Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][C@H:9]2[C@H:18]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@@H:17]([CH2:27][OH:28])[O:16][C@@:10]2([OH:15])[C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(CC(O)=O)=O.C(O)(=O)C>C[O-].[Na+].CO>[C:1]1([CH2:7][O:8][C@H:9]2[C@H:18]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@@H:17]([CH2:27][OH:28])[O:16][C:10]2([OH:15])[C:11]([O:13][CH3:14])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@]1(O)O[C@H](CO)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: CC(=O)CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C1(O)O[C@H](CO)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
A solution of 4.25 g of 3,4-bis-O-(phenylmethyl)-alpha-D-arabino-hexulofuranosonic acid, methyl ester, diacetate in 45 ml of 1.0M sodium methoxide in methanol was stirred at 25° for 20 minutes, treated with 4.1 ml of acetic acid, and concentrated. The residue was partitioned with ethyl acetate and water. The organic layer was washed with water and brine, dried, and concentrated. The residue was subjected to chromatography on silica gel to give an oil, CMR δ 53.3 (CH3OCO).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([N:15](C(OC(C)(C)C)=O)[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:13][CH:14]=1>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:13][CH:14]=1
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)c1ccc(Br)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CNc1ccc(Br)cn1
Reaction time: 0.75 h
Yield: 100.4 %

Procedure:
A 50% solution of TFA in CH2Cl2 (200 mL) was added to 5-bromo-2-[N-(tert-butoxycarbonyl)-N-(methoxycarbonylmethyl)amino]pyridine (16.5 g, 46 mmole). After stirring for 45 min the reaction was concentrated to dryness, and the residue was diluted with 1.0 N Na2CO3 (300 mL). The mixture was extracted with EtOAc (300 mL), and the organic layer was washed with brine, dried (Na2SO4), and concentrated to dryness under vacuum. The title compound (11.32 g, 100%) was obtained as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J=2.3 Hz, 1H), 7.48 (dd, 1H), 6.40 (d, J=8.8 Hz, 1H). 4.95 (br s, 1H), 4.12 (d, J=5.5 Hz, 2H), 3.78 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([OH:8])[CH2:7][CH2:6][CH2:5]1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C>C1COCC1>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:1][CH2:2][CH2:3][C:4]2([OH:8])[CH2:7][CH2:6][CH2:5]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: OCCC1(O)CCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCCC2(O)CCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In an atmosphere of nitrogen, potassium tert-butoxide was added under ice-cooling to a mixture of cyclobutanone, ethyl chloroacetate and THF, spending 40 minutes, followed by stirring at 0° C. for 2 hours, raising the temperature to room temperature, and stirring at room temperature for 1 day, thereby obtaining ethyl 1-oxaspiro[2,3]hexane-2-carboxylate. A diethyl ether solution of the resulting ethyl 1-oxaspiro[2,3]hexane-2-carboxylate was added to a THF suspension of lithium aluminum hydride under ice-cooling in an atmosphere of nitrogen, followed by stirring at room temperature for 7 hours to obtain 1-(2-hydroxyethyl)cyclobutanol. A mixture of the resulting 1-(2-hydroxyethyl)cyclobutanol, 4-methylbenzenesulfonyl chloride, triethylamine and THF was stirred at room temperature for 16 hours to obtain 2-(1-hydroxycyclobutyl)ethyl 4-methylbenzenesulfonate.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]([CH3:18])[C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([Cl:39])=[C:24]([NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=2)[CH:25]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C.CN(C)C1C=CN=CC=1>[Cl:39][C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[C:9]([N:8]([CH3:7])[CH3:18])[CH:10]=2)=[CH:25][C:24]=1[NH:26][C:27](=[O:38])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1
Reactant: COc1ccc(C(=O)Nc2cc(N)ccc2Cl)cc1OC
Reactant: CN(C)c1cccc(C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(N(C)C)c3)ccc2Cl)cc1OC
Reaction time: 4 h
Yield: 24.1 %

Procedure:
