Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH2:3]([CH:5]1[C:13]2[C:12]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:11][CH:10]=[N:9][C:8]=2[CH2:7][S:6]1)[CH3:4].[C:20]([O:24][C:25]([NH:27][C@H:28]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(N(CC)CC)C>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][C@@H:28]([NH:27][C:25](=[O:26])[O:24][C:20]([CH3:22])([CH3:21])[CH3:23])[C:29]([N:17]2[CH2:16][CH2:15][N:14]([C:12]3[C:13]4[CH:5]([CH2:3][CH3:4])[S:6][CH2:7][C:8]=4[N:9]=[CH:10][N:11]=3)[CH2:19][CH2:18]2)=[O:30])=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: CCC1SCc2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC1SCc2ncnc(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.6 %

Procedure:
To a solution of 5-ethyl-4-(piperazin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine dihydrochloride (50 mg, 0.15 mmol) and (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (46 mg, 0.15 mmol) in DCM (10 mL) and triethylamine (1 mL) was added HBTU (59 mg, 0.15 mmol). The mixture was stirred at room temperature for 3 hours. The solvent was removed and the residue was purified by silica gel chromatography, eluting with DCM/ethyl acetate (1:1) to give tert-butyl (R)-3-(4-chlorophenyl)-1-(4-(5-ethyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (50 mg, 60%). 1H NMR (CDCl3, 400 MHz) δ 8.53 (s, 1H), 7.26-7.14 (m, 4H), 5.36 (m, 1H), 4.82 (m, 1H), 4.62 (m, 1H), 4.14 (m, 1H), 3.80-2.90 (m, 8H), 1.94 (m, 1H). 1.68 (m, 1H), 1.54 (m, 1H), 1.42 (s, 9H), 0.94 (m, 3H). MS (APCI+) [M+H]+ 533.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[CH2:12][NH:11][CH:10]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]2([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])[C:18]#[N:19])[CH:5]=[CH:6][CH:7]=1.C([O-])(O)=O.[Na+].[C:34](Cl)([Cl:36])=[O:35]>ClCCl>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[CH2:12][N:11]([C:34]([Cl:36])=[O:35])[CH:10]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]2([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])[C:18]#[N:19])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CC1NCC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: O=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)CC1N(C(=O)Cl)CC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a solution of rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-2-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile prepared in Example 3 (0.3 g, 0.71 mmol) in dichloromethane (5 mL) was added saturated aqueous NaHCO3 solution (5 mL). The temperature of the mixture was lowered to 0° C., and a solution of phosgene (Aldrich, 20% in toluene, 0.67 mL, 1.28 mmol) was added dropwise via a syringe. The reaction mixture was stirred at room temperature for 30 min, then diluted dichloromethane. The organic layer was separated, the aqueous layer was extracted with dichloromethane (2×). The combined organic layers were washed with water, brine, dried over MgSO4, and concentrated to give crude rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl chloride as a light yellow oil (0.34 g, 100%).
Reaction SMILES: Br[C:2](=[CH2:12])[CH2:3][O:4]CC1C=CC=CC=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][C:30]=1B1OC(C)(C)C(C)(C)O1)[C:18]([O:20]CC1C=CC=CC=1)=[O:19]>CN(C=O)C.Cl[Pd](Cl)([P+](C1CCCCC1)(C1CCCCC1)C1C=CC=CC=1)[P+](C(C)(C)C)(C(C)(C)C)C(C)(C)C.[Pd]>[OH:4][CH2:3][CH:2]([C:30]1[CH:29]=[CH:28][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[O:14][CH3:13])[CH3:12]
Reactant: C=C(Br)COCc1ccccc1
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1B1OC(C)(C)C(C)(C)O1
Agent: CC(C)(C)[P+](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[P+](c1ccccc1)(C1CCCCC1)C1CCCCC1
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)ccc1C(C)CO
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Dichloro-[dicyclohexyl(phenyl)phosphaniumyl]-tritert-butylphosphaniumyl-palladium (981 mg, 0.150 mmol) and 2-bromoallyloxymethylbenzene (341 mg, 1.50 mmol) were dissolved in DMF (1 mL). A solution of benzyl 3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.11 g, 3.00 mmol) in DMF (3 mL) was added the mixture was heated at 90° C. for 3 h. The mixture was then filtered through Celite using ethyl acetate. The filtrate was then washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue from step 1 was taken up in isopropanol (2 mL) and was added to 10% Pd/C (160 mg, 0.150 mmol). The vessel was purged with nitrogen and a balloon of hydrogen was added and the reaction mixture was allowed to stir overnight. The reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was partitioned between aqueous 2M Na2CO3 and ethyl acetate. The layers were separated and the organic phase was discarded. To the aqueous phase was added 1M HCl until the solution was pH 3. The solution was then extracted with EtOAc (3×) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated to provide 4-(1-hydroxypropan-2-yl)-3-methoxybenzoic acid. ESI-MS m/z calc 210.1, found 211.1 (M+1)+. Retention time: 1.19 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[I-].[Na+].Cl[CH2:28][C:29](=[O:31])[CH3:30]>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:19][CH2:28][C:29](=[O:31])[CH3:30])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: O=c1[nH]c2cc(Cl)ccc2c(O)c1-c1ccccc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)COc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12
Reaction time: 24 h

