Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.C([C:6]1[C:7](=[O:17])[O:8][C:9]([OH:16])=[C:10](C(=O)C)[C:11]=1[OH:12])(=O)C>[Pd].O1CCCC1>[OH:12][C:11]1[CH2:10][C:9](=[O:16])[O:8][C:7](=[O:17])[CH:6]=1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1C=C(O)CC(=O)O1
Reaction time: 16 h

Procedure:
A mixture of 3.5 g. (0.01 mol) of 1-nitro-3,5-bis-ethoxyoxamoylbenzene (prepared from 3,5-diaminonitrobenzene by reaction with ethoxyoxalyl chloride in pyridine) in 100 ml. of methanol was hydrogenated over 200 mg. of 10% palladium-on-carbon at 50 psi. Reduction was complete in 16 hours. To the mixture was added tetrahydrofuran (about 100 ml.) to dissolve the precipitate, the catalyst was filtered and to the filtrate containing 3,5-bis-ethoxyoxamoylaniline was added 2.12 g. (0.01 mol) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one. This mixture was heated under reflux while 100 ml. of volatile solvent was collected by distillation. Heating was stopped, 50 ml. of methanol was added and the product collected by filtration, giving 5-acetyl-3-[3,5-bis-ethoxyoxamoylphenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 195° C.
Reaction SMILES: [C:1]([O:4][CH2:5][O:6][C:7](=[O:21])[C:8]([NH:19][NH2:20])([CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)(=[O:3])[CH3:2].BrC1[C:32]2[C:27](=[CH:28][CH:29]=C[CH:31]=2)C(=O)O1>>[O:3]=[C:1]1[C:2]2[C:29](=[CH:28][CH:27]=[CH:32][CH:31]=2)[CH:5]([O:6][C:7](=[O:21])[C:8]([NH:19][NH2:20])([CH3:18])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=2)[O:4]1
Reactant: O=C1OC(Br)c2ccccc21
Reactant: CC(=O)OCOC(=O)C(C)(Cc1ccc(O)c(O)c1)NN
Product: CC(Cc1ccc(O)c(O)c1)(NN)C(=O)OC1OC(=O)c2ccccc21

Procedure:
Following the procedure for preparation of compound 104, and substituting bromomethyl acetate with bromophthalide, provided the title compound 122 as a mixture of diastereomers. MS (ESI) m/z 359.03 (M+H+).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[S:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2[NH:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][CH:27]=[CH:26]3)[CH:14]=1>>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([NH:22][C:19]3[CH:18]=[CH:17][N:16]=[C:15]4[CH:14]=[C:13]([C:6]5[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=5)[S:21][C:20]=34)=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: Brc1cc2nccc(Nc3ccc4[nH]ccc4c3)c2s1
Product: CSc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from 4-(methylthio)benzeneboronic acid and (2-bromo-thieno[3,2-b]pyridin-7-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 17. 1H NMR (400 MHz, DMSO) d 11.4 (s, 1H), 10.6 (s, 1H), 8.30 (d, 1H), 7.53 (m, 9H), 7.05 (d, 1H), 6.43 (s, 1H), 2.48 (s, 3H); LC-MS: 388 (MH+); HPLC RT: 6.07 minutes.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH2:14]([C@H:16]1[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][CH2:18][C@@H:17]1[OH:24])[CH3:15]>CC(C)=O>[CH2:14]([C@H:16]1[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][CH2:18][C:17]1=[O:24])[CH3:15]
Reactant: CC[C@H]1CC(C)(C)CC[C@@H]1O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC[C@H]1CC(C)(C)CCC1=O
Reaction time: 0.17 h
Yield: 93.5 %

Procedure:
2.8 ml of Jones' reagent (2.5 M, 7.0 mmol), prepared according to Fieser, vol. 1, p. 142 (CrO3 +H2SO4 +H2O) were added dropwise to a stirred solution of (+)-(1S,2S)-2-ethyl-4,4-dimethyl-1-cyclohexanol (1.09 g, 7.0 mmol) in acetone (70 ml) at 5°. The temperature rose to 7°, and a green suspension was formed. Stirring was continued for 10 min, the reaction mixture was then poured on a mixture of ice/NaCl/pentane, extracted with pentane, washed, dried, concentrated, and the crude product (1.40 g) was distilled in a bulb-to-bulb apparatus (oven 70°, 3 Torr). 1.01 g of (+)-(2S)-2-ethyl-4,4-dimethyl-1-cyclohexanone were obtained (yield 91%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]([NH2:38])=[O:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[C:1]([O:5][C:6]([N:8]([C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36](=[O:37])[NH2:38])=[CH:26][CH:25]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NC(=O)OC(C)(C)C
Reactant: NC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cccc([N+](=O)[O-])c1N(Cc1ccc(-c2ccccc2C(N)=O)cc1)C(=O)OC(C)(C)C
Yield: 74.9 %

