Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:5]=1[C:6]#[N:7])([O-])=O.[CH:15]1([OH:19])[CH2:18][CH2:17][CH2:16]1>>[NH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([O:19][CH:15]2[CH2:18][CH2:17][CH2:16]2)[C:5]=1[C:6]#[N:7]
Reactant: OC1CCC1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: N#Cc1c(N)cccc1OC1CCC1
Yield: 34 %

Procedure:
Prepared in a similar manner as example 111c from 2,6 dinitrobenzonitrile and cyclobutanol to provide 2-amino-6-cyclobutoxybenzonitrile (298 mg, 34%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.69 (m, 1H), 1.85 (m, 1H), 2.14 (m, 2H), 2.52 (m, 2H), 4.98 (pent, J=7.3 Hz, 1H), 7.55 (dd, J=8.2, 1.1 Hz, 1H), 7.87 (t, J=8.2 Hz, 1H), 7.92 (dd, J=8.4, 1.3 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([CH3:24])[C:21]([C:25]2[NH:29][C:28]([CH2:30][CH:31]3CCOC3)=[N:27][N:26]=2)=[CH:20][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].C(CC(NN)=O)#[N:37].O1CCC(CC(NN)=O)C1>>[C:31]([CH2:30][C:28]1[NH:29][C:25]([C:21]2[C:22]([CH3:24])=[CH:23][C:2]([CH3:1])=[C:3]([CH:20]=2)[C:4]([N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[CH2:10][CH2:11]2)=[O:5])=[N:26][N:27]=1)#[N:37]
Reactant: Cc1cc(C)c(-c2nnc(CC3CCOC3)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: N#CCC(=O)NN
Agent: NNC(=O)CC1CCOC1
Product: Cc1cc(C)c(-c2nnc(CC#N)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(2,4-dimethyl-5-(5-((tetrahydrofuran-3-yl)methyl)-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 130), using 2-cyanoacetohydrazide (compound 139.1) instead of 2-(tetrahydrofuran-3-yl)acetohydrazide (compound 130.4). m/z (ES+) 425 (M+H)+. 1H-NMR (300 Hz, CD3OD): δ 7.70 (d, J=8.4 Hz, 2H), 7.54-7.42 (m, 3H), 7.35 (s, 1H), 4.87-4.80 (m, 1H), 4.12 (s, 2H), 3.77-3.65 (m, 1H), 3.27-3.23 (m, 1H), 3.09-2.99 (m, 2H), 2.55 (s, 3H), 2.43 and 2.33 (2 singlets, amide rotamers, ArCH3, 3H), 2.05-2.00 (m, 1H), 1.83-1.76 (m, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]1=[O:13]>COC(OC)N(C)C.C(Cl)Cl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4](=[CH:1][N:2]([CH3:11])[CH3:3])[C:3]1=[O:13]
Reactant: Cn1c(=O)cc(O)c2ccccc21
Agent: COC(OC)N(C)C
Solvent: ClCCl
Product: CN(C)C=C1C(=O)c2ccccc2N(C)C1=O

Procedure:
A suspension of 1-methyl-4-hydroxy-2(1H)-quinolinone (1.0 gm) in dimethyl formamide dimethyl acetal (5 ml) and methylene chloride (2.0 ml) was refluxed for 1 hour. The resulting dark orange solution was evaporated under reduced pressure to afford 1-methyl-3-dimethylaminomethylene-(1H)-quinolin-2,4-dione. MS: m/e 230 (M+). ##STR37##
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[N:5][CH:4]=1)#[CH:2].[CH:13]1([C:16]2[CH:17]=[C:18]([NH:30][C:31](=[O:40])[C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[C:34](I)[CH:33]=3)[CH:19]=[CH:20][C:21]=2[CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH2:15][CH2:14]1>>[N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:1]#[C:2][C:36]2[CH:37]=[C:32]([CH:33]=[CH:34][C:35]=2[CH3:38])[C:31]([NH:30][C:18]2[CH:19]=[CH:20][C:21]([CH2:22][N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)=[C:16]([CH:13]3[CH2:15][CH2:14]3)[CH:17]=2)=[O:40])=[CH:4][N:5]=1
Reactant: C#Cc1cnnc2ccccc12
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C3CC3)c2)cc1I
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C3CC3)c2)cc1C#Cc1cnnc2ccccc12

