Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([S:17]([C:20]3[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>O1CCCC1>[CH2:34]([NH:36][C:37]([NH:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([S:17]([C:14]2[CH:13]=[CH:12][C:11](/[CH:10]=[CH:9]/[C:6]3[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=3)=[CH:16][CH:15]=2)(=[O:19])=[O:18])[CH:21]=1)=[O:38])[CH3:35]
Reactant: CCN=C=O
Reactant: Nc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3)cc2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3)cc2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 24.5 %

Procedure:
A mixture of [3-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)phenyl]amine hydrochloride (Example 212, 100 mg, 0.26 mmol) and triethylamine (0.05 mL, 0.36 mmol) in tetrahydrofuran (2 mL) was cooled to 0° C. and ethyl isocyanate (0.08 mL, 0.31 mmol) added. The reaction was allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4 and evaporated. The residue was purified by flash column chromatography on silica, eluting with 40% ethyl acetate/isohexane, followed by trituration with diethyl ether to give the title compound as a white solid (27 mg, 24%). δH (500 MHz, d6 DMSO): 8.85 (1H, s), 8.15 (1H, s), 7.86 (2H, d, J=8.4 Hz), 7.79 (2H, d, J=8.4 Hz), 7.67 (2H, dd, J=5.7, 8.5 Hz), 7.50-7.48 (1H, m), 7.43-7.40 (3H, m), 7.27 (1H, d, J=16.5 Hz), 7.22 (2H, t, J=8.8 Hz), 6.20 (1H, t, J=5.4 Hz), 3.12-3.06 (2H, m), 1.03 (3H, t, J=7.1 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH:13]([C:33]#[C:34][CH3:35])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:36].[OH-].[NH4+:38].CCO>O>[NH2:38][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH:13]([C:33]#[C:34][CH3:35])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:36]
Reactant: CC#CC1CN(S(=O)(=O)c2cnc(Cl)c(F)c2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC#CC1CN(S(=O)(=O)c2cnc(N)c(F)c2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 150 °C
Yield: 37 %

Procedure:
A 20-mL microwave vial was charged with 2-(4-(4-((6-chloro-5-fluoro-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (165 mg, 0.30 mmol), aq. ammonium hydroxide (3 mL, 30% solution, 15.4 mmol, J. T. Baker, Phillipsburg, N.J.) and EtOH (3 mL). The is reaction vessel was sealed and the mixture heated to 150° C. overnight. The reaction was diluted with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organics were dried (Na2SO4), filtered, and concentrated to give an oil that was purified via column chromatography on silica gel (0-10% MeOH in CH2Cl2) to give 2-(4-(4-((6-amino-5-fluoro-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (60 mg) as a mixture of two isomers.
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[CH:9]=[CH:10][C:11]2[S:15][N:14]=[C:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]=2[CH:22]=1)([O-])=O.C(=O)([O-])O.[Na+].C(Cl)Cl>C(OCC)(=O)C.[Fe]>[NH2:5][C:8]1[CH:9]=[CH:10][C:11]2[S:15][N:14]=[C:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]=2[CH:22]=1
Reactant: CCOC(=O)Cc1nsc2ccc([N+](=O)[O-])cc12
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1nsc2ccc(N)cc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A 10% acetic acid solution (31.0 mL) is stirred at 50° C., treated with iron powder (0.656 g), treated dropwise with a solution of ethyl 5-nitro-1,2-benzisothiazole-3-acetate (1.03 g, 3.88 mmol) in ethyl acetate, stirred at 50° C. for two hours, treated with additional iron powder (0.305 g), stirred at 50° C. for 15 minutes, and poured into saturated sodium hydrogen carbonate solution. The resultant aqueous mixture is extracted with ethyl acetate. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain an oil. Column chromatography of the oil using silica gel and methylene chloride gives the title product as a yellow oil.
Reaction SMILES: Cl.Cl.[CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])=[CH:16]3)[CH2:8][CH2:7]1)([CH3:5])[CH3:4].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH:3]([N:6]1[CH2:7][CH2:8][CH:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22]([N:24]2[CH2:29][CH2:28][N:27]([S:38]([CH3:37])(=[O:40])=[O:39])[CH2:26][CH2:25]2)=[O:23])=[CH:16]3)[CH2:10][CH2:11]1)([CH3:5])[CH3:4]
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCNCC4)cc3c2)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Reaction time: 8 h

