Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[N:19](COC(=O)C(C)(C)C)[C:18](=[O:36])[N:17]([CH2:37][CH2:38][O:39][CH2:40][CH3:41])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl>O1CCCC1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]([CH2:23][C:24]#[C:25][CH3:26])[C:21]3[C:20](=[O:27])[NH:19][C:18](=[O:36])[N:17]([CH2:37][CH2:38][O:39][CH2:40][CH3:41])[C:16]=3[N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2CCOCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)[nH]c(=O)n2CCOCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-[7-(2-Butynyl)-1-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (50 mg) and potassium carbonate (15 mg) were dissolved in N,N-dimethylformamide (1.2 ml), and 2-bromoethylethyl ether (12 μl) was added to the solution. The mixture was stirred at 60° C. for 2 hours, diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After the organic layer was concentrated by distillation, the residue was purified by silica gel column chromatography to give 4-[7-(2-butynyl)-1-(2,2-dimethylpropionyloxymethyl)-3-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester from the elution fraction of hexane-ethyl acetate (2:1). The obtained 4-[7-(2-butynyl)-1-(2,2-dimethylpropionyloxymethyl)-3-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester was dissolved in a solvent mixture of tetrahydrofuran (1.0 ml) and methanol (0.5 ml), sodium hydride (5 mg) was added to the solution, and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation to give 4-[7-(2-butynyl)-3-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester. A quarter of the obtained 4-[7-(2-butynyl)-3-(2-ethoxyethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester was dissolved in trifluoroacetic acid (0.5 ml), and the solution was stirred at room temperature for 30 minutes. After the solvent was removed by distillation, a half of the residue was purified by HPLC with a reversed phase column using water-acetonitrile-trifluoroacetic acid system as elution solvent to give 3.2 mg of the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[C:9]([S:17][CH3:18])=[N:10][C:11]([CH3:16])=[CH:12][C:13]=1[S:14][CH3:15])=[O:6].[SH:19][C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[O:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[S:19][CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[C:9]([S:17][CH3:18])=[N:10][C:11]([CH3:16])=[CH:12][C:13]=1[S:14][CH3:15])=[O:6]
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CCCBr
Reactant: Sc1nc2ccccc2o1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cc(C)nc(SC)c1NC(=O)CCCSc1nc2ccccc2o1
Temperature: 80 °C
Reaction time: 3 h
Yield: 53.2 %

Procedure:
To a DMF (2 ml) solution of this amide (105 mg, 0.3 mmol) and 2-mercaptobenzoxazole (50 mg, 0.33 mmol) were added 18-crown-6 (8 mg, 0.03 mmol) and potassium carbonate (50 mg, 0.36 mmol), and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through preparative thin-layer chromatography (eluent—hexane:ethyl acetate=3:2, eluted twice) to obtain 67 mg (yield 53%) of the desired compound as a colorless needle crystal.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH2:17][N:18]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[O:16])=[CH:10][CH:9]=2)[N:7]=1.[Br:35]Br>C(O)(=O)C.O>[ClH:1].[NH2:2][C:3]1[S:4][C:5]([Br:35])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([CH2:17][N:18]([C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[C:19](=[O:27])[C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[O:16])=[CH:12][CH:13]=2)[N:7]=1
Reactant: BrBr
Reactant: Nc1nc(-c2ccc(NC(=O)CN(C(=O)c3ccc(F)cc3)c3ccc(F)cc3)cc2)cs1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(-c2ccc(NC(=O)CN(C(=O)c3ccc(F)cc3)c3ccc(F)cc3)cc2)c(Br)s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
N-{[4-(2-aminothiazol-4-yl)phenylcarbamoyl]methyl}-4-fluoro-N-(4-fluorophenyl)benzamide monohydrochloride (200 mg) was dissolved in a mixed solvent of acetic acid (10 ml) and water (5 ml), mixed with bromine (20 μl) under ice-cooling and then stirred at room temperature for 5 minutes. The reaction solution was concentrated under a reduced pressure, and the residue was dissolved in ethyl acetate (30 ml)-saturated sodium bicarbonate aqueous solution (20 ml). The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate and then concentrated under a reduced pressure. The residue was dissolved in ethyl acetate (5 ml) and mixed with 4 M hydrogen chloride in ethyl acetate solution (0.15 ml), and the thus precipitated solid was collected by filtration, dried and then recrystallized from methanol-ether, thereby obtaining 184 mg of N-{[4-(2-amino-5-bromothiazol-4-yl)phenylcarbamoyl]methyl}-4-fluoro-N-(4-fluorophenyl)benzamide monohydrochloride (colorless powder).
Reaction SMILES: [N:1]1([C:7](=[O:24])[CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([OH:12])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:25][CH:26]([CH2:40][CH3:41])[C@@H:27]([C:29]1[N:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][N:30]=1)[OH:28]>>[N:1]1([C:7](=[O:24])[CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([NH:25][C@H:26]([C:27]([C:29]2[N:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][N:30]=2)=[O:28])[CH2:40][CH3:41])=[O:12])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1
Reactant: CCC(N)[C@H](O)c1noc(-c2ccccc2)n1
Product: CC[C@H](NC(=O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1)C(=O)c1noc(-c2ccccc2)n1

