Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[N:16]([CH3:19])[NH:15][C:14]3=[O:20])[CH:10]=[N:9]2)=[C:5]([CH3:21])[O:4][N:3]=1.C(N(CC)CC)C.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(#N)C>[CH2:29]([N:15]1[C:14](=[O:20])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:21])[CH:12]=2)[C:17](=[O:18])[N:16]1[CH3:19])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: BrCc1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]n(C)c2=O)cn1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1Cn1cc(-n2c(=O)n(C)n(Cc3ccccc3)c2=O)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 20.4 %

Procedure:
4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-methyl-1,2,4-triazolidine-3,5-dione (example 10-64) (785 mg, 2.7 mmol) was dissolved in acetonitrile (50 mL). Triethylamine (1 g, 10 mmol) and benzyl bromide (510 mg, 3 mmol) were added and the reaction was stirred at ambient temperature for 12 hours. The mixture was then concentrated on the rotovap, dissolved in methanol (5 mL) and purified by reversed phase HPLC (5-95% acetonitrile in H2O:25 minute gradient). The pure fractions were pooled and concentrated and the product was recrystallized form ethanol to afford 1-benzyl-4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2-methyl-1,2,4-triazolidine-3,5-dione (210 mg, 20%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ2.13 (s, 3H), 2.39 (s, 3H), 3.09 (s, 3H), 4.81 (s, 2H), 5.18 (s, 2H), 7.30-7.35 (m, 5H), 7.76 (s, 1H), 8.18 (s, 1H). MS M+H calculated 381.1. found 381.1. Melting point: 124-126° C. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.02 μM.
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:17][CH2:18][CH2:19][N:20]3[C:24](=[O:25])[C:23]4[C:22](=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:21]3=[O:30])[CH2:3][CH2:2]2)=[N:8]1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 3-(piperazin-1-yl)benzo[d]isothiazole (1.75 g, 8.0 mmol), N-(3-bromopropyl)-phthalimide (1.96 mmol, 7.3 mmol) and K2CO3 (2.21 g, 16.0 mol) in DMF (10 mL) was stirred at 80° C. for 3 hours. The reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (150 mL). The organic phase was dried over MgSO4 and evaporated under vacuum. The residue was further purified by flash column chromatography to provide 2-(3-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)propyl)isoindoline-1,3-dione as an intermediate (1.49 g, 3.67 mmol, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:31]=[N:30][C:14]3[N:15]=[C:16]([NH:19][C:20]4[C:25]([N+:26]([O-])=O)=[CH:24][CH:23]=[CH:22][C:21]=4[CH3:29])[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:31]=[N:30][C:14]3[N:15]=[C:16]([NH:19][C:20]4[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][C:21]=4[CH3:29])[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(-c2cnc3nc(Nc4c(C)cccc4[N+](=O)[O-])ncc3c2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(OC)cc(-c2cnc3nc(Nc4c(C)cccc4N)ncc3c2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 31.7 %

Procedure:
To a solution of 6-(3,5-dimethoxyphenyl)-N-(2-methyl-6-nitrophenyl)pyrido[2,3-d]pyrimidin-2-amine (100 mg, 0.24 mmol) in ethanol (5 mL) and water (5 mL) was added iron powder (110 mg, 1.92 mmol) and ammonium chloride (100 mg, 1.920 mmol). The mixture was stirred at 100° C. for 1 hour, cooled to RT, filtered and concentrated. The residue was purified by Preparative HPLC to afford N1-(6-(3,5-dimethoxyphenyl)pyrido[2,3-d]pyrimidin-2-yl)-6-methylbenzene-1,2-diamine (29.5 mg, 32%) as a yellow solid. MS (ES+) C22H21N5O2 requires: 387. Found: 388 [M+H]+; 1H-NMR (500 MHz, DMSO-d6) δ ppm 9.30, 9.21 (br, br, 2H), 8.95 (s, 1H), 8.60 (d, 1H, J=3.0 Hz), 6.96-6.92 (m, 3H), 6.63 (d, 1H, J=5.5 Hz), 6.55 (t, 1H, J=2.0 Hz), 6.50-6.48 (m, 1H), 4.79 (s, 2H), 3.84 (s, 6H), 2.08 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[N:10][C:9]=2[O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.Cl.[CH3:34][O:35]/[N:36]=[C:37](\[CH:40]1[CH2:42][CH2:41]1)/[CH2:38][NH2:39]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]([NH:39][CH2:38]/[C:37](/[CH:40]3[CH2:42][CH2:41]3)=[N:36]/[O:35][CH3:34])=[O:16])[CH:11]=[N:10][C:9]=2[O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:20])[F:21])=[CH:4][CH:3]=1
Reactant: C[C@H](Oc1ncc(C(=O)O)nc1-c1ccc(Cl)cc1)C(F)(F)F
Reactant: CO/N=C(/CN)C1CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CO/N=C(/CNC(=O)c1cnc(O[C@@H](C)C(F)(F)F)c(-c2ccc(Cl)cc2)n1)C1CC1
Yield: 45.5 %

