Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)(Cl)Cl.C(O)(C)C>[C:1]1([C@H:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCCc2c1c1cccc3c1n2C(c1ccccc1)CO3
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: O=C1CCCc2c1c1cccc3c1n2[C@H](c1ccccc1)CO3
Yield: 49.3 %

Procedure:
1-Phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one (0.600 g) is dissolved in a minimum volume of chloroform and isopropanol is added to give a final volume of 15 mL. The solution is injected onto a 5×50 cm column of 20 micron Chiralcel OD (Chiral Technologies) held at 30° C. The sample is eluted with 30% isopropanol in heptane (V/V) at 75 mL/min while monitoring at 245 nm using a Merck/Sepracor ST-140 HPLC with closed loop peak shaving and recycling capability. About 70% of the front part of the broad peak that eluted between 25-32 minutes is collected and about 40% of the tail of the second peak that eluted between 29-37 minutes is collected. The central portions of these overlapping peaks are recycled and complete resolution is obtained on the second pass. The appropriate fractions are pooled and the solvent is removed on a rotary evaporator. The residues are assayed on a 0.46×25 cm Chiralcel OD-H column at ambient temperature using 25% isopropanol in heptane at 0.5 mL/min and detection at 244 nm. The earlier eluting enantiomer (0.297 g, Rt=21.7 min) assayed for 97.6% ee. Chromatography on silica gel using acetone/hexane (20/80) gave 0.296 g of (R)-(−)-1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one; [α]D=81° (CH2Cl2). The eluting enantiomer (0.261 g, Rt=26.8 min) assayed for >99% ee. Chromatography on silica gel using acetone/hexane (20/80) gave 0.254 g of (S)-(+)-1-phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one. [α]D=+84° (CH2Cl2).
Reaction SMILES: [N:1]1[CH2:2][CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=3[S:7][C:6]=12.C(O)(=O)C.[O-:19][C:20]#[N:21].[K+].[OH-].[NH4+]>O>[N:1]1[CH2:2][CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[C:11]([NH:14][C:20]([NH2:21])=[O:19])[CH:12]=[CH:13][C:8]=3[S:7][C:6]=12
Reactant: N#C[O-]
Reactant: Nc1ccc2c(c1)N1CCCN=C1S2
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1ccc2c(c1)N1CCCN=C1S2
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3 parts of 3,4-dihydro-2-H-pyrimido[2,1-b]benzothiazol-7-amine in 16 parts of acetic acid are added 32 parts of water. Then there is added dropwise a solution of 1.46 parts of potassium cyanate in 32 parts of water (slightly exothermic reaction). Upon completion, stirring is continued overnight at room temperature. The reaction mixture is alkalized with ammonium hydroxide and the whole is stirred while cooling at 10° C. The precipitated product is filtered off and crystallized twice: first from 2-methoxyethanol and then from 1-butanol, yielding 0.6 parts of N-(3,4-dihydro-2H-pyrimido[2,1-b]benzothiazol-7-yl)urea; mp. 245.9° C.
Reaction SMILES: [OH-].[K+].Cl.[OH:4][C:5]1[C:6]([CH2:11][OH:12])=[N:7][CH:8]=[CH:9][CH:10]=1.[CH3:13]I.Cl>CS(C)=O>[OH:12][CH2:11][C:6]1[C:5]([O:4][CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: OCc1ncccc1O
Reactant: CI
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cccnc1CO
Reaction time: 0.5 h
Yield: 31.3 %