Procedure:
To a solution of [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone dihydrochloride (82 mg, 0.22 mmol) in dichloromethane (2 ml) were added triethylamine (4.2 eq, 0.13 ml) and methanesulfonyl chloride (1.4 eq, 0.02 ml). The mixture was stirred overnight, diluted with dichloromethane and washed with 1N aqueous sodium bicarbonate solution. The phases were separated, the aqueous phase extracted with dichloromethane, and the combined organic phases washed with brine and dried over magnesium sulfate. The crude product was purified by column chromatography on silica gel (1:0 to 5:1 dichloromethane/methanol eluant) to afford the title compound as an off-white solid. MS (m/z): 449.2 (M+H)+.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(OOC(C)(C)C)(C)(C)C>>[CH:10]1([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCCCCCCCO
Reactant: C1CCCCC1
Agent: CC(C)(C)OOC(C)(C)C
Product: CCCCCCCCOC1CCCCC1
Temperature: 90 °C
Yield: 42 %

Procedure:
Into a pressure vessel 1-octanol (160 μL, 1 mmol, 1 eq) was added and diluted with cyclohexane (1.080 mL, 10 mmol, 10 eq). To this stirring solution was added 1 mol % of a stock solution of {[Cl2NN]Cu}2(benzene) from the catalyst stock solution described in Example 4 (200 μL=0.01 mmol). After adding of tert-butyl peroxide (220 μL, 1.2 mmol), the pressure vessel was sealed and heated to 90° C. for 24 hr. The catalyst was separated by exposing the mixture to air and filtering through Celite®. After removing cyclohexane under vacuum, the residue was analyzed by 1H NMR and GC/MS to determine the yield and consumption of starting materials. 1H NMR Yield: 42%.
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>O>[N:18]1([CH2:17][CH2:16][NH:15][C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Reactant: NCCN1CCCC1
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(NCCN2CCCC2)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
A mixture of tert-butyl 4-fluorobenzoate (2.14 g) and 1-(2-aminoethyl)pyrrolidine (1 mL) is stirred at 120° C. for one day. After cooling, to the reaction mixture is added water and the mixture is extracted with ethyl acetate (×2). The extract is concentrated by centrifugal concentrator and the residue is purified by flash column chromatography on NH-silica gel (Solvent; n-hexane:ethyl acetate=8:1→4:1) to give tert-butyl 4-[[2-(1-pyrrolidinyl)ethyl]amino]benzoate (1.62 g, yield; 51%) as an oil. MS (APCI) m/z: 291 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:41])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[C:28]([S:30]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)(=[O:32])=[O:31])[CH:27]=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:44][S:45]([CH2:48][CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)(=[O:47])=[O:46]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:41])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:54]3[CH2:55][CH2:56][N:51]([CH2:50][CH2:49][CH2:48][S:45]([CH3:44])(=[O:46])=[O:47])[CH2:52][CH2:53]3)=[O:22])[C:10]([C:24]3[CH:29]=[C:28]([S:30]([N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)(=[O:31])=[O:32])[CH:27]=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1ccc(S(=O)(=O)N2CCCC2)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCCN1CCNCC1
Agent: Cl
Product: CCOc1ccc(S(=O)(=O)N2CCCC2)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-5-(pyrrolidine-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C38H48N5O6S2Cl2 [(M+H)+] 804.2418, observed 804.2413
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([SH:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:16]([O:19][C:20]([N:22]1[CH2:26][C@H:25](OS(C)(=O)=O)[CH2:24][C@H:23]1[CH2:32][CH2:33][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[C:39](=[O:41])[NH2:40])=[O:21])[CH:17]=[CH2:18]>CN(C)C=O>[CH2:16]([O:19][C:20]([N:22]1[CH2:26][C@@H:25]([S:15][C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:24][C@H:23]1[CH2:32][CH2:33][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[C:39](=[O:41])[NH2:40])=[O:21])[CH:17]=[CH2:18]
Reactant: O=C(S)c1ccccc1
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1ccnc1C(N)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@@H](SC(=O)c2ccccc2)C[C@H]1CCn1ccnc1C(N)=O
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of potassium t-butoxide (8.42 g) in dimethylformamide (70 ml) was added thiobenzoic S-acid (9.27 ml) dropwise at -20° C. under dry ice--acetone bath. After the addition, the solution was warmed to room temperature, and then stirred for 75 minutes. To the solution was added a solution of (2R,4R)-1-allyloxycarbonyl-2-[2-(2-carbamoylimidazol-1-yl)ethyl]-4-methylsulfonyloxypyrrolidine (14.5 g) in dimethylformamide (70 ml) and the mixture was heated to 85° C. and stirred for 2 hours. After cooling to room temperature, the mixture was quenched by the addition of water (280 ml) and extracted with ethyl acetate (140 ml×3). The combined extract was washed with aqueous saturated sodium bicarbonate solution (140 ml×2), water (200 ml×2), and brine (200 ml×2), and then dried over magnesium sulfate. The solvent was evaporated and the residue was chromatographed on a 150 g of silica gel eluting with a mixture of chloroform and methanol (95:5, V/V) to give (2R,4S)-1-allyloxycarbonyl-4-benzoylthio-2-[2-(2-carbamoylimidazol-1-yl) ethyl]pyrrolidine (11.2 g) as a yellow paste.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.Br[CH2:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=1)=O>C(#N)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=3)[N:1]=2)[CH:4]=1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1
Reactant: Nc1ccc(Cl)cn1
Solvent: CC#N
Product: O=[N+]([O-])c1cc(-c2cn3cc(Cl)ccc3n2)ccc1C(F)(F)F
Yield: 96.6 %