Procedure:
To a suspension of (S)-6-(4-chlorophenyl)-5-(1,1,1-trifluoropropan-2-yloxy)-pyrazine-2-carboxylic acid (0.2 g, 577 μmol, Eq: 1.00) in dimethylformamide (4 ml) were added under argon TBTU (204 mg, 635 μmol, Eq: 1.1), ethyldiisopropylamine (373 mg, 478 μl, 2.88 mmol, Eq: 5) and (E)-2-amino-1-cyclopropylethanone O-methyl oxime hydrochloride (104 mg, 635 μmol, Eq: 1.1) and the mixture was stirred at room temperature for 18 h overnight. The reaction mixture was partitioned between ethyl acetate and 10% aqueous citric acid, the phases were separated and the organic phase was dried over MgSO4; filtered; concentrated and purified by flash chromatography (silica gel, 20 g, 5% to 50% ethyl acetate in heptane) to yield the title compound as white crystals (0.12 g, 45.5%, m.p.: 149-152° C.). MS (EI): 457.1 (M+H).
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH2:18][C:19]3[CH:20]=[C:21]([C:25]([OH:27])=O)[O:22][C:23]=3[CH3:24])[CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36]([NH2:39])(=[O:38])=[O:37].Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.ClCCl.C(#N)C>[F:28][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]([CH2:18][C:19]3[CH:20]=[C:21]([C:25]([NH:39][S:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[CH3:29])(=[O:37])=[O:38])=[O:27])[O:22][C:23]=3[CH3:24])[CH3:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: Cc1oc(C(=O)O)cc1CN(C)c1ccc(-c2ccc(OC(F)F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccccc1S(=O)(=O)NC(=O)c1cc(CN(C)c2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.9 %

Procedure:
A stirred solution of 4-{[(4′-difluoromethoxy-biphenyl-4-yl)-methyl-amino]-methyl}-5-methyl-furan-2-carboxylic acid (176) (21 mg, 0.054 mmoles), 2-methyl-benzenesulphonamide (19 mg, 0.108 mmoles) and 4-(N,N-dimethylamino)-pyridine (1 mg) in a mixture of dichloromethane (8 ml) and acetonitrile (2 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (11.4 mg, 0.060 mmoles). The mixture was stirred at room temperature for 18 hours under an argon atmosphere. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to afford compound 177(2.9 mg) as a solid. LC/MS System D; Rt=11.21 mins, m/z (ES+)=541 (M+H for C28H26F2N2O5S).
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:48])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:41]=5[F:47])[CH2:37][CH2:36]4)=[O:34])=[C:28]([F:49])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.[CH3:51][N:52]1[CH2:57][CH2:56][CH:55]([NH:58][CH3:59])[CH2:54][CH2:53]1>CN(C)C=O>[F:47][C:41]1[CH:42]=[C:43]([F:46])[CH:44]=[CH:45][C:40]=1[NH:39][C:38]([C:35]1([C:33]([NH:32][C:29]2[CH:30]=[CH:31][C:26]([O:25][C:23]3[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:8]([N:58]([CH3:59])[CH:55]4[CH2:56][CH2:57][N:52]([CH3:51])[CH2:53][CH2:54]4)=[O:7])[CH:24]=3)=[CH:27][C:28]=2[F:49])=[O:34])[CH2:37][CH2:36]1)=[O:48]
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4F)CC3)c(F)c2)ccn1
Reactant: CNC1CCN(C)CC1
Solvent: CN(C)C=O
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5F)CC4)c(F)c3)ccn2)CC1
Reaction time: 8 h
Yield: 14 %

