Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C12CC(CC1)CCO2.[CH3:9][C:10]1[CH2:14][C:13](C(OCC)=O)([C:15]([O:17]CC)=[O:16])[CH2:12][CH:11]=1>>[CH3:9][C:10]1[CH2:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][CH:11]=1
Reactant: CCOC(=O)C1(C(=O)OCC)CC=C(C)C1
Agent: C1CC2CCC(C2)O1
Product: CC1=CCC(C(=O)O)C1

Procedure:
When m is 1, n is 2 and p is 1, the ring syste is a 2-oxabicyclo[3.2.1]octane, another subclass of this invention. For example, compound XIIp ##STR26## in which R2, R5 and R6 are methyl, can be prepared by saponification and decarboxylation of diethyl 1-methylcyclopent-1-ene-4,4-dicarboxylate, prepared by the procedure of E. E. Schweiger and G. J. O'Neill, J. Org. Chem., 30, 2082 (1965), to provide 1-methylcyclopent-1-ene-4-carboxylic acid. The resulting carboxylic acid is homologated in the manner proscribed for the compounds XIp, and subsequently treated similarly to the acid of subclass IX.
Reaction SMILES: O=S(Cl)Cl.[Br:5][C:6]1[CH:7]=[C:8]([CH2:12]O)[CH:9]=[N:10][CH:11]=1.[C-:14]#[N:15].[K+].CO>O>[Br:5][C:6]1[CH:7]=[C:8]([CH2:12][C:14]#[N:15])[CH:9]=[N:10][CH:11]=1
Reactant: [C-]#N
Reactant: OCc1cncc(Br)c1
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: O
Product: N#CCc1cncc(Br)c1
Temperature: 0 °C

Procedure:
To SOCl2 (26.7 ml) cooled with an ice-bath was added portionwise (5-bromo-pyridin-3-yl)-methanol (ABCR, Karlsruhe, Germany, 26.6 mmol). The RM was refluxed for 1 h then was cooled at 0° C. and quenched with diethyl ether. The resulting precipitate was filtered, washed with cooled diethyl ether and dried under vacuum at 50° C. The solid was mixed with potassium cyanide (64.5 mmol), MeOH (35 ml) and water (14 ml) and the RM was refluxed for 2 h. The RM was cooled, quenched with aqueous K2CO3 and extracted with diethyl ether (3×). The combined organic layers dried over Na2SO4, filtered and evaporated to give the title compound as a purple solid. (HPLC: tR 2.16 min (Method A); M+H=197, 199 MS-ES)
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([C:13]3[N:14]=[C:15]4[C:21]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:20][N:19](COCC[Si](C)(C)C)[C:16]4=[N:17][CH:18]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].CO.[Cl:40][CH2:41][Cl:42]>FC(F)(F)C(O)=O>[NH4+:6].[OH-:27].[Cl:40][CH2:41][Cl:42].[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([C:13]3[N:14]=[C:15]4[C:21]([C:22](=[O:27])[C:23]([CH3:25])([CH3:24])[CH3:26])=[CH:20][NH:19][C:16]4=[N:17][CH:18]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(NC4CCCC4)c3)nc12
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(NC4CCCC4)c3)nc12
Product: [NH4+]
Yield: 53 %

Procedure:
A solution of 1-[2-(3-Cyclopentylamino-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (0.1781 g, 0.361 mmol) in 1 mL of dichloromethane and 1 mL of trifluoroacetic acid was stirred for 3 h then concentrated to a yellow oil. The oil was dissolved in 1 mL of methanol and the solution was treated with potassium hydroxide (0.24 g, 4.34 mmol). Preparative thin layer chromatography (50% 60:10:1 CH2Cl2:MeOH:NH4OH/dichloromethane) afforded 0.070 g (53% yield) of 1-[2-(3-Cyclopentylamino-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:16][CH2:17]OCC.C([Mg]Cl)=C.[Cl-].[NH4+]>O1CCCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:16]=[CH2:17])([OH:7])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:14][CH:15]=1
Reactant: CCOCC
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: C=C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)(c1ccccc1)c1ccc(O)cc1
Reaction time: 8 h

