Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C@H:10]([CH3:32])[CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17](C(OC(C)(C)C)=O)[C:16]([C:28]([O:30][CH3:31])=[O:29])=[CH:15]3)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>CO>[C:1]1([C@H:7]([NH:9][C@H:10]([CH3:32])[CH2:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:28]([O:30][CH3:31])=[O:29])=[CH:15]3)[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc2cc(C[C@@H](C)N[C@H](C)c3ccccc3)ccc2n1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc2cc(C[C@@H](C)N[C@H](C)c3ccccc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.2 %

Procedure:
A solution of 1-tert-butyl 2-methyl 5-((2R)-2-{[(1R)-1-phenylethyl]amino}propyl)-1H-indole-1,2-dicarboxylate (Preparation 16, 20.48 g, 46.9 mmol) was treated with 4M hydrogen chloride in methanol and the resulting solution left to stir at room temperature for 16 hours and then heated at 50° C. for a further 2 hours. The solvent was removed in vacuo to give a solid which was crystallised from a mixture of methanol (125 ml) and diisopropylether (50 ml) to give the title compound as a colourless crystalline solid (9.34 g, d.e.>98% as determined by 1H NMR).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13]>CO.[H][H].[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:16])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13]
Reactant: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1Cl
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CCN(CC)CCOc1ccc(N)cc1Cl

Procedure:
41.0 g (150 mmol) of 3-chloro-4-(2-diethylaminoethoxy)nitrobenzene (IV.1.a) is dissolved in 250 mL of methanol and hydrogenated for 5 hours at ambient temperature at a pressure of 50 psi with hydrogen and 4.0 g of Raney nickel as catalyst. Then the catalyst is filtered off and the solvent is eliminated. The residue is recrystallized from petroleum ether and dried in vacuo. Yield: 33.0 g (91% of theory); Rf value: 0.40 (silica gel, methylene chloride/methanol/ammonia=9:1:0.01); C12H19ClN2O; EII mass spectrum: m/z=243/245 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[N:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CN(C)C=O>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([C:10]2[CH:15]=[CH:14][C:13](=[O:16])[N:12]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Cn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)[nH]c2)c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(N)nc(-c2cccc(F)c2)c(-c2ccc(=O)n(-c3ccccc3)c2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.7 %

Procedure:
In a flask were placed 2-amino-6-(3-fluorophenyl)-3-methyl-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone (40 mg, 0.13 mmol), copper acetate (3 mg, 0.01 mmol), phenylboronic acid (31 mg, 0.26 mmol), pyridine (21 μL, 0.26 mmol) and N,N-dimethylformamide (2 mL), followed by stirring at room temperature for 24 hour. After filtering off the insoluble matters, the filtrate was purified by HPLC, to give the title compound (16 mg). MS m/e (ESI) 389 (MH+).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12](O)[CH3:13])=[CH:8][CH:7]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].P(Cl)(Cl)[Cl:16]>CC(C)=O.N1C=CC=CC=1>[Cl:16][CH:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:1][CH:2]=[C:3]([CH3:5])[CH3:4])=[CH:7][CH:8]=1)[CH3:13]
Reactant: ClP(Cl)Cl
Reactant: CC(C)=CCc1ccc(C(C)O)cc1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC(C)=CCc1ccc(C(C)Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
166 g of 1-(p-prenylphenyl)ethanol was dissolved in a mixture of 870 ml of acetone and 34.5 g of pyridine. While the solution was maintained at 0° C., 60.1 of phosphorus trichloride was added over the course of about 2 hours. The mixture was stirred at room temperature for 2 hours. Acetone was distilled off, and n-hexane and cold water were added to the mixture. The n-hexane layer was washed successively with a 1.6% aqueous solution of sodium hydroxide and water, dried and concentrated to give 174.6 g of 1-chloro-1-(p-prenylphenyl)ethane.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.[C:6]([C:9]1[CH:40]=[CH:39][C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[C:22]3[CH:23]=[CH:24][C:25]([O:30][CH3:31])=[C:26]([CH:29]=3)C#N)=[CH:17][CH:16]=2)=[C:11]([CH2:41][CH2:42][CH3:43])[C:10]=1[OH:44])(=[O:8])[CH3:7]>>[OH:44][C:10]1[C:11]([CH2:41][CH2:42][CH3:43])=[C:12]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH:21]([C:22]3[CH:29]=[CH:26][C:25]([O:30][CH3:31])=[C:24]([C:5]4[N:1]=[N:2][NH:3][N:4]=4)[CH:23]=3)[O:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)=[CH:19][CH:20]=2)[CH:39]=[CH:40][C:9]=1[C:6](=[O:8])[CH3:7]
Reactant: CCCc1c(OCc2ccc(C(OC3CCCCO3)c3ccc(OC)c(C#N)c3)cc2)ccc(C(C)=O)c1O
Reactant: c1nnn[nH]1
Product: CCCc1c(OCc2ccc(C(OC3CCCCO3)c3ccc(OC)c(-c4nn[nH]n4)c3)cc2)ccc(C(C)=O)c1O

