Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([Li])CCC.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([OH:39])=[C:30]([C:32](=[O:38])[C:33](OCC)=[O:34])[CH:31]=1.Cl>ClCCl.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:33](=[O:34])[C:32](=[O:38])[C:30]3[CH:31]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]=3[OH:39])=[CH:17][CH:18]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)C(=O)c1cc(Cl)ccc1O
Reactant: COc1ccc(CCc2ccc(N)cc2)cc1OC
Agent: Cl
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(CCc2ccc(NC(=O)C(=O)c3cc(Cl)ccc3O)cc2)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.3 %

Procedure:
Under an argon atmosphere, a tetrahydrofuran (20 ml) solution of 4-[2-(3,4-dimethoxyphenyl)ethyl]benzenamine (2.50 g, 9.72 mmol) is cooled to 0° C. n-Butyllithium (2.3M, 4.2 ml, 9.72 mmol) is added, and the resulting solution is stirred for 15 minutes. A tetrahydrofuran (10 ml) solution of ethyl 5-chloro-2-hydroxy-α-oxobenzenacetate (0.74 g, 3.24 mmol) is then added, after which the solution is allowed to warm to ambient temperature over a 30 minute period. The contents are then poured into 5% hydrochloric acid (100 ml) and extracted into ethyl acetate. The organics are washed with 10% sodium bicarbonate and brine, then dried (sodium sulfate), and concentrated to give 1.51 g of a crude solid. Chromatography (Kieselgel 60, dichloromethane) affords N-[4-[2-(3,4-dimethoxyphenyl)ethyl]phenyl]-2-hydroxy-5-chloro-α-oxobenzeneacetamide (0.86 g, 61%), mp 128°-130° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([NH:14]C)[CH2:11][C@@H:10]([C:16](=[O:39])[N:17](C2CC2)[C:18]2[CH:19]=[CH:20][C:21]3[O:26][C:25]([CH3:28])([CH3:27])[C:24](=[O:29])[N:23]([CH2:30][CH2:31][CH2:32][O:33][CH3:34])[C:22]=3[CH:35]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:40]1([C:46]2([C:49]([OH:51])=O)[CH2:48][CH2:47]2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([NH:14][C:49]([C:46]2([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:47][CH2:48]2)=[O:51])[CH2:11][C@@H:10]([C:16](=[O:39])[NH:17][C:18]2[CH:19]=[CH:20][C:21]3[O:26][C:25]([CH3:27])([CH3:28])[C:24](=[O:29])[N:23]([CH2:30][CH2:31][CH2:32][O:33][CH3:34])[C:22]=3[CH:35]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: CN[C@H]1C[C@@H](C(=O)N(c2ccc3c(c2)N(CCCOC)C(=O)C(C)(C)O3)C2CC2)CN(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCCN1C(=O)C(C)(C)Oc2ccc(NC(=O)[C@@H]3C[C@H](NC(=O)C4(c5ccccc5)CC4)CN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (3R,5S)-3-{Cyclopropyl-[4-(3-methoxy-propyl)-2,2-dimethyl-3-oxo-3,4-di hydro-2H-benzo[1,4]oxazin-6-yl]-carbamoyl}-5-methylamino-piperidine-1-carboxylic acid tert-butyl ester (110 mg, 0.2 mmol) and 1-phenyl-1-cyclopropanecarboxylic acid (40 mg, 0.24 mmol) in DMF (2 mL) are added EDCI. HCl (60 mg, 0.3 mmol) and HOAt (40 mg, 0.3 mmol) at 0° C. After stirred at rt overnight, the reaction mixture is diluted with EtOAc. The mixture is washed with water and dried over Na2SO4, filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography to afford (3R,5S)-3-[4-(3-Methoxy-propyl)-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylcarbamoyl]-5-[(1-phenylcyclopropanecarbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a white amorphous, which is treated with 4 N HCl in 1,4-dioxane (3 mL). The solution is concentrated under reduced pressure to give the title compound as a yellow powder. MS: 589 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.01 min.
Reaction SMILES: [CH2:1]([SH:6])[CH:2]([SH:5])[CH2:3][CH3:4].Cl[CH:8]([CH3:12])[C:9](=O)[CH3:10]>>[CH2:3]([CH:2]1[CH2:1][S:6][C:9]([CH3:10])=[C:8]([CH3:12])[S:5]1)[CH3:4]
Reactant: CC(=O)C(C)Cl
Reactant: CCC(S)CS
Product: CCC1CSC(C)=C(C)S1
Yield: 35 %

