Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[S:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=1.[BrH:15]>O>[Br:15][C:6]1[S:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=1
Reactant: Br
Reactant: Nc1nnc(C(F)(F)F)s1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1nnc(Br)s1
Yield: 87 %

Procedure:
A solution of 69 g (1.0 mole) of sodium nitrite in 150 ml of water was added dropwise over the course of 1.5 hours, while stirring, to a solution, cooled to +5° C, of 84.5 g (0.5 mole) of 2-amino-5-trifluoromethyl-1,3,4-thiadiazole in a mixture of 400 ml of hydrogen bromide (48% strength) and 100 ml of water. Thereafter, the evolution of the nitrous gases and of the nitrogen was completed by stirring at 25° C (1 hour). The product separated out as a dark brown, heavy liquid and was abstracted from the reaction mixture by repeated extraction with a total of 500 ml of methylene chloride. After washing with 2 × 100 ml of water, drying over sodium sulfate and careful distillation of the solvent, the residue was fractionated in vacuo through a short column. 101 g (87% of theory) of 2-bromo-5-trifluoromethyl-1,3,4-thiadiazole of boiling point 55° C/10 mm Hg were obtained. ##STR80##
Reaction SMILES: [C:1]1([CH:7]([C:15]([OH:17])=[O:16])[NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[CH3:19].[H-].[Na+].O>O1CCCC1.C(OCC)(=O)C>[C:1]1([CH:7]([C:15]([OH:17])=[O:16])[N:8]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C(NC(=O)C(F)(F)F)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)C(F)(F)F)C(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
A mixture of 2-phenyl-N-(trifluoroacetyl)-glycine (2.5 g, 0.01 mol) and iodomethane (11.35 g, 0.08 mol) in tetrahydrofuran is treated portionwise with a 60% dispersion of sodium hydride in mineral oil (1.2 g, 0.03 mol NaH), stirred at ambient temperatures for 1 hour, heated at reflux temperature for 17 hours, cooled to room temperature, diluted with ethyl acetate followed by 1 mL of water and concentrated in vacuo to a wet yellow solid residue. The residue is dispersed in a mixture of ether and water. The ether layer is washed with a sodium bicarbonate solution. The aqueous phases are combined, acidified with 10% HCl and extracted with ethyl acetate. The ethyl acetate extract is washed sequentially with water, sodium thiosulfate and saturated sodium chloride solution, dried over MgSO4 and concentrated in vacuo to give a pale yellow solid which is recrystallized for methylcyclohexane to give the title compound as white crystals, 0.5 g, (19.1% yield), mp 124°-126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20](=[O:39])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([S:29]([N:32]3[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]3)(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[C:6]([N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9](=O)[C:10](=[O:12])[CH3:11])[CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CO>[C:10]([C:9]1[N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[C:5]([C:20](=[O:39])[C:21]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([N:32]3[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]3)(=[O:31])=[O:30])=[CH:27][CH:28]=1)=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=2)(=[O:12])[CH3:11]
Reactant: CC(=O)C(=O)N(c1ccccc1)c1cc(Cl)ccc1C(=O)CCc1ccc(S(=O)(=O)N2CCC(O)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)c1c(Cc2ccc(S(=O)(=O)N3CCC(O)CC3)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 80 °C

Procedure:
To N-(5-chloro-2-{3-[4-(4-hydroxypiperidine-1-sulfonyl)-phenyl]-propionyl}-phenyl)-2-oxo-N-phenyl-propionamide in MeOH was added K2CO3 (0.096 g), and the mixture heated at 80° C. for 1.5 h, then concentrated. The residue was taken up in EtOAc/H2O, and the aqueous layer washed with EtOAc (2×25 mL). The combined organic layers were dried over Na2SO4, and the solvent removed under reduced pressure. The residue was chromatographed on anhydrous silica (20% EtOAc/hexanes 0-5 min; 60% EtOAc/hexanes 15-20 min; 100% EtOAc 22-35 min) to provide 2-acetyl-7-chloro-3-[4-(4-hydroxypiperidine-1-sulfonyl)-benzyl]-1-phenyl-1H-quinolin-4-one (compound 70). Mp=145.5-147.2° C.; M+H 551.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:7][CH:6]=1
Reactant: BrCCCCCOc1ccccc1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCCCCOc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with (5-bromopentoxy)benzene (1.4 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was purified by HPLC (dichloromethane-hexane; 4:1) to provide 0.9 g of analytically pure alpha-oxo-4-[[(5-phenoxy)pentyl]oxy]benzeneacetic acid methyl ester which failed to crystallize.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:11]([CH:12]=O)=[CH:10][N:9]=[C:8]([Cl:14])[CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>CC(O)=O>[C:1]([NH:5][C:6]1[C:11]([CH2:12][NH:20][C:19]2[CH:21]=[CH:22][C:16]([F:15])=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=2)=[CH:10][N:9]=[C:8]([Cl:14])[CH:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Nc1cc(Cl)ncc1C=O
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(C)Nc1cc(Cl)ncc1CNc1ccc(F)c([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 64.5 %