Procedure:
Using the method of tetrazole formation described in Example 1 with 5-[[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-2-methoxy-benzonitrile (1.00 g, 1.89 mmol), the title compound is obtained (0.620 g, 1.10 mmol, 58%): MS (m/z): 571 (M−1).
Reaction SMILES: C1([O:7][CH:8]2[CH:13]3[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]3)[CH:9]2[CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)C=CC=CC=1.N1C=CC=C(C=O)C=1.Cl.N12CCC(CC1)C(=O)C2.[OH-].[K+].N1C=CC=C(C=C2C(=O)C3CCN2CC3)C=1>CO.[Ni]>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH2:16][CH:9]2[CH:8]([OH:7])[CH:13]3[CH2:12][CH2:11][N:10]2[CH2:15][CH2:14]3)[CH:18]=1
Reactant: c1ccc(OC2C3CCN(CC3)C2Cc2cccnc2)cc1
Agent: [Ni]
Agent: Cl
Agent: O=C1C(=Cc2cccnc2)N2CCC1CC2
Solvent: CO
Product: OC1C2CCN(CC2)C1Cc1cccnc1

Procedure:
The manner in which 3-(phenyloxy)-2-(3-pyridylmethyl)-1-azabicyclo[2.2.2]octane of the present invention is synthesized can vary. For example, pyridine-3-carboxaldehyde and quinuclidin-3-one hydrochloride (commercially available from Aldrich) are reacted together in the presence of methanolic potassium hydroxide as described in Neilsen and Houlihan, Org. React. 16: 14-38 (1968). This aldol condensation product, 2-(3-pyridylmethylene)-1-azabicyclo[2.2.2]octan-3-one, is then dissolved in methanol and hydrogenated in the presence of Raney nickel catalyst to afford 2-(3-pyridylmethyl)-1-azabicyclo[2.2.2]octan-3-ol. This alcohol is then etherified with phenol via Mitsunobu coupling with diethylazidocarboxylate and triphenylphosphine, as described by Guthrie et al., J. Chem. Soc., Perkin Trans I45: 2328 (1981), to afford the desired product, 3-(phenyloxy)-2-(3-pyridylmethyl)-1-azabicyclo[2.2.2]octane.
Reaction SMILES: O[CH:2]([C:4]1[O:5][C:6](=[O:28])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[F:29][C:30]1[CH:31]=[C:32]([C:38]2[C:46]3[C:41](=[N:42][CH:43]=[N:44][C:45]=3[NH2:47])[NH:40][N:39]=2)[CH:33]=[C:34]([O:36][CH3:37])[CH:35]=1>>[NH2:47][C:45]1[N:44]=[CH:43][N:42]=[C:41]2[N:40]([CH:2]([C:4]3[O:5][C:6](=[O:28])[C:7]4[C:12]([C:13]=3[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]5[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]5)[CH:15]=3)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH3:3])[N:39]=[C:38]([C:32]3[CH:33]=[C:34]([O:36][CH3:37])[CH:35]=[C:30]([F:29])[CH:31]=3)[C:46]=12
Reactant: COc1cc(F)cc(-c2n[nH]c3ncnc(N)c23)c1
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1cccc(CN2CCN(C)CC2)c1
Product: COc1cc(F)cc(-c2nn(C(C)c3oc(=O)c4ccccc4c3-c3cccc(CN4CCN(C)CC4)c3)c3ncnc(N)c23)c1
Yield: 34.2 %

