Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:23]([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CC(C)=O>[CH2:27]([O:26][C:24](=[O:25])[CH:23]([N:6]1[C:5]2[CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[C:2]([F:1])=[CH:3][C:4]=2[O:9][CH2:8][C:7]1=[O:10])[CH3:29])[CH3:28]
Reactant: O=C1COc2cc(F)c([N+](=O)[O-])cc2N1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)N1C(=O)COc2cc(F)c([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
A suspension of 7-fluoro-6-nitro-4H-benzo[1,4]oxazin-3-one (3.50 g, 16.50 mmol) and K2CO3 (3.42 g, 24.75 mmol) in acetone (100 mL) was stirred at rt for 15 min. A solution of ethyl 2-bromopropanoate (5.97 g, 33.0 mmol) in acetone (60 mL) was added dropwise and the reaction mixture was heated at reflux for 5 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was dissolved in DCM (50 mL) and washed with water (50 mL). The organic phase was separated and dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 0-30% EtOAc in petroleum ether) to give 2-(7-fluoro-6-nitro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester as a white solid (3.29 g, 64%). 1H NMR (DMSO-d6, 400 MHz): δ 7.89 (d, J=7.2 Hz, 1H), 7.39 (d, J=11.6 Hz, 1H), 5.28 (q, J=7.2 Hz 1H), 4.86 (s, 2H), 4.02-4.16 (m, 2H), 1.48 (d, J=7.2 Hz, 3H), 1.12 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[S:10][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]([C:26]3[O:27][C:28]4[C:33]([C:34](=[O:43])[C:35]=3[C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH3:25])[N:15]=2)=[CH:12][CH:13]=1)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]([C:26]3[O:27][C:28]4[C:33]([C:34](=[O:43])[C:35]=3[C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH3:25])[N:15]=[C:14]([C:11]3[S:10][C:9]([CH2:8][NH2:7])=[CH:13][CH:12]=3)[C:22]=12
Reactant: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccc(CNC(=O)OC(C)(C)C)s2)c2c(N)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccc(CN)s2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.3 %

Procedure:
To a solution of Example 102 (0.070 g, 0.114 mmoles) in dichloromethane (3 ml), TFA (0.1 ml) was added under nitrogen atmosphere stirred at room temperature. After 3 h, the reaction mixture was concentrated, neutralised with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as yellow solid (0.030 g, 51% yield). MP: 275-278° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 8.06 (s, 1H), 8.05 (dd, J=7.9, 1.5 Hz, 1H), 7.85 (m, 1H), 7.66 (d, J=8.3 Hz, 1H), 7.53 (t, J=7.2 Hz, 1H), 7.28 (m, 2H), 7.09 (d, J=3.5 Hz, 1H), 7.05 (dt, J=8.7, 2.4 Hz, 1H), 6.92 (br s, 2H), 6.02 (q, J=7.1 Hz, 1H), 4.03 (s, 2H), 1.87 (d, J=7.1 Hz, 3H). Mass: 513.27 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:14]([CH3:15])=[C:13]([CH3:16])[S:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>CN(C=O)C>[Br:17][C:11]1[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=1[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1scc(C(=O)c2ccc(Cl)cc2)c1C
Solvent: CN(C)C=O
Product: Cc1sc(Br)c(C(=O)c2ccc(Cl)cc2)c1C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a solution of (4-chlorophenyl)(4,5-dimethylthiophen-3-yl)methanone (1.99 g, 7.94 mmol) in DMF (15 mL) was added N-bromosuccinimide (1.55 g, 8.71 mmol) in one portion. After 2 h, the reaction mixture was partitioned between water and MTBE. The aqueous layer was extracted with MTBE and the combined organic layer was washed with 1% sodium thiosulfate, water, dried over Na2SO4 and concentrated to give light yellow solids. The resultant solids was purified on Biotage system (gradient elution 1% EtOAc:99% Hexanes to 4% EtOAc:96% Hexanes) to give the titled compound as yellow solids (2.40 g, 7.28 mmol, 92% yield). LC/MS m/z 329 [(M (35Cl, 79Br)+H]+ and m/z 331 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2[CH:21]=1.[CH3:22][NH:23][CH3:24]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:23]([CH3:24])[CH3:22])=[CH:21][C:10]=3[S:11][CH:12]=2)=[CH:15][CH:16]=1
Reactant: Fc1ccc(-c2csc3cc(OCCCBr)ccc23)cc1
Reactant: CNC
Product: CN(C)CCCOc1ccc2c(-c3ccc(F)cc3)csc2c1

