Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H]1(N2C3N=C(N)NC(=O)C=3N=C2)O[C@H](CO)C[C@H]1O.[C@@H:20]1(N2C3N=C(N)NC(=O)C=3N=C2)[O:27][C@H:24]([CH2:25][OH:26])[C@@H:22]([OH:23])[CH2:21]1.[Cl:39][C:40]1[N:48]=[C:47]2[C:43]([NH:44][CH:45]=[N:46]2)=[C:42]([NH2:49])[N:41]=1>>[CH2:21]1[C@H:20]([N:46]2[C:47]3[N:48]=[C:40]([Cl:39])[N:41]=[C:42]([NH2:49])[C:43]=3[N:44]=[CH:45]2)[O:27][C@H:24]([CH2:25][OH:26])[C@H:22]1[OH:23]
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)C[C@H]2O)c(=O)[nH]1
Product: Nc1nc(Cl)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Yield: 81 %

Procedure:
Stereoselective glycosylation of sodium salts of halopurines and analogues with 2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranosyl chloride gave β-nucleoside anomers via predominant Walden inversion,17,18 and ammonolysis/deprotection gave CldAdo.19 Although the sodium salt glycosylation usually gave good anomeric stereoselectivity, minor quantities of α anomers and >10% of N7 regioisomers were usually formed.20,21 This requires separations and results in diminished yields of the desired N9 product. Carson et al.1 had reported an enzymatic transfer of the 2-deoxy sugar from thymidine to 2-chloroadenine (ClAde). Holy and coworkers noted that cells of a strain of Escherichia coli performed glycosyl transfer from 2′-deoxyuridine to 2-chloro-6-[(dimethylaminomethylene)amino]purine to give a derivative of CldAdo.22 Very recently Barai, Mikhailopulo, and coworkers23 described an E. coli-mediated glycosyl transfer synthesis of 2,6-diamino-9-(3-deoxy-β-D-erythro-pentofuranosyl)purine,24 and its enzymatic deamination to 3′-deoxyguanosine.24 They reported glycosyl transfer from 2′-deoxyguanosine to ClAde, and claimed a yield of 81% of CldAdo (based on ClAde).23 However, a 3:1 ratio of dGuo/ClAde was employed, so the yield of CldAdo was <27% based on dGuo.
Reaction SMILES: [OH-].[K+].[C:3]1([S:9]([C:12]2[C:13]([O:29][CH2:30][C:31](OCC)=[O:32])=[N:14][N:15]3[C:20]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:19][C:18]([CH3:28])=[N:17][C:16]=23)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O.O1CCOCC1.C1COCC1>[C:3]1([S:9]([C:12]2[C:13]([O:29][CH2:30][CH2:31][OH:32])=[N:14][N:15]3[C:20]([N:21]4[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]4)=[CH:19][C:18]([CH3:28])=[N:17][C:16]=23)(=[O:10])=[O:11])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)COc1nn2c(N3CCN(C)CC3)cc(C)nc2c1S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(N2CCN(C)CC2)n2nc(OCCO)c(S(=O)(=O)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 32382.8 %

Procedure:
A solution of 0.126 g of KOH in 5 ml of H2O was added to a solution of 0.61 mg of ethyl 2-[3-benzenesulphonyl-5-methyl-7-(4-methyl-piperazin-1-yl)-pyrazolo[1,5-a]pyrimidin-2-yloxy]-acetate in 20 ml of dioxan/THF 1:1 and stirred at RT for 2.5 hrs. The reaction solution was evaporated and the residue was partitioned between H2O and CH2Cl2. The aqueous phase was washed three times with 30 ml of CH2Cl2,and the combined organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2,CH2Cl2/MeOH 9:1) of the residue and crystallization from EtOH yielded 0.18 g (18%) of 2-[3-benzenesulphonyl-5-methyl-7-(4-methyl-piperazin-1-yl)-pyrazolo[1,5-a]pyrimidin-2-yloxy]-ethanol as colorless crystals. M.p. 177.5-178°.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18](/[C:21](/[CH3:25])=[CH:22]/[CH2:23][OH:24])=[CH:17][CH:16]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([O:28][C@@H:29]([CH2:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:27]>>[C:1]([C:5]1[CH:6]=[C:7]([C:15]2[CH:16]=[CH:17][C:18](/[C:21](/[CH3:25])=[CH:22]/[CH2:23][O:24][C:39]3[CH:38]=[CH:37][C:36]([CH2:35][C@H:29]([O:28][CH2:26][CH3:27])[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:41][CH:40]=3)=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C/C(=C\CO)c1ccc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(C(C)(C)C)cc(C(C)(C)C)c3)cc2)cc1)OCC
Yield: 74.1 %

