Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[C:4]([CH2:14][O:15][Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.[CH2:26]([O:33][C@@H:34]1[C@@H:40]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@H:39]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@@H:38]([CH2:57][O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[O:37][CH:35]1O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:13][O:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C@H:35]2[C@H:34]([O:33][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@@H:40]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@H:39]([O:49][CH2:50][C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[C@@H:38]([CH2:57][O:58][CH2:59][C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)[O:37]2)=[CH:3][C:4]=1[CH2:14][OH:15]
Reactant: COc1c(CO[Si](C(C)C)(C(C)C)C(C)C)cc(Br)c2ccccc12
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Product: COc1c(CO)cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2ccccc12
Yield: 84.9 %

Procedure:
With similar method described in Step 3 of Example 92, ((4-bromo-1-methoxynaphthalen-2-yl)methoxy)-triisopropylsilane (compound 68b, 21.3 g, 50.3 mmol) and 2,3,4,6-tetra-O-benzyl-D-glucopyranose (compound 2, 22.6 g, 41.9 mmol) were converted to title compound (25.3 g, 85%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=[N:12][C:11]=2[C:22]([O:24]CC)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH2:31]>>[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH:31][C:22]([C:11]1[N:12]=[N:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:15][C:10]=1[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[O:24]
Reactant: CCOC(=O)c1nnc(-c2ccccc2)cc1-c1cccc([N+](=O)[O-])c1
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)c1nnc(-c2ccccc2)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 92.8 %

Procedure:
A mixture of ethyl 4-(3-nitrophenyl)-6-phenyl-3-pyridazinecarboxylate (1.0 g) and 2-dimethylaminoethylamine (0.75 g) was heated for 30 minutes at 90° C. with stirring. After allowing to cool at ambient temperature, the resulting precipitates were collected by filtration, recrystallized from diethyl ether to give 3-(2-dimethylaminoethylcarbamoyl)-4-(3-nitrophenyl)-6-phenylpyridazine (1.04 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]([OH:16])[CH2:11][O:12][CH2:13][CH2:14][OH:15])[CH:8]=[CH:9][C:2]1=2.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.Cl.C(OCC)C>N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]([OH:16])[CH2:11][O:12][CH2:13][CH2:14][O:15][S:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[CH:8]=[CH:9][C:2]1=2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCC(O)c1ccc2sccc2c1
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCC(O)c2ccc3sccc3c2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 51.9 %

Procedure:
In 54 ml of pyridine was dissolved 9.0 g of 1-(benzo[b]thiophen-5-yl)-2-(2-hydroxyethoxy)ethanol. To the solution was added, at -25° C., 7.2 g of p-toluenesulfonyl chloride. The mixture was allowed to stand at 0°-5° C. for 24 hours and further at room temperature for 4 hours. The reaction mixture was added to a mixture of 103 ml of 6N hydrochloric acid, 50 ml of ice water and 100 ml of diethyl ether. The resulting mixture was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with 30 ml of diethyl ether. The extract was combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=10/1) to obtain 7.7 g of colorless oily 1-(benzo[b]thiophen-5-yl)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethanol.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:20]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O)([O-:22])=[O:21].[N+](C1C=C(C=CC=1)[CH:37]([Cl:39])[Cl:38])([O-])=O>C(Cl)(Cl)(Cl)Cl>[Cl:38][C:37]([Cl:39])=[CH:26][C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1cccc(C(Cl)Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(C=C(Cl)Cl)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of 32.8 g. of triphenylphosphine in 70 ml. of carbon tetrachloride is stirred for 3 hours at 60° C. to prepare in situ the reagent triphenylphosphine dichloromethylene. A solution of 18.9 g. of 3-nitro benzaldehyde in 60 ml. of carbon tetrachloride is added and the mixture is continued to be stirred at 60° C. for an additional 2 hours, when vapour phase chromatography indicates that all the starting 3-nitrobenzenealdehyde has disappeared and two new peaks in a ratio of 1:1 show the formation of a mixture of ββ-dichloro3-nitrostyrene and 3-nitrobenzalchloride. The reaction mixture is decanted from the solid residues and concentrated in vacuo to an oil. This is treated with ether, and again separated from some solid precipitate and the solution is again concentrated in vacuo. The oily residue is then carefully distilled in high vacuo to give essentially pure β,β-dichloro-3-nitrostyrene.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[C:12]([C:43](O)=[O:44])=[C:13]([N:28]([CH2:34][C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])[C:29](OCC)=[O:30])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:46][CH:47]1[CH2:52][CH2:51][CH:50]([OH:53])[CH2:49][CH2:48]1>>[CH2:1]([N:8]([CH2:10][C:11]1[C:12]2[C:43](=[O:44])[N:46]([CH:47]3[CH2:52][CH2:51][CH:50]([OH:53])[CH2:49][CH2:48]3)[C:29](=[O:30])[N:28]([CH2:34][C:35]3[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=3[F:42])[C:13]=2[S:14][C:15]=1[C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:20][CH:21]=1)[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N(Cc1c(F)cccc1F)c1sc(-c2ccc(NC(=O)NOC)cc2)c(CN(C)Cc2ccccc2)c1C(=O)O
Reactant: NC1CCC(O)CC1
Product: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(C2CCC(O)CC2)c(=O)n3Cc2c(F)cccc2F)cc1
Yield: 48.2 %