Procedure:
To a solution of [4-(4-{[1-(2,4-Difluorophenylcarbamoyl)cyclopropanecarbonyl]amino}-3-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (116 mg) in N,N-dimethylformamide (2.0 ml) was added 1-methyl-4-(methylamino)piperidine (0.150 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:1 to the resultant residue. The solid was collected by filtration. The solid was dried under aeration to provide the titled compound as white powder (14.0 mg, 14%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:23][C:22]3[C:21](=[O:24])[N:20]([CH2:25][CH2:26][CH3:27])[C:19](=[O:28])[N:18]([CH2:29][CH2:30][CH3:31])[C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:38][Si:39]([CH3:46])([CH3:45])[CH2:40][CH2:41][O:42][CH2:43]Cl>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:23]([CH2:43][O:42][CH2:41][CH2:40][Si:39]([CH3:46])([CH3:45])[CH3:38])[C:22]3[C:21](=[O:24])[N:20]([CH2:25][CH2:26][CH3:27])[C:19](=[O:28])[N:18]([CH2:29][CH2:30][CH3:31])[C:17]=3[N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(OCc4ccccc4)cc3)nc2n(CCC)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1c(=O)c2c(nc(-c3ccc(OCc4ccccc4)cc3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.4 %

Procedure:
A mixture of 8-(4-benzyloxy-phenyl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (1.2 g, 2.9 mmol) and potassium carbonate (1.19 g, 8.6 mmol), were taken in DMF (15 ml) and 2-(trimethylsilyl)ethoxymethyl chloride (1.52 ml, 8.6 mmol) was added drop wise at 0° C. and mixture was stirred at room temperature for 20 hours. The mixture was cooled to 10° C. and diluted with water, extracted with ethyl acetate. The organic layer was washed with saturated brine solution and dried over Na2SO4. Solvent was removed and residue obtained was further purified by column chromatography to obtain pure 8-(4-benzyloxy-phenyl)-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (1.12 g, 71%).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([C@@H:23]3[NH:27][C@@:26]([CH3:32])([C:28](OC)=[O:29])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.[NH3:48]>>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]([CH3:43])([CH3:42])[C:14]([N:16]([CH3:41])[C:17]2[C:18]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[CH3:40])=[CH:19][C:20]([C@@H:23]3[NH:27][C@@:26]([CH3:32])([C:28]([NH2:48])=[O:29])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:4]=[C:3]([C:2]([F:44])([F:45])[F:1])[CH:8]=1
Reactant: N
Reactant: COC(=O)[C@@]1(C)CC[C@H](c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)N1
Solvent: CO
Product: Cc1cc(F)ccc1-c1cc([C@H]2CC[C@](C)(C(N)=O)N2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 48 h
Yield: 65.5 %

Procedure:
Methyl (5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinate (Intermediate 9, 25 mg, 0.039 mmol) was dissolved in 7N ammonia solution in MeOH (3 ml, 21.0 mmol) and the reaction mixture was stirred for 48 hours at 60° C. The solvent was evaporated and the residue was purified by flash chromatography on silica gel (Companion system; eluent: from 99:1 Dichloromethane/MeOH to 95:5 Dichloromethane/MeOH; 12 g cartridge) affording the title compound (16 mg, 0.026 mmol, 65.5% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[O:11][CH3:12].Br[CH:14]=[C:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[C:25]([Cl:26])[C:20]=2[CH2:19][CH2:18][C:17]2[CH:27]=[CH:28][CH:29]=[CH:30][C:16]1=2>>[Cl:26][C:25]1[C:20]2[CH2:19][CH2:18][C:17]3[CH:27]=[CH:28][CH:29]=[CH:30][C:16]=3[C:15](=[CH:14][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:11][CH3:12])[CH:4]=3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: Clc1cccc2c1CCc1ccccc1C2=CBr
Reactant: COc1cc(B(O)O)ccc1Cl
Product: COc1cc(C=C2c3ccccc3CCc3c(Cl)cccc32)ccc1Cl
Yield: 70.6 %

Procedure:
Following procedures essentially as described in Example 219, below, and using 4-chloro-3-methoxyphenylboronic acid (160 mg,0.85 mmol) with 5-bromomethylene-1-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (249 mg, 0.78 mmol) to give 440 mg crude product. Purify by chromatography to give 210 mg (71%) colorless oil. HPLC (ISO90-10M) shows 51% at t=7.62 min and 45% at t=9.86 min.
Reaction SMILES: O1CCOCC1.[CH:7]1([CH:10](O)[C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[CH2:9][CH2:8]1.[BrH:20]>O>[CH3:18][S:17][C:14]1[CH:15]=[CH:16][C:11](/[CH:10]=[CH:7]/[CH2:8][CH2:9][Br:20])=[CH:12][CH:13]=1
Reactant: Br
Reactant: CSc1ccc(C(O)C2CC2)cc1
Solvent: O
Solvent: C1COCCO1
Product: CSc1ccc(/C=C/CCBr)cc1
Reaction time: 0.5 h