Procedure:
The title compound (429 mg, 74%) was prepared as a colourless gum from (E)-3-(3′,5′-di-tert-butyl-biphenyl-4-yl)-but-2-en-1-ol (350 mg, 1.04 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (260 mg, 1.09 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH3:25])[C:17]([CH3:24])=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])=[CH:10][CH:9]=1)[NH2:6].[Cl:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:30]=1[C:31](Cl)=[O:32].CCN(C(C)C)C(C)C>ClCCl>[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH3:25])[C:17]([CH3:24])=[CH:18][C:19]=2[C:20]([F:21])([F:22])[F:23])=[CH:12][CH:13]=1)[NH:6][C:31]([C:30]1[C:29]([Cl:28])=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:38])=[O:32]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Reaction time: 0.08 h
Yield: 94.9 %

Procedure:
To a suspension of 4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester hydrochloride salt (150 mg, 0.37 mmol) and 2,6-dichlorobenzoyl chloride (85 mg, 0.4 mmol) in dichloromethane (6 mL) was added DIEA (257 μL, 1.48 mmol) at room temperature. After 5 min, a clear solution was obtained which was stirred for 48 h. Then, the mixture was concentrated and the residue was dissolved in ethyl acetate (50 mL). The ethyl acetate solution was washed with 0.5 N HCl (50 mL), saturated NaHCO3 solution (50 mL) and brine solution (50 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave crude product, which was purified by silica gel chromatography on a Biotage (40 m) column to give 190 mg (95% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C25H21Cl2F3N2O4 (M+Na) 563.0724. found 563.0726. f) Preparation of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine
Reaction SMILES: [CH:1]([C@H:4]1[N:9]=[C:8]([O:10][CH3:11])[CH2:7][N:6]=[C:5]1[O:12][CH3:13])([CH3:3])[CH3:2].C([Li])CCC.Cl[CH2:20][CH2:21][P:22]([CH3:29])(=[O:28])OCC(C)C.[O:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>CCCCCC>[CH:1]([C@H:4]1[N:9]=[C:8]([O:10][CH3:11])[C@H:7]([CH2:20][CH:21]=[P:22]([CH2:29][O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:28])[N:6]=[C:5]1[O:12][CH3:13])([CH3:3])[CH3:2]
Reactant: CC(C)COP(C)(=O)CCCl
Reactant: COC1=N[C@H](C(C)C)C(OC)=NC1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCCCOC[P+]([O-])=CC[C@@H]1N=C(OC)[C@@H](C(C)C)N=C1OC
Temperature: -75 °C
Reaction time: 0.25 h