Procedure:
The procedure of Example 1 (a) is repeated, using 1,2-butanedithiol and 3-chloro-2-butanone to give 2-ethyl-2,3-dihydro-5,6-dimethyl-1,4-dithiin as a colorless oil, bp 68°-81°/0.7, yield 35%, NMR 1.01 (3t), 1.4-2.9 (2m), 1.87 (6s), 2.6- 3.4 (3m). IR, 2910 (sh); 1610 (sh); 1410, 1220 (sh); 1155 (sh); 1070, 735, 700.
Reaction SMILES: [CH2:1]1[C:6]2([O:11][CH:10]=[CH:9][C:8](=[O:12])[CH2:7]2)[CH2:5][CH2:4][NH:3][CH2:2]1.FC(F)(F)C(O)=O.C(N(CC)CC)C.[CH:27]([O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][C:32]=1[CH3:40])([CH3:29])[CH3:28]>C(Cl)Cl>[CH:27]([O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([N:3]2[CH2:2][CH2:1][C:6]3([O:11][CH:10]=[CH:9][C:8](=[O:12])[CH2:7]3)[CH2:5][CH2:4]2)=[O:36])=[CH:33][C:32]=1[CH3:40])([CH3:29])[CH3:28]
Reactant: Cc1cc(C(=O)Cl)ccc1OC(C)C
Reactant: O=C1C=COC2(CCNCC2)C1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCC3(CC2)CC(=O)C=CO3)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 11-oxa-3-azaspiro[5.5]undec-9-en-8-one; 2,2,2-trifluoroacetic acid (2.42 g, 8.6 mmol) in CH2Cl2 (35 mL) was added triethylamine (10.9 mL, 78.2 mmol) followed by the addition of 4-isopropoxy-3-methyl-benzoyl chloride (1.83 g, 8.60 mmol) in CH2Cl2 (5 mL) dropwise. The mixture was stirred at room temperature overnight. The mixture was diluted with CH2Cl2, washed with water, dried over MgSO4, filtered and concentrated to dryness. The crude material was purified by column chromatography (30-50% ethyl acetate-Hex) to provide 3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3-azaspiro[5.5]undec-9-en-8-one (2.65 g) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.27 (t, J=4.0 Hz, 1H), 7.25-7.17 (m, 2H), 6.81 (d, J=8.1 Hz, 1H), 5.43 (d, J=6.1 Hz, 1H), 4.56 (dd, J=12.1, 6.0 Hz, 1H), 4.43-3.61 (m, 2H), 3.33 (s, 2H), 2.55 (s, 2H), 2.20 (s, 3H), 2.13 (d, J=13.2 Hz, 2H), 1.61 (s, 2H), 1.35 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 343.18, found 344.3 (M+1)+; Retention time: 1.50 minutes (3 minute run).
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]CCCCCCCC>CO>[CH2:4]([O:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:30][CH:31]=1)/[CH:5]=[CH:6]/[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCC/C=C/COc1ccc(C(=O)O)cc1