Procedure:
A mixture of methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (1.8 g), 4'-bromomethylbiphenyl-2-carboxamide (1.8 g) and K2CO3 (0.86 g) in acetonitrile (25 ml) was heated for 6 hours under reflux. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over MgSO4. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel to afford a yellow syrup (2.3 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl[C:11]1[N:16]=[C:15]([Cl:17])[C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:11]2[N:16]=[C:15]([Cl:17])[C:14]([C:18]([F:20])([F:21])[F:19])=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: FC(F)(F)c1cnc(Nc2ccc(Cl)c(Cl)c2)nc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4.86 g of 3,4-dichloroaniline dissolved in 10 ml of dioxane are added to 6.51 g of 2,4-dichloro-5-trifluoromethyl-pyrimidine in 40 ml of dioxane at ambient temperature. Then 6 ml of 5 M potassium carbonate solution are added and the mixture is stirred for three days at ambient temperature. It is then filtered through Alox B (20 ml) and washed with dioxane. The filtrate is concentrated by evaporation, the residue dissolved in 50 ml methylene chloride and this solution is cooled in a bath of dry ice and acetone. The precipitate is suction filtered and the filtrate is cooled again. After suction filtering again the precipitates are combined and the filtrate is concentrated by evaporation. The residue is separated by chromatography through an RP18 column (gradient: acetonitrile: H2O=20:80 to 80:20).
Reaction SMILES: [CH3:1][C:2]([OH:17])([CH3:16])[CH2:3][O:4][C:5]1([CH3:15])[CH2:14][CH2:13][C:8]2(OCC[O:9]2)[CH2:7][CH2:6]1.Cl.CC(C)=O>O>[OH:17][C:2]([CH3:16])([CH3:1])[CH2:3][O:4][C:5]1([CH3:15])[CH2:14][CH2:13][C:8](=[O:9])[CH2:7][CH2:6]1
Reactant: CC(C)(O)COC1(C)CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(O)COC1(C)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.8 %

Procedure:
A mixture of 2-methyl-1-[(8-methyl-1,4-dioxaspiro[4.5]dec-8-yl)oxy]propan-2-ol (1.81 g), 3N hydrochloric acid (20 mL) and acetone (20 mL) was stirred at room temperature for 18 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=80/20→65/35 (volume ratio)] to give the title compound as a colorless oil (1.05 g, 71%).
Reaction SMILES: [OH-].[Na+].O1CCOCC1.[CH2:9]([O:11][C:12](=[O:44])[C:13]([NH:37][C:38]([O:40][CH2:41][CH:42]=[CH2:43])=[O:39])([CH2:19][C:20]1[O:24][N:23]=[C:22]([CH:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:21]=1)C(OCC)=O)[CH3:10]>C(OCC)(=O)C.S(=O)(=O)(O)O>[C:33]([O:32][C:30]([N:26]1[CH2:27][CH2:28][CH2:29][CH:25]1[C:22]1[CH:21]=[C:20]([CH2:19][CH:13]([NH:37][C:38]([O:40][CH2:41][CH:42]=[CH2:43])=[O:39])[C:12]([O:11][CH2:9][CH3:10])=[O:44])[O:24][N:23]=1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)OC(C)(C)C)no1)(C(=O)OCC)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)OC(C)(C)C)no1)C(=O)OCC
Reaction time: 8 h

Procedure:
Sodium hydroxide, 1M, (21.5 mL, 21.5 mmol) was added in portions over 30 minutes to a dioxane (22 mL) solution of 2-allyloxycarbonylamino-2-[3-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-isoxazol-5-ylmethyl]-malonic acid diethyl ester (10.95 g, 21.5 mmol). After stirring overnight, the reaction had not gone to completion. An additional 0.2 equivalents of 1M sodium hydroxide (4.2 mL, 4.2 mmol) was added and stirring continued for 3 hours. The reaction was diluted with ethyl acetate (50 mL) and 1M sulfuric acid (23 mL) was added dropwise at 0° C. The aqueous portion was extracted twice with ethyl acetate. The combined organic portions were dried over magnesium sulfate and concentrated in vacuo to give a the title compound. The crude product was used directly in the next step without separation of the unreacted diester. MS (Cl) m/z 382.2 (M−99).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=O)[CH:15]=2)[C:10]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:20])=[C:9]1[CH:31]([CH3:33])[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:35][OH:36].N1C=CC=CC=1>CO>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](/[CH:17]=[N:35]/[OH:36])[CH:15]=2)[C:10]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:20])=[C:9]1[CH:31]([CH3:33])[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C=O)cc2n1Cc1ccccc1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(/C=N/O)cc2n1Cc1ccccc1
Temperature: 65 °C
Reaction time: 12 h