Procedure:
5.53 g (0.03 mol) of (3R)-(-)-3-isopropyl-2,5-dimethoxy-3,6-dihydropyrazine ([α]D25 =-107.5°, c=1 in ethanol) are dissolved in 50 ml of absolute tetrahydrofuran, and 20.6 ml of a 1.6-molar solution of n-butyllithium in n-hexane are added at -75° C. The reaction mixture is stirred at -75° C. for 15 minutes. A solution, previously cooled to -60° C., of 6.1 g (0.031 mol) of 2-methylpropyl 2-chloroethyl(methyl)phosphinate in 30 ml of tetrahydrofuran is added dropwise in the course of 7 minutes at -75° C. The reaction mixture is stirred for 6 hours at -75° C. and then for 14 hours at room temperature. The solvent is removed completely in vacuo and the residue is taken up in 60 ml of diethyl ether. This solution is extracted once with 60 ml of water and once with 30 ml of saturated sodium chloride solution. The organic phase is dried over MgSO4 and completely freed from solvents. The residue is distilled in a high vacuum. This gives 8.84 g (85.1% of theory) of (3R,6S)-3-isopropyl-6-[2-(3-methylpropoxymethylphosphoryl)ethyl]-2,5-dimethoxy-3,6-dihydropyrazine as a low-melting solid of boiling point 155°-162° C./0.001 bar.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH2:12][C:13]([N:15]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:14]>O1CCCC1>[NH:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:15]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:13](=[O:14])[CH2:12][NH:11][C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:10])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1ccccc1Nc1ccccc1
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2Nc2ccccc2)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
3-Methylphenyl isocyanate (1.07 g) is added at a temperature in the region of 20° C. to a solution of tert-butyl 2-[2-amino-N-(2-anilinophenyl)acetamido]acetate (2.6 g) in anhydrous tetrahydrofuran (20 cc). The solution obtained is stirred for 2 hours at a temperature in the region of 20° C. and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residual oil is purified by chromatography on silica (0.063-0.2 mm) (150 g) contained in a column 2 cm in diameter [eluent: cyclohexane/ethyl acetate (50:50 by volume)], collecting 20-cc fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallisation in ethyl acetate, tert-butyl 2-{N-(2-anilinophenyl)-2-[3-(3-methylphenyl)ureido]acetamido}acetate (1.15 g), m.p. 180° C., is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:13]1[C:25]2[CH:24]([CH2:26][O:27][C:28]([NH:30][CH2:31][CH2:32][OH:33])=[O:29])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:33][CH2:32][CH2:31][NH:30][C:28]([O:27][CH2:26][CH:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:25]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:29])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(NCCO)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCOC(=O)c1ccc([N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 4-nitrobenzoylchloride (4.0 g, 21.6 mmoles) and N-(9-fluorenyl-methoxycarbonyl)ethanolamine (7.3 g, 25.9 mmoles) in 160 ml of methylene chloride is added triethylamine (3.1 ml, 22.6 mmoles). The mixture is stirred at room temperature for one hour, then is diluted with 400 ml of methylene chloride. The organic solution is washed with two portions of 200 ml of water and one portion of 200 ml of a saturated aqueous solution of sodium chloride. The organic phase is dried with Na2SO4, filtered and concentrated in vacuo. The resulting pale yellow solid is triturated in ethyl acetate. Filtration afforded 7.347 g of the title compound (79%). 400 MHz 1H NMR (DMSO-d6) δ: 8.32 (d, J=8.4 Hz, 2H), 8.20 (d, J=8.8 Hz, 2H), 7.87 (d, J=7.3 Hz, 2H), 7.66 (d, J=7.3 Hz, 2H), 7.61 (t, J=5.7 Hz, 1H), 7.39 (t, J=7.5 Hz, 2H), 7.28 (t, J=7.5 Hz, 2H), 4.4-4.3 (m, 4H), 4.20 (t, J=6.8 Hz, 1H), 3.45-3.35 (m, 2H). LCMS: 433 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[In].[CH2:12]([O:14][C:15](=[O:20])[C:16](Br)([F:18])[F:17])[CH3:13].[NH4+].[Cl-]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:7]([OH:8])[C:16]([F:18])([F:17])[C:15]([O:14][CH2:12][CH3:13])=[O:20])[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Cl-]
Agent: [In]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(F)(F)C(O)c1cc(Br)ccc1F
Temperature: 30 °C
Reaction time: 24 h

Procedure:
To an ice cooled solution of 5-bromo-2-fluorobenzaldehyde (10.0 g, 49.2 mmol) in dry DMF (14 mL), Indium powder (8.48 g, 73.7 mmol) was added and stirred for 15 min. ethylbromodifluoroacetate (9.48 ml [14.98 g], 73.7 mmol) in dry DMF (10 mL) was added to the resultant reaction mixture and temperature of the reaction mixture was allowed to warm to rt (30° C.). Stirring continued for 24 h. TLC analysis of the reaction mixture indicated the product formation. Reaction mixture was treated with aqueous saturated NH4Cl solution and the crude product was extracted with ethyl acetate (500 mL) by washing with water, brine and the organic layer was dried over anhydrous Na2SO4. The organic layer was concentrated and the crude product was purified by column chromatography on silica gel using 4% Ethyl acetate in Hexane to obtain title compound as a colorless thick liquid. Yield=12.0 g (75%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:10]=[CH:9][NH:8][N:7]=1.[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([NH:19][C:20]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:10]=[CH:9][NH:8][N:7]=1)=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCCNc1cc[nH]n1
Reactant: O=C(N=C=S)c1ccccc1
Product: O=C(NC(=S)NCCCNc1cc[nH]n1)c1ccccc1