Procedure:
The ester 35 g 565 mg, 1.95 mmol), and lithium hydroxide monohydrate (817 mg, 19.5 mmol) in 20 ml methanol were reacted according to the procedure for compound 36a. The yield was 482 mg (89% of a white powder.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:14]2[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[C:8](=[O:16])[C:7]2[N:17]([CH3:20])[N:18]=[CH:19][C:6]1=2)[CH3:4].ICC[CH2:24][CH2:25][CH2:26][I:27].[CH3:28]N(C)C=O>>[I:27][C:26]1[CH:25]=[CH:24][CH:4]=[C:3]([N:5]2[C:14]3[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=3[C:8](=[O:16])[C:7]3[N:17]([CH3:20])[N:18]=[CH:19][C:6]2=3)[CH:28]=1
Reactant: ICCCCCI
Reactant: CN(C)C=O
Reactant: CCn1c2ccc(C)cc2c(=O)c2c1cnn2C
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc2c(c1)c(=O)c1c(cnn1C)n2-c1cccc(I)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a suspension of sodium hydride (60-72% in mineral oil, 0.14 g, 3.5 mmol), which was washed with hexane and dried in vacuo, in N,N-dimethylformamide (25 ml) was added a N,N-dimethylformamide solution of 1,7-dimethyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one (EXAMPLE 47, step 2, 0.5 g, 2.3 mmol) at 0° C. The mixture was allowed to warm up to room temperature and stirred for 1 h. After 1,5-diiodopentane (1.74 ml, 11.7 mmol) was added at 0° C., the mixture was stood at room temperature for 2 days. Additional sodium hydride (60-72% in mineral oil, 92 mg, 2.3 mmol) was added at room temperature. The mixture was stirred for 6 h, quenched with water and extracted with ethyl acetate (50 ml×2). The organic layer was dried over magnesium sulfate and concentrated. Purification by column chromatography on silica gel eluting with ethyl acetate/hexane (1:1) gave 436 mg (46%) of the title compound as a yellow solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][N:9]1[C:17](=[O:18])[C:16]2[N:15](CC=C)[C:14]([Cl:22])=[N:13][C:12]=2[N:11]([CH2:23][CH2:24][CH2:25][CH3:26])[C:10]1=[O:27])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:34]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N1CCOCC1>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>[CH2:23]([N:11]1[C:12]2[N:13]=[C:14]([Cl:22])[NH:15][C:16]=2[C:17](=[O:18])[N:9]([CH2:8][CH2:7][CH2:6][N:44]2[CH2:45][CH2:46][N:41]([CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:42][CH2:43]2)[C:10]1=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCOS(C)(=O)=O)c(=O)n2CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCN1
Product: CCCCn1c(=O)n(CCCN2CCN(Cc3ccccc3)CC2)c(=O)c2[nH]c(Cl)nc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 24.1 %

Procedure:
A solution of 3-[3-butyl-8-chloro-2,6-dioxo-7-(2-propen-1-yl)-2,3,6,7-tetrahydro-1H-purin-1-yl]propyl methanesulfonate (0.08 g, 0.19 mmol) in DMF (5 ml) was treated with potassium carbonate (0.08 g, 0.6 mmol) and 1-benzylpiperazine (0.04 g, 0.23 mmol) and then heated at 70° C. for 2 h. The mixture was cooled, evaporated to dryness and partitioned between 10 ml of DCM and 10 ml of water. The organic phase was evaporated to dryness and the residue dissolved in anhydrous THF (5 ml). The solution was cautiously degassed by the repeated application of vacuum to the reaction mixture and subsequent backfilling with nitrogen gas and then treated with tetrakis(triphenylphosphine)palladium(0) (0.010 g, 0.009 mmol) and morpholine (0.200 ml, 2.3 mmol) and the mixture stirred for 2 h in a nitrogen atmosphere. The mixture was evaporated and the residue taken up in 5 ml of methanol and added to a 2 g aminopropyl SPE cartridge which was then washed with methanol and the product eluted using a 3% solution of acetic acid in methanol. Product-containing fractions were pooled and evaporated to dryness. The product was then purified by flash chromatography using a gradient elution from DCM/2% Acetic acid to DCM/20% MeOH/2% Acetic acid and the final product freeze-dried from 1,4-dioxan to give the title compound as a white solid (0.021 g, 24%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:6]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: Cc1ncc(C(CN)N2CCOCC2)cn1
Product: Cc1ncc(C(CNC(=O)c2cccc(F)c2Cl)N2CCOCC2)cn1