Procedure:
To a stirred suspension of 7-chloro-4-hydroxy-3-phenyl-2(1H)-quinolone (0.50 g 0.0018 mol), sodium hydrogen carbonate (1.55 g, 0.018 mol) and sodium iodide (0.20 g) in N,N-dimethylformamide (20 ml) was added chloroacetone (0.20 g, 0.0020 mol). The reaction was stirred for 24 h, then the product was precipitated by the addition of water (50 ml). The product was collected by filtration, washed with water (3×10 ml) and dried under vacuum at 60° C. Recrystallisation from ethyl acetate/60-80 petrol gave a white crystalline solid; yield=390 mg, mp=185°-186° C.; Found: C, 66.20; H, 4.33; N, 4.20; C18H14ClNO3 requires C, 65.96; H, 4.31; N, 4.27. δ (360 MHz, DMSO-d6), 1.84 (3H, s, CH3CO), 4.26 (2H, s, CH2), 7.26 (1H, dd, J=8.7 and 2.1 Hz, 6-H), 7.30-7.46 (6H, m, aromatics), 8.02 (1H, d, J=8.7 Hz, 5-H), 11.90(1H, s, br, NH). MS (CI) m/z=328 (MH)+.
Reaction SMILES: II.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2.N[C:15](N)=[S:16].[OH-].[Na+].[CH3:20][O:21][C:22](=[O:25])CBr>O.CO>[CH3:20][O:21][C:22](=[O:25])[CH2:15][S:16][C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([O:4][CH3:3])[CH:6]=2)[NH:10][CH:9]=1
Reactant: COC(=O)CBr
Reactant: COc1ccc2[nH]ccc2c1
Reactant: NC(N)=S
Agent: II
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)CSc1c[nH]c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Triiodide synthesis: Into a round bottom flask, KI (5.00 g, 30.1 mmol) was mixed with I2 (5.1 g, 20.0 mmol) in 20 mL water. The mixture was stirred at room temperature for 24 hours. To a solution of 5-methoxyindole (10, 200 mg, 1.36 mmol) and thiourea (110 mg, 1.44 mmol) in methanol (10 mL), triiodide, freshly prepared from the previous day (440 mg, 1.5 mmol) was added over a 20 minute period, and the combined mixture stirred at room temperature for 40 min. The solvent was reduced to half of its volume and 10 N NaOH (5 mL) was added to the flask and heated at 95° C. for one hour under an inert atmosphere. The resulting suspension was filtered hot and the solid rinsed with water. Filtrate was cooled to room temperature and bromoacetic acid methyl ester (241 mg, 1.6 mmol) was added. This mixture was stirred vigorously for an hour and the organic layer was extracted with diethyl ether. The aqueous layer was acidified with 1 N HCl and extracted with ether. The desired product was isolated after flash silica column chromatography using gradient solvent 5-10% EtOAc/hexane. (15 mg, 4.4%)
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][N:20]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:28])[O:4][N:3]=1.C(N=C(N(C)C)N(C)C)(C)(C)C.Br[CH2:42][CH:43]([CH3:46])[CH2:44][CH3:45]>C(#N)C>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([N:18]([C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:26])[CH3:27])=[CH:21][N:20]=3)[CH2:42][CH:43]([CH3:46])[CH2:44][CH3:45])(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2ccc(C(C)C)cn2)cc1
Reactant: CCC(C)CBr
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Product: CCC(C)CN(c1ccc(C(C)C)cn1)S(=O)(=O)c1ccc(OCc2c(C)noc2C)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 4.6 %

