Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][C:15](=[O:17])[CH2:14][C:13](=[O:18])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[CH2:20](O)[CH3:21]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][C:15](=[O:17])[CH:14]=[C:13]([O:18][CH2:20][CH3:21])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCO
Reactant: COc1ccc(C2CC(=O)CC(=O)C2)cc1OC
Agent: Cl
Product: CCOC1=CC(=O)CC(c2ccc(OC)c(OC)c2)C1
Yield: 29.1 %

Procedure:
5-(3,4-Dimethoxyphenyl)cyclohexan-1,3-dione (31.8 g) was suspended in ethanol (500 ml), and concentrated hydrochloric acid (20 ml) was added prior to reflux for 3 hours. After the reaction solvent was concentrated under reduced pressure, it was dissolved in chloroform and washed with saturated sodium bicarbonate water. After drying with anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure producing crude crystals which were then washed with diethyl ether to give 10.3 g of 5-(3,4-dimethoxyphenyl)-3-ethoxy-2-cyclohexen-1-one (29.1%).
Reaction SMILES: C[CH2:2][N:3](C(C)C)[CH:4](C)C.[C:10]([O:14][C:15]([NH:17][C@H:18]1[CH2:23][CH2:22][CH2:21][C@H:20]([C:24]([OH:26])=O)[CH2:19]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].Cl.CNC.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:10]([O:14][C:15](=[O:16])[NH:17][C@H:18]1[CH2:23][CH2:22][CH2:21][C@H:20]([C:24](=[O:26])[N:3]([CH3:4])[CH3:2])[CH2:19]1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H](C(=O)O)C1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(=O)[C@H]1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.4 %

Procedure:
DIPEA (1.8 mL, 10.3 mmol) was added at RT to a mixture of racemic trans 3-tert-butoxycarbonylamino-cyclohexanecarboxylic acid (1.00 g, 4.109 mmol), dimethylamine hydrochloride (0.0.503 g, 6.17 mmol), and EDCI (1.182 g, 6.17 mmol) in 13 mL of DCM. The resulting mixture was stirred at RT for 16 hours before being partitioned between H2O and DCM. The aqueous layer was back extracted twice with DCM. The combined organic layers were dried (Na2SO4), filtered, and evaporated. The residue was purified by SiO2 flash chromatography (DCM/MeOH 0 to 5% MeOH) to give 0.438 g (39%) of racemic trans 3-dimethylcarbamoyl-cyclohexyl carbamic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13].[CH:16]([N:19]=[C:20]=S)([CH3:18])[CH3:17].C(OCC)(=O)C>O>[CH:16]([NH:19][C:20]1[NH:1][C:2]2[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][C:3]=2[S:12](=[O:14])(=[O:13])[N:15]=1)([CH3:18])[CH3:17]
Reactant: CC(C)N=C=S
Reactant: Nc1cc(C(F)(F)F)ccc1S(N)(=O)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)NC1=NS(=O)(=O)c2ccc(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from 2-amino-4-trifluoromethylbenzenesulfonamide and isopropyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 294-297° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 1.20 (d, 6H, CH(CH3)2), 3.95 (m, 1H, CH(CH3)2), 7.42 (br., 1H, NH), 7.56 (m, 2H, ArH), 7.99 (d, 1H, ArH), 10.55 (br.s, 1H, NH); MS: m/e 307 (M+, 33%); (C11H12N3F3O2S1.H2O) calc. C, 40.6; H, 4.3; N, 12.9; found C, 41.0; H, 4.1; N, 13.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[CH:15][CH:14]=[C:13]2[CH2:17][OH:18])=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:26]([Si:30](Cl)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:29])([CH3:28])[CH3:27]>ClCCl.CN(C)C1C=CN=CC=1>[Si:30]([O:18][CH2:17][C:13]1[N:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[CH:16]=[CH:15][CH:14]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1ccc(-n2cccc2CO)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(-n2cccc2CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 5 °C