Procedure:
From 2-chloro-3-fluorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-morpholinoethanamine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([Br:15])=[CH:17][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1CN
Reactant: O=C(O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCCC1CNC(=O)c1ccc(Br)cc1
Reaction time: 3 h
Yield: 100 %

Procedure:
To 2-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.00 g, 4.97 mmol) and 4-bromo-benzoic acid (996 mg, 4.97 mmol) in DMF (25 mL) was added N-methylmorpholine (655 μl, 5.96 mmol) and HATU (1.89 g, 4.97 mmol). After stirring for 3 hours the reaction was concentrated then diluted with EtOAc and washed with 1N HCl, saturated NaHCO3, and brine. The organic phase was then dried over Na2SO4 and concentrated. The crude material was purified by silica gel chromatography (20-50% EtOAc-hexanes gradient) to afford 2-[(4-bromo-benzoylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.91 g, 4.97 mmol, quantitative yield). LCMS-ESI+: calc'd for C17H24BrN2O3: 383.1 (M+H+). Found: 383.6 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([CH2:20][CH2:21][OH:22])[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:13]([CH3:15])[CH3:14])[C:8](=[O:12])[N:9]([CH3:11])[N:10]=1.CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:19]=[C:18]([CH2:20][C:21]([OH:26])=[O:22])[CH:17]=[C:16]([Cl:23])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:13]([CH3:15])[CH3:14])[C:8](=[O:12])[N:9]([CH3:11])[N:10]=1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(CCO)cc2Cl)nn(C)c1=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC(C)c1cc(Oc2c(Cl)cc(CC(=O)O)cc2Cl)nn(C)c1=O
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
A solution of 6-[2,6-dichloro-4-(2-hydroxy-ethyl)-phenoxy]-4-isopropyl-2-methyl-pyridazin-3-one (36) (330 mg, 0.92 mmol) in acetone (5 mL) was treated with Jones Reagent (0.51 mL of a 2.7M solution,) slowly dropwise at 10° C. The resulting red reaction mixture was stirred at 10° C. for 30 min. The reaction mixture was then concentrated under vacuum. The resulting residue was diluted with ethyl acetate (25 mL) and water (20 mL) and was treated with sodium bisulfite (100 mg). The resulting mixture was shaken and turned from red to green. The aqueous layer was separated and was re-extracted with ethyl acetate (25 mL). The organic layers were combined and washed with a saturated aqueous sodium chloride solution. The organic layer was separated, dried with sodium sulfate, filtered, and concentrated under vacuum. The resulting solid was recrystallized from ethyl acetate and dried under vacuum overnight to afford [3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-acetic acid (37) (70 mg, 19%) as a white solid; EI(+)-HRMS) m/z calcd for C16H16Cl2N2O4 (M+H)+ 371.0560, found 371.0561. Molecular Weight=371.2229; Exact Mass=370.0487
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].F[C:18]1C=CC=C(C=C)C=1O>>[C:1]([Si:5]([O:8][C:9]1[C:14]([CH:15]=[CH2:18])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1cccc(F)c1O
Reactant: Cc1cccc(F)c1O[Si](C)(C)C(C)(C)C
Product: C=Cc1cccc(F)c1O[Si](C)(C)C(C)(C)C

