Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]1[O:17][C:16]2[CH:15]=[CH:14][C:13]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:12][C:11]=2[O:10]1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:18]([C:13]1[CH:14]=[CH:15][C:16]2[O:17][CH2:9][O:10][C:11]=2[CH:12]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc2c(c1)OCO2

Procedure:
N-Bromosuccinimide (3.95 g, 22.2 mmol) and AlBN (0.098 g, 0.06 mMol) were added to a solution of methyl (3,4-methylenedioxyphenyl)acetate (3.9 g, 21.2 mmol) in carbon tetrachloride and the mixture was refluxed for 2.5 h. The reaction was cooled and filtered. The flitrate was concentrated in vacuo and the residue obtained was purified by flash chromatography on silica-gel using 10% ethyl acetate-hexane. Yield 2.6 g (oil).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[C:5](Cl)=[O:6])[CH3:2].[C:9]([C:12]1[CH:31]=[CH:30][C:15]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]([C:25]([CH3:29])=[CH:26][C:27]=2[Br:28])[NH2:24])=[C:14]([CH2:32][CH2:33][CH3:34])[C:13]=1[OH:35])(=[O:11])[CH3:10].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:8])[C:5]([NH:24][C:23]1[C:25]([CH3:29])=[CH:26][C:27]([Br:28])=[C:21]([O:20][CH2:19][CH2:18][CH2:17][O:16][C:15]2[CH:30]=[CH:31][C:12]([C:9](=[O:11])[CH3:10])=[C:13]([OH:35])[C:14]=2[CH2:32][CH2:33][CH3:34])[CH:22]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCCc1c(OCCCOc2cc(N)c(C)cc2Br)ccc(C(C)=O)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1c(OCCCOc2cc(NC(=O)C(=O)OCC)c(C)cc2Br)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In the course of approximately 5 minutes a solution of 12.3 ml of chloro-oxalic acid ethyl ester in 30 ml of methylene chloride is added dropwise to a solution, cooled to 0° C., of 43.6 g (100 mmol) of 3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-bromo-6-methylaniline and 15.3 ml of triethylamine in 400 ml of methylene chloride and the whole is then stirred for a further 90 minutes at room temperature. The reaction mixture is poured onto ice-water and the organic phase is separated off, washed with water, dried over sodium sulphate and concentrated under reduced pressure. Crystallisation from ethyl acetate/ether/petroleum ether yields N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-bromo-6-methylphenyl}-oxamic acid ethyl ester having a melting point of 100°-102°.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)[NH:9][C:8]2=[O:21].B(Br)(Br)Br.[OH-].[Na+].Cl>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1)[NH:9][C:8]2=[O:21]
Reactant: COc1cccc2c(=O)[nH]c(-c3ccc(C#N)cc3)nc12
Agent: BrB(Br)Br
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(-c2nc3c(O)cccc3c(=O)[nH]2)cc1
Yield: 13.9 %

Procedure:
8-Methoxy-2-(4-cyanophenyl)quinazolin-4-[3 H]-one (0.2 g, 0.72 mmol) was suspended in a 1.0 M solution of BBr3 in DCM (3.6 ml) to give a brown suspension, which was refluxed for 48 hours. The solvent was directly distilled from the reaction vessel to leave a -brown solid, which was hydrolysed with 10% aq. NaOH solution to give a clear, yellow solution. The solution was neutralised with dilute HCl, whereupon a yellow precipitate formed. The reaction mixture was extracted into an excess of EtOAc. The organic layers were combined, dried (MgSO4) and filtered. The solvent was removed under vacuum to leave a cream solid. The product (108 mg) was purified by column chromatography, using DCM:MeOH (95:5) as the eluent, to give a cream solid (26.4 mg, 0.1 mmol), 14%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: OCCCC#Cc1ccc2c(ccn2-c2ccc(F)cc2)c1
Solvent: CCO
Product: OCCCCCc1ccc2c(ccn2-c2ccc(F)cc2)c1
Yield: 79.3 %