Procedure:
A solution of 2-amino-5-chloropyridine (0.064 g, 0.5 mmol) and 2-bromo-1-[3-nitro-4-(trifluoromethyl)phenyl]ethanone (0.156 g, 0.5 mmol) in acetonitrile (3 ml) is stirred at 100° C. for 18 hr. The mixture is concentrated and purified on silica (0 to 100% EtOAc in hexanes) to give the title compound (165 mg, 97% yield). LCMS m/z=342.3 [M+H]+, tR=2.86 min.
Reaction SMILES: NC1C=CN(C2C(O)(C)C(O)C(CO)O2)C(=O)N=1.[C:19]([SiH2:23][O:24][C:25]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH:26]1[O:30][CH:29]([N:31]2[CH:36]=[CH:35][C:34]([N:37]=[CH:38][N:39]([CH3:41])[CH3:40])=[N:33][C:32]2=[O:42])[C:28]([OH:44])([CH3:43])[CH:27]1[OH:45])([CH3:22])([CH3:21])[CH3:20].[C:58]([NH:65][C@H:66]([C:70](O)=[O:71])[CH:67]([CH3:69])[CH3:68])([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:19]([SiH2:23][O:24][C:25]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[CH:26]1[CH:27]([O:45][C:70](=[O:71])[CH:66]([NH:65][C:58]([O:60][C:61]([CH3:62])([CH3:64])[CH3:63])=[O:59])[CH:67]([CH3:69])[CH3:68])[C:28]([OH:44])([CH3:43])[CH:29]([N:31]2[CH:36]=[CH:35][C:34]([N:37]=[CH:38][N:39]([CH3:40])[CH3:41])=[N:33][C:32]2=[O:42])[O:30]1)([CH3:20])([CH3:21])[CH3:22]
Reactant: CN(C)C=Nc1ccn(C2OC(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)C(O)C2(C)O)c(=O)n1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC1(O)C(O)C(CO)OC1n1ccc(N)nc1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OC1C(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2ccc(N=CN(C)C)nc2=O)C1(C)O

Procedure:
In another preferred embodiment of the present invention, compound (6) is reacted with Me2NCH(OMe)2 in DMF to form (7), N-[1-(3,4-dihydroxy-5-hydroxymethyl-3-methyl-tetrahydro-furan-2-yl)-2-oxo-1,2-dihydro-pyrimidin-4-yl]-N,N-dimethylformamidine, which is the amino-protected form of (i); reacting (2) with TBDPSCl and imidazole in DCM to provide the 5′-silyl-protected form of (6) as N′-{1-[5-(tert-butyl-diphenyl-silanyloxymethyl)-3,4-dihydroxy-3-methyl-tetrahydro-furan-2-yl]-2-oxo-1,2-dihydro-pyrimidin-4-yl}-N,N-dimethyl-formamidine (8), where the use of DCM provides the advantage of having greater control over disilyl by-product formation; reacting (8) with N—Boc-L-valine, EDC and DMAP in DCM at room temperature to form 2-tert-butoxycarbonylamino-3-methyl-butyric acid 2-(tert-butyl-diphenyl-silanyloxy-methyl)-5-[4-(dimethylamino-methyleneamino)-2-oxo-2H-pyrimidin-1-yl]-4-hydroxy-4-methyl-tetrahydro-furan-3-yl ester (2); removing the silyl and amino-protecting groups by reacting (9) with NH4F in MeOH in the presence of approximately 10 mole equivalents of ethyl acetate to prevent cleavage of the 3′-O-valinyl ester by liberated ammonia, and refluxing the mixture to provide 2-tert-butoxycarbonylamino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester (10); and finally, reacting (10) with HCl in EtOH to provide 2-amino-3-methyl-butyric acid 5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-hydroxy-2-hydroxymethyl-4-methyl-tetrahydro-furan-3-yl ester, dihydrochloride salt (11) as a final product.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[C:21]([O:33][CH3:34])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH3:34][O:33][C:21]1[CH:20]=[C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]4)[C:17]=23)[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: CN1CCNCC1
Reactant: COc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccn1
Product: COc1cc(Nc2ncnc3[nH]nc(OCCN4CCN(C)CC4)c23)ccc1OCc1ccccn1
Yield: 59 %