Procedure:
Potassium hydroxide (41.66 g, 0.744 mol) was ground under nitrogen and stirred in DMSO (130 ml, anhydrous) for 20 min. 3-Hydroxy-2-hydroxymethyl pyridine hydrochloride [Aldrich] (47 g, 0.248 mol) was added and stirred for 30 min in an ice bath. Methyl iodide (35.2 g, 0.248 mol, 15.43 ml) in DMSO (20 ml) was added dropwise to the solution and then allowed to stir overnight at room temperature. 5N HCl was added to pH 1 and the solution was extracted with dichloromethane (5×500 ml). The aqueous was then basified with 5N NaOH to pH 14 and extracted with dichloromethane (3×500 ml). The organics (base wash) were dried over sodium sulfate, and concentrated leaving tan colored crystals. The solid was recrystallized (50% ethyl acetate/hexanes) providing 10.8 g (32%) of the titled product as light tan crystals:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:13][CH2:14][OH:15])=[CH:7][CH:6]=1)=O.[NH2:24][C:25]1[C:30]([CH:31]([OH:33])[CH3:32])=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[OH:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:24]=[C:25]3[C:30]([CH:31]([OH:33])[CH3:32])=[CH:29][CH:28]=[CH:27][N:26]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: CC(O)c1cccnc1N
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(O)c1cccn2cc(-c3ccc(C[C@@H](CCO)NC(=O)OC(C)(C)C)cc3)nc12

Procedure:
A mixture of 1,1-dimethylethyl ((1S)-1-{[4-(bromoacetyl)phenyl]methyl}-3-hydroxypropyl)carbamate (1.00 g, 2.59 mmol), 1-(2-amino-3-pyridinyl)ethanol (0.358 g, 2.59 mmol), and solid sodium bicarbonate (0.272 g, 3.24 mmol) in isopropanol (25 mL) was heated at reflux for 3.5 h. and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water and brine, dried (Na2SO4), and concentrated. The resulting pale yellow solid was used in the next reaction without further purification. MS (ES+) m/e 426 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][NH:11][N:10]=1.N#N.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][N:11]([C:31](=[O:33])[CH3:32])[N:10]=1
Reactant: COc1ccc2c(c1)CNN=C2Cc1c(Cl)cncc1Cl
Reactant: CC(=O)Cl
Agent: N#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CN(C(C)=O)N=C2Cc1c(Cl)cncc1Cl
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
As an alternative to the previous synthesis, the title compound was prepared starting from a solution of 4-(3,5-dichloro-pyridin-4-ylmethyl)-7-methoxy-1,2-dihydro-phthalazine (2 g, 6.2 mmoles), prepared as described in example 22, in dry THF (60 ml) under stirring and dry N2 at 0° C. The mixture was added with triethylamine (1.57 g, 15.5 mmoles), then with acetyl chloride (0.44 ml, 6.2 mmoles). After 10 minutes the mixture was brought to room temperature and kept at such temperature for 2.5 hours, then poured into water/ice and extracted more times with CH2Cl2. The organic phases were washed with 5% NaOH and water, anhydrified and brought to dryness to give a solid which, by crystallisation from acetonitrile (70 ml), gave 1.95 g of the title compound having the same physochemical characteristics set forth at point A.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].I[CH2:23][CH3:24].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:23][CH3:24])[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: CCI
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1CC
Temperature: 25 °C
Reaction time: 72 h
Yield: 103.6 %

Procedure:
A mixture of ethyl 5-chloro-1H-indole-2-carboxylate (500 mg, 2.17 mmol), potassium carbonate (450 mg, 3.25 mmol), iodoethane (260 μL, 3.25 mmol) and N,N-dimethylformamide (10.8 mL) was stirred at room temperature for 3 days. To the reaction solution was added water, and the mixture was extracted with ethyl acetate twice. The organic layer was combined, washed with water three times, and the organic layer was filtered through diatomaceous earth, followed by silica gel, and then the filtrate was concentrated under reduced pressure to give ethyl 5-chloro-1-ethyl-1H-indole-2-carboxylate (566 mg, 100%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[C:10](=[O:11])[C@@H:9]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C@H:8]1[C@@H:23]([OH:26])[CH2:24][OH:25].[C:32](N1C=CN=C1)(N1C=CN=C1)=[O:33]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[C:10](=[O:11])[C@@H:9]([NH:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C@H:8]1[C@@H:23]1[CH2:24][O:25][C:32](=[O:33])[O:26]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2[C@@H](O)CO)cc1OC
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2[C@@H]2COC(=O)O2)cc1OC
Yield: 96.5 %