Procedure:
A solution of 20 g. of 4-hydroxy-benzphenone in 180 ml. of dry ether is added, within about 30 minutes, to a 0° C solution of 184 ml. of a 3.4 molar tetrahydrofuran solution of vinyl magnesium chloride, and the reaction mixture is stirred at the same temperature for additional 1 hour. The mixture is allowed to stand at room temperature overnight. Thereafter the mixture is poured onto ice water containing ammonium chloride. The etheral phase is separated, washed with water until neutral, dried over anhydrous magnesium sulfate, and the solvent is evaporated. 22.6 g. of crude 4-hydroxy-α-vinyl-benzhydrol are obtained. After recrystallization from a mixture of ethyl acetate and n-hexane, the product melts at 104°-105° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]=O)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:51][N:52]1[CH2:58][CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:55]6[CH2:56][CH2:57][CH2:58][N:52]([CH3:51])[CH2:53][CH2:54]6)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CN1CCCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(C=O)c3)ccc2OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(CN4CCCN(C)CC4)c3)ccc2OC)c1

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-4-(methyloxy)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide (54 mg, 0.00008 mol) in DCM, 1-methylhexahydro-1H-1,4-diazepine (13.7 mg, 15.2 μL, 0.00012 mol) and sodium triacetoxyborohydride (34 mg., 0.00016 mol) and AcOH (6 μL) were agitated overnight on a shaker. LC-MS was used to monitor the reaction. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. Purification was carried out on Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a chalky white solid. Further purification was carried out on an Agilent HPLC with RP-CH3CN:H2O-conc. aq. NH3 gradient [4.5 mg (7.25%)]. LC-MS m/z 773.5 (M+H)+.
Reaction SMILES: [CH:1]([C:5](O)([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])C#C)=[C:2]([CH3:4])[CH3:3].O1CC[CH2:16][CH2:15]1.[OH2:19]>FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:4][C:2]([CH2:1][CH:5]=[CH:8][C:9](=[O:19])[CH2:10][CH2:11][CH2:12][CH2:15][CH3:16])=[CH2:3]
Reactant: O
Reactant: C#CC(O)(C=C(C)C)CCCCC
Reactant: C1CCOC1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Product: C=C(C)CC=CC(=O)CCCCC
Reaction time: 7 h

Procedure:
3-Isobutenyl-1-octyn-3-ol (0.180 g; 10-3 mole) is kept at a temperature in the region of 40° C. and protected from light, in the presence of silver trifluoromethanesulphonate (0.257 g; 10-3 mole) in a mixture (10 cc) of tetrahydrofuran and water (3:1 by volume). After reacting for 7 hours the reaction mixture is treated under the conditions described in Example 1. 2-Methyl-1,4-undecadien-6-one (0.132 g) is obtained, having the following characteristics:
Reaction SMILES: [Na].N.[C:3]1([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:22](Br)[CH3:23]>O.CCOCC>[C:3]1([C:9]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH3:23])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCBr
Reactant: c1ccc(C(c2ccccc2)c2ccncc2)cc1
Agent: N
Agent: [Na]
Solvent: CCOCC
Solvent: O
Product: CCC(c1ccccc1)(c1ccccc1)c1ccncc1
Reaction time: 0.33 h