Procedure:
To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-formyl-2-isopropyl-1H-indole-3-carboxamide (Compound 53, 12 mg, 0.027 mmol) in MeOH (6 ml) was hydroxylamine hydrochloride (6.0 mg, 0.081 mmol) and pyridine (3 mg, 0.16 mmol). The mixture was stirred at 65° C. for 12 h, and then added concentrated in vacuo. The residue was purified by chromatography on silica gel (0→40% EtOAc-hexanes) to yield the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35](O)=[O:36])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:17]([N:24]1[C:32]2[C:27](=[CH:28][C:29](/[C:33](/[CH3:38])=[CH:34]/[C:35]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:36])=[CH:30][CH:31]=2)[CH:26]=[CH:25]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCn1ccc2cc(/C(C)=C/C(=O)O)ccc21
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: CCCCCCCn1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
217 mg of compound 8 was obtained in a similar manner to those described in the Examples 1 and 2 using 701 mg of ethyl 4-(2-aminophenoxy)butyrate and 470 mg of 3-(1-heptylindol-5 -yl)isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:23]=[CH:22][C:7]([C:8]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[O:9])=[CH:6][CH:5]=1.N12CCCN=C1CCCCC2.Cl>C1COCC1>[CH:3]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[O:9])=[CH:6][CH:5]=1)=[CH2:2]
Reactant: COc1ccc(S(=O)(=O)NC(=O)c2ccc(CCBr)cc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: C=Cc1ccc(C(=O)NS(=O)(=O)c2ccc(OC)cc2)cc1

Procedure:
A solution of 35.85 g (0.09 mol) of N-[4-(2-bromoethyl)benzoyl]-4-methoxybenzenesulfonamide, 27.40 g (0.18 mol) of 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) and 375 ml of THF was stirred at room temperature for 19.5 hrs. Solid formed within 30 mins. The mixture was poured into dilute HCl giving an oily precipitate which crystallized. The solid was collected, washed with water, redissolved in methylene chloride, dried over magnesium sulfate and concentrated to an oil which crystallized. The solid was collected, recrystallized from toluene, collected, washed with ligroine and dried.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[CH:11]=1)=O.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2>>[O:10]1[C:6]2[CH:5]=[CH:4][C:3]([CH:1]=[C:16]3[C:15]4[C:19](=[CH:20][CH:21]=[C:13]([F:12])[CH:14]=4)[NH:18][C:17]3=[O:22])=[CH:11][C:7]=2[CH2:8][CH2:9]1
Reactant: O=Cc1ccc2c(c1)CCO2
Reactant: O=C1Cc2cc(F)ccc2N1
Product: O=C1Nc2ccc(F)cc2C1=Cc1ccc2c(c1)CCO2