Procedure:
To a solution of 4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-isopropylpyridin-2-yl)benzenesulfonamide (156 mg, 0.389 mmol) in acetonitrile (4 mL) stirred in air at 20° C., was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (133 mg, 0.777 mmol). The reaction mixture was stirred at 20° C. for 1 hour, then 1-bromo-2-methylbutane (117 mg, 0.777 mmol) was added. The reaction then heated by microwaves to 150° C., for 30 minutes. After cooling the solvent was removed in vacuo and diluted with ethyl acetate. The organic phase was washed with water (5 mL), then dried using a hydrophobic frit. The solvent was removed in vacuo to give the crude product as an orange oil. Purification of the crude was attempted using flash silica (Si) chromatography (0-25% ethylacetate-cyclohexane gradient) followed by mass directed autoprep (ammonium carbonate modifier), however impurities still remained. A final purification using a silica (Si) cartridge (eluting with a gradient of 0-25% ethyl acetate-cyclohexane) provided a small amount of clean product (8.5 mg) as a colourless oil. LCMS (2 min, High pH) Rt 1.48 mins, m/z (ES+) 472 (M+H).
Reaction SMILES: I[C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C(=O)(O)[O-].[Na+].[CH3:13][O:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[C:18](B(O)O)=[CH:17][N:16]=1.CO>COCCOC.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[C:18]([C:2]2[S:3][CH:4]=[C:5]([CH3:7])[N:6]=2)=[CH:17][N:16]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: Cc1csc(I)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: COCCOC
Product: COc1ncc(-c2nc(C)cs2)c(OC)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 106.2 %

Procedure:
2-iodo-4-methyl-1,3-thiazole (prepared according to procedure described in JACS 123 (6), 1017-1022, (2001), 250 mg, 1.111 mmol) was dissolved in 1,2-Dimethoxyethane (DME) (4.629 ml). Pd(Ph3P)4 (64.2 mg, 0.056 mmol) was added and the mixture was stirred at room temperature for 10 minutes. 1M aqueous sol. Sodium bicarbonate (4.443 ml, 4.44 mmol) and [2,4-bis(methyloxy)-5-pyrimidinyl]boronic acid (409 mg, 2.222 mmol) were added and the resulting mixture was stirred at 85° C. for 2 hours. The mixture was allowed to cool to rt and it was diluted with DCM (5 mL). The aqueous was separated and extracted with DCM (2×5 mL). The organics were combined and dried (Na2SO4 then rotaevaporator) to give a yellow solid that was purified by silica chromatography (Biotage SP1, 25+M), eluting with DCM:MeOH from 100:0 to 9:1 to afford the title compound as a pale yellow solid (280 mg, 78% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[CH2:8]([SH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N+:16]([CH3:19])([O-:18])=[O:17].C(N)CN>C(#N)C>[CH2:8]([S:15][C:4]1([CH2:19][N+:16]([O-:18])=[O:17])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C[N+](=O)[O-]
Reactant: SCc1ccccc1
Reactant: O=C1CCOCC1
Solvent: CC#N
Solvent: NCCN
Product: O=[N+]([O-])CC1(SCc2ccccc2)CCOCC1
Yield: 64 %

Procedure:
A mixture of tetrahydro-4H-pyran-4-one (10.3 g), benzylmercaptan (25.6 g), nitromethane (62.8 g), ethylenediamine (6.18 g) and acetonitrile (150 ml) was heated overnight under reflux. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography to give the title compound (17.6 g, yield 67%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (3:1, volume ratio).
Reaction SMILES: [CH:1]([Cl:3])=[CH2:2].C(OC([O:10][O:11][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])=O)(C)C>>[C:15]([O:14][C:12]([O:11][O-:10])=[O:13])([CH3:17])([CH3:1])[CH3:16].[CH:1]([Cl:3])=[CH2:2]
Reactant: CC(C)OC(=O)OOC(=O)OC(C)C
Agent: C=CCl
Product: CC(C)(C)OC(=O)O[O-]
Reaction time: 6 h