Procedure:
The similar reaction as described in Example 5 by using 4-(N-benzyl-N-methylaminomethyl)-2-(N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylic acid (10.0 g, 15.65 mmol) and 4-aminocyclohexanol (3.61 g, 31.30 mmol) gave N-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-3-(4-hydroxycyclohexyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea (5.20 g, 48%) as white crystals. The similar reaction as described in Reference Example 18 by using the compound (500 mg, 0.72 mmol) gave the title compound (180 mg, 41%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[CH:4][C:3]=1[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20]C)[CH:16]=2)[CH:11]=1.B(Br)(Br)Br>>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]2
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(F)c1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2ccc3cc(O)ccc3c2)c(F)c1

Procedure:
The title compound was prepared by 2-(2-fluoro-4-methoxyphenyl)-6-methoxynaphthalene (1.12 g, 3.97 mmol) with boron tribromide (23.8 mL of 1.0 M solution in CH2Cl2, 23.8 mmol) according to method D to yield 0.92 g (91%) of a white solid: mp 208-209° C.; 1H NMR (DMSO-d6): δ 6.66-6.75 (2H, m), 7.08-7.13 (2H, m), 7.41 (1H, dd, J=9.37 Hz, J=8.57 Hz), 7.49-7.53 (1H, m), 7.72 (1H, d, J=8.64 Hz), 7.80 (1H, d, J=8.76 Hz), 7.86 (1H, s), 9.79 (1H, s), 10.01 (1H, s); MS (ESI) m/z255 (M+H)+, MS (ESI) m/z253 (M−H)−.
Reaction SMILES: Cl.[C:2]([NH:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8])(=[O:4])[CH3:3].[CH3:18]O>>[C:2]([NH:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[C:7]([O:9][CH3:18])=[O:8])(=[O:4])[CH3:3]
Reactant: CO
Reactant: CC(=O)NC(Cc1ccc(Br)cc1)C(=O)O
Agent: Cl
Product: COC(=O)C(Cc1ccc(Br)cc1)NC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (5 mL, 20 mmol) was added to an ambient temperature solution of 2-(acetylamino)-3-(4-bromophenyl)propanoic acid (10 g, 34.9 mmol) in methanol (50 mL). After stirring at ambient temperature overnight, the reaction mixture was concentrated in vacuo to afford methyl 2-(acetylamino)-3-(4-bromophenyl)propanoate which was used in the subsequent step without further purification.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][OH:6].[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][C:18]#[N:19]>CO.O>[OH:6][N:5]=[C:18]([NH2:19])[CH2:17][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([Br:7])[CH:9]=2)[NH:13][CH:12]=1
Reactant: NO
Reactant: N#CCc1c[nH]c2ccc(Br)cc12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC(Cc1c[nH]c2ccc(Br)cc12)=NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.2 %