Oxalyl chloride (0.11 ml) was added dropwise to a stirred suspension of 3-dimethylaminobenzoic acid (0.18 g) in methylene chloride (10 ml) at 20° C. DMF (2 drops) was added and the reaction mixture was stirred for 4 hours. The solvent was evaporated to give a solid. The solid was dissolved in methylene chloride (15 ml) and added dropwise over 5 minutes to a stirred mixture of N-(5-amino-2-chlorophenyl)-3,4-dimethoxybenzamide (0.306 g), triethylamine (0.4 ml), 4-dimethylaminopyridine (0.005 g) and methylene chloride (5 ml). The resultant mixture was stirred at 20° C. for 18 hours. The reaction mixture was washed with water and with a saturated, aqueous sodium bicarbonate solution, dried (MgSO4) and evaporated. The residual oil was purified by column chromatography on silica gel using a 99:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.109 g), m.p. 98-99° C.;
Reaction SMILES: [NH2:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1.C(Cl)Cl.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].Cl>O.C(N(CC)CC)C>[CH2:13]([N:12]([CH2:16][CH:17]=[CH2:18])[C:4]1[N:3]=[C:2]([NH:1][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=1)[CH:14]=[CH2:15]
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C=CCN(CC=C)c1nc(NC(=O)OCc2ccccc2)n2oc(=O)nc2n1

Procedure:
4.0 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one are suspended in 50 ml. of methylene chloride and 5 ml. of triethylamine and cooled to 0° C. 5 ml. of benzyl chloroformate are slowly added dropwise while stirring. The mixture is then stirred at 0° C. for 1 hour, subsequently treated with water and adjusted to pH 4 with 2-N hydrochloric acid. The aqueous phase is extracted twice with methylene chloride and the combined organic extracts are dried over sodium sulfate and evaporated. The residue is recrystallized from methylene chloride and diethyl ether, there being obtained pure benzyl 5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazine-7-carbamate, having a melting point of 171°-173° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([C@H:26]([NH:38][C:39](=[O:49])[O:40][C@@H:41]1[C@H:48]2[C@H:44]([O:45][CH2:46][CH2:47]2)[O:43][CH2:42]1)[C@H:27]([OH:37])[CH2:28][NH:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:19]([C@H:26]([NH:38][C:39](=[O:49])[O:40][C@@H:41]1[C@H:48]2[C@H:44]([O:45][CH2:46][CH2:47]2)[O:43][CH2:42]1)[C@H:27]([OH:37])[CH2:28][N:29]([S:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)(=[O:17])=[O:16])[O:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CNOC1CCCCC1)O[C@H]1CO[C@H]2OCC[C@H]21
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CN(OC1CCCCC1)S(=O)(=O)c1ccc(OCc2ccccc2)cc1)O[C@H]1CO[C@H]2OCC[C@H]21
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
A mixture of 4-benzyloxybenzenesulfonyl chloride (65 mg; 0.230 mmol), (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[(cyclohexyloxy)amino]-2-hydroxypropylcarbamate (100 mg, 0.230 mmol), diisoproylethylamine (0.042 mL, 0.242 mmol) and 4-dimethylaminopyridine (˜1 mg) in anhydrous tetrahydrofuran (3 mL) was stirred at ambient temperature under an Argon atmosphere for 16 hours. An additional quantity of 4-benzyloxybenzenesulfonyl chloride (13 mg, 0.046 mmol) and 4-dimethylaminopyridine (˜1 mg) was added and the reaction was heated at reflux for approximately 2 hours. After cooling to ambient temperature, the reaction mixture was partitioned between ethyl acetate and aqueous hydrochloric acid. The phases were separated and the organic layer was then washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The crude product was purified on flash grade silica gel eluting with 1:1 ethyl acetate hexane. Fractions containing the product were combined and evaporated in vacuo and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-[{[4-(benzyloxy)phenyl]sulfonyl}(cyclohexyloxy)amino]-2-hydroxypropylcarbamate (143 mg, 91%). H1-NMR (chloroform-D3): 1.27 (m, 6H), 1.61 (m, 5H), 2.07 (m, 2H), 2.91 (m, 4H), 3.10 (b, 1H), 3.68 (m, 2H), 3.89 (m, 4H), 4.19 (m, 1H), 4.84 (m, 1H), 5.01 (m, 1H), 5.12 (s, 2H), 5.64 (d, 1H), 7.05 (d, 2H), 7.28 (m, 1OH), 7.71 (d, 2H). MS(ESI): 703(M+Na).