Procedure:
To a solution of 1-(4-ethoxycarbonylphenyl)-2-hydroxymethylpyrrole (8.97 g) in dichloromethane (90 ml) was added triethylamine (12.1 ml), 4-dimethylaminopyridine (100 mg) and tert-butylchlorodiphenylsilane (10.6 ml) in that order at 5° C. under nitrogen atmosphere. After stirring for half an hour at 5° C., the mixture was allowed to warm to ambient temperature and stirred for 13.5 hours. The mixture was washed with water and brine, dried, concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution by ethyl acetate/n-hexane=1/7) to yield 2-tert-butyldiphenylsilyloxymethyl-1-(4-ethoxycarbonylphenyl)pyrrole (18.67 g) as an oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:12][C:11]3([CH2:21][C:20](=[O:22])[C:19]4[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:27][O:28]C5CCCCO5)=[O:26])[CH:18]=4)[O:13]3)[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(Cl)Cl.O1CCOCC1>[C:1]1([CH2:7][CH2:8][N:9]2[CH2:12][C:11]3([CH2:21][C:20](=[O:22])[C:19]4[C:14](=[CH:15][CH:16]=[C:17](/[CH:23]=[CH:24]/[C:25]([NH:27][OH:28])=[O:26])[CH:18]=4)[O:13]3)[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(CCc3ccccc3)C1)O2)NOC1CCCCO1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(/C=C/c1ccc2c(c1)C(=O)CC1(CN(CCc3ccccc3)C1)O2)NO
Yield: 88.8 %

Procedure:
(E)-3-[1′-(2-Phenyl-ethyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (180 mg, 0.39 mmol) in DCM (7 ml) was treated with 4 M HCl in dioxane (1 ml) as described in Example 30, Step C, giving (E)-3-[1′-(2-phenyl-ethyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-hydroxy-acrylamide (131 mg, hydrochloride salt) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=[O:26])=[CH:20][CH:19]=1.Cl.CN(CCCN=C=NCC)C>C(#N)C>[OH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:26])=[CH:20][CH:19]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: Nc1ccccc1-c1cc2ccccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Product: O=C(Cc1ccc(O)cc1)Nc1ccccc1-c1cc2ccccc2[nH]1
Temperature: 23 °C
Reaction time: 16 h
Yield: 74.8 %

Procedure:
1 g (4.8 mmol) 2-(2-Aminophenyl) indole was dissolved in 200 ml acetonitrile. 1.46 g (9.6 mmol, 2 eq) of 4-hydroxyphenylacetic acid were dissolved in 50 ml acetonitrile and added to the solution. To the mixture were added 1.84 g (9.6 mmol, 2 eq) of EDC (dimethylaminopropyl ethylcarbodiimide hydrochloride). The reaction mixture was stirred at 23° C. for 16 hours. The solvent was removed and the residue was dissolved in 100 ml ethylacetate:methanol (10:1). It was extracted twice with 100 ml of aqueous 1M HCl as well as 100 ml of aqueous, saturated sodium bicarbonate solution. The aqueous phases were re-extracted with EtOAc, respectively. The combined organic phases were dried over magnesium sulfate. The crude product was chromatographed on silica using a ethylacetate/hexane gradient (10%–50%) to obtain 1.23 g of the amide as a pink colored powder in an overall yield of 75%. 100% Purity by LC/MS (230 DAD) Mass-spec [M+H+]=343.9 1H NMR (MeOH-d4): 3.60 s (2H), 6.10 s (1H), 6.70 d, 8 Hz (2H), 7.03 t, 8 Hz (1H), 7.09–7.13 m (3H), 7.25 t, 7 Hz (1H), 7.34 m (2H), 7.49 d, 8 Hz (1H), 7.53 d, 8 Hz (1H), 7.95 d, 8 Hz (1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[C:14]([F:21])[CH:13]=1.[CH:22]1([NH2:25])[CH2:24][CH2:23]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH:25][CH:22]2[CH2:24][CH2:23]2)=[O:17])=[C:14]([F:21])[CH:13]=1
Reactant: NC1CC1
Reactant: O=C(O)c1ccc(-c2ncnc3ccc(Cl)cc23)cc1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CC1)c1ccc(-c2ncnc3ccc(Cl)cc23)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.7 %

Procedure:
0.2 g 4-(6-chloroquinazolin-4-yl)-2-fluorobenzoic acid (compound in Production Example 386), 41 mg cyclopropylamine and 0.12 mL triethylamine were dissolved in 6 mL dichloromethane, then 320 mg benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate was added thereto, and the mixture was stirred at room temperature for 3 hours. The reaction solution was purified by NH silica gel column chromatography (hexane/ethyl acetate) and then recrystallized from methanol/ethyl acetate/ether, to give 162 mg of the title compound as colorless crystals.
Reaction SMILES: [C:1]1([CH:7]([NH:9][CH:10]([CH3:13])[CH2:11][OH:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[Cl:30]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:30][C:22]1[CH:23]=[C:24]([N:9]([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[CH:10]([CH3:13])[CH2:11][OH:12])[CH:25]=[CH:26][C:21]=1[F:20]
Reactant: CC(CO)NC(C)c1ccccc1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(CO)N(c1ccc(F)c(Cl)c1)C(C)c1ccccc1
Reaction time: 24 h