Procedure:
The title compound can be synthesized from 4-ethynylcinnoline and N-(3-cyclopropyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-iodo-4-methylbenzamide in a manner similar to that described for Example 1 (nitro reduction performed in a manner similar to that described for Example 10; 0.25M in MeOH/10% AcOH). 4-ethynylcinnoline is prepared from 4-bromocinnoline and ethynyltrimethylsilane according to the 2 steps procedure described in Example 1.
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Cu][C:11]#[N:12].O>CN(C=O)C.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>[OH:8][C:4]1[C:3]([CH3:9])=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:11]#[N:12]
Reactant: Cc1c(O)cccc1Br
Reactant: N#C[Cu]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(O)cccc1C#N
Temperature: 120 °C
Reaction time: 16 h
Yield: 49.2 %

Procedure:
To a solution of 3-bromo-2-methylphenol (20.0 g) in DMF (250 mL) were added copper(I) cyanide (19.0 g) and tetrakis(triphenylphosphine)palladium(0) (3.70 g), and the mixture was heated with stirring at 120° C. for 16 hr under nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was filtered. The filtrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with tert-butyl methyl ether to give the title compound (7.00 g).
Reaction SMILES: [C:1]1([C:7](=[N:16][NH2:17])[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1([S:24]([CH2:27][C:28](OCC)=[O:29])(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[O-]CC.[Na+]>C(O)C>[C:18]1([S:24]([C:27]2[C:28](=[O:29])[NH:17][N:16]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:25])=[O:26])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NN=C(C(=O)c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CS(=O)(=O)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1[nH]nc(-c2ccccc2)c(-c2ccccc2)c1S(=O)(=O)c1ccccc1
Yield: 34 %

Procedure:
Benzilmonohydrazone (20.3 g) and ethyl α-phenylsulfonylacetate (22.8 g) were charged to a dry reaction flask in absolute ethanol (250 ml). With stirring, sodium ethoxide (6.8 g) was added portionwise When addition was complete, the reaction was heated to reflux for 12 hours. During this time, a 10 percent excess (2.3 g) of the ester was added. The cooled solution was quenched in an equal volume of water and concentrated HCl was added to precipitate a solid. The product was filtered from the cold mixture and recrystallized from ethanol to obtain the title compound as a white solid (34 percent yield), m.p. 254°-256° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:38]([O:40][C:41]([C:43]1([NH2:52])[CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1)=[O:42])[CH3:39].CCN(C(C)C)C(C)C>CCO.ClCCl.C(Cl)Cl>[CH2:38]([O:40][C:41]([C:43]1([NH:52][C:11]([C:10]2[C:4]3[O:3][C:2]([CH3:1])=[CH:6][C:5]=3[CH:7]=[CH:8][CH:9]=2)=[O:13])[CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1)=[O:42])[CH3:39]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: Cc1cc2cccc(C(=O)O)c2o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2cccc3cc(C)oc23)Cc2ccccc2C1
Yield: 136.9 %

Procedure:
To a 25 mL vial containing a stirring bar, 2-methylbenzofuran-7-carboxylic acid (0.343 g, 1.95 mmol) is charged with dry DCM (6 mL). Stirring is initiated. HBTU (738 mg, 1.95 mmol) is added. The 2-aminoindane-2-carboxylic acid ethyl ester (400 mg, 1.95 mmol) is added followed by DIPEA (0.75 mL, 4.31 mmol). The reaction is allowed to stir for 16 h. Analysis by tlc of the reaction mixture (silica, 10% EtOH/dichloromethane) indicates complete consumption of the starting amine. The contents of the reaction flask are diluted with EtOAc (50 mL) and transferred to a separatory funnel. This is washed consecutively with dilute aqueous HCl (3%, 25 mL), saturated aqueous NaHCO3 (25 mL) and brine (25 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 0.97 g of yellow oil. This material is dissolved in 10 mL of DCM. This is purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 15% EtOAc in heptanes for 3 column volumes followed by a linear gradient to 90% over 15 column volumes and then 100% EtOAc for 2 column volumes with a ramp of 1 column volume. 25 mL fractions are collected. Fractions 2 through 7 are combined and evaporated in vacuo to a constant weight to give 0.63 g of amorphous white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:31][CH2:30][CH2:29][N:28]([CH3:32])[CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.O>[CH3:32][N:28]1[CH2:29][CH2:30][CH2:31][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26][CH2:27]1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CN1CCCN(c2nnc3ccc(F)cn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
To a solution of Intermediate A (183 mg, 1.12 mmol) in DMF (3 mL) was added NaH (60% dispersion in oil, 149 mg, 2.24 mmol) and the mixture stirred at RT for 0.5 h. A solution of Intermediate 69a (400 mg, 1.12 mmol) in DMF (3 mL) was added and the mixture stirred at 60° C. for 1.5 h. The cooled mixture was diluted with water and extracted with DCM (3×20 mL) and DCM-MeOH (4:1, 2×25 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-25% [2M NH3 in MeOH] in DCM, to give the title compound as a dark brown gum (179 mg, 41%). LCMS (Method 3): Rt 0.44 min, m/z 393 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([S:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=O)[CH3:23])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])[N:4]=1.Cl.[CH3:26][O:27][NH2:28].C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([S:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[N:28][O:27][CH3:26])[CH3:23])[C:13]=2[C:14]([O:16][CH3:17])=[O:15])[N:4]=1
Reactant: COC(=O)c1c(Sc2nc(OC)cc(OC)n2)cccc1C(C)=O
Reactant: CON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CON=C(C)c1cccc(Sc2nc(OC)cc(OC)n2)c1C(=O)OC
Temperature: 25 °C
Yield: 60 %