Procedure:
Similarly prepared according to the procedure for Example 43 but using 4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid and (S)-2-amino-1-(5-phenyl-[1,2,4]oxadiazol-3-yl)-butan-1-ol; MS: 569 (MH+), LCMS retention time 4.1 min; 1H NMR (CDCl3) 8.18 (d, J=7.9 Hz, 2H), 7.74–7.31 (m, 9H), 5.27 (m, 1H), 4.25 (m, 2H), 3.71–3.41 (m, 8H), 2.95 (m, 1H), 2.78–2.70 (m, 2H), 2.10 (m, 1H), 1.85 (m, 1H), 1.0 (m, 3H).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][C@H:8]2[C:19]#[N:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[C:1]1([CH:7]2[CH2:11][N:10]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9][CH:8]2[CH2:19][NH2:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#C[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCC1CN(Cc2ccccc2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.9 %

Procedure:
To a solution of 5.7 g (0.022 mole) of trans-4 -phenyl-1-(phenylmethyl)-3-pyrrolidinecarbonitrile (Helv. Chim. Acta, 64, 2203 (1981)) in 30 ml tetrahydrofuran was added 0.83 g (0.022 mmol) of lithium aluminum hydride in portions under nitrogen. The reaction mixture was then stirred at room temperature for 18 hours. To the resulting suspension were added 1 ml of water, 0.8 ml of 40% sodium hydroxide, and 3 ml of water. The grainy precipitate was filtered and washed with tetrahydrofuran. The combined filtrates were concentrated to give 5.5 g of 4-phenyl-1-(phenylmethyl)-3-pyrrolidinemethanamine.
Reaction SMILES: C(N)(=O)C.COC.I.Br.C([O:12][C:13](=[O:37])[C@H:14]([CH2:19][C:20]1[CH:25]=[C:24]([I:26])[C:23]([O:27][C:28]2[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=2)=[C:22]([I:36])[CH:21]=1)[NH:15]C(=O)C)C>>[I:26][C:24]1[CH:25]=[C:20]([CH:21]=[C:22]([I:36])[C:23]=1[O:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[CH2:19][C@@H:14]([C:13]([OH:37])=[O:12])[NH2:15]
Reactant: CCOC(=O)[C@H](Cc1cc(I)c(Oc2ccc(OC)cc2)c(I)c1)NC(C)=O
Agent: Br
Agent: CC(N)=O
Agent: COC
Product: N[C@@H](Cc1cc(I)c(Oc2ccc(O)cc2)c(I)c1)C(=O)O

Procedure:
Many patent and non-patent literature describe the use of an intermediate called Bis (p-anisyl)iodonium bromide in the preparation of Levothyroxine sodium. Hillmann (Z. Naturforch 1956; 11b:424-425) describes a process for the assembly of the biphenyl-ether system present in Levothyroxine, wherein a key coupling reaction is initiated between N-Acetyl 3,5-diiodo-L-tyrosine ethyl ester, derived from the stepwise protective conversion of amine as amide and acid as ester of 3,5 diido-L-tyrosine, and Bis (p-anisyl)iodonium bromide in the presence of copper metal or powder as a catalyst to afford (S)—N-acetyl-3,5-diiodo-4-p-methoxyphenoxyphenylalanine ethyl ester, with 87% yield. All the three protective groups in (S)—N-acetyl-3,5-diiodo-4-p-methoxyphenoxyphenylalanine ethyl ester, viz. acetamide, methyl ether, ethyl ester were cleaved using a mixture of Hydroiodic acid and Hydrobromic acid to give 3,5-Diiodothyronine. 3,5-Diiodothyronine on subsequent iodination with iodine gave L-thyroxine of an yield that corresponds to 92%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[CH:6]=[N:5]2.CN(C=O)C.O=P(Cl)(Cl)[Cl:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:20])[CH:6]=[N:5]2
Reactant: O=c1cnc2cc(Br)ccc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1cnc2cc(Br)ccc2n1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
6-bromoquinoxalin-2(1H)-one (9.0 g, 40 mmol) was dissolved in POCl3 (50 mL) and DMF (2 mL) was added at RT. The mixture was heated at 50° C. for 2 hours. After completion of the reaction it was cooled to RT and was poured slowly into ice cold water. The mixture was stirred for 30 minutes and then filtered to afford crude product.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][OH:25])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][OH:25]
Reactant: OCCc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: OCCc1ccc(O)cc1O
Yield: 99.3 %