Procedure:
In analogy to example 3.1, 6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and dimethylamine were converted to yield {3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-dimethyl-amine as colorless oil, MS: 330 (MH+).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][N:13]3[CH:20]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.[ClH:26].[CH2:27]([OH:29])[CH3:28]>>[ClH:26].[C:1]1([NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18](=[NH:19])[O:29][CH2:27][CH3:28])=[CH:14][N:13]3[CH:20]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: N#Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=N)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A suspension of 300 mg of N-phenyl-6-cyanoimidazo[1,2-a]pyridine-2-carboxamide (Intermediate 2) in 25 mL of ethanol containing 0.5 mL of DMF is cooled to 0° C. and then treated for 1 hour 40 minutes with hydrogen chloride gas. The reaction mixture is stirred at room temperature for 16 hours and then concentrated under reduced pressure to a small volume. The precipitate is filtered off by suction and washed with ethanol and ethyl ether to give 296 mg of ethyl 2-phenylcarbamoylimidazo[1,2-a]pyridine-6-carboximidate hydrochloride (1:1) in the form of a white solid, which is used without further purification for the rest of the synthesis.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[N:6][C:7]([Cl:23])=[CH:8][C:9]=1[C:10]([C:12]1[CH:21]=[C:20]([CH3:22])[C:15]2[NH:16][C:17](=[O:19])[O:18][C:14]=2[CH:13]=1)=[O:11].I[CH3:25]>CN(C=O)C>[Cl:3][C:4]1[N:5]=[N:6][C:7]([Cl:23])=[CH:8][C:9]=1[C:10]([C:12]1[CH:21]=[C:20]([CH3:22])[C:15]2[N:16]([CH3:25])[C:17](=[O:19])[O:18][C:14]=2[CH:13]=1)=[O:11]
Reactant: CI
Reactant: Cc1cc(C(=O)c2cc(Cl)nnc2Cl)cc2oc(=O)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2cc(Cl)nnc2Cl)cc2oc(=O)n(C)c12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
85 mg (2.1 mmol) sodium hydride (55%, suspension in mineral oil) were added to 0.65 g (2.0 mmol) 6-(3.6-dichloro-pyridazine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one in 10 mL DMF while cooling with ice. The reaction mixture was stirred for 20 min. Then 0.19 mL (3.1 mmol) iodomethane were added while cooling with ice and the mixture was stirred for 2 h at RT. The reaction mixture was mixed with ice water, the precipitate formed was suction filtered and dried.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].O=[C:12]([CH2:19][CH2:20][CH3:21])[CH2:13][C:14](OCC)=[O:15]>>[OH:15][C:14]1[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=[C:12]([CH2:19][CH2:20][CH3:21])[CH:13]=1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: N#Cc1ccnc(NN)c1
Product: CCCc1cc(O)n(-c2cc(C#N)ccn2)n1
Yield: 44 %

Procedure:
The title compound was prepared in 44% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 3-oxohexanoate according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C12H12N4O, 229; Found, 229.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N:7]1([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8]1.[NH2:21][C:22]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:32]=[CH:31][C:23]=1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].Cl>C(OCC)(=O)C.C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[C:35]1([C:33]2[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])=[C:22]([NH:21][C:16](=[O:18])[C:15]3[CH:14]=[CH:13][C:12]([N:7]4[CH:8]=[CH:9][CH:10]=[CH:11]4)=[CH:20][CH:19]=3)[CH:34]=2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Reactant: O=C(O)c1ccc(-n2cccc2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-n2cccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.015 mL of N,N-dimethylformamide was added to a mixed solution of 2.0 mL of methylene chloride and 0.024 mL of oxalyl chloride containing 47 mg of 4-(1H-pyrrol-1-yl)benzoic acid and stirred at room temperature for 30 minutes. 67 mg of tert-butyl 2-amino-4-phenylbenzoate and 0.090 mL of triethylamine were added to the reaction mixture at room temperature sequentially and stirred at the same temperature for 30 minutes. Ethyl acetate and 1.0 mol/L hydrochloric acid were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; chloroform] to obtain 64 mg of tert-butyl 4-phenyl-2-(4-(1H-pyrrol-1-yl)benzamido)benzoate as white solid.
Reaction SMILES: [O-:1][Mn](=O)(=O)=O.[K+].[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:18]=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.N1C=CC=CC=1>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:18]([OH:1])=[O:19])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C(=O)O)cc1OCc1ccccc1
Yield: 88.5 %