Procedure:
By the procedure of Example 46, reacting 3-(3-aminopropylamino)pyrazole (prepared as in Example 53) with benzoyl isothiocyanate gives N-benzoyl-N'-[3-(3-pyrazolylamino)propyl]thiourea.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:9]=1)=[O:7].C(O[Mg][CH2:31][SiH:32]([CH3:34])[CH3:33])(C)C.[Cl-]>O1CCCC1>[OH:7][C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:9]=1)[CH:31]([SiH:32]([CH3:33])[CH3:34])[O:7][CH:6]([CH3:8])[CH3:2]
Reactant: O=C(c1cccc(OCc2ccc3ccccc3c2)c1)c1nccs1
Reactant: CC(C)O[Mg]C[SiH](C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)OC([SiH](C)C)C(O)(c1cccc(OCc2ccc3ccccc3c2)c1)c1nccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-(naphth-2-ylmethoxy)phenyl 2-thiazolyl ketone (4.84 g; Note f. above) in tetrahydrofuran (5 ml) was added dropwise to a solution of isopropoxydimethylsilylmethylmagnesium chloride [prepared as described in J. Org. Chem., 1983, 48, 2120 from chloromethylisopropoxydimethylsilane (4.2 g) and magnesium powder (0.6 g) in tetrahydrofuran (7 ml)]. The mixture was stirred at ambient temperature for 1 hour, washed with saturated aqueous solution of ammonium chloride and then with a saturated aqueous solution of sodium chloride. The organic layer was separated, dried (Na2SO4) and evaporated to give 2-[1-hydroxy-2-isopropoxydimethylsilyl-1-(3-(naphth-2-ylmethoxy)phenyl)ethyl]thiazole as an oil.
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[F:11][C:12]([F:26])([F:25])[S:13]([O:16][C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=1[Cl:24])(=[O:15])=[O:14].N1C=CC=CC=1.C(N(CC)CC)C>ClCCl.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:26][C:12]([F:11])([F:25])[S:13]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:3]#[C:2][CH2:1][N:4]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)=[CH:19][C:18]=1[Cl:24])(=[O:15])=[O:14]
Reactant: O=S(=O)(Oc1ccc(Br)cc1Cl)C(F)(F)F
Reactant: C#CCN1CCCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1ccc(C#CCN2CCCCCC2)cc1Cl)C(F)(F)F

Procedure:
1.96 g of 1-prop-2-ynylazepane (compound 4.1) are added, under inert atmosphere, to 4 g of 4-bromo-2-chlorophenyl trifluoromethanesulphonate (compound IIIa.1), 0.062 g of copper iodide, 10 ml of pyridine and 20 ml of triethylamine, followed by 0.457 g of the catalyst dichlorobis(triphenylphosphine)palladium. The reaction mixture is heated at the reflux point for 2 hours, the solvents are evaporated off under reduced pressure, and the residue obtained is taken up in dichloromethane, washed in water and dried over magnesium sulphate. After evaporating off the solvents under reduced pressure, the residue obtained is purified by chromatography on a column of silica gel, eluting with an 80/20 cyclohexane/ethyl acetate mixture; m.p.=192° C.
Reaction SMILES: C[O:2][C:3]1[C:21]([CH3:22])=[C:20]([CH3:23])[C:19]([O:24]C)=[C:18]([CH3:26])[C:4]=1[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:15][CH2:16][CH3:17])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12].[O:27]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:26][C:18]1[C:19](=[O:24])[C:20]([CH3:23])=[C:21]([CH3:22])[C:3](=[O:2])[C:4]=1[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:15][C:16](=[O:27])[CH3:17])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12]
Reactant: CCOc1ccc(Cc2c(C)c(OC)c(C)c(C)c2OC)cc1C(=O)O
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CC(=O)Oc1ccc(CC2=C(C)C(=O)C(C)=C(C)C2=O)cc1C(=O)O
Yield: 68 %