Procedure:
400 mg (1.4 mmol) 5-[1-(4-Fluoro-phenyl)-1H-indol-5-yl]-pent-4-yn-1-ol in 10 ml EtOH were hydrogenated in the presence of 25 Mg PtO2. The suspension was filtered and the crude material purified by column chromatography on silica gel with hexane/EtOAc to yield 330 mg (79%) 5-[1-(4-Fluoro-phenyl)-1H-indol-5-yl]-pentan-1-ol as colorless viscous oil, MS: 297 (M).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([O:11][CH3:12])[C:3]=1[C:13]([F:16])([F:15])[F:14].O.O.[Sn](Cl)(Cl)(Cl)Cl>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([O:11][CH3:12])[C:3]=1[C:13]([F:14])([F:15])[F:16]
Reactant: COc1c([N+](=O)[O-])ccc(Cl)c1C(F)(F)F
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(N)ccc(Cl)c1C(F)(F)F

Procedure:
To a solution of 1-chloro-3-methoxy-4-nitro-2-(trifluoromethyl)benzene (1.73 g, 6.74 mmol) in EtOAc (40 mL) was added tin chloride dihydrate (3.04 g, 13.5 mmol). The reaction mixture was heated at reflux for 3 h. The crude reaction mixture was purified by column chromatography (SiO2, EtOAc in hexanes) to give the title compound. LCMS: (FA) ES+ 226.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([CH:14]=1)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1>[Pd].C(O)C>[NH2:15][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:14][C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Cc1ccc([N+](=O)[O-])c(Nc2ccccn2)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(N)c(Nc2ccccn2)c1
Reaction time: 3 h

Procedure:
A mixture of 5-methyl-2-nitro-N-(2-pyridyl)aniline (3.8 g, 16.6 mmol), 5% palladium on carbon (500 mg) in ethanol (100 ml) was stirred under a hydrogen atmosphere for 3 h. The mixture was filtered through a pad of celite and the filtrate was concentrated to dryness to give 3.3 g (quant.) of the titled compound as gray solids. 1H-NMR (CDCl3) δ: 8.17-8.10 (1H, m), 7.46-7.38 (1H, m), 7.00 (1H, s), 6.90 (1H, d, J=8.1 Hz), 6.76-6.62 (2H, m), 6.46-6.39 (1H, m), 6.29 (1H, br.s), 3.71 (2H, br.s), 2.24 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:30])[CH2:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[CH:16][S:17][C:10]=12.[CH2:31]([N:33]1[CH:37]=[C:36](C2SC3C(=NC=CC=3OC3C=CC(N)=CC=3F)C=2)[N:35]=[CH:34]1)[CH3:32]>>[CH2:31]([N:33]1[CH:37]=[C:36]([C:16]2[S:17][C:10]3[C:11](=[N:12][CH:13]=[CH:14][C:9]=3[O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:18][C:19](=[O:30])[CH2:20][C:21]([NH:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[O:22])=[CH:3][C:2]=3[F:1])[CH:15]=2)[N:35]=[CH:34]1)[CH3:32]
Reactant: O=C(CC(=O)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1)Nc1ccccc1
Reactant: CCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Product: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5)cc4F)c3s2)c1
Yield: 57 %

Procedure:
Following the procedure described for compound 5a (example 1, step 5) but substituting amine 9 for compound 15, title compound 5d was obtained in 57% yield. MS (m/z): 516.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=1.[N:19]1[C:26](Cl)=[N:25][C:23](Cl)=[N:22][C:20]=1Cl.Cl>C1(C)C(C)=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][N:19]2[CH2:26][N:25]([NH:1][C:2]3[CH:18]=[CH:17][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=3)[CH2:23][N:22]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])=[CH:17][CH:18]=3)[CH2:20]2)=[CH:18][CH:17]=1)=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCOC(=O)c1ccc(N)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: Cl
Solvent: Cc1ccccc1C
Product: CCCCCCCCOC(=O)c1ccc(NN2CN(Nc3ccc(C(=O)OCCCCCCCC)cc3)CN(Nc3ccc(C(=O)OCCCCCCCC)cc3)C2)cc1
Temperature: 90 °C