Procedure:
1.0 g of methyl 2-[(4,6-dimethoxypyrimidin-2-yl)thio]-6-acetylbenzoate and 0.5 g of methoxyamine hydrochloride were dissolved in 6 ml of methanol, and the resultant solution was refluxed for 15 minutes. After cooling the mixed liquor to room temperature, 0.8 g of potassium carbonate was added to this liquor and the resultant liquor was heat-refluxed for 3 hours. The reaction liquor was poured into a large amount of water, and an oily product thus precipitated was extracted with ethyl acetate. The ethyl acetate layer was washed with water, and was dried to distill off ethyl acetate under reduced pressure. The residue thus obtained was purified by chromatography to obtain 0.65 g of the aimed compound (refractive index=1.5709) at a yield of 59%.
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH2:17]([NH:24][C:8]([NH:7][N:6]=[CH:5][C:4]1[C:12]([Cl:16])=[CH:13][CH:14]=[CH:15][C:3]=1[Cl:2])=[NH:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Reactant: NCc1ccccc1
Agent: I
Solvent: CCO
Product: N=C(NCc1ccccc1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 11.7 g. of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydroiodide (U.S. Pat. No. 3,657,337) and 3.37 g. of benzylamine in 25 ml. of ethanol is heated at reflux for 18 hours and then evaporated to dryness under reduced pressure. The residue is partitioned between 80 ml. of diethyl ether and 100 ml. of water and the aqueous extract is made alkaline with ammonia. A pale yellow solid is recovered by filtration and recrystallized from aqueous ethanol, giving the desired product as colorless crystals, m.p. 133°-135° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][O:26][CH3:27].[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][CH2:25][O:26][CH3:27])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:29]([CH3:28])(=[O:31])=[O:30])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCN
Reactant: CS(=O)(=O)Cl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCNS(C)(=O)=O
Yield: 74.1 %

Procedure:
Using the general method of Example 242, 1-(8-aminooctyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (800 mg, 2.17 mmol) was reacted with methanesulfonyl chloride (172 μL, 2.17 mmol) to provide 720 mg of N-{8-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]octyl}methanesulfonamide as a yellow powder, m.p. 109-110° C. Analysis: Calculated for C22H33N5O3S: %C, 59.04; %H, 7.43; %N, 15.65; Found: %C, 58.78; %H, 7.38; %N, 15.48.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][CH:39]1[CH2:44][CH2:43][N:42]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:48]3[CH2:49][CH2:50][CH:45]([N:42]4[CH2:43][CH2:44][CH:39]([CH3:38])[CH2:40][CH2:41]4)[CH2:46][CH2:47]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC1CCN(C2CCNCC2)CC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCC(C)CC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 4-methyl-[1,4′]bipiperidinyl (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C40H52Cl2N5O2 [(M+H)+] 704.3493, observed 704.3492.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12](=[O:30])[N:13]([CH2:15][CH2:16][O:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=4)[N:21]=[CH:20][CH:19]=3)[CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[C:38](Cl)(=[O:44])[O:39][CH2:40][CH:41]([CH3:43])[CH3:42]>C(Cl)Cl>[CH3:29][O:28][C:24]1[CH:23]=[C:22]2[C:27]([C:18]([O:17][CH2:16][CH2:15][N:13]3[C:12](=[O:30])[CH:11]=[CH:10][C:9]([C:4]4[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([NH:1][C:38](=[O:44])[O:39][CH2:40][CH:41]([CH3:43])[CH3:42])[CH:3]=4)=[CH:14]3)=[CH:19][CH:20]=[N:21]2)=[CH:26][CH:25]=1
Reactant: COc1ccc2c(OCCn3cc(-c4ccc(C)c(N)c4)ccc3=O)ccnc2c1
Reactant: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(OCCn3cc(-c4ccc(C)c(NC(=O)OCC(C)C)c4)ccc3=O)ccnc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.1 %