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.COC(=O)CC1C=CC([O:27][CH2:28]/[CH:29]=[C:30](/[C:32]2[CH:44]=[CH:43][C:42]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:35][C:34]=3[CH:33]=2)\[CH3:31])=CC=1>C1COCC1>[CH:33]1[C:34]2[CH2:35][C:36]3[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:42]=2[CH:43]=[CH:44][C:32]=1/[C:30](/[CH3:31])=[CH:29]/[CH2:28][OH:27]
Reactant: COC(=O)Cc1ccc(OC/C=C(\C)c2ccc3c(c2)Cc2ccccc2-3)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C/C(=C\CO)c1ccc2c(c1)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 1M solution of DIBAL-H in toluene (15 ml, 15 mmol) was added dropwise, at −70° C. over 30 min, to a stirred solution of (E)-{4-[3-(9H-fluoren-2-yl)-but-2-enyloxy]-phenyl}-acetic acid methyl ester (2.0 g, 7.2 mmol) in dry THF (100 ml) and stirred for 30 min. The mixture was warmed to room temperature, and stirred for 1.5 h. The mixture quenched with methanol (2 mL), added 1N HCl (30 ml) and the product extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with brine, dried (MgSO4), and evaporated to give the crude (E)-3-(9H-fluoren-2-yl)-but-2-en-1-ol.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:6](Cl)=[O:7])#[N:2].[C:15]([C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([N+:26]([O-])=O)C=1)C(O)=O)#[N:16].C([N:31](CC)CC)C>ClCCl>[N:26]1[CH:24]=[CH:23][CH:19]=[CH:18][C:17]=1[C:15]1[N:16]=[C:6]([C:5]2[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[O:7][N:31]=1
Reactant: N#Cc1cc(C(=O)Cl)cc([N+](=O)[O-])c1
Reactant: CCN(CC)CC
Reactant: N#Cc1cc(C(=O)O)cc([N+](=O)[O-])c1
Solvent: ClCCl
Product: N#Cc1cc(-c2nc(-c3ccccn3)no2)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
Using the general procedure for the preparation of acid chlorides, 3-cyano-5-nitrobenzoyl chloride was prepared from 3-cyano-5-nitrobenzoic acid (1.0 g, 5.1 mmol). A solution of the acid chloride in dichloromethane (5 mL) at 0° C. was treated with pyrid-2-ylamidoxime (700 mg, 5.1 mMol) and triethylamine (2.1 mL, 15.3 mmol) and then stirred at ambient temperature for 1 hour. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in N,N-dimethylformamide (5 mL) and heated at 110° C. for 4 hours. Standard work up and silica gel chromatography using hexanes:ethyl acetate:dichloromethane (3.5:0.5:4) afforded 149 mg (50%) of 3-(2-pyridyl)-5-(3-cyano-5-nitrophenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), 6 (ppm): 9.35 (d, 1H), 8.91 (s, 1H), 8.89 (d, 1H), 8.75 (s,1H), 8.26 (d, 1H), 7.94 (m, 1H), 7.53 (m, 1H).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([C@@H:15]2[CH2:19][C:18](=[N:20][O:21][CH3:22])[CH2:17][N:16]2[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][CH:26]=2)=[O:24])[N:11]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+].[CH3:53][N:54]([CH2:56][C:57]([OH:59])=O)[CH3:55].C(Cl)CCl>CN(C1C=CN=CC=1)C>[C:28]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]=[CH:26][C:25]([C:23]([N:16]2[CH2:17][C:18](=[N:20][O:21][CH3:22])[CH2:19][C@H:15]2[C:12]2[N:11]=[C:10]([CH2:9][NH:8][C:57](=[O:59])[CH2:56][N:54]([CH3:55])[CH3:53])[O:14][N:13]=2)=[O:24])=[CH:30][CH:29]=1
Reactant: CN(C)CC(=O)O
Reactant: CON=C1C[C@@H](c2noc(CNC(=O)OC(C)(C)C)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CON=C1C[C@@H](c2noc(CNC(=O)CN(C)C)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
4-{[(2S,4EZ)-2-(5-{[(tert-butoxycarbonyl)amino]methyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl (Example 50) was treated with a 25% TFA/DCM solution at 0° C. The reaction was monitored by LC/MS and stopped after completion. The reaction was then made basic with sodium carbonate solution (10%) and extracted with DCM. The combined organic phases were dried over magnesium sulfate. Solvent removal afforded a crude product, which was used without purification in the next step. The residue was dissolved in DCM at room temperature, DMAP (1.1 equivalent) and (dimethylamino)acetic acid (1 equivalent) were added. The reaction mixture was then cooled down to 0° C. and EDC (1.1 equivalent) was added portion-wise. After stirring for 1 hour at 0° C., the reaction mixture was allowed to warm to room temperature. The reaction was monitored by TLC and LC/MS. Usually after 12 hours stirring at RT, the reaction mixture was hydrolyzed, washed with sodium carbonate solution (10%), dried over MgSO4, and evaporated in vacuo to give a crude product. Flash chromatography on silica gel, eluting with 60% EtOAc in hexane, gave the title compound as a mixture of E- and Z-isomers in 45% yield (88.1% purity by HPLC).