Procedure:
To 10 ml of dioxane solution containing 5 g of 1-(cyclopropyl, hydroxymethyl)-4-methylthiobenzene was added dropwise 6 ml of 47% of hydrobromic acid under an ice-cooled condition, then the mixture was stirred for 30 minutes, and the reaction mixture was concentrated under a reduced pressure. To the residue thus obtained was added water, then extracted with ether, the extract was washed with water and dried with anhydrous sodium sulfate, and concentrated to dryness. The residue was recrystallized from methanol to yield 2.2 g of 4-(4'-methylthiophenyl)-3(E)-butenylbromide in the form of colorless flake-like crystals. Melting point: 54°-56° C.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[N:16]=[C:15]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH2:25][CH3:26])[CH:18]=4)[O:14][N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:29]([C@@H:31]1[O:33][CH2:32]1)Cl>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH:1]1([C:6]2[CH:11]=[C:10]([C:12]3[N:16]=[C:15]([C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([O:24][CH2:29][C@@H:31]5[CH2:32][O:33]5)=[C:19]([CH2:25][CH3:26])[CH:18]=4)[O:14][N:13]=3)[CH:9]=[C:8]([O:27][CH3:28])[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1O
Reactant: ClC[C@H]1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCc1cc(-c2nc(-c3cc(OC)nc(C4CCCC4)c3)no2)cc(C)c1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.8 %

Procedure:
A mixture of 4-[3-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-5-yl]-2-ethyl-6-methyl-phenol (150 mg, 395 μmol) and (R)-epichlorohydrine (366 mg, 3.95 mmol) in isopropanol (4 mL) and 3 N aq. NaOH (1 mL) is stirred at rt for 72 h. The mixture is diluted with EA (50 mL), washed with 1 M aq. NaOH solution (20 mL) followed by brine (20 mL), dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates using heptane:EA 1:1 to give 2-cyclopentyl-4-[5-((S)-3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-6-methoxy-pyridine (96 mg) as a pale yellow oil; LC-MS**: tR=1.02 min, [M+H]+=436.18.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[NH:18][C:19](=[O:21])[CH3:20])[C:3]1=[O:22].O([C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:43])([F:42])[F:41])[CH:38]=2)[N+:33]([O-:44])=[CH:32][N:31]=1)C1C=CC=CC=1.C(N(CC)C(C)C)(C)C>CC(O)C>[C:19]([NH:18][C@@H:8]1[CH2:9][C@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:11][CH2:12][C@@H:7]1[N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:43])([F:41])[F:42])[CH:38]=3)[N+:33]([O-:44])=[CH:32][N:31]=2)[C:3]1=[O:22])(=[O:21])[CH3:20]
Reactant: [O-][n+]1cnc(Oc2ccccc2)c2cc(C(F)(F)F)ccc21
Reactant: CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](Nc2nc[n+]([O-])c3ccc(C(F)(F)F)cc23)C1=O
Temperature: 120 °C
Yield: 110.5 %

