Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC(O[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH:21]=2)[C:17]([O:19][CH3:20])=[O:18])=[O:10])=CC=1)([O-])=O.C(#N)C.Cl.Cl.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH2:41][CH2:40][CH:39]([CH2:42][CH2:43][CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)[CH2:38][CH2:37]2)[N:31]=1>CCOC(C)=O>[CH3:29][C:30]1[N:31]=[C:32]([N:36]2[CH2:41][CH2:40][CH:39]([CH2:42][CH2:43][CH:44]3[CH2:49][CH2:48][N:47]([C:9]([O:11][C:12]4[CH:13]=[N:14][CH:15]=[C:16]([CH:21]=4)[C:17]([O:19][CH3:20])=[O:18])=[O:10])[CH2:46][CH2:45]3)[CH2:38][CH2:37]2)[CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)c1cncc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: Cc1cccc(N2CCC(CCC3CCNCC3)CC2)n1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cncc(OC(=O)N2CCC(CCC3CCN(c4cccc(C)n4)CC3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
Methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (505 mg) was added to an acetonitrile (10 ml) solution of 2-methyl-6-[4-(2-piperidin-4-ylethyl)piperidin-1-yl]pyridine dihydrochloride (520 mg) and TEA (0.50 ml), followed by stirring at room temperature for 3 hours. The reaction liquid was diluted with EtOAc, washed with an aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform:methanol=98:2 (v/v)) to obtain methyl 5-{[(4-{2-[1-(6-methylpyridin-2-yl)piperidin-4-yl]ethyl}piperidin-1-yl}carbonyl]oxy}nicotinate (424 mg).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=1[NH2:16].CCN(CC)CC>C1COCC1>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:16][C:15]2[C:14]([F:13])=[CH:20][CH:19]=[CH:18][C:17]=2[F:21])[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Reactant: Nc1c(F)cccc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1nc(Cl)c(C=O)c(Nc2c(F)cccc2F)n1
Temperature: 55 °C
Yield: 69.8 %

Procedure:
To a solution of 4,6-dichloro-2-(methylthio)-5-pyrimidinecarbaldehyde (10.0 g, 44.8 mmol) in THF (250 mL) was added 2,6-difluoroaniline (5.35 mL, 49.3 mmol, 1.1 eq) followed by Et3N (12.6 mL, 89.6 mmol, 2 eq). The reaction mixture was heated to 55° C. for about 22 h before concentrated. The slurry was re-dissolved in DCM (250 mL) and washed with H2O (2×100 mL), then concentrated and further washed with acetone (2×10 mL) to give 9.87 g (70%) of pure 4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5-pyrimidinecarbaldehyde. LC-MS m/z 316 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4](Cl)[N:3]=1.C(NC(C)C)(C)C.[C:31]1([CH:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:38][NH2:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17](=[O:20])[CH2:18][CH3:19])[C@@H:13]([OH:21])[C@H:12]2[OH:22])=[C:4]([NH:39][CH2:38][CH:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:3]=1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: NCC(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
N-[(1S,2R,3S,4R)-4-(2,6-Dichloro-purin-9-yl)-2,3-dihydroxy-cyclopentyl]-propionamide (160 mg, 0.44 mmol) is dissolved in THF (5 ml) under an atmosphere of argon. Diisopropylamine (69 mg, 0.53 mmol) is added followed by 2,2-diphenylethylamine (96 mg, 0.49 mmol) and the reaction mixture is stirred at 50° C. The reaction is shown to be complete by LCMS after 2 hours. The solvent is removed in vacuo and the title compound is obtained after purification by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water—0.1% TFA). 1H nmr (MeOD, 400 MHz); 8.00 (s, 1H), 7.40-7.15 (m, 10H), 4.75 (m, 1H), 4.60 (m, 1H), 4.50 (m, 1H), 4.20 (m, 3H), 3.95 (m, 1H), 2.85 (m, 1H), 2.40 (q, 2H), 2.10 (m, 1H), 1.20 (t, 3H), MS (ES+) m/e 521 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]3[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=3[F:26])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[C:31]([O:35][CH3:36])=[N:32][C:33]=1[Cl:34].C(=O)([O-])[O-].[K+].[K+]>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>[Cl:27][C:28]1[CH:29]=[C:30]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]4[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=4[F:26])(=[O:14])=[O:13])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[C:31]([O:35][CH3:36])=[N:32][C:33]=1[Cl:34]
Reactant: COc1nc(Cl)c(Cl)cc1B(O)O
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nccc2c1
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+]
Product: COc1nc(Cl)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Temperature: 40 °C