Procedure:
3.7 g (11.1 mmole) 2-[2,4-di(benzyloxy)phenyl]-1-ethanol was hydrogenated in 100 ml ethyl acetate using Pd/C (10%) as catalyst. The reaction mixture was filtered and the filtrate was evaporated in vacuo to give 1.7 g (yield 99%) of 2-(2,4-dihydroxyphenyl)-1-ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]([S:18][C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)([N:15]([CH3:17])[CH3:16])[C:12]2[CH:26]=[CH:27][CH:28]=[CH:29][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH2:30].[OH2:31].O.O.O.O.C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.[Mg+2].S([O-])([O-])=O.[Na+].[Na+].O>ClCCl.CO>[CH3:3][C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]([S:18]([C:19]2[CH:20]=[CH:21][C:22]([Br:25])=[CH:23][CH:24]=2)(=[O:31])=[O:30])([N:15]([CH3:17])[CH3:16])[C:12]2[CH:26]=[CH:27][CH:28]=[CH:29][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:2]
Reactant: O
Reactant: CN(C)C1(Sc2ccc(Br)cc2)CN(C(=O)OC(C)(C)C)CCc2ccccc21
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: O=S([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Product: CN(C)C1(S(=O)(=O)c2ccc(Br)cc2)CN(C(=O)OC(C)(C)C)CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.3 %

Procedure:
(4-Bromo-phenylsulfanyl)-dimethylamino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (2.8 g, 6.0 mmol) in dichloromethane (5 ml) was added to magnesium monoperoxyphthalate hexahydrate (MMPP) (7.4 g, 80%) in dichloromethane (20 ml) and methanol (3 ml) at 0° C. dropwise. After addition the mixture was allowed to warm to room temperature and stirred for 1 h then a further portion of MMPP (1 g) was added and stirred for a further 1 h. Sodium sulfite solution (10%, 300 ml) was added and the mixture stirred thoroughly for 30 min). Water (3 L) and dichloromethane (400 ml) were then added and the organic layer separated and washed with sodium bicarbonate solution (500 ml), water (2×1 L) and brine (500 ml) then evaporated in vacuo. Chromatography on silica eluting with 0-20% ethyl acetate/hexane afforded 3.22 g of the subtitled compound. MH+ 510.
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[N:14]=[C:13](Br)[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([O:28][CH:29]=[CH:30][Sn](CCCC)(CCCC)CCCC)[CH3:27]>CN(C=O)C>[CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[N:14]=[C:13]([CH:27]=[CH:26][O:28][CH2:29][CH3:30])[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2nc(Br)n(Cc3ccccc3)c2ncn1Cc1ccccc1
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCOC=Cc1nc2c(=O)n(Cc3ccccc3)cnc2n1Cc1ccccc1
Temperature: 70 °C