Procedure:
Example 5, Alternative Preparation, Step 3: To a solution of N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)cyclohexyl)acetamide (50 mg, 0.161 mmol; see Example 1, Step 10) and 4-phenoxy-6-(trifluoromethyl)quinazoline 1-oxide (99 mg, 0.161 mmol) in i-PrOH (2 ml) was added N,N-diisopropylethylamine (0.056 ml, 0.322 mmol). The vessel was sealed under argon and heated in a microwave for 1 hr at 120° C. LC/MS found: (M+H)+=523.3 as the major product peak. The mixture was concentrated and purified by automated flash chromatography (40 g silica gel, eluting with 8:92 10% cNH4OH/MeOH). The fractions containing the desired product were pooled and concentrated in vacuo. The residue was crystallized from CH2Cl2 and hexane. The two crops were combined and dried under vacuum to afford the title compound, 4-((S)-1-((1S,2R,4R)-2-acetamido-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylamino)-6-(trifluoromethyl)quinazoline 1-oxide (93 mg). Analysis by 1H-NMR showed that this material contained ˜0.75 molar equivalents of CH2Cl2. 1H-NMR (400 MHz, d4-MeOH): δ 8.99 (s, 1H), 8.81 (s, 1H), 8.62 (d, J=8.9 Hz, 1H), 8.32 (dd, J=9.0, 1.5 Hz, 1H), 5.28 (t, J=8.4 Hz, 1H), 4.59 (br s, 1H), 4.05 (m, 1H), 3.55-3.65 (m, 2H), 3.43 (m, 1H), 2.75 (br s, 1H), 2.55 (m, 1H), 2.27 (s, 3H), 2.1-2.3 (m, 3H), 2.02 (s, 3H), 2.0 (m, 1H), 1.65-1.7 (m, 3H), 1.12 (d, J=6.0 Hz, 3H), 1.06 (d, J=6.0 Hz, 3H). LC/MS found: [M+H]+=523.33.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([C:16]#[N:17])[CH:3]=1.IN1[C:23](=O)[CH2:22][CH2:21][C:20]1=[O:25]>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([C:16]#[N:17])[C:3]=1[C:23]1[O:25][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc(Cl)c(-n2nc(C#N)cc2N)c(Cl)c1
Solvent: CC#N
Product: Cc1cc(Cl)c(-n2nc(C#N)c(-c3ccco3)c2N)c(Cl)c1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-methylphenyl)pyrazole (1 g) in acetonitrile (15 ml) at room temperature was added N-iodosuccinimide (0.845 g). Stirring was continued for 10 minutes and the mixture was then evaporated to dryness. The residue was taken up in dioxane (20 ml). Furan-2-boronic acid (0.845 g), tetrakis(triphenylphosphine)palladium(0) (0.35 g) and a solution of potassium carbonate (2.8 g) in water (8 ml) were added. The mixture was heated under reflux for 24 hours, then cooled and partitioned between ether and water. The separated aqueous layer was extracted with ether and the combined ether layers were washed with brine, dried and evaporated. The green oily residue was purified by column chromatography on silica gel eluted with hexane:dichloromethane (1:2). Combination and evaporation of suitable fractions followed by recrystallisation from toluene gave the title compound as a white solid, m.p. 191.5-192.5° C.
Reaction SMILES: COC1C=CC(C[N:8]2[C:13]3[NH:14][N:15]=[C:16]([NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:12]=3[C:11](=[O:24])[N:10]([CH3:25])[C:9]2=[O:26])=CC=1.C(O)(C(F)(F)F)=O.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[CH3:25][N:10]1[C:11](=[O:24])[C:12]2[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:15][NH:14][C:13]=2[NH:8][C:9]1=[O:26]
Reactant: COc1ccc(Cn2c(=O)n(C)c(=O)c3c(Nc4ccccc4)n[nH]c32)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)[nH]c2[nH]nc(Nc3ccccc3)c2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution of 7-(4-Methoxybenzyl)-5-methyl-3-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (6.6 g, 17.5 mmol) in CH2Cl2 (200 mL) added TFA (30 mL) slowly at room temperature, followed by adding trifluoromethanesulfonic acid (10 mL) dropwise. After the reaction mixture is stirred at r.t. for 2 hours, solvent is removed under reduced pressure, and then 200 mL of 1N NaOH is added with cooling. The mixture is extracted with ethyl acetate five times, dried over Na2SO4, and then filtered. The filtrate is evaporated to dryness to give 4.3 g of crude product as white solids (Yield: 96%). MS (ESI) m/z 258.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[I:23]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:23])=[CH:4][C:3]=1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COc1cc(F)c(C2CCN(C(=O)OC(C)(C)C)CC2)cc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred mixture of tert-butyl 4-(2-fluoro-4-methoxyphenyl)piperidine-1-carboxylate (Step A; 255 mg; 0.825 mmol) in MeOH. (15 mL) was treated with iodine (345 mg; 1.107 mmol) and silver sulfate (281 mg; 1.107 mmol). The reaction was stirred at room temperature for 2 h. The reaction was filtered through Celite and the filtrate was concentrated in vacuo. The residue was redissolved in ether (50 mL) and washed with H2O (50 mL). The aqueous layer was extracted with ether (3×50 mL) and the combined extracts were washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-10% EtOAc/hexanes gradient) to afford tert-butyl 4-(2-fluoro-5-iodo-4-methoxyphenyl)piperidine-1-carboxylate as a colorless glass. The aqueous layer was then re-extracted with EtOAc (3×100 mL) and the combined extracts were dried (MgSO4), filtered, and the solvent was removed under reduced pressure until a precipitate formed. This solid was collected by filtration and dried in a vacuum oven to afford 4-(2-fluoro-5-iodo-4-methoxyphenyl)piperidine as a off-white solid.