Procedure:
A mixture of 4-(tert-butylamino)-6-chloronicotinaldehyde (4.0 g, 18.9 mmol), 4-fluoro-3-nitroaniline (2.9 g, 18.9 mmol) and NaBH(OAc)3 (7.1 g, 37.8 mmol) in CH3COOH (80 mL) was heated to 80° C. for 10 h. The reaction was concentrated under reduced pressure to give a sticky solid, which was suspended in ice water. The mixture was neutralized (pH 7) with 2N aqueous NaOH solution and was extracted with EtOAc. The extracts were washed with brine, dried Na2SO4) and concentrated in vacuo. Purification of the residue by chromatography provided N-tert-butyl-2-chloro-5-((4-fluoro-3-nitrophenylamino)methyl)pyridin-4-amine (4.3 g, 65% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.87 (s, 1 H), 7.32 (m, 1 H), 7.27 (m, 1 H), 7.04 (m, 1 H), 6.68 (s, 1 H), 6.52 (m, 1 H), 5.46 (s, 1 H), 4.17 (d, J=4.8 Hz, 2 H), 1.36 (s, 9 H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[OH:22][C:23]1[C:24]([CH3:39])=[C:25]([CH3:38])[C:26]2[O:31][C:30]([CH3:35])([CH2:32][CH2:33]O)[CH2:29][CH2:28][C:27]=2[C:36]=1[CH3:37]>ClCCl>[Br:20][CH2:33][CH2:32][C:30]1([CH3:35])[CH2:29][CH2:28][C:27]2[C:36]([CH3:37])=[C:23]([OH:22])[C:24]([CH3:39])=[C:25]([CH3:38])[C:26]=2[O:31]1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCO)O2
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCBr)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To 11.0 g (0.042 mol) of triphenylphosphine in 200 ml of dichloromethane is added dropwise a solution of 6.71 g (0.042 mol) of bromine in 50 ml of dichloromethane. The solution is stirred for 30 min at room temperature, then 10.0 g (0.04 mol) of 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-ethanol (CAS 79907-48-5) is added. The resulting solution is refluxed for 4 hours, allowed to cool overnight, washed with a solution of 15 g of sodium carbonate in 200 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated. The resulting oil is crystallized from methanol to give 9.22 g of 3,4-dihydro-2-(2-bromoethyl)-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[C:25]#[CH:26])=[O:19])([CH3:16])([CH3:15])[CH3:14].O>N(C(C)C)C(C)C.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.[Cu]I>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[C:25]#[C:26][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#CC1CCCN1C(=O)OC(C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1ccc(C#CC2CCCN2C(=O)OC(C)(C)C)cc1
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
A suspension of ethyl 4-iodobenzoate (1.7 mL, 10 mmol), Pd(PPh3)4 (578 mg, 0.5 mmol), and CuI (190 mmol, 1 mmol) in i-Pr2NH (20 mL) was stirred for 0.5 hr under N2. To this mixture was added a solution of 1-(tert-butoxycarbonyl)-2-ethynylpyrrolidine (1.95 g, 10 mmol) in i-Pr2NH (20 mL) for over 10 min. After stirring for 3 hr at room temp, the mixture was poured into H2O and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, and evaporated. The residue was chromatographed on silica-gel with n-hexane-AcOEt (10:1, v/v) as eluent to give 2.77 g (81%) 1-(tert-butyloxycarbonyl)-2-(2-(4-ethoxycarbonylphenyl)ethynyl) pyrrolidine as a colorless oil. 1H-NMR (CDCl3) δ 1.37 (3 H, t, J=6.8 Hz), 1.49 (9 H, s), 1.85–2.12 (4 H, m), 3.37–3.51 (2 H, m), 4.37 (2 H, q, J=6.8 Hz), 4.54–4.77 (1 H, m), 7.44 (2 H, d, J=7.8 Hz), 7.96 (2 H, d, J=7.8 Hz)
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8](=[O:25])[C:7]2([CH2:29][CH2:28][CH2:27][CH2:26]2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:30]=[N+:31]=[N-:32].[Na+].Cl.Cl.N1CCNCC1.[OH-].[Na+]>CN(C)C=O.O>[CH3:4][CH2:3][CH2:2][CH2:1][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[N:32]=[N:31][NH:30][N:24]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[C:7]2([CH2:26][CH2:27][CH2:28][CH2:29]2)[N:6]=1
Reactant: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: C1CNCCN1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC1=NC2(CCCC2)C(=O)N1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Temperature: 25 °C
Yield: 52.2 %