Procedure:
215.23 g (0.5 mol) of benzyl (2S,3S)-1-(3,4-dimethoxybenzyl)-2-[1(R),2-dihydroxyethyl]-4-oxo-3-azetidinecarbamate were dissolved In 3 l of THF at the boiling temperature. 12.61 g (0.75 mol) of 1,1'-carbonyldiimidazole were added. The mixture was boiled under reflux for 4 hours. The THF was subsequently removed by concentration, the oily residue was taken up in 1.5 l of dichloromethane, washed once with 500 ml of 1N aqueous hydrochloric acid, twice with 1 l of water each time and once with 500 ml of saturated, aqueous sodium chloride solution and dried over magnesium sulphate with the addition of about 7 g of fuller's earth. The solvent was removed by concentration. After drying there were obtained without further purification 220.3 g (yield: 96%) of pure product. M.p.: 135°-136° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([NH:14][C@@H:15]2[CH2:18][C@@H:17]([NH:19]C(=O)OC(C)(C)C)[C:16]2([CH3:28])[CH3:27])[C:11]([C:29]#[N:30])=[CH:10][N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:19][C@@H:17]1[CH2:18][C@@H:15]([NH:14][C:12]2[C:11]([C:29]#[N:30])=[CH:10][N:9]=[C:8]([NH:7][CH2:6][CH2:5][C:4]3[CH:31]=[CH:32][CH:33]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)[C:16]1([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](Nc2nc(NCCc3cccc(Cl)c3)ncc2C#N)C1(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)[C@H](N)C[C@H]1Nc1nc(NCCc2cccc(Cl)c2)ncc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
To a solution of tert-butyl ((1R,3R)-3-((2-((3-chlorophenethyl)amino)-5-cyanopyrimidin-4-yl)amino)-2,2-dimethylcyclobutyl)carbamate (102 mg, 0.22 mmol) in dry DCM (2 mL) was added TFA (1.5 mL) dropwise under cooling in an ice-water bath. The resulting mixture was stirred at room temperature for 30 min. After removal of the organic solvent, the residue was neutralized with ammonia and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the crude, which was purified by standard methods to afford the title compound (43.8 mg, 0.118 mmol, 54% yield). 1H NMR (400 MHz, CD3OD) δ (ppm) 8.06 (s, 1H), 7.29-7.15 (m, 4H), 4.33 (dd, J1=5.6 Hz, J2=9.2 Hz, 1H), 3.72-3.50 (m, 2H), 3.18-3.12 (m, 1H), 2.93-2.86 (m, 2H), 2.45-2.39 (m, 1H), 2.17-2.12 (m, 1H), 1.20 (s, 3H), 0.98 (s 3H). MS (ESI) m/z 371.2 [M+H]+.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[F:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[CH2:21][C:22]1[N:26]2[N:27]=[C:28]([C:31](=O)[CH3:32])[CH:29]=[CH:30][C:25]2=[N:24][CH:23]=1>>[F:10][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[CH2:21][C:22]1[N:26]2[N:27]=[C:28](/[C:31](=[N:2]/[N:3]3[CH2:7][C:6](=[O:8])[NH:5][C:4]3=[O:9])/[CH3:32])[CH:29]=[CH:30][C:25]2=[N:24][CH:23]=1
Reactant: NN1CC(=O)NC1=O
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Agent: Cl
Product: C/C(=N\N1CC(=O)NC1=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 39 %

Procedure:
The title compound was prepared from 1-aminoimidazolidine-2,4-dione hydrochloride and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 39% yield. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.39 (s, 1H), 8.91 (dd, 1H), 8.40 (d, 1H), 8.24 (d, 1H), 8.04 (d, 1H), 7.94 (m, 2H), 7.82 (d, 1H), 7.55 (q, 1H), 4.64 (s, 2H), 4.50 (s, 2H), 2.40 (s, 3H). LCMS (method A): [MH]+=418, tR=4.62 min.
Reaction SMILES: C[N:2]([C:7](=[O:32])[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:18][C:17]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)([C:19]([F:22])([F:21])[F:20])[O:16][N:15]=2)=[CH:10][C:9]=1[CH3:31])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[K+].Cl>CO.O>[Cl:30][C:25]1[CH:24]=[C:23]([C:17]2([C:19]([F:21])([F:20])[F:22])[O:16][N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:2][CH2:3][C:4]([OH:6])=[O:5])=[O:32])=[C:9]([CH3:31])[CH:10]=3)[CH2:18]2)[CH:28]=[C:27]([Cl:29])[CH:26]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N(C)CC(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCC(=O)O
Temperature: 25 °C
Yield: 95 %