Procedure:
A mixture of 1,9-dibenzyl-6,9-dihydro-6-oxo-8-bromopurine (20) (1.20 g, 3.04 mmol) bis(triphenylphosphine)palladium(II)chloride (0.213 g, 0.3 mmol) and ethoxyvinyl-(tributyl)tin (2.19 g, 6.07 mmol) in dry DMF (50 mL) was heated under N2 at 70° C. for 22 h. DMF was distilled off and the resulting residue dissolved in EtOAc (100 ml) and filtered through a pad of celite. The solvent was distilled off and the residue was purified by flash chromatography (EtOAc:hexane, 6:4). Yield 0.989 g (88%). Mp 167-168° C. 1H NMR (CDCl3) δ 1.26 (t, 3H, CH3, J=7.5 Hz), 3.86 (q, 2H, CH2J=7 Hz), 4.46 (d, 1H, CH, J=2.5 Hz), 5.26 (s, 2H, benzylic CH2), 5.32 (d, 1H, CH2 J=3 Hz), 5.60 (s, 2H, benzylic C2), 7.10-7.37 (m, 10H, Ar—H) 7.99 (s, 1H, purine C2—H). 13C NMR (CDCl3) δ 14.1, 47.8, 49.1, 63.8, 90.2, 123.5, 126.6, 126.6, 127.5, 127.5, 128.2, 128.7, 128.7, 128.9, 129.1, 129.1, 136.2, 136.7, 146.2, 146.9, 148.9, 151.9, and 156.6. FAB-HRMS: [M+H]+ Calcd. for C23H23N4O2 387.1821. Found 387.1815.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1Cl)[C:5]([OH:7])=[O:6].[NH2:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+].O>[NH2:1][C:2]1[CH:3]=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][C:10]=1[C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:12])[CH:18]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Nc1cc(C(=O)O)ccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Product: Nc1cccc(-c2ccc(C(=O)O)cc2N)c1
Yield: 111.3 %

Procedure:
The general procedure described in Example 3 was used with 3-amino-4-chloro-benzoic acid (172 mg, 1.00 mmol), 3-aminophenylboronic acid (190 mg, 1.40 mmol), Pd(OAc)2 (2.2 mg, 0.010 mmol, 1 mol %), sodium 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-3′-sulfonate (10.0 mg, 0.020 mmol, 2 mol %), K2CO3 (552 mg, 4.00 mmol), water (3.0 mL), 12 h, 100° C. The product was isolated as a light brown oil (254 mg, 99%). 1H NMR (400 MHz, CDCl3/d4-MeOH) δ: 7.35 (m, 2H), 7.10 (t, 1H, J=7.6 Hz), 7.02 (d, 1H, J=8.0 Hz), 6.70-6.60 (m, 3H). 13C NMR (125 MHz, CDCl3/d4-MeOH) δ: 169.4, 146.6, 143.4, 139.4, 132.4, 129.9, 129.7, 129.0, 119.8, 118.9, 115.8, 115.5, 114.8. IR (neat, cm−1): 3419, 1645, 1016. EI-MS for C13H12N2O2: Theoretical [M+H]=229.0977. Found: 229.0982. Anal. Calcd for C13H12N2O2: C, 68.41; H, 5.30. Found: C, 68.29; H, 5.29.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:17]([O:19][CH3:20])=[O:18].CCCCCCC.CC(O)C>C(#N)C>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][C@@H:5]1[CH2:10][C@@H:9]([C:11]2[O:15][NH:14][C:13](=[O:16])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1CCC(C)(C)C
Solvent: CCCCCCC
Solvent: CC(C)O
Solvent: CC#N
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1CCC(C)(C)C
Yield: 42.4 %

Procedure:
Trans-methyl 2-(3,3-dimethylbutyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (194 mg, 0.63 mmol) was subjected to chiral preparative HPLC (Column: Chiralpak IC (250×20), 5 μm particle size, mobile phase: Heptane/IPA 85/15, flow rate 18 mL/min) to yield (2R,4S)-methyl 2-(3,3-dimethylbutyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (83 mg, 43%), Chiral purity 99.3% ee, Optical rotation [α]D20=−12.3 (acetonitrile, c=1)
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([CH2:11][OH:12])[CH2:6]1.[C:13]([O:17][C:18](=[O:21])[CH2:19]Br)([CH3:16])([CH3:15])[CH3:14].[OH-].[Na+]>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][CH2:3][O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([CH2:11][O:12][CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:21])[CH2:6]1
Reactant: COCO[C@@H]1CCC[C@H](CO)C1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCO[C@@H]1CCC[C@H](COCC(=O)OC(C)(C)C)C1
Temperature: 10 °C
Yield: 66.5 %