Procedure:
The title compound was made in a similar way as that of example 134, step a, from 3-(1-hydroxyethyl)-4-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-isochromen-1-one (Intermediate B49, 350 mg, 0.925 mmol) and 3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate G1, 264 mg, 1.017 mmol) to give 3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-isochromen-1-one (196 mg, 0.316 mmol, 34.2% yield) as a brown solid.
Reaction SMILES: C([O:4][C:5]1[C:12]([Br:13])=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][C:6]=1[Br:14])(=O)C.O.NN.O>C1COCC1.CO>[Br:13][C:12]1[CH:11]=[C:8]([CH:7]=[C:6]([Br:14])[C:5]=1[OH:4])[CH:9]=[CH2:10]
Reactant: C=Cc1cc(Br)c(OC(C)=O)c(Br)c1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=Cc1cc(Br)c(O)c(Br)c1
Reaction time: 0.67 h

Procedure:
10 g of 4-acetoxy-3,5-dibromostyrene are dissolved in 50 ml THF and 25 ml methanol, 12 g hydrazine hydrate (80% aqueous solution) is added, and the cloudy mixture is then converted into a clear solution by adding 3 ml of water. After 40 minutes it is acidified with a:semi-concentrated HCl to pH2 and extracted twice with ether the ether phase is washed twice with waterand dried over sodium sulfate and the ether is removed with a rotary evaporator at room temperature under aspirator vacuum. 8.5 g of crude product remain, from which 6.45 g of white crystals (mp 74° C.) areobtained by recrystallization from petroleum ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]([OH:15])=[O:14])[CH2:9][CH2:10]2)=[CH:5][CH:4]=1>[C].[Pd].CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](=[CH:5][CH:4]=1)[CH2:7][CH:8]([C:13]([OH:15])=[O:14])[CH2:9][CH2:10]2
Reactant: COc1ccc2c(c1)CCC(C(=O)O)=C2
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)CCC(C(=O)O)C2

Procedure:
A mixture of 7-methoxy-1,2-dihydro-3-naphthoic acid (0.22 g), 5% palladium-carbon (0.1 g) and methanol (20 ml) is subjected to catalytic reduction at room temperature under atmospheric pressure of H2. After hydrogen absorption has ceased, the catalyst is filtered off, and the filtrate is evaporated to dryness under reduced pressure to give 6-methoxy-1,2,3,4-tetrahydro-2-naphthoic acid as colorless powder. To this product are added 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (0.4 g), triethylamine (0.5 g) and N,N-dimethylformamide (10 ml), and the mixture is stirred. To this solution is added dropwise at room temperature diethyl phosphorocyanidate (1 ml). The mixture is stirred for one hour. After addition of water (100 ml), the reaction mixture is extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane:acetone=1:1). The resulting oily product is dissolved in ethanol and the solution is treated with 5N ethanolic hydrogen chloride (1 ml). The mixture is diluted with ethyl ether, and then resulting precipitates are collected by filtration to give 1-(6-methoxy-1,2,3,4-tetrahydro-2-naphthoyl)-4-(3,4,5-trimethoxybenzyl) piperazine hydrochloride (0.35 g) as colorless prisms, m.p. 220°-225° C. (decomp.).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].ClCCl.Cl[C:9]([CH3:17])([CH2:11][CH2:12][C:13](Cl)([CH3:15])[CH3:14])[CH3:10].[C:18]1([OH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[Cl-].[Cl-].C>[CH3:10][C:9]1([CH3:17])[CH2:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:22]2[CH:23]=[C:18]([OH:24])[CH:19]=[CH:20][C:21]1=2
Reactant: Oc1ccccc1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(O)ccc21
Temperature: 35 °C
Yield: 90.8 %