Procedure:
5-(2,5-Dimethoxy-3,4,6-trimethylbenzyl)-2-etoxybenzoic acid (1.25 g, 2.56 mmol) was dissolved in a mixed solution of acetonitrile (30 ml) and water (10 ml) and after adding thereto CAN (3.50 g, 6.39 mmol), the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=2:1) and then recrystallized from ether to obtain the titled compound (0.800 g, 1.74 mmol, 68%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](OC(=O)C)(=[O:7])[CH3:6].[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH:20]=[CH:19]2)=[O:15]>ClC(Cl)C>[CH3:12][O:13][C:14]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:26])=[O:27])[CH:20]=[C:19]2[C:5](=[O:7])[CH3:6])=[O:15]
Reactant: COC(=O)c1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reactant: CC(=O)OC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc2c(c1)c(C(C)=O)cn2S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
To a suspension of 10.7 g (80 mmol) of aluminum chloride in dichloroethane (80 ml) was added dropwise 4.83 g (40 mmol) of acetic anhydride. After stirring for 15 min, to the mixture was added dropwise 6.31 g (20 mmol) of the above-mentioned 1-benzenesulfonylindole-5-carboxylic acid methyl ester in dichloroethane (60 ml). After stirring for 2 hours at room temperature, to the mixture were added 5.33 g (40 mmol) of aluminum chloride and 2.04 g (20 mmol) of acetic anhydride. After stirring for 30 min, the mixture was poured into ice-water, extracted with ethyl acetate. The extract was washed twice with water, aqueous sodium bicarbonate and dried, and then concentrated. The obtained crystal was washed with isopropyl ether to give 6.82 g of 3-acetyl-1-benzenesulfonylindole-5-carboxylic acid methyl ester. Yield: 96%.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH3:20][S:21]([O:10][CH:8]([CH2:7][O:6][C:5]1[CH:11]=[CH:12][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:9])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)COc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(COc1ccc(Cl)cc1)OS(C)(=O)=O
Temperature: -8 °C
Reaction time: 1 h

Procedure:
To a solution of 37.4 g of 3-(p-chlorophenoxy)propan-2-ol and 41 ml of triethylamine in 500 ml of dichloromethane stirred and chilled at -8° C. is added dropwise 18.7 ml of methanesulfonyl chloride in 50 ml of dichloromethane. After stirring at -8° C. for 1 hour, the solution is washed with 350 ml portions of ice cold water, 1N HCl, saturated NaCl, saturated NaHCO3 and saturated NaCl. The organic layer is dried (MgSO4) and the solvent removed under reduced pressure to give 54 g of product as white crystals, mp 72°-78° C.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([C:21]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:25][CH2:24][NH:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].CO>C(OCC)(=O)C>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:23]3[CH2:24][CH2:25][C:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:22]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: c1ccc(C2(c3ccccc3)CCNC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccccc2)(c2ccccc2)C1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 3,3-diphenylpyrrolidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 68% overall yield. FDMS m/e=412 (M+ of free base). mp 193°-194°. α[D]589 =-9.11 (c=0.33, methanol).
Reaction SMILES: C[CH:2]([O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[CH:37][CH:36]=1)[C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][O:15][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][CH:7]=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:15][CH2:14][CH2:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3](=[O:33])[CH2:2][O:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])=[CH:39][CH:40]=2)=[CH:11][CH:10]=1
Reactant: CC(Oc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)COc1ccc(CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(OCC(=O)COc2ccc(CCCO)cc2)cc1
Temperature: 70 °C
Yield: 97.7 %

Procedure:
A solution of methyl 3-[4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-propanone (1.44 g, 2.25 mmol) in tetrahydrofuran (35 ml) was treated at 22° C. with acetic acid (0.8 ml) followed by 5 ml (5 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. The mixture was then heated at 70° C. for 4 hours. The cooled reaction mixture was then diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate, 7:3) gave 0.88 g (97%) of the title material as oil.
Reaction SMILES: [NH:1]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[NH2:2].[F:10][C:11]([F:17])([F:16])[CH2:12][N:13]=[C:14]=[O:15].C1COCC1>C1C=CC=CC=1>[F:10][C:11]([F:17])([F:16])[CH2:12][NH:13][C:14]([NH:2][NH:1][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:15]
Reactant: O=C=NCC(F)(F)F
Reactant: CC(C)(C)OC(=O)NN
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)NNC(=O)NCC(F)(F)F
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
To a stirred solution of tert-butyl hydrazinecarboxylate (1.0 g, 8 mmol) in anhydrous benzene (10.0 mL) was added 1,1,1-trifluoro-2-isocyanatoethane (1.06 g, 8 mmol) neat via syringe to give a gelatin like mixture. Anhydrous THF was added to give a clear solution which was stirred for 10 minutes, after which time the reaction mixture was evaporated to afford the title compound as a white solid (1.62 g, 79%): 1H NMR (400 MHz, CDCl3) δ 6.63 (s, 1H), 6.40 (d, J=2.2 Hz, 1H), 5.84 (s, 1H), 3.88 (qd, J=9.0, 6.6 Hz, 2H), 1.48 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −73.20. This material is used without further purification.