Procedure:
75 g of octyl p-aminobenzoate and 18.5 g of cyanuric chloride in 1,000 ml of xylene were heated at 140° C. for 8 hours. After the evolution of hydrogen chloride was complete, the reaction solution was cooled to 90° C., washed twice with saturated sodium bicarbonate solution and once with water and then cooled to room temperature. The white crystals precipitated were filtered off under suction.
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(C)(C)C.[N:15]1C=CC=CC=1.C1(C)C=CC=CC=1>>[C:8]1([S:11]([NH2:15])(=[O:13])=[O:12])[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccncc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)c1ccccc1

Procedure:
Reaction with p-tert-butylbenzenesulphonyl chloride in pyridine/toluene at room temperature yielded pure 4-tert-butyl-N-[3-(2-tetrahydropyranyloxyethoxy)-2-methoxy-phenoxy)-phenyl]-benzenesulphonamide. MS: Mt/ e=555.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:12][NH:13][O:14][CH3:15].C(N(CC)CC)C.C(Cl)CCl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:13]([O:14][CH3:15])[CH3:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CNOC
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a solution of 16.7 g (108.4 mmol) (4-fluorophenyl)acetic acid in dry methylene chloride under nitrogen atmosphere was added 13.8 g (141.5 mmol) N,O-dimethyl-hydroxyl amine, 20 mL triethylamine, 14.2 g (119.3 mmol) 4-dimethylaminopyridine (DMAP) and 27 g (140.6 mmol) EDC. The reaction mixture was stirred at RT for 2 hr then transferred to a separatory funnel. The mixture was washed consecutively with 2 N aq. HCl, brine, saturated aq. NaHCO3 and brine. The organic layer was dried over drying agent, filtered and the solvent evaporated under vacuum to give 21 g of the crude title compound which was used without further purification. 1H-NMR (CDCl3): δ: 7.26 (2 H, m), 7.02 (2 H, m), 3.77 (2 H, s), 3.65 (3 H, s), 3.21 (3 H, s).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[N:18]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:41])([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH:1]1([CH2:4][NH:5][C:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:21]3[CH2:22][CH2:23][CH2:24][N:18]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]([C:32]([OH:41])([C:37]([F:38])([F:39])[F:40])[C:33]([F:36])([F:34])[F:35])=[CH:30][CH:31]=4)[CH2:19][CH2:20]3)=[O:14])=[CH:15][CH:16]=2)=[O:17])[CH2:2][CH2:3]1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Reactant: OC(c1ccc(CN2CCCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Reaction time: 24 h
Yield: 63.8 %

Procedure:
To a mixture of 4-(3-(cyclopropylmethyl)ureido)benzoic acid (2.134 mmol, 0.5 g), 2-(4-((1,4-diazepan-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (2.134 mmol, 0.761 g) and triethylamine (5.34 mmol, 0.744 mL, 0.540 g) in dichloromethane (30 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.56 mmol, 0.491 g). The reaction was stirred for 24 hours then was chromatographed on silica eluting with dichloromethane to dichloromethane/methanol (6%) then re-chromatographed on silica eluting with ethyl acetate to ethyl acetate/methanol (2%) to give the title compound (780 mg). MS (ESI) m/z 573.0 [M+H]+
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([NH2:10])[CH:5]=1.Br[C:12]1[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=[C:16]([Br:18])[CH:17]=1>>[Br:18][C:16]1[CH:17]=[C:12]([NH:10][C:6]2[CH:5]=[C:4]([CH2:3][O:2][CH3:1])[N:8]([CH3:9])[N:7]=2)[C:13](=[O:20])[N:14]([CH3:19])[CH:15]=1
Reactant: COCc1cc(N)nn1C
Reactant: Cn1cc(Br)cc(Br)c1=O
Product: COCc1cc(Nc2cc(Br)cn(C)c2=O)nn1C
Yield: 71.4 %