Procedure:
To a solution of sodium methoxide (16.92 mL, 0.074 mol, 25 wt %/methanol) in methanol (120 mL) was added powdered hydroxylamine hydrochloride (5.66 g, 0.0814 mol). The mixture was heated at reflux for 1 hour. 5-Bromo-3-indolylacetonitrile (8.8 g, 0.37 mol) was added and refluxing was continued overnight. Refluxing was continued for a further 3 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to obtain a pale yellow solid. The solid was suspended in water (100 mL), stirred for 1/2 hour, filtered, air dried and stirred in ether (40 mL) to give 7.91 g (71%) of product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2=[N:6][C:7](=[O:9])[N:8]=[C:4]2[CH:3]=1.[I-].[K+].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CN(C=O)C>[CH2:15]([N:1]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])[C:2]1[CH:11]=[CH:10][C:5]2=[N:6][C:7](=[O:9])[N:8]=[C:4]2[CH:3]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Nc1ccc2c(c1)=NC(=O)N=2
Reactant: CCCCCCCCCCCCBr
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCN(CCCCCCCCCCCC)c1ccc2c(c1)=NC(=O)N=2
Temperature: 60 °C
Reaction time: 72 h
Yield: 76.4 %

Procedure:
5-Aminobenzimidazolone (0.1348 g, 0.904 mmol), potassium iodide (0.1513 g, 0.911 mmol), and dry DMF (20 mL) are mixed in a 100 mL round bottom flask under an inert atmosphere. The reaction is heated to 60° C. and 1-bromododecane (0.45 mL, 1.88 mmol) is added. After 3 days at 60° C., the reaction is cooled to room temperature to give a brown suspension. The solid is filtered, washed with deionized water, and dried in vacuo to give 5-(didodecylamino)-2-benzimidazolone as a white solid (0.334 g). The product is identified by 1H and 13C NMR spectroscopy and ESI-MS and is of satisfactory purity.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[N:3]=[N:2]1.S(Cl)([Cl:15])=O>C(Cl)Cl>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([Cl:15])=[O:12])[N:3]=[N:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCCCc1c[nH]nn1
Solvent: ClCCl
Product: O=C(Cl)CCCCc1c[nH]nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 5-(1H-1,2,3-triazol-4-yl)pentanoic acid (Example 20, step 3) (100 mg, 0.591 mmol) in DCM (5 mL) at RT under nitrogen was added thionyl chloride (0.518 mL, 7.09 mmol). The reaction mixture was stirred at rt for 2 hours and concentrated under reduced pressure to afford the title product.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[S:32])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([N:17]2[CH2:18][CH2:19][N:14]([C:11]3[N:12]=[CH:13][C:8]4[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=4[N:10]=3)[CH2:15][CH2:16]2)=[S:32])=[CH:26][CH:25]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Reactant: S=C=Nc1ccc(Cl)cc1
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4ccc(Cl)cc4)CC3)nc21