Procedure:
To a solution of 5-(3-amino-4-methylphenyl)-1-(2-(7-methoxyquinolin-4-yloxy)ethyl)pyridin-2(1H)-one (0.10 g, 0.25 mmol) in 10 mL of CH2Cl2 at rt was added triethylamine (0.083 ml, 0.60 mmol) followed by isobutyl chlorocarbonate (0.048 ml, 0.37 mmol). The reaction was stirred at rt for 4 hours and was then concentrated in vacuo. The residue was dissolved in 50 mL of EtOAc and the resulted organic phase was washed with 20 mL of satd. NaHCO3 followed by 20 mL of brine. The organic solution was dried over Na2SO4 and concentrated in vacuo. The residue was washed with 50% hex/EtOAc to give white solid as desired product (0.0879 g, 70% yield). MS (ESI pos. ion) m/z (MH+): 502.1. Calc'd Exact Mass for C29H31N3O5: 501.23.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:33])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[S:17][C:13]=3[C:12](=[O:24])[N:11]=[C:10]2[CH2:25][S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:5]=[CH:6][CH:7]=1.B1([O-])OO1.[OH2:38].[OH2:39].O.O.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([CH3:33])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[S:17][C:13]=3[C:12](=[O:24])[N:11]=[C:10]2[CH2:25][S:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:39])=[O:38])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1Cn1c(CSc2ccccc2)nc(=O)c2sc(N3CCOCC3)nc21
Reactant: O
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: Cc1c(Cl)cccc1Cn1c(CS(=O)(=O)c2ccccc2)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-5-[(phenylthio)methyl][1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (37 mg, 0.074 mmol) in Acetic Acid (371 Ml) was added to a stirred suspension of sodiumperborate tetrahydrate (45.6 mg, 0.297 mmol) and Acetic Acid (371 μl). The mixture was stirred at room temperature overnight, and then concentrated. The residue was taken up in dichloromethane/water and eluted through a hydromatrix cartridge. The eluate was concentrated and purified by reversed-phase HPLC to provide 4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-5-[(phenylsulfonyl)methyl][1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one. (8 mg, 20%); LC/MS: MS (ES+) m/e 531 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 3H), 3.49-3.55 (m, 4H), 3.64-3.71 (m, 4H), 4.82 (s, 2H), 5.64 (s, 2H), 6.43 (d, J=7.6 Hz, 1H), 7.13 (m, 1H), 7.39 (d, J=7.83 Hz, 1H), 7.65 (t, J=7.8 Hz, 2H), 7.75-7.83 (m, 1H), 7.84-7.90 (m, 2H).
Reaction SMILES: CN(C=O)C.[S:6]([Cl:10])(Cl)(=[O:8])=[O:7].[CH2:11]([C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[CH:19]=2)=[CH:15][CH:14]=1)[CH3:12]>>[CH2:11]([C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[S:6]([Cl:10])(=[O:8])=[O:7])=[CH:15][CH:14]=1)[CH3:12]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCc1ccc(Cc2cc3ccccc3s2)cc1
Solvent: CN(C)C=O
Product: CCc1ccc(Cc2sc3ccccc3c2S(=O)(=O)Cl)cc1