Procedure:
The title compound was prepared in an analogous way to tert-butyl(2-fluoro-6-methylphenoxy)dimethylsilane in Step A of Intermediate J using 2-fluoro-6-vinylphenol. 1H NMR (500 MHz, CDCl3) δ 7.26 (m, 1H), 7.03 (dd, J=17.8, 11.1, 1H), 6.96 (m, 1H), 6.89-6.81 (m, 1H), 5.68 (dd, J=17.8, 1.3, 1H), 5.34-5.24 (m, 1H), 1.02 (s, 9H), 0.19 (d, J=2.4, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16](NC1C=C2OCOC2=CC=1C(=O)C)=[O:17])(=[O:10])=[O:9].[NH2:32][C:33]1[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[CH:37][C:34]=1[C:35]#[N:36].NC1C=C2OCOC2=CC=1C(=O)C>>[Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:32][C:33]1[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[CH:37][C:34]=1[C:35]#[N:36])=[O:17])(=[O:9])=[O:10]
Reactant: COc1cc(N)c(C#N)cc1OC
Reactant: CC(=O)c1cc2c(cc1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl)OCO2
Agent: CC(=O)c1cc2c(cc1N)OCO2
Product: COc1cc(C#N)c(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)cc1OC

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-cyano-4,5-dimethoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide was prepared by the method set forth for N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide (EXAMPLE 148) except that 2-amino-4,5-dimethoxybenzonitrile was used in stead of 2′-amino-4′,5′-(methylenedioxy)acetophenone. N-(4-chloro-3-methyl-5-isoxazolyl)-2-[{2-cyano-4,5-dimethoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide was obtained via HPLC purification as a light brown powder (36% yield, m.p. 53-56° C.).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[CH2:16]([O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 131.3 %

Procedure:
To an ice cold solution of 4-hydroxybenzonitrile (0.50 g, 4.19 mmol) in 10 ml of acetone was added potassium carbonate (0.76 g, 5.49 mmol) followed by benzyl bromide (0.32 ml, 2.73 mmol). The reaction mixture was stirred at 25° C. overnight under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), the reaction mixture was evaporated to dryness under vacuum, added 50 ml water and extracted with ethyl acetate (3×40 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified over silica gel (100-200 M, 10% EtOAc-Hexane) to get the desired product (0.75 g, 85%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([Sn](CCCC)(CCCC)CCCC)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH:26]([S:29]([N:32]1[C:36]2[CH:37]=[C:38](I)[CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[NH2:42])(=[O:31])=[O:30])([CH3:28])[CH3:27]>CN(C)C=O.C(OCC)(=O)C>[CH:26]([S:29]([N:32]1[C:36]2[CH:37]=[C:38]([C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=3[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[NH2:42])(=[O:30])=[O:31])([CH3:28])[CH3:27]
Reactant: CCCC[Sn](CCCC)(CCCC)c1sc(C)nc1-c1ccccc1
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(I)cc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2)c(-c2ccc3nc(N)n(S(=O)(=O)C(C)C)c3c2)s1
Temperature: 25 °C
Yield: 2 %

Procedure:
Stir a mixture of 2-methyl-4-phenyl-5-(tributylstannyl)thiazole (0.1 g, 0.21 mmol), 1-isopropylsulfonyl-2-amino-6-iodobenzimidazole (0.07 g, 0.21 mmol), and (acetonitrile)palladium(II) chloride (0.021 mmol) in dry dimethylformamide (2 mL) at 100° C. for 4 hours under a nitrogen atmosphere. Cool to room temperature and dilute with ethyl acetate (20 mL). Wash sequentially with water (3×5 mL) and saturated aqueous sodium chloride (3×5 mL), dry over sodium sulfate, and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 7:1 dichloromethane:acetonitrile to provide the title compound as a white solid in 2% yield. MS(ES+): m/z=413.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[S:11]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1)(=[O:14])(=[O:13])[NH2:12]>>[S:11]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][N:22]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:19][CH:20]=1)(=[O:14])(=[O:13])[NH2:12]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=Cc2ccc(Cl)cc2)cc1
Yield: 60 %