Procedure:
1.0 g of (cis-3-methoxymethoxycyclohexyl)methanol and 3.3 g of tert-butylbromoacetate are dissolved in 30 ml of toluene, and 0.50 g of tetrabutylammonium hydrogensulfate is added. The suspension is cooled to 10° C. 10 ml of 50% strength NaOH are added to the suspension. The mixture is allowed to warm to room temperature, and after 3 h the aqueous phase is removed and extracted with methyl tert-butyl ether. The combined organic phases are dried over MgSO4 and concentrated. Flash column chromatography on silica gel (heptane/ethyl acetate 10/1->2/1) gives 1.10 g of tert-butyl (cis-3-methoxymethoxycyclohexylmethoxy)acetate as a colorless oil. C15H28O5 (288), LCMS(ESI): 306 (M++H2O).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42](O)=[O:43].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:42](=[O:43])[C:41]1[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=1[CH2:39][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:19]1=[O:18]
Reactant: Cc1ccc(N)c(C)c1
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: Cc1ccc(NC(=O)c2ccccc2CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c(C)c1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2,4-dimethylaniline to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2,4-dimethylphenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (90%) as a colorless solid: mp 207-208° C.; 1H NMR (300 MHz, DMSO-d6) δ9.95 (s, 1H), 7.69-7.61 (m, 1H), 7.49-7.34 (m, 2H), 7.31-7.13 (m, 4H), 7.09-6.95 (m, 3H), 6.89 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.40 (s, 1H), 5.20-5.01 (m, 2H), 4.86 (d, J=8.9 Hz, 1H), 4.71 (d, J=8.9 Hz, 1H), 4.47 (t, J=8.7 Hz, 2H), 2.93 (t, J=8.7 Hz, 2H), 2.25 (s, 6H); 13C NMR (75 MHz, DMSO-d6) δ177.9, 167.7, 161.6, 161.2, 142.8, 136.6, 135.6, 134.4, 133.9, 133.5, 132.7, 131.3, 130.8, 129.1, 128.4, 127.8, 126.9, 126.7, 124.2, 123.6, 120.9, 120.4, 119.6, 109.7, 92.9, 80.4, 72.6, 65.4, 57.5, 41.4, 28.8, 21.0, 18.4, 15.6; MS (ES+) m/z 517.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[Br:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>C(OCC)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[NH:33][C:32]1[CH:34]=[CH:35][C:29]([Br:28])=[CH:30][CH:31]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (5 g, 23 mmol) was dissolved in 250 mL dry diethyl ether under Ar, cooled in an ice water bath, added dry pyridine (11.3 mL, 139 mmol) followed by the dropwise addition of oxalyl chloride (6.1 mL, 69 mmol). A precipitate forms immediately. The reaction was stirred vigorously at 0° C. for one hour, then at ambient temperature for one hour. Added 100 mL diethyl ether, filtered off solids washing with diethyl ether. Concentrated the filtrates to an off white oil. Redissolved (3.66 g, 15 mmol) oil in 40 mL dry DCM under Ar, cooled to 0° C., added 4.6 mL pyridine followed by 4-bromoaniline (2.7 g, 15 mmol). The reaction was allowed to warm to ambient temperature, stirred for 3 hours then concentrated. Redissolved in 100 mL EtOAc, washed with 1 N HCl (2×100 mL), brine (100 mL), dried with MgSO4, filtered and concentrated to yield title compound. (4.56 g, 80%) APCI (AP−): 369.0, 370.0 (M−H)−.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[I:6][C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9].C(N(CC)CC)C>ClCCl>[I:6][C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH:9][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1I
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccccc1I
Reaction time: 1.5 h
Yield: 75.4 %

Procedure:
Methanesulfonyl chloride (4.4 mL, 57 mmol) was added to a 0° C. dichloromethane (200 mL) solution containing 2-iodoaniline (5.0 g, 23 mmol) and triethylamine (9.6 mL, 69 mmol). The resulting mixture was stirred for 90 minutes, washed with HCl (0.5 M). The organics were separated then dried over sodium sulfate and concentrated in vacuo. The residue was then treated with potassium hydroxide (2.0 M in 1:1 methanol:water, 75 mL) for 30 min. This material was then diluted with dichloromethane and washed with HCl (1.0 N, 300 mL). The organics were separated then dried over sodium sulfate and concentrated to provide the title compound (5.15 g) as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]([NH2:13])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(O)(=O)[C@H]([C@@H](C(O)=O)O)O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:6]([NH2:13])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:14][CH:15]=1
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Product: N[C@@H](c1ccccc1)c1ccc(Cl)cc1

Procedure:
The racemic 4-chlorobenzhydrylamine was treated with D-tartaric acid, and then sequentially recrystallized ten times from water (as described by Clemo, et al., J. Chem. Soc., (1939), 1958-1960) to provide (S)-4-chlorobenzhydrylamine of high optical purity (ee>98%, according to chiral HPLC).