Procedure:
To a mixture of aluminum trichloride (3.0 g, 22.5 mmol), dichloromethane (50 ml) and 2,5-dichloro-2,5-dimethylhexane (15.0 g, 81.9 mmol) is added dropwise into a solution of phenol (7.7 g, 81.90 mmol) in 50 ml of methane dichloride, then the reaction mixture is heated for 4 hours at 35° C. After cooled, the reaction mixture is poured into ice (200 g) and extracted with ether (3×80 ml). The organic phase is washed with 10% NaHCO3 solution (2×150 ml), dried over MgSO4 and evaporated to give a crude product, which is crystallized from ethanol to give the title compound (15.20 g, 84%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([SH:15])[CH2:12][CH2:13][CH3:14].[CH3:16][C:17]1[CH:18]=[C:19]([C:34]2[S:38][C:37]([N:39]3[CH2:45][CH2:44][CH2:43][NH:42][C:41](=[O:46])[CH2:40]3)=[N:36][CH:35]=2)[CH:20]=[C:21]([NH:23][C:24]2[N:29]=[C:28](S(C)(=O)=O)[CH:27]=[CH:26][N:25]=2)[CH:22]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:11]([S:15][C:26]1[CH:27]=[CH:28][N:29]=[C:24]([NH:23][C:21]2[CH:20]=[C:19]([C:34]3[S:38][C:37]([N:39]4[CH2:45][CH2:44][CH2:43][NH:42][C:41](=[O:46])[CH2:40]4)=[N:36][CH:35]=3)[CH:18]=[C:17]([CH3:16])[CH:22]=2)[N:25]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCS
Reactant: Cc1cc(Nc2nccc(S(C)(=O)=O)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCSc1ccnc(Nc2cc(C)cc(-c3cnc(N4CCCNC(=O)C4)s3)c2)n1
Reaction time: 0.25 h
Yield: 47.7 %

Procedure:
Sodium bis(trimethylsilyl)amide (164 μL, 1.0 M, 0.164 mmol) was added to a solution of 1-butanethiol (28.1 μL, 0.262 mmol) stirring in DMF (327 μL) at room temperature in an oven-dried vial. Stirred for 15 minutes, then added 4-[5-(3-methyl-5-{[4-(methylsulfonyl)-2-pyrimidinyl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (30 mg, 0.065 mmol). Stirred at room temperature for 30 minutes, diluted with ethyl acetate (10 mL), and washed with 1:1 water:brine (10 mL). The organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purified by CombiFlash (100:0 to 0:20 dichloromethane:methanol) to afford 4-[5-(3-{[4-(butylsulfanyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (14.6 mg, 0.031 mmol, 48% yield) as a white solid. MS APCI: [M+H]+ m/z 469.2. 1H NMR (500 MHz, DMSO) δ 9.52 (s, 1H), 8.13 (d, J=5.3 Hz, 1H), 7.60 (dd, J=4.9 Hz, 10.3 Hz, 2H), 7.45 (s, 1H), 7.43 (s, 1H), 6.92 (s, 1H), 6.72 (d, J=5.3 Hz, 1H), 4.16 (s, 2H), 3.84-3.73 (m, 2H), 3.25-3.12 (m, 4H), 2.26 (s, 3H), 1.78 (m, 2H), 1.59 (m, 2H), 1.35 (dd, J=7.4 Hz, 14.9 Hz, 2H), 0.83 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][C:13]1[C:21]([CH3:22])=[CH:20][C:16]2[N:17]=[CH:18][NH:19][C:15]=2[CH:14]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:17]2[C:16]3[CH:20]=[C:21]([CH3:22])[C:13]([CH3:12])=[CH:14][C:15]=3[N:19]=[CH:18]2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: Cc1cc2nc[nH]c2cc1C
Solvent: CCCCO
Product: Cc1cc2ncn(-c3nc(Cl)nc4[nH]cnc34)c2cc1C
Reaction time: 17 h
Yield: 43.4 %

Procedure:
283 mg of 2,6-dichloropurine, 5 ml of butanol and 219 mg of 5,6-dimethylbenzimidazole are mixed and brought to a temperature of 100° C. for approximately 17 hours. The mixture is allowed to return to ambient temperature. Partial drying, washing with isopropanol and drying under vacuum at 50° C. are carried out, and 194 mg of expected product are obtained, in the form of cream-colored crystals.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:11]1[CH:16]=[C:15]([N:17]([CH3:19])[CH3:18])[CH:14]=[CH:13][C:12]=1[N:20]([CH3:22])[CH3:21].ClC1C=CC=C(C(OO)=[O:31])C=1>C(OCC)(=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([C:11]1[CH:16]=[C:15]([N:17]([CH3:18])[CH3:19])[CH:14]=[CH:13][C:12]=1[N:20]([CH3:22])[CH3:21])=[O:31]
Reactant: CN(C)c1ccc(N(C)C)c(Sc2nc3ccccc3[nH]2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(N(C)C)c(S(=O)c2nc3ccccc3[nH]2)c1
Reaction time: 1 h