Procedure:
A solution of 4-chlorobenzaldehyde (5 mmol) and 4-sulfamylphenylhydrazine hydrochloride was subjected to the General Procedure. The title compound, melting point 181–182° C., was obtained in 60% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[NH2:10][CH2:11][C@@H:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]1[OH:25].[O:26]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[ClH:1].[NH2:9][C:3]1[N:4]=[CH:5][N:6]=[C:7]([NH:10][CH2:11][C@@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[OH:25])[C:2]=1[C:36]1[CH:37]=[CH:38][C:33]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CN)[C@H](O)C1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: Nc1ncnc(Cl)c1Cl
Product: Cl
Product: Nc1ncnc(NC[C@@H]2CCNC[C@H]2O)c1-c1ccc(Oc2ccccc2)cc1

Procedure:
(3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-3-ol hydrochloride was prepared from 5,6-dichloropyrimidin-4-amine, (3S,4S)-tert-butyl 4-(aminomethyl)-3-hydroxypiperidine-1-carboxylate, and (4-phenoxyphenyl)boronic acid according to general scheme 3 using methods S1, S2, and S3.
Reaction SMILES: [C:1]([S:14]([NH2:17])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].O[Li:19].O.CC(OC)(C)C.[CH2:27]1[CH2:34][O:33][S:30](=[O:32])(=[O:31])[CH2:29][CH2:28]1>COCCOC>[C:1]([S:14]([NH:17][CH2:34][CH2:27][CH2:28][CH2:29][S:30]([O:33][Li:19])(=[O:32])=[O:31])(=[O:16])=[O:15])([C:4]([C:7]([C:10]([F:13])([F:11])[F:12])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: NS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=S1(=O)CCCCO1
Reactant: [Li]O
Solvent: O
Solvent: COC(C)(C)C
Solvent: COCCOC
Product: [Li]OS(=O)(=O)CCCCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 7 %

Procedure:
C4F9SO2N(H)C4H8SO3Li was prepared essentially according to the procedure described in Preparation 3 replacing C4F9SO2NH(C2H4OH) with C4F9SO2NH2 (15.0 g; 0.05 moles), and the corresponding amounts of the following were used: LiOH—H2O (2.32 g; 0.055 moles), MTBE (100 mL), DME (100 mL), and 1,4-butanesultone (7.5 g; 0.055 moles). A waxy white solid was isolated (1.57 g; 7% yield).
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11](O)=[O:12])=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]2=[O:29])[CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:63]([NH:66][NH2:67])(=[O:65])[CH3:64]>C(OCC)(=O)C.CC(N(C)C)=O>[C:63]([NH:66][NH:67][C:11]([C:10]1[N:2]([CH3:1])[C:3]2[C:8]([N:9]=1)=[C:7]([N:14]1[CH2:19][CH2:18][CH:17]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[NH:22][C:21]3=[O:29])[CH2:16][CH2:15]1)[N:6]=[CH:5][N:4]=2)=[O:12])(=[O:65])[CH3:64]
Reactant: CC(=O)NN
Reactant: Cn1c(C(=O)O)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(=O)NNC(=O)c1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
In a 10 mL round bottomed flask, 9-Methyl-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxylic acid (185 mg, 0.51 mmol, 1 equiv) and HATU (290 mg, 0.76 mmol, 1.5 equiv) were suspended anhydrous DMA (2 mL). Diisopropylethylamine (175 μL, 1.0 mmol, 2 equiv) followed by acetic hydrazide (45 mg, 0.61 mmol, 1.2 equiv) were added and the reaction stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (20 mL), and the extracted with water (20 mL), and aqueous hydrochloric acid solution (0.1 M, 40 mL). The combined aqueous layers were then neutralized to pH=7 with saturated aqueous sodium bicarbonate. The resulting precipitate was filtered off, washed with water (2 mL) and acetonitrile (1 mL) and air dried yielding 135 mg of N′-acetyl-9-methyl-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carbohydrazide in 59% yield. 1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 9.91 (s, 1H), 8.29 (s, 1H), 7.18-7.08 (m, 1H), 6.87 (dt, 3H), 4.52 (t, 1H), 3.92 (d, 3H), 2.31 (s, 2H), 1.86 (s, 3H), 1.79 (d, 2H). MS (EI) for C21H23N9O3: 450 (MH+).