Procedure:
Pipemidic acid (58 mg, 0.191 mmol) and 4-chlorophenyl isothiocyanate (27 mg, 0.159 mmol) were used. Purification on silica yielded compound 28 in Table 1, below (50 mg, 67%). 1H NMR (300 MHz, CDCl3) δ 9.34 (s, 1H), 8.68 (s, 1H), 7.36-7.34 (m, 2H), 7.17 (d, J=8.70 Hz, 2H), 4.39-4.28 (m, 2H), 4.28-3.93 (m, 8H), 1.49 (t, J=6.68 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH2:16]([C:18]1[S:22][C:21]([CH2:23][NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)[CH3:17]>>[CH2:16]([C:18]1[S:22][C:21]([CH2:23][N:24]([C:25]2[CH:26]=[CH:27][C:28]([CH:31]([CH3:32])[CH3:33])=[CH:29][CH:30]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:20][CH:19]=1)[CH3:17]
Reactant: CCc1ccc(CNc2ccc(C(C)C)cc2)s1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Product: CCc1ccc(CN(C(=O)C2CCCc3ccc(OC)cc32)c2ccc(C(C)C)cc2)s1
Yield: 14.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.82 g) and [(5-ethylthiophen-2-yl)methyl](4-isopropylphenyl)amine (1.04 g) as starting materials, N-[(5-ethylthiophen-2-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.26 g) was obtained. MS (ESI)m/z: 448 [MH]+
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH2:12][C:13]([CH2:15][CH3:16])=[O:14])=[C:9]([Br:17])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:18]1(=O)[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH2:19]1.Cl.CN(C)CCCN=C=NCC.CN(C1C=CC=CN=1)C>C(Cl)Cl>[Br:1][C:2]1[C:10]([O:11][CH2:12][C:13]([CH2:15][CH3:16])=[O:14])=[C:9]([Br:17])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:18]1[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH:19]=1)=[O:5]
Reactant: O=C1CCCC(=O)C1
Reactant: CCC(=O)COc1c(Br)ccc(C(=O)O)c1Br
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CCC(=O)COc1c(Br)ccc(C(=O)OC2=CC(=O)CCC2)c1Br

Procedure:
0.415 g (1.10 mmol) of 2,4-dibromo-3-(ethylcarbonylmethoxy)benzoic acid, 0.140 g (1.20 mmol) of cyclohexane-1,3-dione, 0.222 g (1.10 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 0.001 g of dimethylaminopyridine were stirred in 30 ml of CH2Cl2 at room temperature for 3 h. The mixture was then diluted with CH2Cl2 and washed with 0.5 N HCl, with water, with saturated NaHCO3 solution and again with water. The combined organic phases were dried over Na2SO4 and evaporated to dryness, giving 3-oxo-1-cyclohexenyl 2,4-dibromo-3-(ethylcarbonylmethoxy)benzoate in the form of a yellow resin which was sufficiently pure for the subsequent reaction.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[CH:5]=[C:4]([C@@H:13]([NH:15][C:16]2[N:24]=[CH:23][N:22]=[C:21]3[C:17]=2[N:18]=[CH:19][N:20]3[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[CH3:14])[N:3]=1.[CH3:34]B(O)O.C([O-])([O-])=O.[Na+].[Na+]>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>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:20]2[CH:19]=[N:18][C:17]3[C:21]2=[N:22][CH:23]=[N:24][C:16]=3[NH:15][C@H:13]([C:4]2[N:3]=[C:2]([CH3:34])[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][C:10]=3[Cl:12])[CH3:14])=[CH:27][CH:28]=1
Reactant: CB(O)O
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(Cl)n4)ncnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C)n4)ncnc32)cc1
Temperature: 25 °C