Procedure:
A solution of KMnO4 (24.81 g, 0.157 mole) in water (100 ml) was added under stirring with a solution of tetrabutylammonium bromide (50.61 g, 0.157 mole) in water (200 ml), diluting with further water (200 ml). The solid was separated by filtration, squeezed and dissolved in pyridine (300 ml). The solution was dropped into a solution of 3-benzyloxy-4-methoxy-benzaldehyde (38.2 g, 0.157 mole), prepared as described in example 52, in pyridine (150 ml) in water bath. After 3 hours the mixture was brought to acidic pH with 1N HCl, the solid was filtered off and the mother liquors were extracted more times with CH2Cl2. The organic phase was anhydrified, concentrated and the residue taken up in 1N NaOH and washed with ethyl ether. The aqueous solution was acidified and extracted twice with CH2Cl2, brought to dryness, discoloured with TONSIL® and concentrated to small volume. The precipitate was filtered to give 35.869 g of the title compound (yield: 88%).
Reaction SMILES: CN.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:15]2[S:16][C:17]([C:21]([O:23]CC)=O)=[C:18]([CH3:20])[N:19]=2)[CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12].COC1C=C(C=C(OC)C=1OC)[C:31]([NH2:33])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=S.ClC(C(C)=O)C(OCC)=O>C(O)CCC.C(O)C>[CH3:20][C:18]1[N:19]=[C:15]([C:7]2[CH:6]=[C:5]([O:4][CH3:3])[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=2)[S:16][C:17]=1[C:21]([NH:33][CH3:31])=[O:23]
Reactant: COc1cc(C(N)=O)cc(OC)c1OC
Reactant: CCOC(=O)c1sc(-c2cc(OC)c(OC)c(OC)c2)nc1C
Agent: CCOC(=O)C(Cl)C(C)=O
Agent: CN
Agent: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CCO
Solvent: CCCCO
Product: CNC(=O)c1sc(-c2cc(OC)c(OC)c(OC)c2)nc1C
Reaction time: 240 h
Yield: 60 %

Procedure:
Into a mixture of 80 ml of 40% solution of methylamine and 420 ml of ethanol, 16.9 g of ethyl 2-(3,4,5-trimethoxyphenyl)-4-methylthiazole-5-carboxylate which had been prepared by heating a mixture of 3,4,5-trimethoxybenzamide, phosphorus pentasulfide, ethyl α-chloroacetoacetate and n-butylalcohol under a reflux condenser for 5 hours was dissolved and the solution was left for 10 days at room temperature. Then the solution was condensed to solid under a reduced pressure. The thus obtained residue was recrystallized from an aqueous ethanolic solution to obtain the object as colourless minute aciculate melting at 177.5° to 179.5° C. in an amount of 10.5 g corresponding to the yield of 60%.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[N:10]=[C:11]([NH2:14])[S:12][CH:13]=1)[NH2:7].[N:16]1([S:22]([NH:25][C@H:26]([C:34](O)=[O:35])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:24])=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.C(N(CC)CC)C.CN(C)C=O>[ClH:1].[CH3:3][O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[N:10]=[C:11]([NH2:14])[S:12][CH:13]=1)[NH:7][C:34](=[O:35])[C@H:26]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[NH:25][S:22]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)(=[O:24])=[O:23]
Reactant: COC(=O)[C@@H](N)Cc1csc(N)n1
Reactant: O=C(O)[C@H](Cc1ccccc1)NS(=O)(=O)N1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1csc(N)n1)NC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)N1CCOCC1
Temperature: 5 °C
Reaction time: 8 h