Procedure:
The procedure described in Example 55 was repeated using 2-[(4-{[3-methoxy-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl methanesulfonate and N-methylpiperazine to give the title compound in 59% yield; NMR Spectrum: 2.10 (s, 3H), 2.52 (hidden by DMSO, 8H), 2.78 (t, 2H), 3.81 (s, 3H), 4.42 (t, 2H), 5.16 (s, 2H), 7.01 (d, 1H), 7.20 (dd, 1H), 7.36 (t+d, 2H), 7.54 (d, 1H), 7.84 (td, 1H), 8.26 (s, 1H), 8.36 (s, 1H), 8.58 (d, 1H); Mass Spectrum: 491 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([Br:12])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].I[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[C:1]([C:5]1[CH:6]=[C:7]([Br:12])[CH:8]=[CH:9][C:10]=1[O:11][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(Br)ccc1O
Reactant: CCCCCCI
Product: CCCCCCOc1ccc(Br)cc1C(C)(C)C
Yield: 95.8 %

Procedure:
Following the basic procedure of Example 46(a), by reacting 4.58 g (0.02 mol) of 3-tert-butyl-4-hydroxybromobenzene with 3.3 ml (0.022 mol) of 1-iodohexane, 6 g (97%) of 3-tert-butyl-4-hexyloxybromobenzene were obtained in the from of a colorless oil.
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([O:12][C:13]([N:15]1[CH2:19][CH:18]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=3)[CH:24]=[CH:23][N:22]=2)[CH2:17][CH:16]1[C:33](=[O:50])[NH:34][C:35]1([C:40]([NH:42][S:43]([O:46][CH:47]2[CH2:49][CH2:48]2)(=[O:45])=[O:44])=[O:41])[CH2:37][CH:36]1[CH:38]=[CH2:39])=[O:14])([CH3:11])([CH3:10])[CH3:9]>CCOC(C)=O.CCO>[C:8]([O:12][C:13]([N:15]1[CH2:19][CH:18]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=3)[CH:24]=[CH:23][N:22]=2)[CH2:17][CH:16]1[C:33](=[O:50])[NH:34][C:35]1([C:40]([NH:42][S:43]([O:46][CH:47]2[CH2:49][CH2:48]2)(=[O:44])=[O:45])=[O:41])[CH2:37][CH:36]1[CH2:38][CH3:39])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2nccc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)NS(=O)(=O)OC1CC1
Agent: O=C([O-])C(F)(F)F
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC1CC1(NC(=O)C1CC(Oc2nccc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)NS(=O)(=O)OC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
To the trifluoroacetate salt of 2-(1-cyclopropoxysulfonylaminocarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (181 mg, 0.253 mmol) Rh/AlO3 (37.2 mg, 5 wt %) was added and the mixture was suspended in EtOAc (4.5 mL) and EtOH (1.0 mL). The reaction flask was flushed with H2 gas and the reaction was allowed to stir at room temperature under a hydrogen atmosphere for 3 h. The reaction was filtered through a syringe tip filter (0.45 μM) and washed with ethanol. The filtrate was concentrated and then filtered through a C-18 RP SPE column (Phenomenex Strata, 1 g) and washed with methanol. The filtrate was concentrated and purified on silica (12 g, 0-7% MeOH/CH2Cl2) to give 2-(1-cyclopropoxysulfonylaminocarbonyl-2-ethyl-cyclopropylcarbamoyl)-4-(6-methoxy-isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (151 mg, 83%). LCMS found 619.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([Cl:19])=[N:16][C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:13]=2[C:12]([I:24])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25](C1N=C(Cl)C2NC(C)=C(I)C=2N=1)CCC>>[CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([Cl:19])=[N:16][C:15]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:14][C:13]=2[C:12]([I:24])=[C:11]1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCc1nc(Cl)c2c(n1)c(I)cn2COCc1ccccc1
Reactant: CCCCc1nc(Cl)c2[nH]c(C)c(I)c2n1
Product: CCCCc1nc(Cl)c2c(n1)c(I)c(C)n2COCc1ccccc1