Procedure:
A mixture of 2-n-butyl-3-[(2′-cyanobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4,4]-non-1-en-4-one (10 g), sodium azide (7.7 g) and piperazine dihydrochloride (7.5 g) in N,N-dimethylformamide (30 ml) was refluxed for 7 hours under stirring. The reaction was cooled to room temperature and 20 ml water was added. The reaction mixture was adjusted to pH of about 12 using 10% NaOH solution. The alkaline solution was washed with toluene (15 ml) and the aqueous phase was neutralized to pH of 6.5 using concentrated HCl. The resulting suspension was stirred for 3 hours at room temperature and filtered to obtain irbesartan (5.8 g, 98% purity by HPLC). Recrystallization of the Product using ethanol results in 5.2 g of irbesartan with 99.94% purity and content of the impurity 2-n-butyl-3-[(2′-carboxamidobiphenyl-4-yl)methyl]-1,3-diazaspiro-[4,4]-non-1-en-4-one: 0.07%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:16][C:17]1[C:18](=[O:37])[N:19]([CH2:24][CH2:25][C@@:26]([CH3:36])([S:32]([CH3:35])(=[O:34])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:20]=[CH:21][C:22]=1I.O>O1CCOCC1.[Pd]>[F:16][C:17]1[C:18](=[O:37])[N:19]([CH2:24][CH2:25][C@@:26]([CH3:36])([S:32]([CH3:35])(=[O:33])=[O:34])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:20]=[CH:21][C:22]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)[C@@](C)(CCn1ccc(I)c(F)c1=O)S(C)(=O)=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@](C)(CCn1ccc(-c2ccccc2)c(F)c1=O)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
Pd EnCat™ (172 mg, 0.067 mmol) was added to a mixture of potassium carbonate (298 mg, 2.16 mmol), phenylboronic acid (132 mg, 1.08 mmol), and ethyl (2R)-4-(3-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (288 mg, 0.647 mmol) in 1,4-dioxane:water (10 ml, 4:1) in a 20 ml vial. The vial was sealed and the reaction was heated to 80° C. and allowed to stir overnight at that temperature. The reaction was allowed to cool to RT, filtered and the catalyst was washed with methanol (20 mL) and dichloromethane (20 mL). The combined filtrates were concentrated and the crude product was purified via flash chromatography using an Analogix SF15-12g column and an eluant of ethyl acetate in heptane (60-100%) to afford the title compound as a white solid (131 mg, 51.2%). LC-MS m/z 396.1 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (t, J=7.12 Hz, 3 H) 1.79 (s, 3 H) 2.46-2.67 (m, 2 H) 3.14 (s, 3 H) 3.99-4.16 (m, 1 H) 4.22-4.44 (m, 3 H) 6.24-6.39 (m, 1 H) 7.10-7.22 (m, 1 H) 7.38-7.55 (m, 3 H) 7.54-7.63 (m, 2 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH:7]([NH:17][C:18]([NH:20][CH:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:19])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH3:35][Sn:36]([CH3:46])([CH3:45])[C:37]1[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6](=[O:34])[CH:7]([NH:17][C:18]([NH:20][CH:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:41][C:40]1[CH:43]=[CH:44][C:37]([Sn:36]([CH3:35])([CH3:46])[CH3:45])=[CH:38][CH:39]=1)=[O:19])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Sn](C)(C)c1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)NC(CCCCN)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)CCC(NC(=O)NC(CCCCNCc1ccc([Sn](C)(C)C)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
To a solution of 2-[3-(5-Amino-1-tert-butoxycarbonyl-pentyl)-ureido]-pentanedioic acid di-tert-butyl ester (150 mg, 0.31 mmol) in DCE (10 mL) was added 4-Trimethylstannanyl-benzaldehyde (82 mg, 0.31 mmol) followed by sodium triacetoxyborohydride (98 mg, 0.47 mmol) and the reaction was stirred overnight at 40° C. The reaction was concentrated and purified by column chromatography using hexanes/ethyl acetate as eluent to afford the desired product (88 mg, 38%) as a thick syrup which begins to solidify upon standing. 1H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J=7.4 Hz, 2H), 7.30 (d, J=7.4 Hz, 2H), 6.27 (m, 2H, NH's), 3.96 (m, 4H), 2.74 (bm, 2H), 2.21 (m, 2H), 1.87 (m, 2H), 1.65-1.19 (m, 7H), 1.35 (m, 27H, t-Bu's), 0.23 (s, 9H). ESMS m/z: 742 (Sn-cluster).
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:4]=[C:5]([CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:6]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][C:7]=2[CH:13]=1.C([Li])CCC.[CH2:39]([O:46][C:47]1[CH:54]=[CH:53][C:50]([CH:51]=O)=[CH:49][CH:48]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCCC1>[CH2:39]([O:46][C:47]1[CH:48]=[CH:49][C:50]([CH:51]=[CH:14][C:5]2[C:6]3[O:10][C:9]([CH3:11])([CH3:12])[CH2:8][C:7]=3[CH:13]=[C:3]([F:2])[CH:4]=2)=[CH:53][CH:54]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC1(C)Cc2cc(F)cc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2O1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(F)cc(C=Cc3ccc(OCc4ccccc4)cc3)c2O1
Reaction time: 3 h