Procedure:
Into an autoclave of 300 ml capacity made of stainless steel, there were charged 0.6 g of BPAC of 94% purity, 29.4 g of vinyl chloride (hereinafter referred to as VCL) of 100% purity and 0.01 g of diisopropylperoxydicarbonate of 99% purity and further 100 ml of 0.2% aqueous solution of polyvinyl alcohol (degree of saponification 89%). After the atmospheric environment in the autoclave was replaced with nitrogen, polymerization was carried out at 52° C. for 6 hours.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12]/[C:13](=[CH:18]\[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)/[CH2:14][CH2:15][CH2:16][OH:17].C(OCC)C>ClCCl>[CH3:12]/[C:13](=[CH:18]\[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)/[CH2:14][CH2:15][CH:16]=[O:17]
Reactant: C/C(=C\c1ccccc1)CCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: C/C(=C\c1ccccc1)CCC=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
Solid pyridinium chlorochromate (4.21 g, 0.02 mol) was added in one portion to a cooled (−10° C.) solution of (4E)-4-methyl-5-phenyl-4-penten-1-ol (2.25 g, 0.013 mol) in dry dichloromethane (50 ml) under nitrogen. After 30 minutes, the reaction was warmed up to room temperature. After 1 hour, diethyl ether (250 ml) was added to the reaction. After stirring for 10 minutes, the reaction was filtered through silica gel and the solid rinsed with diethyl ether. The solvent was removed under vacuum and the residue was purified by column chromatography on silica gel (eluent: heptanes/ethyl acetate 25:1) followed by bulb-to-bulb distillation (82° C./0.002 mbar). 1.21 g (yield=53%) of the desired product was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]#[CH:14])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1>C1COCC1.CCCCCC>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]#[C:14][CH:27]([C:26]2[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=2)[OH:28])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](C#CC(O)c2ccc(Cl)cc2)COC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (S)-4-ethynyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (3.16 g; CAS 173065-16-2) in dry THF (20 ml) under an argon atmosphere at −78° C. was added dropwise a solution of n-butyllithium in hexane (10.5 ml, 1.6 M solution) and stirring continued for 30 min. A solution of 4-chlorobenzaldehyde (2.17 g) in THF (10 ml) was added dropwise and the mixture was stirred for a further 2 h at −78° C. The reaction mixture was then quenched by careful addition of water (12 ml) and allowed to warm to room temperature. The mixture was diluted with ethyl acetate and washed with saturated brine. The combined organic phase was dried over sodium sulphate, filtered and concentrated in vacuo. The reside was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-4-[3-(4-chloro-phenyl)-3-hydroxy-prop-1-ynyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (mixture of epimers) as a yellow oil. MS (ISP): 426.1 ([{37Cl}M+OAc]−), 424.1 ([{35Cl}M+OAc]−).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[C:33]([O:34][CH3:35])=[CH:32][C:20]([CH2:21][O:22][C:23]([NH:25][CH:26]([CH3:31])[CH2:27][C:28](O)=[O:29])=[O:24])=[C:19]([N+:36]([O-:38])=[O:37])[CH:18]=1.CC(C)N=C=NC(C)C>C1COCC1>[O:13]=[C:12]1[CH:11]=[CH:10][C:9](=[O:14])[N:8]1[C:5]1[CH:4]=[CH:3][C:2]([O:1][C:28](=[O:29])[CH2:27][CH:26]([NH:25][C:23]([O:22][CH2:21][C:20]2[CH:32]=[C:33]([O:34][CH3:35])[C:17]([O:16][CH3:15])=[CH:18][C:19]=2[N+:36]([O-:38])=[O:37])=[O:24])[CH3:31])=[CH:7][CH:6]=1
Reactant: O=C1C=CC(=O)N1c1ccc(O)cc1
Reactant: COc1cc(COC(=O)NC(C)CC(=O)O)c([N+](=O)[O-])cc1OC
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: COc1cc(COC(=O)NC(C)CC(=O)Oc2ccc(N3C(=O)C=CC3=O)cc2)c([N+](=O)[O-])cc1OC
Temperature: 0 °C

Procedure:
1-(4-Hydroxy-phenyl)-pyrrole-2,5-dione (1 mmol), NHS (1.0 mmol) and 3-(4,5-dimethoxy-2-nitro-benzyloxycarbonylamino)-butyric acid (1 mmol) is dissolved in THF (3 mL). The solution is cooled to 0° C. and treated dropwise with DIC (1.2 mmol). The cooling bath is removed after 1 hour and the reaction mixture is left at room temperature o/n. The solvent is evaporated in vacuo and the pure product (3-(4,5-dimethoxy-2-nitro benzyloxycarbonyl-amino)-butyric acid 4-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-phenyl ester) is isolated by silica column purification using EtOAc-heptane (1:4 then 1:2 then 1:1) as eluent.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[OH:17])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:18]Br>C(=S)=S>[Br:18][CH:7]1[C:6]2[C:15](=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=2)[C:14](=[O:16])[C:13]2[C:12]([OH:17])=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: BrBr
Reactant: O=C1c2c(O)cccc2Cc2cccc(O)c21
Solvent: S=C=S
Product: O=C1c2c(O)cccc2C(Br)c2cccc(O)c21
Temperature: 50 °C
Yield: 77.6 %