Procedure:
(S)-9-(4-Methoxybenzyl)-N-(1-(1,8-dichloroisoquinolin-3-yl)ethyl)-9H-purin-6-amine (1) (2.0 g, 4.2 mmol, 1.0 eq), methylboronic acid (277 mg, 4.62 mmol, 1.1 eq), Pd (PPh3)4(485 mg, 0.42 mmol, 0.1 eq) and Na2CO3(1.34 g, 12.6 mmol, 3.0 eq) were suspended in a mixture of 1,4-dioxane (30 mL) and water (10 mL). The resulting mixture was degassed and back-filled with argon three times and then stirred at reflux under argon for 16 h. The mixture was allowed to cool to RT, concentrated in vacuo and the residue was purified by column chromatography on silica gel (1-3% MeOH-DCM) to afford the product, (S)-9-(4-methoxybenzyl)-N-(1-(8-chloro-1-methylisoquinolin-3-yl)ethyl)-9H-purin-6-amine (168). Compound 168 was then converted to compound 169 using the analogous procedures for the synthesis of 151 in Example 91 except that pyridin-3-ylboronic acid was used in place of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. The PMB group of compound 169 was then subsequently deprotected using Method L to afford compound 170. ESI-MS m/z: 382.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:31])=[C:4]2[N:10]=[C:9]([CH2:11][CH2:12][CH3:13])[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27]([NH2:30])(=[O:29])=[O:28])=[CH:17][CH:16]=3)[C:5]2=[N:6][CH:7]=1.[CH2:32]([S:36](Cl)(=[O:38])=[O:37])[CH2:33][CH2:34][CH3:35].CO>N1C=CC=CC=1>[CH2:32]([S:36]([NH:1][C:2]1[C:3]([CH3:31])=[C:4]2[N:10]=[C:9]([CH2:11][CH2:12][CH3:13])[N:8]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27]([NH2:30])(=[O:29])=[O:28])=[CH:19][CH:20]=3)[C:5]2=[N:6][CH:7]=1)(=[O:38])=[O:37])[CH2:33][CH2:34][CH3:35]
Reactant: CCCc1nc2c(C)c(N)cnc2n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: CCCCS(=O)(=O)Cl
Solvent: CO
Solvent: c1ccncc1
Product: CCCCS(=O)(=O)Nc1cnc2c(nc(CCC)n2Cc2ccc(-c3ccccc3S(N)(=O)=O)cc2)c1C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a mixture of 6-amino-7-methyl-2-propyl-3-[2'-(aminosulfonyl)[1,1']biphenyl-4-yl]methyl-3H-imidazo[4,5-b]pyridine (80 mg, 0.15 mmol) in pyridine (0.5 mL) at 0° C. was added butylsulfonyl chloride (0.02 mL, 0.15 mmol). The mixture was stirred for 1 h, then 1 mL of MeOH was added and the mixture was concentrated. Purification (SiO2, 5% MeOH-EtOAc) gave 50 mg of 6-[(Butylsulfonyl)amino]-7-methyl-2-propyl-3-[2'-(aminosulfonyl)[1,1']-biphenyl-4-yl]methyl-3H-imidazo[4,5-b]pyridine as a solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([N:13]([CH2:21][C:22](O)=[O:23])[C:14]2[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:11])=[N:8][CH:9]=1)([CH3:3])[CH3:2].[CH2:25]([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=1)[CH3:26]>>[CH2:25]([N:27]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=1)[C:22](=[O:23])[CH2:21][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][N:8]=1)(=[O:11])=[O:12])[C:14]1[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=1)[CH3:26]
Reactant: CCNCc1cccc(C)n1
Reactant: Cc1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)C)cn2)c1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1cccc(C)c1)S(=O)(=O)c1ccc(C(C)C)cn1

Procedure:
prepared by reaction of [(5-isopropyl-pyridine-2-sulfonyl)-m-tolyl-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][O:6][C:7]1[CH:20]=[C:11]2[N:12]([CH2:16][C:17]([OH:19])=O)[CH2:13][CH2:14][CH2:15][N:10]2[C:9](=[O:21])[N:8]=1.[F:26][C:27]1([F:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[F:25])[CH2:5][O:6][C:7]1[CH:20]=[C:11]2[N:12]([CH2:16][C:17]([N:30]3[CH2:31][CH2:32][C:27]([F:33])([F:26])[CH2:28][CH2:29]3)=[O:19])[CH2:13][CH2:14][CH2:15][N:10]2[C:9](=[O:21])[N:8]=1
Reactant: O=C(O)CN1CCCn2c1cc(OCc1ccc(F)c(F)c1)nc2=O
Reactant: FC1(F)CCNCC1
Product: O=C(CN1CCCn2c1cc(OCc1ccc(F)c(F)c1)nc2=O)N1CCC(F)(F)CC1