Procedure:
To a solution of ((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methyl)triphenyl phosphonium chloride (648) (500 mg, 1.09 mmol) in anhydrous tetrahydrofuran at room temperature (10 mL) was added n-butyllithium (0.67 mL, 1.31 mmol, 2 M in hexane). After stirring for 10 min 4-(benzyloxy)benzaldehyde (231 mg, 1.09 mmol) was added and stirred for an additional 3 hours. The reaction was quenched with water and extracted with ethyl acetate. The combined organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (20%) to give 7-(4-(benzyloxy)styryl)-5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran as a cis/trans mixture (649).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[O:6])[CH2:3][CH2:2]1.C([O-])=O.[NH4+]>CO.[Pd]>[CH:1]1([NH:4][C:5]([C@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(NC1CC1)[C@H]1CCCN1c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1ccc(N2CCC[C@@H]2C(=O)NC2CC2)cc1
Yield: 95.9 %

Procedure:
(R)-1-(4-Nitro-phenyl)-pyrrolidine-2-carboxylic acid cyclopropylamide (Method 60; 142 g, 5.1 mmol) was dissolved in MeOH (50 ml), to this was added ammonium formate (1.6 g, 26 mmol) and palladium (0.1 g). The reaction was heated at reflux for 60 minutes; reaction decolourised. MeOH was removed in vacuo and saturated ammonium chloride (50 ml) was added, the system was extracted with DCM (2×100 ml), dried and solvent removed in vacuo to yield the title compound as a brown gum (1.20 g, 96%). Product rapidly turned black on exposure to air. The product was used immediately without any purification; m/z 246.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[CH2:19]=[O:20]>C(#N)C.CCOCC>[Br:1][C:2]1[C:3]([OH:8])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH:19]=[O:20]
Reactant: Oc1ccccc1Br
Reactant: C=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOCC
Product: O=Cc1cccc(Br)c1O
Yield: 69.2 %

Procedure:
2-Bromophenol (2 g, 11.5 mmol) was dissolved in anhydrous acetonitrile (25 mL) and the solution was charged with anhydrous (<1.5% water) magnesium chloride (4.4 g, 46 mmol) and dry triethylamine (12.5 mL, 86.3 mmol). The mixture was stirred for minutes and paraformaldehyde (2.8 g, 92 mmol) was added. The mixture was heated to a gentle reflux for 1 to 3 hours and then cooled. The mixture was poured onto an ether/5% citric acid mixture and the ether layer separated. The ether layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated by evaporation. Product purified from the residue by chromatography on silica gel employing 30% ethyl acetate/hexanes to give 3-bromo-2-hydroxybenzaldehyde (1.6 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:18]([OH:20])=O)=[C:14]([Cl:17])[CH:15]=2)[C:10]([CH3:22])([CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:39]1(OC(N(C)C)=[N+](C)C)[C:43]2[N:44]=CC=C[C:42]=2N=N1.ONC(=N)C>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:18]3[O:20][N:44]=[C:43]([CH3:42])[N:39]=3)=[C:14]([Cl:17])[CH:15]=2)[C:10]([CH3:21])([CH3:22])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cc(C(=O)O)c(Cl)cc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC(=N)NO
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1noc(-c2cc3c(cc2Cl)N(C(=O)OC(C)(C)C)CC3(C)C)n1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 47.1 %