Procedure:
2-[(1-phenylethyl)amino]propan-1-ol (5-5, 0.027 g, 0.151 mmol) in CH2Cl2 (1.0 mL) was treated with Cu(OAc)2 (0.041 g, 0.227 mmol), pyridine (0.024 mL, 0.302 mmol), and 4-fluoro-3-chloro-phenylboronic acid (0.026 g, 0.149 mmol). 4 A MS (20 mg) were added and the resulting solution stirred 24 h. Upon completion, the reaction mixture was filtered and the filtrate was purified by reverse phase liquid chromatography (Semi-prep YMC C-18 Column 5% CH3CN/H2O up to 95% CH3CN/H2O) to give 2-[(3-chloro-4-fluorophenyl)(1-phenylethyl)amino]propan-1-ol (5-6) as a brown oil. MS 308.3 found 308.8 (M+H+) required.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:28][CH3:29].O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:28][CH3:29])[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A solution of (R)-benzyl 3-(tert-butoxycarbonylamino)piperidine-1-carboxylate (5.00 g, 14.95 mmol, Example E) in dry DMF (50 mL) was added dropwise to a suspension of sodium hydride 60% in mineral oil (0.7176 g, 17.94 mmol) in dry DMF (10 mL). The mixture was stirred at 0° C. for 1 hour and allowed to stir at room temperature for 2 hours. The mixture was then cooled to 0° C. and treated dropwise with iodoethane (1.315 mL, 16.45 mmol). The reaction mixture was stirred at 0° C. for 2 hours and allowed to warm to room temperature over 18 hours. Water (50 mL) was added, and the mixture was extracted into EtOAc (3×70 mL). The organic layers were combined, washed with water (3×20 mL), dried (MgSO4), filtered, and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (Biotage Flash 40M+) eluting with 20% EtOAc/hexane to provide (R)-benzyl 3-(tert-butoxycarbonyl(ethyl)amino)piperidine-1-carboxylate (5.01 g, 92% yield) as an oil. LCMS (APCI+) m/z 363 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25][N:26]([CH3:33])[C:27](=[O:32])[O:28][CH2:29][CH2:30][CH3:31])=[C:20]([F:34])[CH:19]=1>C(Cl)Cl>[Cl:14][C:15]1[CH:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[CH:35][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([C:7](=[O:8])[NH:6][C:4]([C:3]2[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])=[O:5])[S:25][N:26]([CH3:33])[C:27]([O:28][CH2:29][CH2:30][CH3:31])=[O:32])=[C:20]([F:34])[CH:19]=1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: CCCOC(=O)N(C)SNc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Solvent: ClCCl
Product: CCCOC(=O)N(C)SN(C(=O)NC(=O)c1c(F)cccc1F)c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Reaction time: 4 h

Procedure:
A solution of 2.0 g of 2,6-difluorobenzoyl isocyanate in 10 ml of dry methylene chloride was added rapidly to a stirred solution of 4.5 g of 32 in 20 ml of the same solvent at room temperature. After stirring for 4 hours the solvent was removed under reduced pressure, and the residue was purified by chromatography twice on silica, using first methylene chloride and then diethyl ether as eluent. The product thus obtained was finally purified by crystallization from diethyl ether/light petroleum to give 35, as colourless crystals, m.p.: 98°-99° C.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:14][C:3]1[CH:2]=[CH:1][C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2[nH]c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
16 g of carbazole was dissolved in 80 ml of N,N′-dimethylformamide. To this was added 18 g of N-bromosuccinimide and allowed the reaction to stir at room temperature overnight. The reaction mixture was poured into water and the precipitated white solid was filtered, washed with methanol and dried under vacuum to obtain 20 g of 3-bromocarbazole. It was further converted to its acetyl derivative by refluxing with acetic anhydride (3 vol) with traces of conc. sulfuric acid. Aqueous workup yielded an off-white solid, which was then washed with n-hexane and dried under vacuum to obtain 23 g 9-acetyl-3-bromocarbazole, quantitatively.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([O:10][CH2:11][C@:12]2([CH3:15])[CH2:14][O:13]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[I:24][C:25]1[CH:26]=[N:27][NH:28][CH:29]=1>CN(C=O)C.CCOC(C)=O>[N+:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([O:10][CH2:11][C@:12]([OH:13])([CH3:15])[CH2:14][N:27]2[CH:26]=[C:25]([I:24])[CH:29]=[N:28]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[C@@]1(COC(=O)c2ccc([N+](=O)[O-])cc2)CO1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@](O)(COC(=O)c1ccc([N+](=O)[O-])cc1)Cn1cc(I)cn1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
(S)-(2-Methyloxiran-2-yl)methyl 4-nitrobenzoate (2.0 g, 8.4 mmol) and cesium carbonate (4.12 g, 12.7 mmol) were added to a solution of 4-iodo-1H-pyrazole (1.64 g, 8.43 mmol) in DMF (30 mL). The mixture was stirred at room temperature for 14 h, then diluted with EtOAc, and washed with hydrochloric acid (1N). The organic layers were separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-60% EtOAc/Hexane) to afford (S)-2-hydroxy-3-(4-iodo-1H-pyrazol-1-yl)-2-methylpropyl 4-nitrobenzoate. MS ESI calc'd. for C14H15IN2O5 [M+H]+ 432. found 432.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7](C(OC(C)(C)C)=O)[CH2:8][C@@H:9]([O:10][S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C@H:5]2[O:4][CH2:3]1.[H][H]>[Pd].C(O)C>[CH3:18][C:17]1[CH:19]=[CH:20][C:14]([S:11]([O:10][C@@H:9]2[CH2:8][NH:7][C@@H:6]3[C@@H:2]([OH:1])[CH2:3][O:4][C@H:5]23)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OC(C)(C)C)[C@H]3[C@@H]2OC[C@@H]3O)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CN[C@H]3[C@@H]2OC[C@@H]3O)cc1
Reaction time: 4.5 h