Procedure:
In a solution of 2.6 g of methyl N-[4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methylbenzoyl]glycine (Compound of the present invention No. 5-128) synthesized similarly to Synthetic Example 5 in 10 ml of methanol, a solution of 1.0 g of potassium hydroxide in 10 ml of water was added with stirring at room temperature, and stirred at the same temperature for further 1 hour. After the completion of the reaction, 10 ml of 12N hydrochloric acid was added and extracted with ethyl acetate (50 ml×1), the organic phase was dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 2.4 g of the aimed product as pale yellow resinous resinous substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>C(#N)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[O:13])[C:8](=[O:12])[N:9]2[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)NC(=O)C2=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc2c(c1)N(CC(=O)OC(C)(C)C)C(=O)C2=O
Yield: 95.5 %

Procedure:
To a solution of 6-methoxyindoline-2,3-dione (350 mg, 1.976 mmol) in acetonitrile (10 ml), K2CO3 (328 mg, 2.371 mmol) and tert-butyl 2-bromoacetate (350 μl, 2.371 mmol) were added, and the mixture was reacted at room temperature overnight. The insoluble inorganic salts were filtered off and the solvent was evaporated obtaining the crude title compound (550 mg, 1.888 mmol, 96% yield). MS/ESI+ 292.1 [MH]+. The crude was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH2:17]([NH2:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:25][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: CCCCCCCCN
Solvent: CCN(CC)CC
Product: CCCCCCCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-(octylamino)-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, n-octylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1>>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)[CH2:3][CH2:2]2)=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(N2CCC(N3CCOCC3)CC2)cc1

Procedure:
The compound was prepared from 4-piperidin-4-yl-morpholine (Example 4) and 4-fluoro-nitrobenzene (Aldrich) following the procedure used in Example 1. MS (m+H)+: 292.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]1[C:40]2[NH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]=2[C:31]([O:41][CH:42]2[O:44][C@H:43]2[CH3:45])=[CH:30][CH:29]=1>CO>[CH2:1]([N:8]([CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH2:10]1)[CH2:45][CH:43]([OH:44])[CH2:42][O:41][C:31]1[C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[NH:39][C:40]=2[CH:28]=[CH:29][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOc1ccc(S(=O)(=O)N2CCC(NCc3ccccc3)C2)cc1
Reactant: C[C@@H]1OC1Oc1cccc2[nH]c3ccccc3c12
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)N2CCC(N(Cc3ccccc3)CC(O)COc3cccc4[nH]c5ccccc5c34)C2)cc1
Yield: 111.5 %

Procedure:
To a solution of benzyl-[1-(4-butoxy-benzenesulfonyl)-pyrrolidin-3-yl]-amine (0.16 g, 0.4 mmol) in methanol (2 ml) was added (2S)-3-(9H-carbazol-4-yloxy)-methyl oxirane (0.12 g, 0.5 mmol) and the mixture was stirred at reflux for 3 days. The methanol was then evaporated, and the residue was washed with a mixture of ether and hexanes to give 0.28 g of an off-white solid; m.p. 73-76° C.; MS (ES) m/z 628.2 (MH+); HRMS (El) Calcd. for C36H41N3O5S (M+): 627.2767, Found: 627.2808.
Reaction SMILES: C([Mg]Br)C.[CH3:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.[CH2:14](Br)[CH:15]=[CH2:16].[Cl-].[NH4+]>CCOCC>[CH3:5][N:6]([CH2:16][CH:15]=[CH2:14])[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1
Reactant: CNc1ccc(Br)cc1
Reactant: C=CCBr
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CCN(C)c1ccc(Br)cc1
Reaction time: 0.5 h