Procedure:
Dissolve 2.5 g. of sodium in 500 ml. of liquid ammonia in the presence of a catalytic amount of ferric nitrate. Add dropwise to the resulting suspension over a 20 minute interval a solution containing 24.5 g. of 4-diphenylmethyl pyridine in 600 ml. of ether. Stir the resulting dark red mixture for an additional 20 minutes, then add 13 g. of ethyl bromide dropwise. Add an additional 500 ml. of ammonia, stir overnight, then add 300 ml. of ether followed by 150 ml. of water. Separate the solvent layers. Wash the ether layer with water until neutral, dry and remove the solvent under reduced pressure to a residue. Distill the residue at 192°-200° C./1.6 to 2 mm. and obtain thereby 14.7 g. of the title compound as an orange colored oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][CH:14]2[CH2:23][CH2:22][N:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]3)[CH2:15]2)=[O:11])=[CH:2]1.ClN1[C:29](=[O:30])[CH2:28][CH2:27]C1=O.BrCCCO.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]1[CH:16]2[N:21]([CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:22][CH2:23][CH:14]1[CH2:13][O:12][C:10]([C:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[N:1]2[CH2:27][CH2:28][CH2:29][O:30][C:2]=12)=[O:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(OCC1CCN2CCCCC2C1)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: OCCCBr
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCC1CCN2CCCCC2C1)c1c2n(c3ccccc13)CCCO2
Yield: 51 %

Procedure:
eq-Quinolizidin-2-ylmethyl 1 H-indole-3-carboxylate was treated initially with N-chlorosuccinimide (1.5 equivalents) for 2 h, then with 3-bromo-1-propanol (2 equivalents) for 16 h, followed by anhydrous potassium carbonate in acetone, using the method described in Example 1b. The crude product was purified using the same chromatography conditions as in Example 1b to afford the title compound as a colourless oil (51%). This was converted to its hydrochloride salt and crystallised from acetone mp 164°-167° C.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[F:11].CC1(C)C(C)(C)OB([C:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH:25]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[C:29]([O:28][C:26]([N:23]1[CH2:22][CH:21]=[C:20]([C:2]2[C:3]([F:11])=[CH:4][CH:5]=[C:6]([F:10])[C:7]=2[O:8][CH3:9])[CH2:25][CH2:24]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COc1c(F)ccc(F)c1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(F)ccc(F)c1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 150 °C

Procedure:
2-Bromo-1,4-difluoro-3-methoxy-benzene (0.7 g, 3.139 mmol) [C.A.S. 1208076-11-2] was added to a stirred solution of 3,6-dihydro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1(2H)-pyridinecarboxylic acid, 1,1-dimethylethyl ester (1.262 g, 4.08 mmol) [C.A.S. 286961-14-6], Pd(PPh3)4 (0.072 g, 0.062 mmol) and K2CO3 (3.5 ml, aqueous sat. solution) in 1,4-dioxane (7 ml). The reaction mixture was heated at 150° C. under microwave irradiation for 10 min. After cooling, the mixture was diluted with water and extracted with Et2O. The organic phase was separated, dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (silica gel; Heptane/EtOAc 90/10 to 80/2 as eluent). The desired fractions were collected and concentrated in vacuo to give a residue that was triturated with Et2O to yield intermediate D52 (0.233 g, 22%).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]3[CH2:14][CH2:13][CH:12]([C:15]([O:17]CC)=[O:16])[C:9]3=[N:10][CH:11]=2)[CH:5]=[N:4][N:3]=[N:2]1.O[Li:21].O>C1COCC1.CO.O.O>[N:1]1([C:6]2[CH:7]=[C:8]3[CH2:14][CH2:13][CH:12]([C:15]([O-:17])=[O:16])[C:9]3=[N:10][CH:11]=2)[CH:5]=[N:4][N:3]=[N:2]1.[Li+:21]
Reactant: [Li]O
Reactant: CCOC(=O)C1CCc2cc(-n3cnnn3)cnc21
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C([O-])C1CCc2cc(-n3cnnn3)cnc21
Product: [Li+]
Reaction time: 0.5 h