Procedure:
Following Example 148a, 1.7 g of 176b and 3.2 g of 3,5-dibromo-1-methylpyridin-2(1H)-one were reacted to give 176c as a yellow solid (2.8 g, 70%). MS: [M+H]+ 327. 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J=2.5, 1H), 7.38 (s, 1H), 6.88 (d, J=2.5, 1H), 5.86 (s, 1H), 4.41 (s, 2H), 3.82 (s, 3H), 3.58 (s, 3H), 3.36 (s, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][O:28]1)[C:4]1[C:5]2[CH2:25][NH:24][CH2:23][CH2:22][C:6]=2[N:7]=[C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[N:9]=1)[CH3:2].[C:32](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH2:1]([N:3]([CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][O:28]1)[C:4]1[C:5]2[CH2:25][N:24]([CH3:32])[CH2:23][CH2:22][C:6]=2[N:7]=[C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[N:9]=1)[CH3:2]
Reactant: CC(=O)O
Reactant: CCN(CC1CCCO1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN(CC1CCCO1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CN(C)CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N4-Ethyl-N2-(4-(oxazol-5-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (125 mg, 0.30 mmol, example 81a) was dissolved in methanol (3 mL). Acetic acid (0.017 mL, 0.30 mmol) was added followed by formaldehyde (0.022 mL, 0.30 mmol). The reaction was stirred at room temperature for 15 minutes and sodium cyanoborohydride (18.7 mg, 0.30 mmol) (MP—CNBH3) was added. The reaction was stirred overnight at room temperature. The MP—CNBH3 was filtered, the solvent evaporated under reduced pressure, the crude dissolved in methanol and purified by preparative HPLC N4-ethyl-6-methyl-N2-(4-(oxazol-5-yl)phenyl)-N4-((tetrahydrofuran-2-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (29.8 mg, 21.04%) as acetate salt. MS (ES+) m/z 435.2 (M+H)+
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:17][CH3:18])=[C:8]([O:15][CH3:16])[C:9]=2[O:13][CH3:14])[CH:4]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl>[CH3:14][O:13][C:9]1[C:8]([O:15][CH3:16])=[C:7]([O:17][CH3:18])[CH:6]=[C:5]2[C:10]=1[CH:11]=[CH:12][C:3]([CH:2]=[O:1])=[CH:4]2
Reactant: COc1cc2cc(CO)ccc2c(OC)c1OC
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1cc2cc(C=O)ccc2c(OC)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-Hydroxymethyl-5,6,7-trimethoxynaphthalene (3.78 g) was dissolved in dichloromethane (100 mL), pyridinium dichromate (8. 61 g) was added to the solution, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was filtered, and insoluble matter was washed with chloroform. After the filtrate was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed with 2 M hydrochloric acid, water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:3 to 1:1) and further recrystallized from ethyl acetate-hexane to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:9])[CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc([C@@H]2CO2)cc1
Reactant: C1CCNC1
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: ClCCl
Product: O[C@@H](CN1CCCC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.5 %