Procedure:
A vial was charged with perfluorophenyl 1-chloroisoquinoline-6-sulfonate (From Step 1 in Example 73; 0.050 g, 0.122 mmol), (5,6-dichloro-2-methoxypyridin-3-yl)boronic acid (0.030 g, 0.134 mmol), potassium carbonate (0.051 g, 0.366 mmol), and Pd(Ph3P)4 (0.014 g, 0.012 mmol). The vial was flushed with Ar (g), then dioxane (0.915 ml) and water (0.305 ml) were added. The reaction was heated at 40° C. for one hour. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 12 g, gradient elution 0-50% EtOAc:Heptane) to afford perfluorophenyl 1-(5,6-dichloro-2-methoxypyridin-3-yl)isoquinoline-6-sulfonate as a white solid. (ESI) 551.0 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([CH3:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8].[N-:13]=[N+:14]=[N-:15].[Na+]>>[N:13]([CH2:2][CH2:3][CH2:4][Si:5]([CH3:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CCO[Si](C)(CCCCl)OCC
Agent: [Na+]
Product: CCO[Si](C)(CCCN=[N+]=[N-])OCC
Temperature: 140 °C

Procedure:
1.0 mole of 3-chloropropylmethyldiethoxysilane and 1.1 moles of sodium azide were heated in the presence of 5 mole percent of the catalyst described in Example 1 (a) for three hours under stirring at 140° C. After the distillation under reduced pressure there was obtained the 3-azidopropylmethyldiethoxysilane in a yield of 94 weight percent.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[CH:27][N:26]=1>>[Cl:24][C:25]1[CH:30]=[C:29]([C:2]2[N:7]=[C:6]3[S:8][C:9]([NH:11][C:12](=[O:23])[C:13]4[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=4)=[N:10][C:5]3=[CH:4][CH:3]=2)[CH:28]=[CH:27][N:26]=1
Reactant: CC1(C)OB(c2ccnc(Cl)c2)OC1(C)C
Reactant: CC(C)(O)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Product: CC(C)(O)c1ccc(C(=O)Nc2nc3ccc(-c4ccnc(Cl)c4)nc3s2)cc1
Yield: 43 %

Procedure:
The titled compound (yield=43%, yellow solid) was prepared using a procedure analogous to that described in connection with 9 (Example 9) except 1D (Example 1) and 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (s, 6H) 5.24 (s, 1H) 7.67 (d, J=8.34 Hz, 2H) 8.12 (d, J=8.34 Hz, 2H) 8.18 (d, J=5.56 Hz, 1H) 8.25 (s, 1H) 8.28-8.37 (m, 2H) 8.55 (d, J=5.31 Hz, 1H) 13.12 (s, 1H); ESI-MS: m/z 425.0 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])=[CH:10][CH:9]=1)=[O:7].[H-].[Na+].I[CH3:28]>CN(C=O)C>[CH3:28][N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])=[CH:10][CH:9]=1)=[O:7]
Reactant: CI
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C(=O)c3ccc[nH]3)cc2)C(=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(C(=O)c3cccn3C)cc2)C(=O)O1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
The title compound of Example 47 (0.14 g, 0.43 mM) in DMF (1.4 ml) was stirred under nitrogen and cooled to 5° C. Sodium hydride (0.019 g of a 60% dispersion in mineral oil, 0.47 mM) was added and the mixture stirred for 15 minutes. Iodomethane (30 μl) was added, the mixture stirred for 10 minutes at 5° C. and at ambient temperature for 2 hours. The mixture was evaporated and the residue partitioned between EtOAc and water. The organic layer was washed with water dried (MgSO4) and evaporated. The residue was purified by column chromatography in dichloromethane, eluting with a gradient increasing in polarity from 2% to 10% MeOH/dichloromethane to give the title product as an oil (0.13 g). MS: 342 (MH+); NMR: 1.83 (3H, s); 3.28 (nH+H2O); 3.42 (2H, t); 3.80 (1H, m); 3.92 (3H, s); 4.9 (1H, t); 4.75 (1H, m); 6.16 (1H, m); 6.64 (1H, m); 7.23 (1H, m); 7.67 (2H, d); 7.80 (2H, d); 8.22 (1H, t).
Reaction SMILES: [NH3:1].[C:2]([C:4]1[CH:5]=[N:6][N:7]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=2)[C:8]=1[CH:9]=[CH:10][C:11](Cl)=[O:12])#[N:3]>O1CCCC1.O>[C:2]([C:4]1[CH:5]=[N:6][N:7]([C:14]2[C:19]([Cl:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=2)[C:8]=1[CH:9]=[CH:10][C:11]([NH2:1])=[O:12])#[N:3]
Reactant: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C=CC(=O)Cl
Reactant: N
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C=CC(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
To a stirred, ice-cold solution of 10 mL (0.15 mole) of concentrated aqueous ammonia in 15 mL of tetrahydrofuran was added dropwise a solution of 0.35 gram (0.001 mole) of 3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylic acid chloride in 15 mL of tetrahydrofuran. Upon completion of the addition, the cooling bath was removed. The reaction vessel was closed by placing a rubber balloon over the open inlet of the reaction vessel. The reaction mixture was then allowed to warm to ambient temperature where it was stirred for one hour. After this time, the reaction mixture was concentrated at 45° C. under reduced pressure to a residual solid. The solid was triturated with petroleum ether and filtered, yielding a solid that did not completely melt at 212° C. The filtrate was concentrated in an air current, yielding a tan-yellow solid. Both solids were stirred in water separately. Each of the solids was then collected by filtration. The tan-yellow solid was triturated with two drops of isopropyl alcohol and petroleum ether. The suspension was cooled in a dry ice bath, and the solid was collected by filtration. The two solids were combined and dried, yielding 0.18 gram of 3-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]- acrylamide, m.p. 208°-210° C., dec. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[NH:34][C:35](=[O:37])[CH3:36])=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(N2C3C=CC(C4NN=NN=4)=CC=3OC3C2=CC=CC=3)CC1)=O)(C)(C)C.[C:70]([OH:76])([C:72]([F:75])([F:74])[F:73])=[O:71].Cl>C(Cl)Cl>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:27]3[CH:26]=[CH:25][C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[NH:34][C:35](=[O:37])[CH3:36])=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][CH2:13]1.[C:70]([OH:76])([C:72]([F:75])([F:74])[F:73])=[O:71]
Reactant: CC(=O)Nc1ccccc1-c1ccc2c(c1)Oc1ccccc1N2C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)OC(=O)N1CCC(N2c3ccccc3Oc3cc(-c4nnn[nH]4)ccc32)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccccc1-c1ccc2c(c1)Oc1ccccc1N2C1CCNCC1