Procedure:
To a mixture of ethyl 3-(1H-tetrazol-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carboxylate (1.5 g, 5.8 mmol) in 50 mL of THF/MeOH/H2O (2:2:1) was added LiOH.H2O (242.8 mg, 5.8 mmol) portionwise. The resulting mixture was stirred for 30 minutes then diluted with 200 mL of water and washed with ether (3×30 mL). The water layer was freeze-dried to afford the title compound: 1H-NMR (400 MHz, D2O) δ ppm 8.68 (s, 1H), 8.07 (s, 1H), 3.97 (t, J=7.6 Hz, 1H), 3.00-3.14 (m, 2H), 2.53-2.59 (m, 1H), 2.17-2.32 (m, 1H).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][CH:3]=1.[C:19]([Si:23]([CH3:44])([CH3:43])[O:24][CH:25]1[C:33]2[C:28](=[C:29](B3OC(C)(C)C(C)(C)O3)[CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(O)C(O)C.O>[Si:23]([O:24][CH:25]1[C:33]2[C:28](=[C:29]([C:2]3[O:6][C:5]([C:7]4[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=4)[C:12]#[N:13])=[N:4][CH:3]=3)[CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:44])[CH3:43]
Reactant: CC(C)Oc1ccc(-c2ncc(Br)o2)cc1C#N
Reactant: CC1(C)OB(c2cccc3c2CCC3O[Si](C)(C)C(C)(C)C)OC1(C)C
Agent: CC(O)C(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CCC4O[Si](C)(C)C(C)(C)C)o2)cc1C#N
Temperature: 0 °C
Yield: 94 %

Procedure:
Prepared using General Procedure 13. A 20 mL microwave vial was charged with 5-(5-bromooxazol-2-yl)-2-isopropoxybenzonitrile INT-32 (200 mg, 0.65 mmol), tert-butyldimethyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)silane INT-30 (243 mg, 0.65 mmol), potassium carbonate (269 mg, 1.95 mmol) and a 3:1 mixture of dimethylethylene glycol/H2O (10 mL). The reaction mixture was degassed by bubbling N2 gas through the stirring solution for 10 min. Pd(PPh3)4 was added and the solution degassed for additional 2 min. The vial was subjected to microwave irradiation at 100° C. for 40 min. The vial was cooled to 0° C. and the resulting solid obtained was collected by filtration, washed with ice water, and dried to afford 290 mg (94%) of 5-(5-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4-yl)oxazol-2-yl)-2-isopropoxybenzonitrile INT-33 as a light yellow solid. LCMS-ESI (m/z) calculated for C28H34N2O3Si: 474.7; found 475.2 [M+H]+, tR=5.90 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.16-7.96 (m, 2H), 7.57-7.42 (m, 1H), 7.24-7.12 (m, 3H), 6.90 (t, J=10.4 Hz, 1H), 5.14 (t, J=7.0 Hz, 1H), 4.57 (dt, J=12.3, 6.1 Hz, 1H), 3.04 (ddd, J=16.1, 9.1, 3.1 Hz, 1H), 2.78 (dt, J=16.1, 8.1 Hz, 1H), 2.43-2.24 (m, 1H), 1.84 (ddd, J=15.8, 12.8, 8.9 Hz, 1H), 1.27 (t, J=5.8 Hz, 6H), 0.86-0.61 (m, 9H), 0.06-0.14 (m, 6H).
Reaction SMILES: [C:1]([Si:5]([CH3:27])([CH3:26])[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([OH:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:25])([CH3:4])([CH3:3])[CH3:2].C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.Cl[C:47]1[CH:54]=[CH:53][CH:52]=[CH:51][C:48]=1[CH2:49]Br>C(#N)C.CN(C=O)C>[CH2:49]([N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C:10]2[CH:9]=[C:8]([CH3:25])[C:7]([O:6][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([CH3:27])[CH3:26])=[C:12]([CH3:13])[CH:11]=2)([OH:24])[C:15]1=[O:23])[C:48]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:47]=1
Reactant: Clc1ccccc1CBr
Reactant: Cc1cc(C2(O)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1cc(C2(O)C(=O)N(Cc3ccccc3)c3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Yield: 81.1 %