Procedure:
Preparation (3R,3aR,6R,6aS)-tert-Butyl 3-hydroxy-6-(tosyloxy)tetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (35b). Ethanol (1.5 mL) was added dropwise to a mixture of 10% palladium on charcoal (20 mg) and anti-(33b) (100 mg, 0.25 mmol) under an atmosphere of argon. The argon was replaced by hydrogen then the suspension was stirred for 4.5 hours before filtering the mixture through celite in vacuo. The filter cake was washed with ethanol (10 mL) then the solvents removed in vacuo from the filtrate. The residue was azeotroped with toluene (2×3 mL) to obtain (3R,3aR,6R,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl 4-methylbenzenesulfonate which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28].[CH3:38][Zn]C.C1(C)C=CC=CC=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:38])[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28]
Reactant: C[Zn]C
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1cc(F)ccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2Cl)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 13.1 %

Procedure:
A solution of N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2,5-difluorobenzenesulfonamide (0.15 g, 0.26 mmol) in 1,4-dioxane (3 mL) with PdCl2(dppf) (0.047 g, 0.064 mmol) was degassed for 5 min. To this mixture was added 2.0M dimethylzinc in toluene (0.39 mL, 0.77 mmol). The reaction mixture was heated to 80° C. After 2 h, the reaction was quenched slowly with MeOH (15 mL) and then was further diluted with DCM (50 mL), filtered through a nylon membrane and evaporated to a crude yellow residue. The residue was purified by silica gel chromatography eluting 0-100% EtOAC/hexanes, followed by 10% EtOH/EtOAc. The resulting solid was dissolved in DCM (10 mL) and hexanes (20 mL) added to afford the title compound as a yellow solid (0.02 g; 13.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.72 (s, 1H), 8.26 (d, J=5.6 Hz, 1H), 7.51-7.60 (m, 2H), 7.40-7.50 (m, 3H), 7.32-7.39 (m, 1H), 6.07 (d, J=5.5 Hz, 1H), 3.71 (t, J=4.8 Hz, 4H), 3.48-3.53 (m, 4H) *Note: The 2-Me group is submerged under the water peak at 2.5 ppm. MS (ESI) 564.1 [M+H]+.
Reaction SMILES: [C:1]([N:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3Cl)[C@H:11](O)[C@@H:10]1O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(NC(C)C)(C)C.[C:41]1([CH:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:48][NH2:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[Cl:24][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@@H:12]2[CH2:13][C@H:9]([N:8]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2])[CH:10]=[CH:11]2)=[C:19]([NH:49][CH2:48][CH:47]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[N:18]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)C1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
(1S,2R,3S,5R)-3-(Di-Boc-amino)-5-(2,6-dichloro-purin-9-yl)-cyclopentane-1,2-diol (13.0 g, 27.66 mmol) is dissolved in THF (250 mil) under an atmosphere of argon. Diisopropylamine (4.28 g, 33.19 mmol) is added followed by 2,2-diphenylethylamine (6.0 g, 30.43 mmol) and the reaction mixture is stirred at 50° C. The reaction is shown to be complete by LCMS after 18 hours. The solvent is removed in vacuo and the reaction mixture is partitioned between dichloromethane (250 ml) and 0.1M HCl (250 ml). The organic layer is washed with water (200 ml) and brine (200 ml), dried over MgSO4, filtered and the solvent is removed in vacuo to give the title compound. 1H nmr (CDCl3, 400 MHz); 8.05(s, 1H), 7.30-7.10(m, 10H), 6.00(m, 1H), 5.70(m, 2H), 5.60(m, 1H), 5.20(m, 1H), 4.30(m, 1H), 4.20(m, 1H), 3.65(m, 1H), 3.05(m, 1H), 2.00(m, 1H), 1.70(m, 1H), 1.40(s, 18H), MS (ES+) m/e 631 (MH+).
Reaction SMILES: O.Cl.Cl.[NH2:4][C:5]1[N:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:8]2[CH2:14][NH:13][CH2:12][CH2:11][C:9]=2[N:10]=1.NC1N=[C:25](C2C=CC(F)=CC=2)[C:26]2CNCCC=2N=1.Cl.Cl.ICC>>[NH2:4][C:5]1[N:6]=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:8]2[CH2:14][N:13]([CH2:25][CH3:26])[CH2:12][CH2:11][C:9]=2[N:10]=1
Reactant: Nc1nc2c(c(-c3ccc(F)cc3)n1)CNCC2
Agent: Cl
Solvent: O
Solvent: CCI
Product: CCN1CCc2nc(N)nc(-c3ccc(F)cc3)c2C1
Yield: 60.8 %