Procedure:
Using an adaptation of the method described in Procedure 6, substituting 4-[3-(2-acetylaminophenyl)-phenoxazin-10-yl]-piperidine-1-carboxylic acid tert-butyl ester, 1j, for 4-[3-(1H-tetrazol-5-yl)-phenoxazin-10-yl]-piperidine-1-carboxylic acid tert-butyl ester, 5a, and a mixture of TFA in methylene chloride for a 4N hydrochloric acid solution, the title compound N-[2-(10-piperidin-4-yl-10H-phenoxazin-3-yl)-phenyl]-acetamide, 2j was obtained as a TFA salt after purification via reverse phase HPLC (eluent gradient: CH3CN in water containing 0.1% TFA). MS m/z (MH+) 400.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[C:27]=1[CH2:28]Cl>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:28][C:27]3[C:26]([F:25])=[CH:33][C:32]([F:34])=[CH:31][C:30]=3[F:35])[N:13]=2)=[CH:23][CH:22]=1
Reactant: Fc1cc(F)c(CCl)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: Fc1cc(F)c(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)c(F)c1
Yield: 34.5 %

Procedure:
The title compound (0.027 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 2,4,6-trifluorobenzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C20H17ClF3N3, 391.11. found, m/z 392.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.30-7.26 (m, 4H), 6.80-6.78 (br m, 2H), 5.25 (s, 2H), 2.94-2.92 (m, 4H), 2.82-2.80 (m, 2H), 2.66-2.62 (m, 2H).
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C@H:5]1[CH2:10][O:9][CH2:8][CH2:7][N:6]1[CH2:11][C@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1.[N+:18]([C:21]1[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C(Cl)Cl>[N+:18]([C:21]1[S:25][C:24]([S:26]([N:16]2[CH2:15][CH2:14][NH:13][C@@H:12]([CH2:11][N:6]3[CH2:7][CH2:8][O:9][CH2:10][C@@H:5]3[CH3:4])[CH2:17]2)(=[O:28])=[O:27])=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: C[C@H]1COCCN1C[C@H]1CNCCN1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)s1
Agent: Cl
Solvent: ClCCl
Product: C[C@H]1COCCN1C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84 %