Procedure:
Using a method similar to Preparation 17 with 3-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-3-hydroxy-1,3-dihydro-indol-2-one (3.83 g, 10 mmol), 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (3.5 ml, 12 mmol) and 2-chlorobenzyl bromide (1.56 mL, 12 mmol) in acetonitrile/DMF (60 mL/20 mL) gives 5.9 g of a crude yellow gum. Purify by flash chromatography (CH2Cl2 to 10% EtOAc/CH2Cl2) gives 3.84 g (76%) of the title compound as a white solid. Mp 147.1° C. MS (ES): m/z=490 (M+1−H2O); 1H NMR(DMSO-d6): δ7.52 (dd, J=1.7, 1.4 Hz, J=7.7, 7.4 Hz, 1H), 7.37-7.14 (m, 5H), 7.05 (t, J=7.7 Hz, 1H), 6.93 (s, 2H), 6.86 (d, J=7.7 Hz, 1H), 6.73 (s, 1H), 4.96 (abq, 2H), 2.11 (s, 6H), 0.98 (s, 9H), 0.16 (s, 6H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[OH-].[K+].C1(C=CC(O)=CC=1)O.O>C1(C)C=CC=CC=1.C(O)(=O)C>[CH:3]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[CH2:2]
Reactant: Cc1cccnc1NS(=O)(=O)c1ccc(CCBr)cc1
Agent: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C=Cc1ccc(S(=O)(=O)Nc2ncccc2C)cc1

Procedure:
4-(2-Bromoethyl)-N-(3-methyl-2-pyridinyl)benzenesulfonamide (183 g, 0.5 mol) and potassium hydroxide (120 g, 1.83 mol) and hydroquinone (1 g) in ethanol (21) was refluxed for 1 h. 51 water was added and the solution acidified with acetic acid. The precipitated product was collected by filtration, washed with water and dried. Yield 137 g (quantitative).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([OH:25])[CH:18]=1.[CH2:26]([N:28]([CH2:32][CH3:33])[C:29](Cl)=[O:30])[CH3:27].C(N(CC)CC)C>CN(C=O)C.N1C=CC=CC=1>[CH2:26]([N:28]([CH2:32][CH3:33])[C:29](=[O:30])[O:25][C:19]1[CH:18]=[C:17]([CH2:16][NH:15]/[CH:14]=[C:5]2\[C:6](=[O:13])[NH:7][C:8](=[O:12])[C:9]3[C:4]\2=[CH:3][C:2]([I:1])=[CH:11][CH:10]=3)[CH:22]=[CH:21][C:20]=1[O:23][CH3:24])[CH3:27]
Reactant: CCN(CC)C(=O)Cl
Reactant: COc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCN(CC)C(=O)Oc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)ccc1OC
Temperature: 80 °C
Reaction time: 4 h
Yield: 56.2 %

Procedure:
To a solution of (4Z)-6-iodo-4-{[(3-hydroxy-4-methoxybenzyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (0.30 g, 0.67 mmol) in 3 mL of N,N′-dimethylformamide and 2 mL of pyridine is added diethylcarbamylchloride (0.10 mL, 0.80 mmol) and 0.21 mL (2.00 mmol) of triethylamine. The reaction mixture is stirred at 80° C. for 4 h and then at room temperature over weekend under N2. Mass spectroscopy suggested the completion of reaction. The reaction mixture is concentrated, and 2 mL of MeOH is added to break up the solid, followed by addition of excess amount of Et2O. The precipitate is filtered, washed successively with water, methanol, ether and hexane, and dried in oven (60° C.) overnight to afford 0.207 g (56.6% yield) of tan solid: mp 128-130° C.; MS (ESI) m/z 548.2 (M−H)−1
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])[NH:5][C:4](=[S:16])[N:3]=1.I[CH2:18][CH3:19].C(=O)(O)[O-].[Na+].O>CS(C)=O>[Cl:15][C:9]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[C:6]1[N:5]=[C:4]([S:16][CH2:18][CH3:19])[N:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: Nc1cc(-c2ccc(Cl)cc2Cl)[nH]c(=S)n1
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCSc1nc(N)cc(-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
67.5 g (248 mmol) of 4-amino-6-(2,4-dichlorophenyl)pyrimidine-2(1H)-thione and 77.37 g (496.04 mmol) of iodoethane are dissolved in 560 ml of dry DMSO and, at RT, 270 ml of a saturated aqueous sodium bicarbonate solution are slowly added. The mixture is stirred at RT for 5 h and then 440 ml of water are added. The precipitate is filtered off with suction, washed with water and sucked dry. It is stirred twice with 100 ml of isopropanol each time and again filtered off with suction. It is washed once more with petroleum ether and the residue is dried under high vacuum. 50.0 g (67% of theory) of the product are obtained as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:25]([OH:27])=O)[C:6]2[N:10]=[C:9]([NH:11][C:12]([C:14]3[N:15]=[CH:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:13])[NH:8][C:7]=2[CH:24]=1)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.S(O)(O)(=O)=O.[NH2:66][C:67]1[NH:68][CH:69]=[CH:70][N:71]=1>O.CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:25](=[O:27])[NH:66][C:67]2[NH:68][CH:69]=[CH:70][N:71]=2)[C:6]2[N:10]=[C:9]([NH:11][C:12]([C:14]3[N:15]=[CH:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:13])[NH:8][C:7]=2[CH:24]=1)#[N:2]
Reactant: Nc1ncc[nH]1
Reactant: N#Cc1cc(C(=O)O)c2nc(NC(=O)c3cc4ccccc4cn3)[nH]c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1cc(C(=O)Nc2ncc[nH]2)c2nc(NC(=O)c3cc4ccccc4cn3)[nH]c2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 4.2 %

