and a reflux condensor were added methyl (3-bromo-5-formyl-4-hydroxyphenyl)acetate (23.3 g, 85.3 mmol, prepared as described in Reference A above), dichloromethane (100 mL), benzyl bromide (15.32 g, 10.64 mL, 89.59 mmol), and N-ethyldiisopropylamine (11.6 g, 15.6 mL, 89.5 mmol). The reaction mixture was heated to reflux for 14 h and then allowed to cool to room temperature. Dichloromethane (100 mL) was added and the organic layer was separated and washed with 200 mL of a 3% solution of NaOH in water. The organic layer was concentrated to give (4-benzyloxy-3-bromo-5-formyl-phenyl)acetic acid methyl ester (30.65 g) as oil.