Procedure:
(2R)-2-(4-Bromophenyl)oxirane (49.93 g, 250.8 mmol) was added to pyrrolidine (35 mL, 421.2 mmol) in a CH2Cl2 (150 mL) solution at 0° C. with magnetic stirring. Montmorillonite K10 clay (5.87 g) was added in one portion. The resulting mixture was stirred at room temperature for 16 h. The mixture was then filtered through a pad of Celite and the filtrate was concentrated to give a white solid. The crude material was recrystallized from Et2O to give (1R)-1-(4-bromophenyl)-2-(1-pyrrolidinyl)ethanol as clear crystals (29.43 g, 109 mmol, 43% yield). MS (ES) m/e 272, 270 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[Cl:12][C:13]1[C:14]([C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)=[CH:15][C:16]2[O:20][C:19]([F:22])([F:21])[O:18][C:17]=2[CH:23]=1.CCN(C(C)C)C(C)C>ClCCl.O1CCCC1.CO.[OH-].[Li+]>[Cl:12][C:13]1[C:14]([C:24]2[CH:25]=[CH:26][C:27]([NH:28][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=3[F:11])=[CH:29][CH:30]=2)=[CH:15][C:16]2[O:20][C:19]([F:22])([F:21])[O:18][C:17]=2[CH:23]=1
Reactant: Nc1ccc(-c2cc3c(cc2Cl)OC(F)(F)O3)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2cc3c(cc2Cl)OC(F)(F)O3)cc1)c1c(F)cccc1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
Under an atmosphere of argon, 2,6-difluorobenzoyl chloride (23 mg, 132 μmol) was added to a stirred solution of 89 (25 mg, 88 μmol) and Hünig's base (46 μL, 34 mg, 264 μmol) in dichloromethane (440 μL) at room temperature. The reaction was stirred for 0.5 h. The solution was diluted with tetrahydrofuran (1 mL), methanol (1 mL) and 1.2 M lithium hydroxide solution (0.5 mL). The mixture was stirred and heated to 60° C. for 10 min then cooled to room temperature, diluted with dichloromethane and dried with sodium sulfate. The mixture was concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-20% ethyl acetate in hexane) provided 90 (12.2 mg, 33%) as a solid: LRESIMS m/z 424.1 [M+H]+, calcd. for C20H11Cl1F4N1O3 424.0.
Reaction SMILES: [NH2:1][C@H:2]([C:14]([O:16][CH3:17])=[O:15])[CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[C:27]([C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>C(Cl)Cl>[C:27]([C:31]1[CH:32]=[CH:33][C:34]([C:35]([NH:1][C@H:2]([C:14]([O:16][CH3:17])=[O:15])[CH2:3][C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)=[O:36])=[CH:38][CH:39]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)c1ccc(C[C@H](N)C(=O)OC)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C[C@H](NC(=O)c2ccc(C(C)(C)C)cc2)C(=O)OC)cc1
Reaction time: 2 h
Yield: 44.6 %

Procedure:
Prepared using General Procedure 3: To the solution of (S)-methyl 4-(2-amino-3-methoxy-3-oxopropyl)benzoate (425.0 mg, 1.79 mmol) in DCM (10 mL) and DIEA (463.0 mg, 3.58 mmol) was added 4-(tert-butyl)benzoyl chloride (556.6 mg, 2.83 mmol) at room temperature. The reaction was stirred for 2 h and the reaction was partitioned between DCM and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by chromatography (EA/hexanes) to afford 317 mg (45%) of (S)-methyl 4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate. LCMS-ESI (m/z) calculated for C23H27NO5: 397.2. found 398.1 [M+H]+, tR=2.31 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 7.97-7.75 (m, 2H), 7.67-7.51 (m, 2H), 7.46-7.26 (m, 2H), 7.14 (d, J=8.3 Hz, 2H), 6.60 (d, J=7.4 Hz, 1H), 5.03 (dt, J=7.4, 5.7 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 3H), 3.28 (dd, J=13.7, 5.8 Hz, 1H), 3.18 (dd, J=13.7, 5.5 Hz, 1H), 1.24 (s, 9H).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[CH3:8][O:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:30]([C:38]([O:40][CH3:41])=[O:39])(=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.S([O-])([O-])(=O)=O.[Mg+2].C>CCOCC.O>[CH3:8][O:9]/[CH:10]=[C:30](\[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)/[C:38]([O:40][CH3:41])=[O:39]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Solvent: CCOCC
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccccc1
Reaction time: 0.75 h
Yield: 50.3 %