Procedure:
1,8-Dihydroxy-9-anthrone (17.3 g) was dissolved in carbon disulphide (1.25 liter) by heating, and the solution was treated dropwise with 18.5 g of bromine with stirring at 50° C. The solution was left stirring at that temperature overnight, then cooled to room temperature and concentrated to one tenth of its volume by removal of the solvent under reduced pressure. The yellow precipitate was filtered off, dried and recrystallised from a petroleum ether (boiling point 40°-60° C.)/chloroform mixture (1:1) to give 10-bromo-1,8-dihydroxy-9-anthrone (18.1 g, 77.5%), melting point 149°-151° C. (with decomposition). [Literature reference, O. E. Schultz and H.-H. Schultze-Mosgau, Arch. Pharm. (Weinheim. Ger.), 1965, 298, 273, gives melting point 148°-150° C. (with decomposition)].
Reaction SMILES: [CH:1]12[O:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([CH2:10][CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)[CH2:2]2.[C:21]([O:25][C:26](=[O:32])[NH:27][CH2:28][CH2:29][CH2:30]Br)([CH3:24])([CH3:23])[CH3:22].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:21]([O:25][C:26](=[O:32])[NH:27][CH2:28][CH2:29][CH2:30][N:7]1[CH2:8][CH:1]2[O:9][CH:5]([CH2:4][N:3]([CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH2:2]2)[CH2:6]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: N#Cc1ccc(OCCN2CC3CNCC(C2)O3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCN1CC2CN(CCOc3ccc(C#N)cc3)CC(C1)O2
Temperature: 60 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
A suspension of 4-[2-(9-Oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl)-ethoxy]-benzonitrile (6.5 g, 0.02 mol, see WO 01/28992), (3-Bromo-propyl)-carbamic acid tert-butyl ester (6.0 g, 0.025 mol) and dry K2CO3 (13.08 g, 0.0946 mol) in 40 ml of dry acetonitrile was stirred at 60° C. overnight under N2 atmosphere. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using 20% ethyl acetate in petroleum ether as eluent to yield sub-title compound (3.5 g) as a liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[F:21][C:22]([Si](C)(C)C)([F:24])[F:23].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]([OH:20])([C:22]([F:24])([F:23])[F:21])[C:16]([F:18])([F:19])[F:17])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(C(=O)C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(Br)cc(C(O)(C(F)(F)F)C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl 3-bromo-5-(trifluoroacetyl)benzoate (1.0 g, 2.8 mmol) was dissolved in THF (28 mL) and trifluoromethyltrimethylsilane (2.0 g, 14.1 mmol) added. The mixture was cooled to 0° C. and TBAF (0.07 g, 0.28 mmol) was added dropwise. After stirring for 15 minute additional TBAF (0.74 g, 2.8 mmol) was added. The mixture was stirred for an additional 15 minutes, allowed to warm to rt and then quenched with 1N HCl, diluted with EtOAc and the layers separated. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give title compound which was used directly step C.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.Cl.[CH2:35]([O:42][CH:43]1[CH2:49][CH:48]2[NH:50][CH:44]1[CH2:45][O:46][CH2:47]2)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+].CC#N>CCOC(C)=O>[CH2:35]([O:42][CH:43]1[CH2:49][CH:48]2[N:50]([CH2:6][C@H:7]3[CH2:12][N:11]([S:13]([C:16]4[S:17][CH:18]=[CH:19][CH:20]=4)(=[O:14])=[O:15])[CH2:10][CH2:9][N:8]3[C:21]3[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:25][CH:26]=3)[CH:44]1[CH2:45][O:46][CH2:47]2)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: c1ccc(COC2CC3COCC2N3)cc1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2C3COCC2C(OCc2ccccc2)C3)cc1)C(F)(F)F
Temperature: 150 °C

Procedure:
A 10 mL vial was charged with ((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (0.207 g, 0.391 mmol, Intermediate B), 6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (endo) (0.100 g, 0.391 mmol, J. Org. Chem. 2010, 75, 1643), potassium carbonate (0.162 g, 1.173 mmol), and 3 mL of MeCN. The tube was sealed and heated in a microwave reactor (Emrys Optimizer Automated Microwave Synthesizer, Uppsala, Sweden) at 150° C. for 1 h. The mixture was diluted with EtOAc, filtered and the filtrate was concentrated and purified via column chromatography on silica gel (0 to 50% EA/Hex) to 2-(4-((2S)-2-((6-(benzyloxy)-3-oxa-8-azabicyclo[3.2.1]oct-8-yl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol as a mixture of four endo isomers (0.130 g).