Procedure:
2,3-Dihydro-5-formylbenzofuran (commercially available) was condensed with 5-fluoro-2-oxindole to give 0.25 g of 3-(2,3-dihydrobenzofuran-5-ylmethylene)-5-fluoro-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]([OH:14])([CH3:13])[C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:15][C@H:16]([C:18]([C:20]1([NH2:40])[N:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[F:33])[C:24]2[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=2[N:22]([CH3:38])[C:21]1=[O:39])=[O:19])[CH3:17]>>[F:8][C:6]1[CH:5]=[C:4]([C:9]([OH:14])([CH3:13])[C:10]([NH:15][C@H:16]([C:18]([C:20]2([NH2:40])[N:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[C:24]3[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=3[N:22]([CH3:38])[C:21]2=[O:39])=[O:19])[CH3:17])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(O)(C(=O)O)c1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)C1(N)N=C(c2ccccc2F)c2ccccc2N(C)C1=O
Product: C[C@H](NC(=O)C(C)(O)c1cc(F)cc(F)c1)C(=O)C1(N)N=C(c2ccccc2F)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure D above using 3,5-difluorophenyl-α-hydroxy-α-methylacetic acid and 3-(L-alaninyl)-amino-2,3-dihydro-1-methyl-5-(2-fluorophenyl)-1H-1,4-Benzodiazepin-2-one (Example 8-b), the title compound was prepared. 1H NMR (CDCl3, 300 MHz) δ=1.43 (3H, d, J=7.1 Hz), 1.79 (3H, s), 3.47 (3H, s), 4.15 (1H, s), 4.58 (1H, p, J=7.3 Hz), 5.45 (1H, d, J=8.0 Hz), 6.70 (1H, m), 7.14-7.27 (3H, m), 7.32-7.47 (6H, m), 7.55-7.63 (3H, m), 7.78 (1H, d, J=7.8 Hz). HRMS calc for C28H27N4O4F2 521.2000 (MH+), Found: 521.2.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][N:12]([CH3:14])[CH3:13])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[N:19]=1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][N:12]([CH3:14])[CH3:13])=[N:7][N:8]2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH2:24])[N:19]=2)=[CH:4][CH:3]=1
Reactant: CN(C)Cc1n[nH]c2cc(Br)ccc12
Reactant: Nc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)Cc1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (6-Bromo-1H-indazol-3-ylmethyl)-dimethyl-amine (523 mg, 2.05 mmol) in DMF (8 mL) was added NaH (60% oil dispersion) (132 mg, 3.29 mmol) at 0° C. The reaction mixture was allowed to warm up to RT and was stirred for 15 min. A solution of 4-chloropyrimidin-2-amine (533 mg, 4.11 mmol) in DMF (3 mL) was added slowly. The resulting mixture was stirred at 60° C. for 18 hr. When the reaction mixture was partitioned between EtOAc (25 mL) and water (10 mL), precipitation occurred. The solid was collected by suction filtration and was washed with EtOAc to give the title compound: 1H NMR (500 MHz, DMSO) δ 2.22 (6H, s), 3.81 (2H, s), 7.04 (1H, d, J=5.52 Hz), 7.06-7.19 (2H, m), 7.50 (1H, m, J=8.51 Hz), 7.92 (1H, d, J=8.51 Hz), 8.27 (1H, d, J=5.52 Hz), 9.11 (1H, d, J=1.26 Hz); LC-MS: m/z=+348.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[N:16][OH:17])[NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[N:4][O:5][N:6]=1.C1N=CN([C:23](N2C=NC=C2)=[O:24])C=1>O1CCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=3)[C:23](=[O:24])[O:17][N:16]=2)=[N:4][O:5][N:6]=1
Reactant: Nc1nonc1C(=NO)Nc1cccc(Cl)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1nonc1-c1noc(=O)n1-c1cccc(Cl)c1
Yield: 95.4 %

Procedure:
A solution of 4-amino-N-(3-chlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (540 mg, 2.1 mmol) and N,N-carbonyldiimidazole (380 mg, 2.3 mmol) in tetrahydrofuran (10 mL) was heated at 80° C. for 1 h. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with 0.1 N HCl (3×75 mL) and brine (75 mL). The organic layer was dried with sodium sulfate, filtered, and concentrated to give the desired product (560 mg, 94%) as a white solid which was used without further purification. LCMS for C10H7ClN5O3 (M+H)+: m/z=279.9.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:16](=[O:18])[CH3:17])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:34]=[CH:33][C:24]2[NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29]([CH3:31])([CH3:30])[C:23]=2[CH:22]=1.Cl>O1CCOCC1.COCCO>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:16](=[O:18])[CH3:17])=[N:7][C:2]([NH:20][C:21]2[CH:34]=[CH:33][C:24]3[NH:25][C:26](=[O:32])[CH2:27][CH2:28][C:29]([CH3:31])([CH3:30])[C:23]=3[CH:22]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: CC(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: CC(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3)ncc1Cl
Yield: 36.2 %

Procedure:
Combined N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-acetamide (96 mg, 0.317 mmol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (81 mg, 0.397 mmol), 4 N HCl in dioxane (100 ul) and 2-methoxyethanol (4 mL). Heated reaction to 120° C. for 7 hours. Evaporated off solvent and purified with normal phase chromatography eluting with 97/3/1 CH2Cl2/MeOH/NH4OH to yield an off-white solid, N-{(1R,2R)-2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-acetamide (54 mg, 36%). mp 227° C.; LCMS: m/z=471.38 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.71 (dd, 1H, J=8.6, 2.3 Hz), 7.32 (m, 1H), 6.91 (d, 1H, J=8.6 Hz), 6.81 (m, 1H), 6.13 (m, 1H), 3.79 (m, 2H), 3.20 (s, 1H), 2.35 (m, 2H), 2.25 (m, 1H), 2.11 (m, 2H), 2.04 (m, 1H), 1.81 (m, 8H), 1.36 (m, 8H).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(C(C)(C)C)cc1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-tert-butylphenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C20H20N4, 317. Found, 317.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N+:22]([CH3:25])([O-:24])=[O:23].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12](=[O:13])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH:8]=[CH:7][C:3]=1[C:4]([CH2:25][N+:22]([O-:24])=[O:23])=[O:6]
Reactant: C[N+](=O)[O-]
Reactant: Cc1ccccc1CC(=O)Nc1ccc(C(=O)O)c(Cl)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1CC(=O)Nc1ccc(C(=O)C[N+](=O)[O-])c(Cl)c1