Procedure:
Prepared similarly to Intermediate 5 from 2-butyl-4-chloro-7-iodo-6-methyl-5H-pyrrolo[3,2-d]pyrimidine
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[C-:8].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[N:25]=[C:24](OP(N3CCOCC3)(N3CCOCC3)=O)[CH2:23][N:22]=[C:21]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[F:47])[C:20]=2[CH:48]=1.C(O)(=O)C>O1CCCC1.O>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[N:25]3[CH:8]=[N:7][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:24]3[CH2:23][N:22]=[C:21]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[F:47])[C:20]=2[CH:48]=1
Reactant: O=P(OC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1)(N1CCOCC1)N1CCOCC1
Reactant: [C-]#[N+]CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ncn2c1CN=C(c1ccccc1F)c1cc(Cl)ccc1-2
Reaction time: 0.17 h

Procedure:
Potassium t-butoxide, 1.4 g (0.0125 mole), was added to a solution of 1.4 g (0.0124 mole) of ethyl isocyanoacetate in 125 ml of dry tetrahydrofuran. After stirring under argon for 10 minutes, 5.07 g (0.01 mole) of 7-chloro-2-[bis(morpholino)-phosphinyloxy]-5-(2-fluorophenyl)-3H-1,4-benzodiazepine was added and stirring was continued for 30 minutes at room temperature. The reaction mixture was then acidified with glacial acetic acid, diluted with water and extracted with methylene chloride. The extracts were washed with saturated sodium bicarbonate solution, dried and evaporated. Crystallization of the residue from ether yielded crystals which were recrystallized from methylene chloride/ether/hexane for analysis, mp 195°-196°.
Reaction SMILES: [C:1]([C:4]1[CH2:5][CH2:6][O:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1)([OH:3])=[O:2].[CH2:15](O)[CH3:16]>S(=O)(=O)(O)O>[CH2:15]([O:2][C:1]([C:4]1[CH2:5][CH2:6][O:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:3])[CH3:16]
Reactant: CCO
Reactant: O=C(O)C1=Cc2ccccc2OCC1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=Cc2ccccc2OCC1

Procedure:
A mixture of 8.2 g (0.043 mol) of 2,3-dihydro-4-carboxybenzoxepine in 150 ml of ethanol and 5 ml of concentrated sulphuric acid is brought to reflux for 6 hours. The reaction mixture is subsequently concentrated under reduced pressure and the residue is taken up in water. The combined mixture is extracted with ethyl acetate. The organic phase is then washed with sodium bicarbonate and then with water and dried over anhydrous sodium sulphate before being concentrated under reduced pressure. 8.5 g of an orange oil are thus obtained.
Reaction SMILES: [CH2:1]([C:4]#[N:5])[CH2:2][OH:3]>O>[C:4]([CH2:1][CH2:2][O:3][CH2:2][CH2:1][C:4]#[N:5])#[N:5]
Reactant: N#CCCO
Solvent: O
Product: N#CCCOCCC#N

Procedure:
The reaction mixture is advantageously worked up by the following procedure: the 3-dialkylaminopropionitrile I together with the water and the byproduct ethylenecyanohydrin III is isolated, for example, with the aid of a thin film evaporator. Thereafter, the remaining high boiling mixture is neutralized with a dilute mineral acid and the bis-(2-cyanoethyl) ether II is isolated from this mixture by fractional distillation under reduced pressure.
Reaction SMILES: CO[C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[CH2:8][CH2:9][S:10]2)=[CH:5][CH:4]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22]N)=[CH:18][CH:17]=1>CCO>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:19](=[CH:20][CH:21]=1)[NH:22][C:7]1[C:6]3[CH:5]=[CH:4][CH:3]=[CH:12][C:11]=3[S:10][CH2:9][C:8]2=1
Reactant: COc1ccc2c(c1)SCCC2=O
Reactant: COc1ccc(NN)cc1
Solvent: CCO
Product: COc1ccc2[nH]c3c(c2c1)CSc1ccccc1-3

Procedure:
7-methoxy-thiochroman-4-one (700 mg, 4.27 mmol) was stirred with (4-methoxy-phenyl)-hydrazine (818 mg, 4.70 mmol, 1.1 eq.) in EtOH (40 mL, 0.1 M) and refluxed for 2 hours. EtOH was then removed from the mixture and EtOAc and saturated NaHCO3 aqueous solution were added. The organic layer was separated, dried over K2CO3 and concentrated. The residue was purified with flash column chromatography (4:1 Hexane:EtOAc) to yield the title product as a brown solid.