Procedure:
The product of step (b) above (1.5 g) was dissolved in ethyl acetate (120 ml) and cooled to -10°. A solution of m-chloroperbenzoic acid (980 mg of 85%) in ethyl acetate (30 ml) was added in one portion and the mixture stirred for 1 hr. The mixture was filtered and the residue taken up in dichloromethane. The dichloromethane was washed with sodium bicarbonate solution, sodium metabisulphite solution, water and brine and then dried and evaporated. Flash chromatography afforded the title compound as an off white solid (857 mg) mp 213°-215° (NMR (CDCl3) delta 7.7 (broad), 7.4 (2H)broad, 7.20(2H)m, 7.12(2H)m, 6.69(1H)d.o.d., 2.79 (6H) 2.60(6H)s.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].Cl[C:39]1[N:44]=[CH:43][CH:42]=[CH:41][N:40]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][C:39]3[N:44]=[CH:43][CH:42]=[CH:41][N:40]=3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Reactant: Clc1ncccn1
Product: COc1ccc(CC2c3cc(Oc4ncccn4)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 2-chloro-pyrimidine
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:9].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:52][C:53]1[CH:75]=[CH:74][C:73]([N:76]2[CH2:81][CH2:80][CH2:79][CH2:78][CH2:77]2)=[CH:72][C:54]=1[C:55]([NH:57][C:58]1[CH:63]=[N:62][C:61]([C:64]2[CH:69]=[CH:68][C:67]([CH3:70])=[C:66]([CH3:71])[CH:65]=2)=[CH:60][N:59]=1)=[O:56]>CN(C)C=O>[CH3:71][C:66]1[CH:65]=[C:64]([C:61]2[N:62]=[CH:63][C:58]([NH:57][C:55]([C:54]3[CH:72]=[C:73]([N:76]4[CH2:81][CH2:80][CH2:79][CH2:78][CH2:77]4)[CH:74]=[CH:75][C:53]=3[NH:52][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][CH:18]=[C:10]([C:8]([NH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][OH:1])=[O:9])[CH:11]=3)=[O:56])=[N:59][CH:60]=2)[CH:69]=[CH:68][C:67]=1[CH3:70]
Reactant: O=C(O)c1cccc(C(=O)NCCOCCO)c1
Reactant: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3N)cn2)cc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(C(=O)NCCOCCO)c3)cn2)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.1 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 3-((2-(2-hydroxyethoxy)ethyl)carbamoyl)benzoic acid (189.3 mg, 0.7.5 mmol, 3.00 equiv) in N,N-dimethylformamide (5 mL), HATU (331.2 mg, 0.87 mmol, 3.50 equiv), N,N-diisopropylethylamine (160.6 mg, 1.24 mmol, 5.00 equiv), and 2-amino-N-(5-(3,4-dimethylphenyl)pyrazin-2-yl)-5-(piperidin-1-yl)benzamide (100 mg, 0.25 mmol, 1.00 equiv). The resulting solution was stirred overnight at 25° C. in an oil bath. The reaction was then quenched with 50 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product (120 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 44.8 mg (28%) of a light yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.36 (s, 1H), 11.06 (s, 1H), 9.38 (d, J=1.5 Hz, 1H), 9.03 (d, J=1.5 Hz, 1H), 8.74˜8.66 (m, 1H), 8.39 (s, 1H), 8.10˜8.01 (m, 3H), 7.92 (s, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.66˜7.51 (m, 2H), 7.37 (s, 1H), 7.29 (d, J=7.8 Hz, 1H), 3.56˜3.34 (m, 13H), 2.32˜2.28 (m, 6H), 1.72˜1.61 (m, 6H). MS (ES, m/z): 637 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:32])=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C@H:9]([C:11]1[N:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13](=[O:25])[C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][C:15]=2[C:21]([F:24])([F:23])[F:22])[CH3:10].[CH:33](OCC)(OCC)OCC>>[C:26]1([N:12]2[C:11]([C@@H:9]([NH:8][C:7]3[CH:6]=[CH:5][N:4]=[C:3]4[S:32][CH:33]=[N:1][C:2]=34)[CH3:10])=[CH:20][C:19]3[C:14](=[C:15]([C:21]([F:23])([F:22])[F:24])[CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:25])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C[C@H](Nc1ccnc(S)c1N)c1cc2cccc(C(F)(F)F)c2c(=O)n1-c1ccccc1
Reactant: CCOC(OCC)OCC
Product: C[C@H](Nc1ccnc2scnc12)c1cc2cccc(C(F)(F)F)c2c(=O)n1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of (S)-3-(1-(3-amino-2-mercaptopyridin-4-ylamino)ethyl)-2-phenyl-8-(trifluoro methyl)isoquinolin-1(2H)-one III-35 (80 mg, 0.175 mmol, 1.0 eq) in triethyl orthoformate (180 mL) was stirred at reflux for 2 h. The reaction mixture was allowed to cool to RT and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (1-2% MeOH-DCM) to afford the product, (S)-2-phenyl-3-(1-(thiazolo[5,4-b]pyridin-7-ylamino)ethyl)-8-(trifluoromethyl)isoquinolin-1(2H)-one III-36. ESI-MS m/z: 467.0 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:16][CH2:15][CH:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[CH:5]2[CH2:4]1)[CH3:2].N1CCC[C@H]1C(O)=O.Br[CH:26]=[C:27]([C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[CH3:28]>CN(C=O)C.[Cu]I>[CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[N:7](/[CH:26]=[C:27](/[C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)\[CH3:28])[C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: CCN1CCC2Nc3ccc(C)cc3C2C1
Reactant: CC(=CBr)c1ccncc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Product: CCN1CCc2c(c3cc(C)ccc3n2/C=C(\C)c2ccncc2)C1
Temperature: 80 °C