Procedure:
This compound was obtained by carrying out the procedure as in Example 42 starting with 19 g (62.5 mmol) of 2-chloro-4-[(2-methylbenzyl)carbonylamino]benzoic acid obtained in step a), 3.18 g of nitromethane, 11 g (67.6 mmol) of diethyl cyanophosphonate, 16.8 g (167 mmol) of triethylamine in 205 ml of DMF dried over a molecular sieve. After chromatography on a silica column (eluent: dichloromethane-methanol 95:5) and recrystallization from a hexane-ethyl acetate mixture, 0.2 g (Yield=1) of a pale yellow powder is obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C@H:23]3[CH3:27])=[CH:14][CH:13]=2)[CH:11]=1)=[O:6].[C:28]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])([CH3:30])[CH3:29].N1C=CN=C1.CN(C)C=O>[Cl-].[Na+].O>[Si:32]([O:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][C@H:23]3[CH3:27])=[CH:14][CH:13]=2)[CH:11]=1)=[O:6])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)NCCO)cn2)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)NCCO[Si](C)(C)C(C)(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
A mixture of N-(2-hydroxyethyl)-1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazole-4-carboxamide prepared in Example 66 (0.500 g), tert-butylchlorodimethylsilane (0.303 g), imidazole (0.273 g) and N,N-dimethylformamide (5.0 mL) was stirred overnight at room temperature. The reaction mixture was diluted with brine and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=1:1) to give the titled compound (0.550 g) as a colorless solid.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16]C(=O)C(F)(F)F)=[CH:10][CH:9]=2)[N:7]=1.[OH-].[Na+]>CO.O>[NH2:16][CH2:15][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[N:7]=[C:3]([NH2:2])[S:4][CH:5]=2)=[CH:13][CH:12]=1
Reactant: Nc1nc(-c2ccc(CCNC(=O)C(F)(F)F)cc2)cs1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NCCc1ccc(-c2csc(N)n2)cc1
Yield: 92 %

Procedure:
4-{4-(2-Aminoethyl)phenyl}-2-thiazolamine: A solution of N-{2-{4-(2-bromoacetyl)phenyl}ethyl}-2,2,2-trifluoroacetamide (5.55 g, 16.4 mmol), prepared in Example 1(b), and thiourea (1.25 g, 16.4 mmol) in isopropanol (60 mL) was heated at reflux for 1 h. The reaction mixture was concentrated under reduced pressure to give crude N-{2-{4-(2-amino-4-thiazolyl)phenyl}ethyl}-2,2,2-trifluoroacetamide hydrobromide (6.51 g, ~100% yield). A solution of the crude hydrobromide and aqueous 4N NaOH (14.3 mL, 57.4 mmol) in MeOH (70 mL) and H2O (10 mL) was heated at reflux for 20 min. The solution was cooled, H2O (30 mL) was added and the MeOH was carefully evaporated under reduced pressure while keeping the solution cool. The resulting suspension was cooled to 0°. The crystals obtained by filtration were washed with cold H2O then air-dried to give 4-{4-(2-aminoethyl)phenyl}-2-thiazolamine (3.3 g, 92% yield): 1H NMR (DMSO-d6) δ 7.69 (d, J=8.2 Hz, 2H), 7.18 (d, J=8.2 Hz, 2H), 7.03 (broad s, 2H), 6.92 (s, 1H), 2.76 (t, J=7.1 Hz, 2H), 2.62 (t, J=7.1 Hz, 2H).
Reaction SMILES: [CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:22]1[CH:27]=[C:26]([NH2:28])[CH:25]=[N:24][CH:23]=1>>[CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([NH:28][C:26]2[CH:27]=[N:22][CH:23]=[N:24][CH:25]=2)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cncnc1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Product: O=C(Nc1cncnc1)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 4b) (100 mg, 0.33 mmol) and 5-pyrimidinamine (CAN 591-55-9, 31.4 mg, 0.33 mmol) as starting materials; off white solid (64 mg, 51.0%). MS (ESI): 381.4 (M+H)+.