Procedure:
To 6-chloro-3,3-dimethyl-2,3-dihydro-indole-1,5-dicarboxylic acid 1-tert-butyl ester (0.067 g, 0.21 mmol) in DMF (1.03 mL) was added N,N-diisopropylethylamine (0.126 μL, 0.72 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.08 g, 0.21 mmol) at room temperature. After stirring for 10 minutes, N-hydroxyacetamidine (0.015 g, 0.41 mmol) was added and the reaction stirred for 18 h. DMF (3.44 mL) was added and the reaction heated to 120° C. for 3 h. Water was added and the mixture extracted with diethyl ether (3×). The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Chromatography (silica gel, gradient elution, 0-60%, EtOAc in petrol 40-60) gave the title compound (36 mg). MS: [M+H]+=364.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[N+:15]([C:5]1[CH:4]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:8]=[CH:7][C:6]=1[C:9]([F:10])([F:11])[F:12])([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: FC(F)(F)c1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(F)(F)F
Temperature: 100 °C
Reaction time: 1 h
Yield: 27.1 %

Procedure:
1,4-Bis(trifluoromethyl)benzene (10.06 g, 47 mmol) in fuming sulfuric acid (20 g) was cooled to 0° C. Fuming nitric acid (8 g) was added cautiously. The mixture was heated to 100° C. and stirred for 1 hour. A mixture of fuming nitric acid (6 g) and fuming sulfuric acid (12 g) was added, and the mixture was heated to 110° C. and stirred for 6 hours. After cooling to r.t., the mixture was poured into ice water (150 g) cautiously, and extracted with chloroform (100 mL×3). The combined organic layers were washed with water (100 mL×2), 10% sodium hydroxide aqueous solution (100 mL×2), and then water (100 mL×2). The resulting organic layers were dried over sodium sulfate, filtered, and concentrated to afford 2-nitro-1,4-bis(trifluoromethyl)benzene as an oil (3.3 g).
Reaction SMILES: C1(C([N:9]2[CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]3[CH2:20][CH:10]2[CH:11]=[CH:12]3)C)C=CC=CC=1>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[CH:10]12[CH2:20][CH:13]([CH2:12][CH2:11]1)[CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:9]2
Reactant: CCOC(=O)C1C2C=CC(C2)N1C(C)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1NC2CCC1C2
Temperature: 45 °C
Reaction time: 24 h
Yield: 22.4 %

Procedure:
To a solution of ethyl 2-(1-phenylethyl)-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate (1.29 g, 4.77 mmol) in ethyl acetate (10 ml) was added 20 wt % Pd(OH)2 (1.47 g), and the mixture was stirred under a hydrogen atmosphere at 45° C. for 24 hours. After a filtration through Celite, the solvent was evaporated. The residue was purified by silica gel column chromatography (1%–3% methanol/chloroform), to give ethyl 2-azabicyclo[2.2.1]heptane-3-carboxylate (0.181 g, 22%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH:11]=[C:12]=[CH:13][CH2:14][CH2:15]Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[I-:17].[Na+].CC(C)=O>O>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]=[C:13]=[CH:14][CH2:15][I:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: CC(C)(C)[Si](C)(C)OCCC=C=CCCCl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCC=C=CCI

Procedure:
A mixture of 0.80 g of 7-chlorohepta-3,4-dien-1-ol t-butyldimethylsilyl ether, 1.0 g of sodium iodide and 5 ml of acetone were refluxed for 24 hours. The reaction mixture was cooled and diluted with 50 ml water. The product was extracted with 100 ml of ether and the ethereal solution washed with brine, dried over potassium carbonate and evaporated to give 7-iodohepta-4,5-dien-1-ol t-butyldimethylsilyl ether.
Reaction SMILES: [CH:1]1([C:4]2[N:5]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]3[C:11]([CH:12]=2)=[C:10]([O:13]C)[CH:9]=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.B(Br)(Br)Br.C(Cl)Cl>>[CH:1]1([C:4]2[N:5]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6]3[C:11]([CH:12]=2)=[C:10]([OH:13])[CH:9]=[CH:8][CH:7]=3)[CH2:2][CH2:3]1
Reactant: COc1cccc2c1cc(C1CC1)n2Cc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc2c1cc(C1CC1)n2Cc1ccccc1
Yield: 52.2 %

Procedure:
By the method used in Example 1, Part D, 630 g (2.3 mmol) of 2-cyclopropyl-4-methoxy-1-(phenylmethyl)-1H-indole was O-demethylated by treating it with 9 mL of 1M BBr3 /CH2Cl2. The crude product was chromatographed on silica gel and eluted with 20% EtOAc/hexane to give 316 mg (52% yield) of 2-cyclopropyl-4-hydroxy-1-(phenylmethyl)-1H-indole as an oil.