Procedure:
2-Ethyl-8-methyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (150 mg, 0.69 mmol) potassium phosphate (292.5 mg, 1.382 mmol), Copper (I) iodide (13.11 mg, 0.069 mmol) and L-proline (15.8 mg, 0.138 mmol) were mixed in DMF and the purged with nitrogen. The contents were heated at 80° C. for 10 min. 4-(1-Bromoprop-1-en-2-yl)pyridine (208 mg, 1.04 mmol) was added, the reaction mixture was purged nitrogen and heated overnight at 140° C. The contents were cooled to RT and poured into water. The precipitate obtained was filtered, dried and purified by HPLC. 1H NMR (CD3OD, freebase) δ (ppm): 8.58 (d, 2H), 7.70 (d, 2H), 7.35 (s, 1H), 7.30 (s, 1H), 7.05 (m, 2H), 3.95 (s, 2H), 3.10 (q, 2H), 2.95 (m, 4H), 2.42 (s, 3H), 2.00 (s, 3H), 1.30 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([O:14][CH3:15])[C:11]([OH:13])=O.[NH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([F:26])[CH:19]=1>>[C:22]([C:21]1[CH:24]=[CH:25][C:18]([CH2:17][NH:16][C:11](=[O:13])[CH:10]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[O:14][CH3:15])=[CH:19][C:20]=1[F:26])#[N:23]
Reactant: N#Cc1ccc(CN)cc1F
Reactant: COc1ccc(C(OC)C(=O)O)c(F)c1
Product: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)c(F)c2)c(F)c1

Procedure:
(RS)-(2-Fluoro-4-methoxy-phenyl)-methoxy-acetic acid (example 15.1) was coupled with 4-aminomethyl-2-fluorobenzonitrile (CAS 368426-73-7) according to general procedure B to give (RS)-N-(4-cyano-3-fluoro-benzyl)-2-(2-fluoro-4-methoxy-phenyl)-2-methoxy-acetamide. Light yellow solid. MS 347.3 ([M+H]+)