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:31]=[CH:30][C:29]3[C:28]4[C:23](=[CH:24][C:25]([Br:32])=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:20]=3[CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.Cl.[CH3:34][O:35][C:36]([NH:38][CH:39]([CH:43]([CH3:45])[CH3:44])[C:40](O)=[O:41])=[O:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CO.O1CCOCC1>[CH3:34][O:35][C:36](=[O:37])[NH:38][CH:39]([C:40]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:31]=[CH:30][C:29]3[C:28]4[C:23](=[CH:24][C:25]([Br:32])=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:20]=3[CH:19]=2)=[CH:16][N:17]=1)=[O:41])[CH:43]([CH3:45])[CH3:44]
Reactant: COC(=O)NC(C(=O)O)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)CCc2cc(Br)ccc2-3)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)CCc2cc(Br)ccc2-3)[nH]1)C(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 95.4 %

Procedure:
To a solution of 2-[5-(7-bromo-9,10-dihydro-phenanthren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (187 mg, 0.38 mmol) in methanol (5 mL) was added 4.0 M solution of HCl in dioxane (2 mL, excess). The mixture was stirred for 3 hours at 50° C. and concentrated under reduced pressure. The residue was treated with ether to remove excess HCl. The obtained white solid was dissolved in DMF (5 mL), to the solution was added 2-methoxycarbonylamino-3-methyl-butyric acid (70 mg, 0.40 mmol), HATU (173 mg, 0.46 mmol) and N,N-diisopropylethylamine (0.66 mL, 3.8 mmol). The mixture was stirred at ambient for 2 hours, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with 1 N NaOH solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (1-{2-[5-(7-bromo-9,10-dihydro-phenanthren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester as an oil (200 mg, 95%). m/z 551.2, 553.2 (M−1-H)+.
Reaction SMILES: [CH:1]([C:3]1[C:8]([C:9]2[C:10]([CH:18]=[O:19])=[CH:11][C:12]3[O:16][CH2:15][O:14][C:13]=3[CH:17]=2)=[C:7]([O:20][CH3:21])[C:6]([O:22][CH3:23])=[C:5]([O:24][CH3:25])[CH:4]=1)=[O:2].[BH4-].[Na+].O.C(OCC)(=O)C>CO>[OH:2][CH2:1][C:3]1[C:8]([C:9]2[C:10]([CH2:18][OH:19])=[CH:11][C:12]3[O:16][CH2:15][O:14][C:13]=3[CH:17]=2)=[C:7]([O:20][CH3:21])[C:6]([O:22][CH3:23])=[C:5]([O:24][CH3:25])[CH:4]=1
Reactant: COc1cc(C=O)c(-c2cc3c(cc2C=O)OCO3)c(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COc1cc(CO)c(-c2cc3c(cc2CO)OCO3)c(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a solution of crude 6-(6-formyl-2,3,4-trimethoxyphenyl)benzo[d][1,3]dioxole-5-carbaldehyde (265 mg, 0.77 mmol) in methanol (7 mL) was added sodium borohydride (80 mg, 2.1 mmol) and the solution was stirred at room temperature for 1 hour. Water (30 mL) and ethyl acetate (30 mL) were then added to the reaction, the layers were separated and the aqueous layer was extracted with ethyl acetate (2×30 mL). The combined extracts were dried over Na2SO4 and filtered. The solvent was removed in vacuo and the residue was purified by flash chromatography over silica gel (40 g), eluting with hexane-ethyl acetate (1:2), followed by crystallisation (ethyl acetate), which yielded (6-(6-(hydroxymethyl)-2,3,4-trimethoxyphenyl)benzo[d][1,3]dioxol-5-yl)methanol as a white solid (230 mg, 86%); m.p. 123-124° C.; High Resolution Mass Spectrometry Found: M+Na+ 371.1105 (C18H20O7Na requires 371.1107); NMR Spectrum δH (300 MHz, CDCl3) 7.00 (2H, s, 7-H), 6.88 (1H, s, 4-H), 6.63 (1H, s, 5′-H), 6.04 (2H, s, 2-H), 4.30 (2H, m, CH2OH), 4.21 (2H, m, CH2OH), 3.93 (3H, s, OCH3), 3.91 (3H, s, OCH3), 3.62 (3H, s, OCH3); NMR Spectrum δC (75 MHz, CDCl3) 56.4, 61.4, 61.5 (CH2), 63.1 (CH2), 63.7, 101.7, 108.7, 110.4, 110.6, 126.6, 129.1, 133.8, 135.5, 142.0, 147.5, 147.8, 151.4, 153.5; νmax/cm−1 (thin film) 3254, 2944, 2889, 1603, 1480, 1410, 1328, 1235, 1146, 1111, 1033, 928; m/z (ES) 412 (MNa2H2O+, 100%), 371 (MNa+, 60); Rf(hexane-ethyl acetate 1:2) 0.14.