Procedure:
A 150-mL round-bottomed flask was charged with (3S)-3-methyl-4-((2R)-2-piperazinylmethyl)morpholine trihydrochloride (0.750 g, 2.43 mmol, step 3), TEA (2.03 mL, 14.6 mmol) and CH2Cl2 (10 mL). To this was added a solution of 5-nitrothiophene-2-sulfonyl chloride (0.560 g, 2.46 mmol, Enamine LLC, Monmouth Jct., NJ) in CH2Cl2 (5 mL). The reaction mixture was stirred at room temperature for 20 min. The reaction mixture was partitioned between water (20 mL) and CH2Cl2 (20 mL). The aqueous phase was extracted with CH2Cl2 (2×20 mL). The combined organic phases were washed with water (40 mL) and saturated aqueous NaCl (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (50 g of silica gel, 0 to 12.5% iPrOH (with 10% NH4OH) in CHCl3) to afford (3S)-4-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-3-methylmorpholine (0.797 g) as a light orange glass.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][B:15]([OH:17])[OH:16])=[C:4](Cl)[N:3]=1.Cl.[OH-:20].[Na+]>>[OH:16][B:15]([OH:17])[CH2:14][CH2:13][CH2:12][CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:20])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: [OH-]
Reactant: Nc1nc(Cl)c2ncn(CCCCB(O)O)c2n1
Agent: Cl
Agent: [Na+]
Product: Nc1nc2c(ncn2CCCCB(O)O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
The compound prepared in Example 3, 2-amino-6-chloro-9-(4-dihydroxyborylbutyl)purine, (0.5 g, 1.85 mmol) was added to aqueous HCl (5 mL, 2N), and the reaction mixture was heated to reflux for 5 hours. After cooling to room temperature, aqueous NaOH (10%) was added to neutralize the reaction mixture to pH 7. Water was evaporated under high vacuum, and methanol was added to the residue to remove the unreacted starting material. The remaining solid was washed with water (3×20 mL), then stirred in water overnight. After filtration, the product was air-dried for 2 days. Yield 81%; Wt. 0.38 g; mp 202°-205° C.; 1H NMR (DMSO-d6) 0.55-0.68 (t, B CH2), 1.20-1.32 (m, B CH2 CH2), 1.62-1.75 (m, B CH2 CH2 CH2), 3.88-3.98 (t, CH2 CH2 N), 6.33-6.50 (s, H2N C2 guanine), 7.40-7.45 (s, (HO)2 B), 7.68-7.71 (s, H C8 guanine), 10.47-10.53 (H N3 guanine). Electrospray Mass Spectrum (MH)+ (low resolution); Calcd. 252.12 (C9H14O3N5B); Found 252.10 (79 ppm).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[N:19][C:20]([C:23](=[O:27])[N:24]([CH3:26])[CH3:25])=[CH:21][CH:22]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].N1(C(C2C=CC(Br)=CN=2)=O)CC[CH2:29]1.COC(C1C=C(O)C2CC(C)(C)OC=2C=1)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:17]2[CH:18]=[N:19][C:20]([C:23]([N:24]3[CH2:25][CH2:29][CH2:26]3)=[O:27])=[CH:21][CH:22]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Oc2ccc(C(=O)N(C)C)nc2)c2c(c1)OC(C)(C)C2
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Agent: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Product: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)nc2)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 161b, from azetidin-1-yl-(5-bromo-pyridin-2-yl)-methanone (167a) (1.37 g, 5.68 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) (1.26 g, 5.58 mmol) to give a white foam (738 mg, 34% yield). 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J=2.78 Hz, 1 H) 8.12 (d, J=8.59 Hz, 1 H) 7.31-7.38 (m, 1 H) 7.27 (s, 1 H) 7.21 (s, 1 H) 4.72 (t, J=7.71 Hz, 2 H) 4.27 (t, J=7.71 Hz, 2 H) 3.89 (s, 3 H) 2.92 (s, 2 H) 2.38 (t, J=7.71 Hz, 2 H) 1.50 (s, 6 H); LCMS for C21H22N2O5 m/z 383.20 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2)([O-:3])=[O:2].[CH3:14]I.[BH4-].[Na+]>>[CH3:14][N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:9]1
Reactant: CI
Reactant: O=[N+]([O-])c1cccc2cnccc12
Agent: [BH4-]
Agent: [Na+]
Product: CN1CCc2c(cccc2[N+](=O)[O-])C1