Procedure:
0.20 g (0.56 mmol) of 6-cyano-2-[(isoquinoline-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid and 0.21 g (0.56 mmol) of HBTU were combined in a flask charged with 3 mL of DMF and 1 mL of DIEA. This reaction mixture was then treated with 0.07 g (0.56 mmol) of 2-amino-imidazole sulfate and stirred at 80° C. for 1 h. The reaction mixture was diluted with water, and the resultant solid precipitate was filtered and washed with saturated NaHCO3. The solid was dissolved with MeOH, evaporated onto silica gel and isolated by flash column chromatography (500 mL DCM/20 mL NH3/MeOH) to yield 10 mg of isoquinoline-3-carboxylic acid [6-cyano-4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 424.0 (M+1)+.
Reaction SMILES: [Si]([O:8][C@H:9]([C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[C:50]([CH2:55][OH:56])[CH:49]=1)[CH2:10][NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([C@@H:32]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:33][CH2:34][N:35]([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])[CH:26]=2)=[CH:16][CH:15]=1)(C(C)(C)C)(C)C.O.[F-].[NH4+]>CO>[NH3:11].[CH:39]([N:35]([CH:36]([CH3:38])[CH3:37])[CH2:34][CH2:33][C@@H:32]([C:27]1[CH:26]=[C:25]([CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][NH:11][CH2:10][C@H:9]([OH:8])[C:48]3[CH:53]=[CH:52][C:51]([OH:54])=[C:50]([CH2:55][OH:56])[CH:49]=3)=[CH:19][CH:18]=2)[CH:30]=[CH:29][C:28]=1[OH:31])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)([CH3:41])[CH3:40]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c(CO)c3)cc2)ccc1O)C(C)C
Agent: [F-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCOc2ccc(CCNC[C@H](O)c3ccc(O)c(CO)c3)cc2)ccc1O)C(C)C
Product: N
Temperature: 40 °C
Reaction time: 8 h

Procedure:
4-[(1R)-1-{[tert-butyl(dimethyl)silyl]oxy}-2-({2-[4-(4-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}butoxy)phenyl]ethyl}amino)ethyl]-2-(hydroxymethyl)phenol (Preparation 63, 311 mg, 0.356 mmol) was dissolved in methanol (4 ml) and water (0.5 ml) and ammonium fluoride (132 mg, 3.56 mmol) was added. The reaction was heated to 40° C. and stirred overnight. Reaction mixture was cooled and solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (100/0/0 to 90/10/1.0 by volume) to furnish the title compound as a glass, 84 mg.