Reaction SMILES: C1(C)C=C[C:4]([S:7](O)(=O)=O)=[CH:3][CH:2]=1.[CH2:12]([SH:15])[CH2:13][CH3:14].[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=O>C1CCCCC1>[CH2:12]([S:15][CH:21]([S:7][CH2:4][CH2:3][CH3:2])[C:17]1[O:16][CH:20]=[CH:19][CH:18]=1)[CH2:13][CH3:14]
Reactant: CCCS
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=Cc1ccco1
Solvent: C1CCCCC1
Product: CCCSC(SCCC)c1ccco1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Into a 100 ml reaction flask equipped with reflux condenser, thermometer and magnetic stirring bar with hot plate and magnetic stirring apparatus is placed 0.5 grams of para-toluenesulfonic acid, 5 ml cyclohexane and 15.2 grams (0.2 moles) of n-propyl mercaptan. Over a period of 25 minutes, 9.6 grams (0.1 mole) of 2-furaldehyde is added with stirring. The reaction mixture is then heated to reflux and refluxed for a period of 10 hours while removing water of reaction. The the end of the 10 hour reflux period, the reaction mass is cooled to room temperature and transferred to a separatory funnel. The reaction mass is washed with one 50 ml portion of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate and filtered. The resulting filtrate is then distilled on a Microvigreux column yielding the following fractions:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][O:12][CH:11]([CH2:14][C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:13][O:12][CH:11]([CH2:14][C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:16])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)=[CH:28][CH:27]=1
Reactant: O=C(CC1CCC(c2ccc(Br)cc2)CO1)OCc1ccccc1
Reactant: Nc1ccc(B(O)O)cc1
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: C1COCCO1
Product: Nc1ccc(-c2ccc(C3CCC(CC(=O)OCc4ccccc4)OC3)cc2)cc1
Temperature: 120 °C
Yield: 80.8 %

Procedure:
To a solution of benzyl 2-(5-(4-bromophenyl)tetrahydro-2H-pyran-2-yl)acetate (300 mg, 0.771 mmol) in dioxane (6 ml) at room temperature was added 4-aminophenylboronic acid (211 mg, 1.541 mmol), Pd(Ph3P)4 (178 mg, 0.154 mmol) and 2M Na2CO3 (1.541 ml, 3.08 mmol) and the mixture was degassed and heated at 120° C. in microwave for 30 min. The reaction was quenched by sat. aq. NH4Cl and was extracted with EtOAc. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (10 to 50% EtOAc (2% TEA)/Heptane) to give the title compound 250 mg (yield 81%). MS (ESI) m/z 402.3 (M+1). Retention time 1.48 min (condition A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:15]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:15]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(Cl)cc1Cl
Yield: 8 %

Procedure:
The product was prepared according to General Procedure 6, described in Example 65, with 2,4-dichlorobenzenesulfonyl chloride (13.5 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 8% yield (1.5 mg). MS (ESI+) calcd mass for C13H9Cl2N5O2S 368.985401, found 368.984681.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCc1ccc(F)cc1
Product: Fc1ccc(CNc2nc(-c3ccno3)nc3sc(C(F)(F)F)cc23)cc1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(4-fluorobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.