Procedure:
Potassium tert-butoxide (9.52 g) was added in a single portion to a stirred suspension of (methoxymethyl)-triphenylphosphonium chloride (34.3 g) in dry ether (300 ml). After 45 minutes, the resulting red suspension was treated with a solution of methyl benzoylformate (8.20 g) in dry ether (100 ml) (colour lightens; exotherm). After 3 hours, the mixture was diluted with water, treated with magnesium sulphate and charcoal, then concentrated under reduced pressure to give the crude produce (36.39 g) as a yellow oil which partially crystallised on standing. This was flushed through silica gel using dichloromethane, then carefully chromatographed using dichloromethane: petrol (2:1) to give E-methyl 3-methoxy-2-phenylpropenoate (4.83 g, 50% yield) as a pale yellow oil, eluted first, infrared (film): 1710, 1630 cm-1, 1H nmr (CDCl3): delta 7.55 (s, olefinic proton), and Z-methyl 3-methoxy-2-phenylpropenoate (3.43 g, 36% yield) as a pale yellow oil, eluted second, infrared (film): 1715, 1630 cm-1, 1H nmr (CDCl3): delta 3.76 (3H,s), 3.90 (3H,s), 6.65 (1H, s), 7.28 (5H,s) ppm.
Reaction SMILES: C([O:5][C:6]1[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:8][C:9]2[O:19][C:12]3([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH2:11][C:10]=2[CH:20]=1)C=CC>CN(C)C1C=CC=CC=1>[C:21]([C:7]1[C:6]([OH:5])=[C:20]([CH:20]([CH3:10])[CH:6]=[CH2:7])[C:10]2[CH2:11][C:12]3([O:19][C:9]=2[CH:8]=1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)([CH3:23])([CH3:24])[CH3:22]
Reactant: CC=CCOc1cc2c(cc1C(C)(C)C)OC1(CCCCCC1)C2
Solvent: CN(C)c1ccccc1
Product: C=CC(C)c1c(O)c(C(C)(C)C)cc2c1CC1(CCCCCC1)O2
Yield: 34.1 %

Procedure:
0.82 g of 5-(2-butenyloxy)-6-t-butyl-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane was dissolved in 3 ml of dimethylaniline and the solution was treated in the same manner as in Example 8-2) to give 0.14 g of 6-t-butyl-5-hydroxy-4-(1-methyl-2-propenyl)-2,3-dihydrobenzofuran-2-spiro-1′-cycloheptane as a white solid (yield 17%).
Reaction SMILES: B(F)(F)F.CCOCC.[OH:10][CH:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16].[C:17]([N:21]=[C:22]=[O:23])([CH3:20])([CH3:19])[CH3:18].C(=O)(O)[O-].[Na+]>ClCCl.[Cl-].[Na+].O>[C:17]([NH:21][C:22]([O:10][CH:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)N=C=O
Reactant: O=C1OCCC1O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)OC1CCOC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
Boron trifluoride diethyl etherate (1.38 g) was added dropwise, over a period of fifteen minutes, to a stirred solution of 3-hydroxytetrahydrofuran-2-one (10.0 g) and t-butylisocyanate (9.7 g) in dry dichloromethane (300 ml), whilst maintaining the temperature below 10° C. The mixture was stirred at room temperature for a further four hours, treated with brine and sufficient aqueous sodium bicarbonate solution to render the aqueous phase basic, then extracted several times with dichloromethane. The extracts were washed with brine, dried over magnesium sulphate and evaporated under reduced pressure to give the title compound (18.5 g, m.p. 104°-106° C.). NMR (CDCl3): δ 1.34(9H,s); 2.28(1H,m); 2.73(1H,m); 4.28(1H,dt); 4.46(1H,dt); 4.90(1H,bs); 5.31(1H,t). MS: M+ 201. The addition can also be catalysed using triethylamine or aqueous hydrogen chloride in place of boron trifluoride. However a rearrangement product can be formed in variable amounts which can necessitate purification of the desired material, for example by chromatography on silica using hexane-ethyl acetate (3:1) as eluant.