Procedure:
280 ml of a solution of ethyl magnesium bromide in ether were added dropwise at less than 20° C. under an inert atmosphere to 50.05 g of N-methyl-4-bromo-aniline and after stirring for 30 minutes, 28 ml of allyl bromide were added thereto over 15 minutes. The mixture was refluxed for 40 minutes and was allowed to cool. 25 ml of a solution N of ethyl magnesium bromide in ether were added thereto dropwise and the mixture was stirred for 25 minutes and poured into iced ammonium chloride solution. The decanted aqueous phase was extracted with methylene chloride and the organic phase was dried and evaporated to dryness to obtain 61.35 g of N-methyl-N-allyl-4-bromo-aniline.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:14][N:15]([CH3:17])[CH3:16])[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])(C)(C)C.[ClH:19].C(OCC)(=O)C>>[ClH:19].[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C@H:8]([NH2:7])[CH2:14][N:15]([CH3:17])[CH3:16]
Reactant: CN(C)C[C@H](CC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)C[C@@H](N)CC(C)(C)C

Procedure:
A solution of ((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-carbamic acid tert-butyl ester (1.6 g, 6.20 mmol, 1.0 equiv.) in dry HCl-ethyl acetate (31 mL) was stirred overnight at room temperature under nitrogen. Ethyl acetate was distilled off under reduced pressure to give crude (S)-4,4,N1,N1-tetramethyl-pentane-1,2-diamine hydrochloride salt (1.4 g) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:50]([OH:52])[CH3:51])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:54]([O:56][CH:57]([CH3:59])[CH3:58])=[O:55].C(N(CC)CC)C>ClCCl>[C:54](=[O:55])([O:52][CH:50]([C@:10]12[O:32][C@:13]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=4)[CH:34]=3)([O:12][CH2:11]1)[C@H:14]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:15]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH:9]2[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:51])[O:56][CH:57]([CH3:59])[CH3:58]
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)OC(=O)OC(C)C)(O3)C(OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.2 %

Procedure:
To a solution of 1-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethanol 1m (0.4 g, 0.56 mmol, obtained from the synthetic method described in step 11 of example 1) in dichloromethane (30 mL) were added isopropyl chloroformate (1.0 mL, 8.34 mmol), triethylamine (1.55 mL, 11.1 mmol) and 4-dimethyl aminopyridine (cat. 5 mg) in turn at room temperature. The mixture was stirred at room temperature for 16 hours. The resulting mixture was quenched with 20 mL of saturated aqueous ammonium chloride, and then extracted with ethyl acetate (40 mL×2). The combined organic layers were washed with saturated brine (20 mL×2), dried over anhydrous brine and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 13a as a light yellow solid (244 mg, 54.2%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.41-7.30 (m, 10H), 7.24-7.11 (m, 5H), 7.08 (m, 2H), 6.90 (m, 2H), 6.76 (m, 2H), 5.01-4.80 (m, 3H), 4.79 (m, 3H), 4.32 (d, 1H), 4.21 (d, 1H), 4.05-3.81 (m, 5H), 3.82-3.71 (m, 2H), 3.66 (d, 1H), 1.40 (t, 3H), 1.29 (d, 3H), 1.26 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[O:14]=[C:15]1[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][N:16]1[CH2:32][C:33](O)=[O:34].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[O:14]=[C:15]1[C:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][N:16]1[CH2:32][C:33]([NH:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1)=[O:34]
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: NCCc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NCCc1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
A solution of 2-(3-(trifluoromethyl)phenyl)ethanamine (0.021 g, 0.112 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.030 g, 0.102 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.029 g, 0.053 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.44-7.50 (m, 1H), 7.23-7.40 (m, 13H), 5.84 (t, J=6.1 Hz, 1H), 3.98 (s, 2H), 3.40 (t, J=6.5 Hz, 2H), 3.32-3.40 (m, 2H), 2.76 (t, J=6.5 Hz, 2H), 2.67 (t, J=7.3 Hz, 2H); MS (ESI−) m/z 465 (M−H)−.