Procedure:
3-(2-Amino-4-thiazolyl)-L-alanine methyl ester dihydrochloride, 12 kg (43.8 mol), 13.8 kg of N-(4-morpholinylsulfonyl)-L-phenylalanine (European Published Patent Application 0399556), 6.0 kg of hydroxybenzotriazole (HOBT), and 110 L of dimethylformamide are charged into a 800 L reactor and cooled to 5° C. Triethylamine, 9.4 kg, is charged over 10 minutes and cooled to 5° C. A solution of 9.5 kg of dicyclohexylcarbodiimide in 350 L of ethyl acetate is charged into the reaction mixture over a 15 minute period at 5° C. The slurry is allowed to warm to room temperature and stirred overnight. The slurry is diluted with 424 L of ethyl acetate and filtered. The cake is washed with 50 L of ethyl acetate. The filtrate is washed with water (2×140 L) and saturated sodium bicarbonate solution (2×150 L). The solution is diluted with 193 L of isopropyl alcohol. After cooling to 5° C., anhydrous hydrogen chloride gas (3.2 kg) is added to precipitate the product. After isolation by filtration, the product is dried at 25° C. under vacuum to give 18 kg of N-(4-morpholinyl-sulfonyl)-L-phenylalanyl-3-(2-amino-4-thiazolyl)-L-alanine methyl ester monohydrochloride as a white solid, 99.6% pure by HPLC; mass spectrum (chemical ionization) 498 M+H.
Reaction SMILES: CS(O[CH2:6][C:7]12[O:39][CH:8]1[C@@H:9]1[C@H:13]([CH2:14]2)[C@H:12](/[CH:15]=[CH:16]/[C@@H:17]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)(=O)=O.C1C2C(=CC=CC=2)C=CC=1.[Na].[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[OH:39][CH:8]1[C:7](=[CH2:6])[CH2:14][C@H:13]2[C@@H:9]1[CH2:10][C@@H:11]([O:31][Si:32]([C:35]([CH3:36])([CH3:38])[CH3:37])([CH3:33])[CH3:34])[C@H:12]2/[CH:15]=[CH:16]/[C@@H:17]([O:23][Si:24]([C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:25])[CH3:26])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCC[C@@H](/C=C/[C@H]1[C@H]2CC3(COS(C)(=O)=O)OC3[C@H]2C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C1C[C@@H]2[C@H](/C=C/[C@H](CCCCC)O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]2C1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
A solution of 917 mg (1.52 mmoles) of (1S,2RS,-3RS,5S,6S,7R)-3-methanesulfonyloxymethyl-2,3-epoxy-6-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-7-t-butyldimethylsilyloxybicyclo[3.3.0]octane obtained in Example 2 in 3 ml of tetrahydrofuran was added to an anion radical solution prepared by reacting naphthalene (1.28 g, 10 mmoles) with sodium (207 mg, 9 mmoles) in 30 ml of tetrahydrofuran at room temperature for I hour. The mixture was stirred at room temperature for 10 minutes and 3.0 g of ammonium chloride was added to the reaction solution. Then, a saturated aqueous solution of ammonium chloride was added and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give a crude product. It was subjected to column chromatography (silica gel 50 g; hexane/ethyl acetate=19/1) to give (1S,2RS,5S,-6S,7 R)-2-hydroxy-3-methylene-6-[(E,3S)-3-t-butyldimethylsilyloxy- 1-octenyl) -7-t-butyldimethylsilyloxybicyclo[3.3.0]octane (605 mg, 1.19 mmoles, 78%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8]([C:10]1[CH:14]=[CH:13][O:12][C:11]=1[CH3:15])=[O:9].[OH-].[Na+].CN([CH:21]=[O:22])C>>[CH3:6][O:7][C:8]([C:10]1[CH:14]=[C:13]([CH:21]=[O:22])[O:12][C:11]=1[CH3:15])=[O:9]
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccoc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(C=O)oc1C
Reaction time: 3 h

Procedure:
Phosphorus oxychloride (33 ml) is added dropwise to a solution of 2-methyl-furan-3-carboxylic acid methyl ester (25.0 g) in DMF (75 ml) under nitrogen at 0° C. After 3 h 30 at 40° C., the reaction mixture is slowly poured onto water at 0° C. and NaOH 5 N is added carefully. The mixture is extracted three times with diethyl ether. The combined organic phases are washed with a saturated aqueous solution of NaHCO3, dried over Na2SO4 and concentrated in vacuo. The crude product is purified by chromatography on silica gel eluting with a mixture of diethyl ether and ethyl acetate (3:1) to yield 5-formyl-2-methyl-furan-3-carboxylic acid methyl ester (22.36 g) as a yellow solid. MS (HPLC/MS): 169 (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].[C:12]12([C:22]3[CH:23]=[C:24](Br)[CH:25]=[CH:26][C:27]=3[O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO.O.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:12]12([C:22]3[CH:23]=[C:24]([C:6]4[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=4)[CH:25]=[CH:26][C:27]=3[O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31])[CH2:13][CH:14]3[CH2:20][CH:18]([CH2:17][CH:16]([CH2:15]3)[CH2:21]1)[CH2:19]2
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1C12CC3CC(CC(C3)C1)C2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(C=O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 78 %