Procedure:
The title compound was prepared as described in Example 17 starting with 2-amino-4-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine dihydrochloride hemihydrate (1.8 g, 5.5 mmol) and iodoethane (0.4 mL, 5.5 mmol) to produce 0.91 g (48%) of 2-amino-4-(4-fluorophenyl)-6-ethyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. m.p. 242°-243° C. MS: 273 (HM+). IR(KBr): 3301, 3132, 2575, 1626, 1604 cm-1. 1H NMR (DMSO-d6) ∂7.63 (m,2H), 7.19 (m,2H), 4.39-3.01 (m,8H), 1.25 (t,J=2.4 Hz, 2H).
Reaction SMILES: [CH2:1](N(CC)CC)C.[CH2:8]=[C:9]([C:14]([O:17]S(F)(=O)=O)([F:16])[F:15])[C:10]([F:13])([F:12])[F:11].O>CO>[F:15][C:14]([F:16])([O:17][CH3:1])[C:9]([C:10]([F:13])([F:12])[F:11])=[CH2:8]
Reactant: C=C(C(F)(F)F)C(F)(F)OS(=O)(=O)F
Reactant: CCN(CC)CC
Solvent: CO
Solvent: O
Product: C=C(C(F)(F)F)C(F)(F)OC
Yield: 51.1 %

Procedure:
Triethylamine (2.5 g, 0.02 mole) is added gradually to CH2═C(CF3)CF2OSO2F (5 g, 0.02 mole) in dry methanol (10 ml) at 10° C. After 20 minutes the reaction mixture is poured into water. The organic layer is separated, washed in turn in dilute aqueous HCl, water, sodium bicarbonate solution, and water, and then dried over MgSO4. Distillation of the dried mixture gives 3,3-difluoro-3-methoxy-2-trifluoromethylpropene (1.8 g, 50% yield). The isomer 1,1-difluoro-2-trifluoromethyl-3-methoxypropene (about 1%) and CH2═C(CF3)COOCH3 (about 3%) are also detected by gas chromatography-mass spectrometry (GC-MS).
Reaction SMILES: [C:1]([C:9]12[O:15]C1[O:13][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]2=[O:21])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)=O.O>[OH:15][C:9]1[C:10](=[O:21])[CH:11]=[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:13][C:1]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=CC(=O)C2(C(=O)c3ccccc3)OC2O1
Solvent: O=CO
Solvent: O
Product: CCOC(=O)c1cc(=O)c(O)c(-c2ccccc2)o1

Procedure:
A solution of ethyl 6-benzoyl-5-oxo-2,7-dioxabicyclo[4.1.0]hept-3-ene-3-carboxylate (3.5 g) in 98-100% formic acid (50 ml) was heated under reflux for 11/2 hours, cooled, diluted with water and extracted with ethyl acetate. The extract was washed with excess sodium bicarbonate solution, dried and evaporated and the solid residue was crystallised twice from chloroform-petroleum ether 60°-80° C. to give the title product (mp 155°-157° C.).