Procedure:
5-Nitroisoquinoline was quaternized with methyl iodide and then reduced using sodium borohydride according to the procedures of Preparations 1 and 2 to give the title compound.
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[O:26])[O:24][C:23]([CH3:28])([CH3:27])[O:22][C:21]=3[CH:29]=2)[C:8](=[O:16])[CH2:9][CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:32]([C:36]1[CH:41]=[CH:40][C:39]([C:42]#[CH:43])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([C:36]1[CH:37]=[CH:38][C:39]([C:42]#[C:43][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]([C:17]3[CH:18]=[CH:19][C:20]4[C:25](=[O:26])[O:24][C:23]([CH3:27])([CH3:28])[O:22][C:21]=4[CH:29]=3)[C:8](=[O:16])[CH2:9][CH2:10][CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)=[CH:30][CH:31]=2)=[CH:40][CH:41]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC1(C)OC(=O)c2ccc(N(Cc3ccc(Br)cc3)C(=O)CCC3CCCC3)cc2O1
Reactant: C#Cc1ccc(C(C)(C)C)cc1
Product: CC1(C)OC(=O)c2ccc(N(Cc3ccc(C#Cc4ccc(C(C)(C)C)cc4)cc3)C(=O)CCC3CCCC3)cc2O1

Procedure:
The titled compound was prepared following the procedure N using N-(4-bromobenzyl)-3-cyclopentyl-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl)propanamide and 4-(tert-butyl)-phenylacetylene as a beige powder (65%). M1(ESI): 564.2. HPLC, Rt: 6.39 min (Purity: 98.9%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.Cl[S:12]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]2)(=[O:14])=[O:13].N1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:12]([C:15]1[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:24])[CH2:18]3)(=[O:13])=[O:14])[CH2:6][CH2:5]2
Reactant: Fc1ccc2c(c1)CCN2
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1Cc2cc(S(=O)(=O)N3CCc4cc(F)ccc43)ccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A mixture of 5-fluoroindoline from above, 5-chlorosulfonyl-2-oxindole (6.1 g, 1.2 equivalent) and pyridine (7.1 mL) in dichloromethane (40 mL) was stirred at room temperature overnight. The reaction was concentrated and the residue was recrystallized from methanol to give 5 g (68% yield) of 5-(5-fluoro-2,3-dihydro-indole-1-sulfonyl)-1,3-dihydro-indol-2-one as a pink-colored solid. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 10.75 (br s, 1H, NH), 7.60 (m, 2H), 7.60 (dd, 1H), 7.02 (m, 2H), 6.90 (d, 1H), 3.89 (t, 2H, CH2), 3.52 (s, 2H, CH2), 2.87 (t, 2H, CH2). MS 331 [M+−1].
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13](Cl)=[N:14][OH:15])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[C:17]([C:19]1[C:20]([NH2:26])=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=1)#[CH:18].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[CH2:12][C:13]1[CH:18]=[C:17]([C:19]2[C:20]([NH2:26])=[N:21][C:22]([NH2:25])=[CH:23][CH:24]=2)[O:15][N:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C#Cc1ccc(N)nc1N
Reactant: CCCCOc1cccc(CC(Cl)=NO)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCOc1cccc(Cc2cc(-c3ccc(N)nc3N)on2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.1 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (3-butoxy-phenyl)-acetohydroximoyl chloride (150 mg, 0.621 mmol) described in Manufacturing Example 65-1-4 and 3-ethynyl-pyridin-2,6-diamine (52.8 mg, 0.396 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (216 μL, 1.55 mmol). This mixture was stirred for 4 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: heptane=1:1˜ethyl acetate) to obtain the title compound (43 mg, 21%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24]C3C=CC=C(C#N)C=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1.BrC[C:36]1[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=1>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH2:24][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[C:42]#[N:43])[C:10](=[O:33])[CH:9]=2)[CH2:3]1
Reactant: N#Cc1cccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)c1
Reactant: N#Cc1ccccc1CBr
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)cc(=O)n(Cc2ccccc2C#N)c1=O

Procedure:
Title compound 18 was prepared by the methods used in the preparation of compound 17, except that α-bromo-o-tolunitrile was used in the place of m-cyano-benzyl bromide. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1) δ 7.64 (d, J=6.8 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.55 (t, J=7.8 Hz, 2 H), 7.44 (t, J=7.6 Hz, 1 H), 7.38 (t, J=7.5 Hz, 1 H), 7.31 (t, J=7.6 Hz, 1H), 7.27 (d, J=7.8 Hz, 1H), 7.12 (d, J=7.8 Hz, 1 H), 5.45 (s, 1 H), 5.15-5.32 (m, 4 H), 3.36-3.47 (m, 2 H), 2.98 (m, 2 H), 2.10 (m, 1 H), 1.91 (m, 1 H), 1.68 (m, 2 H). MS (ES) [m+H] calc'd for C25H25N6O2, 441.2. found 441.2.