Procedure:
A mixture of 4-formylphenyl boronic acid (0.301 g, 2.00 mmol), 3-(1-adamantyl)-4-(t-butyldimethylsilyloxy)bromobenzene (0.768 g, 1.82 mmol, prepared in a similar manner as described by Charpentier, B. et al. in J. Med. Chem. 1995, 38, 4993–5006) and potassium carbonate (0.757 g, 5.47 mmol) in 60 mL of toluene:methanol (4:1) and water (2 mL) was degassed with argon for 30 minutes. Tetrakis(triphenylphosphine) palladium(0) (0.422 g, 0.36 mmol) was added and the mixture heated at reflux for 19 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (eluent: hexane:EtOAc, 97:3) to give 0.500 g of 4-[3-(1-adamantyl)-4-(t-butyldimethylsilyloxy)phenyl]-benzaldehyde (78%) as a solid. 1H NMR (300 MHz; CDCl3): 0.38 (s, 6H), 1.07 (s, 9H), 1.79 (s, 6H), 2.10–2.17 (m, 9H), 6.89 (d, J=8.7 Hz, 1H), 7.34 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 7.52 (d, J=2.4 Hz, 1H), 7.71 (d, J=8.1 Hz, 2H), 7.91 (d, J=8.1 Hz, 2H), 10.02 (brs, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)=[C:4]([F:27])[CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].Cl>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:27][C:4]1[CH:3]=[C:2]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[O:29][CH3:28])[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]1
Reactant: CC(C)c1nn(Cc2ccc(Br)cc2F)c(=O)c(C(=O)NCC(=O)O)c1O
Reactant: COc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1-c1ccc(Cn2nc(C(C)C)c(O)c(C(=O)NCC(=O)O)c2=O)c(F)c1
Yield: 31.2 %

Procedure:
To a 5 ml microwave tube was added N-{[2-[(4-bromo-2-fluorophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 46(b), 75 mg, 0.17 mmol), 2-methoxyphenyl boronic acid (31 mg, 0.20 mmol), potassium carbonate (70 mg, 0.51 mmol), and tetrakis(triphenylphosphine)palladium (0) (6 mg, 5 μmol), 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (5 ml), acidified with 1N HCl (2 ml), and extracted with ethyl acetate (20 ml). The organic phase was washed with brine, dried over MgSO4, filtered, and solvents removed under reduced pressure. The crude residue was purified HPLC chromatography (ODS silica, gradient 15-95% acetonitrile/water) to afford the title compound (25 mg, 0.053 mmol, 31% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.91 (s, 1H), 12.93 (br. s., 1H), 10.16 (t, J=5.56 Hz, 1H), 7.23-7.41 (m, 5H), 7.12 (d, J=7.83 Hz, 1H), 7.03 (dt, J=7.39, 0.88 Hz, 1H), 5.33 (s, 2H), 4.10 (d, J=5.81 Hz, 2H), 3.77 (s, 3H), 3.19 (sept, J=6.86 Hz, 1H), 1.20 (d, J=6.82 Hz, 6H). MS (ES+) m/e 470 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])[CH:3]=1.[CH3:16][Mg]I>C(OCC)C.O>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH3:16])=[C:4]([O:10][C@H:11]([CH2:13][CH:14]=[CH2:15])[CH3:12])[CH:3]=1
Reactant: C[Mg]I
Reactant: C=CC[C@H](C)Oc1cc(C)ccc1C=O
Solvent: CCOCC
Solvent: O
Product: C=CC[C@H](C)Oc1cc(C)ccc1C(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a mixture of (S)-4-methyl-2-(pent-4-en-2-yloxy)benzaldehyde (50 mg, 0.245 mmol) in diethyl ether (2 mL) was added methylmagnesium iodide (0.245 mL, 0.734 mmol) and the mixture was stirred at rt for 1 h. It was then diluted with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 25% EtOAc/hexane to obtain 1-(4-methyl-2-((S)-pent-4-en-2-yloxy)phenyl)ethanol (50 mg, 93%) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.19 (dd, J=7.7, 3.8 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.71 (s, 1H), 5.88 (ddtd, J=17.2, 10.3, 7.0, 3.5 Hz, 1H), 5.22-5.10 (m, 2H), 5.10-4.96 (m, 1H), 4.62-4.47 (m, 1H), 2.94 (dd, J=18.8, 5.4 Hz, 1H), 2.64-2.38 (m, 2H), 2.34 (s, 3H), 1.51 (d, J=6.6 Hz, 3H), 1.37 (dd, J=6.0, 4.0 Hz, 3H).