Procedure:
2-(4-Ethylbenzyl)benzo[b]thiophene-3-sulfonyl chloride was prepared by the method of Example 40B with DMF (5.4 mmoles, 0.42 ml), sulfuryl chloride (4.6 mmoles, 0.37 ml) and 2-(4-ethylbenzyl)benzo[b]thiophene (2.7 mmoles, 0.69 g). Flash chromatography 12% ethyl acetate/hexanes) provided 0.43 g (45%) of an orange solid.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[NH:12][C@@H:13]1[C@@H:20]2[C@@H:16]([CH2:17][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])[CH2:19]2)[CH2:15][CH2:14]1)C(=O)OC(C)(C)C.O1CCOCC1>Cl>[CH3:1][NH:2][C@H:10]([C:11]([NH:12][C@@H:13]1[C@@H:20]2[C@@H:16]([CH2:17][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:28])([F:30])[F:29])[CH2:19]2)[CH2:15][CH2:14]1)=[O:31])[CH2:32][CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)C[C@@H](C(=O)N[C@H]1CC[C@@H]2CN(c3ccccc3C(F)(F)F)C[C@@H]21)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CN[C@@H](CC(C)C)C(=O)N[C@H]1CC[C@@H]2CN(c3ccccc3C(F)(F)F)C[C@@H]21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 4 mL vial tert-butyl methyl((S)-4-methyl-1-oxo-1-((3aR,4S,6aS)-2-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrol-4-ylamino)pentan-2-yl)carbamate from Step 3 (40 mg, 0.080 mmol) was dissolved in 4 N HCl in 1,4-dioxane (1 mL, 4.00 mmol). An oil slowly gummed out of the solution. The reaction was stirred at ambient temperature for 18 hours, and then the solvent was removed under a stream of nitrogen. The crude material was purified using a 4 g silica gel cartridge with 1-10% methanol (2 N ammonia)/dichloromethane to give N2-methyl-N-{(3aR,4S,6aS)-2-[2-(trifluoromethyl)phenyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.28 (d, J=5.2, 1H), 7.66 (d, J=7.8, 1H), 7.46 (t, J=7.4, 1H), 7.27 (d, J=8.3, 1H), 7.11 (t, J=7.7, 1H), 4.56-4.46 (m, 1H), 3.47 (d, J=9.3, 1H), 3.30-3.23 (m, 1H), 3.16-3.09 (m, 1H), 3.02-2.91 (m, 2H), 2.68 (dd, J=14.4, 10.2, 2H), 2.45 (s, 3H), 2.20 (dd, J=11.1, 5.9, 1H), 2.00-1.86 (m, 2H), 1.79-1.70 (m, 1H), 1.69-1.54 (m, 3H), 0.93 (d, J=6.5, 3H), 0.86 (d, J=6.5, 3H); MS (ESI+) m/z 398 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([OH:9])[CH:8]=1.C([O-])([O-])=O.[K+].[K+].[CH2:17](I)[CH3:18]>CN(C=O)C>[CH2:17]([O:9][C:7]1[CH:6]=[C:5]([OH:10])[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=1)[CH3:18]
Reactant: OCc1cc(O)cc(O)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(O)cc(CO)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 41.6 %

Procedure:
To a solution of 5-hydroxymethyl-benzene-1,3-diol (0.5 g, 3.57 mmol, 1.0 equiv) in DMF (5 mL) was added K2CO3 (0.99 g, 7.14 mmol, 2.0 equiv) and ethyl iodide (0.29 mL, 0.43 g, 3.93 mmol, 1.1 equiv) and the reaction mixture stirred under Ar at 60° C. for 4 h. The K2CO3 was removed by filtration, the filtrate extracted with ethyl acetate (3×50 mL), the combined organic phases washed with a sat. solution of sodium chloride (1×50 ml) and dried over Na2SO4. The solvent was removed by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with a gradient of hexane/ethyl acetate (4:1→2:1) providing 0.25 g (42%) of the title compound. 1H NMR (250 MHz, CDCl3): δ 1.40 (t, J=7.0 Hz, 3H), 4.02 (q, J=7.0 Hz, 2H), 4.61 (d, J=5.6 Hz, 2H), 4.91 (br s, 1H), 6.29-6.31 (m, 1H), 6.43 (br s, 1H), 6.49 (br s, 1H). MS (EI): 168.0 [M]+.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH:32]([C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)([CH3:34])[CH3:33]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:41]([C:38]4[CH:39]=[CH:40][C:35]([CH:32]([CH3:34])[CH3:33])=[CH:36][CH:37]=4)(=[O:43])=[O:42])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(C(C)C)cc4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 4-isopropyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=603.7)=97%.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([CH:30]=O)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:30][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cccc2ccccc12
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc2ccccc12

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 1-naphthaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.90 min.; [M+H]+: 376.17 g/mol.