Procedure:
The title compound was prepared by a procedure similar to that described for E13 starting from 2-(8-((3,4-difluorobenzyl)oxy)-6-oxo-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidin-1-yl)acetic acid and 4,4-difluoropiperidine.
Reaction SMILES: [OH:1][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH:5]1[N:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8](=[O:19])[CH2:7][S:6]1.[OH:25]C(CCCCC)/C=C/C1N(CCCCCCC(O)=O)C(=O)CS1>>[OH:1][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])/[CH:3]=[CH:4]/[CH:5]1[N:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8](=[O:19])[CH2:7][S:6]1=[O:25]
Reactant: CCCCCC(O)/C=C/C1SCC(=O)N1CCCCCCC(=O)O
Reactant: CCCCCC(O)CCC1SCC(=O)N1CCCCCCC(=O)O
Product: CCCCCC(O)/C=C/C1N(CCCCCCC(=O)O)C(=O)CS1=O

Procedure:
This compound is prepared essentially by the method as described in Example 2 except that the 7-[2-(3-hydroxyoctyl)-4-oxo-3-thiazolidinyl]heptanoic acid is replaced by 7-[2-(3-hydroxy-1-trans-octenyl)-4-oxo-3-thiazolidinyl]-heptanoic acid. This method affords the title compound as a viscous, essentially colorless oil after purification by column chromatography on silica gel.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=2)[N:13]=1.N1C=CC=CC=1.[C:29](Cl)(=[O:31])[CH3:30]>ClCCl>[F:22][C:2]([F:21])([F:1])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]2[CH:20]=[CH:19][C:17]([NH:18][C:29](=[O:31])[CH3:30])=[CH:16][CH:15]=2)[N:13]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(-c2csc(-c3cnccc3C(F)(F)F)n2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-c2csc(-c3cnccc3C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of compound (156) (0.20 g, 0.63 mmol) in dichloromethane (3 ml) were added pyridine (0.05 ml, 0.63 mmol) and acetyl chloride (0.04 ml, 0.63 mmol) under ice-cooling. The reaction mixture was warmed to room temperature and, after stirring for one hr., partitioned between ethyl acetate and brine. The aqueous layer was extracted with ethyl acetate, and the extracts were combined and dried (MgSO4). The solvent was evaporated under reduced pressure. The obtained residue was crystallized from ethyl acetate to give white crystals (0.17 g, 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH:13]1[CH2:15][CH2:14]1)[C:6](=[O:16])[CH2:5]2.[C:17]([O:21][C:22](=[O:28])[NH:23][CH2:24][C@H:25]1[CH2:27][O:26]1)([CH3:20])([CH3:19])[CH3:18].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C.C(OCC)(=O)C>[C:17]([O:21][C:22](=[O:28])[NH:23][CH2:24][C@H:25]([OH:26])[CH2:27][NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH:13]1[CH2:15][CH2:14]1)[C:6](=[O:16])[CH2:5]2)([CH3:19])([CH3:18])[CH3:20]
Reactant: Nc1cc(F)c2c(c1)CC(=O)N2CC1CC1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC[C@H](O)CNc1cc(F)c2c(c1)CC(=O)N2CC1CC1

Procedure:
5-Amino-1-cyclopropylmethyl-7-fluoro-1,3-dihydro-indol-2-one (1.00 g, 4.55 mmol), (S)-oxiranylmethyl-carbamic acid tert-butyl ester (0.79 g, 4.55 mmol) and lithium trifluoromethanesulfonate (0.618 g, 4.55 mmol) in acetonitrile (20 ml) are heated at 90° C. for 16 hours. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated. Final purification by flash chromatography (70% ethyl acetate/hexane) gives the title compound as a white solid. HPLC r.t. 4.35 min; MS for C20H28FN3O4 m/z 394.1 (M+H)+.