Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[C:4]([CH3:20])[CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)O1.C(=O)([O-])O.[Na+]>O1CCOCC1.O.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[NH2:33][C:32]1[CH:34]=[CH:35][C:29]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:20])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[O:11])=[CH:30][CH:31]=1
Reactant: Cc1cc(Cl)ccc1/C=C/C(=O)c1ccc(=O)n(C)c1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: O=C([O-])O
Solvent: C1=CCCC=CCC1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(N)cc1

Procedure:
In analogy to example 203, step 1, 5-[(E)-3-(4-chloro-2-methyl-phenyl)-acryloyl]-1-methyl-1H-pyridin-2-one (example 323, step 3) was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in the presence of chloro(1,5-cyclooctadiene)rhodium(I) dimer and sodium hydrogencarbonate in 1,4-dioxane and water at 60° C. to give the title compound as a light brown solid, MS (ESI+): m/z=381.3 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)C.[OH-].[Na+]>C(O)C.O>[Cl:21][C:17]1[CH:16]=[C:15]([C:7]2[N:6]([CH2:5][C:4]([OH:22])=[O:3])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21

Procedure:
A mixture of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester (6.0 g, 0.019 mole), sodium hydroxide pellets (0.9 g, 0.023 mole), and 50 ml of ethanol-water (2:1) was refluxed for 1 hour. The reaction mixture was cooled and the ethanol evaporated in vacuo. The residual aqueous mixture was diluted with water (40 ml) and extracted with diethyl ether (2×25 ml). The aqueous portion was acidified with concentrated hydrochloric acid to a pH of 5-6. After precipitation was complete, the solid was collected by filtration, giving 5.9 g (100%). Recrystallization from ethanol gave 4.7 g of cream colored needles, mp 214°-216° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]([CH2:18][C:19]2[CH:40]=[CH:39][C:22]([CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[C:27]([F:38])[CH:26]=3)=[CH:21][CH:20]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)C.O1CCCC1.O>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:7]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:27]([F:38])[CH:26]=3)=[CH:39][CH:40]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(Cn3nc(C(C)(C)C)cc3CCc3ccccc3)cc2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(CCc2ccccc2)n(Cc2ccc(COc3ccc(CCC(=O)O)c(F)c3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
The oil obtained in Example 138 was dissolved in ethanol (3 mL) and tetrahydrofuran (3 mL), and 1 N aqueous sodium hydroxide solution (2 mL) was added. The mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with water, and neutralized with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (Manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1-1:4) to give the title compound (91 mg, yield 18%, 2 steps) as colorless crystals. 1H NMR (CDCl3) δ: 1.32 (9H, s), 2.62 (2H, t, J=7.6 Hz), 2.68-2.76 (2H, m), 2.77-2.85 (2H, m), 2.89 (2H, t, J=7.6 Hz), 4.96 (2H, s), 5.22 (2H, s), 5.97 (1H, s), 6.59-6.66 (2H, m), 6.98-7.12 (5H, m), 7.16-7.34 (5H, m).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:18][C:17](/[CH:19]=[CH:20]/[C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]4)=[C:23]([O:33][CH3:34])[CH:22]=3)=[N:16][C:15]=2[C:35](OC)=[O:36])=[CH:10][CH:9]=1.C(OCC)(=O)C>C1COCC1.[Cl-].[Na+].O>[F:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[NH:18][C:17](/[CH:19]=[CH:20]/[C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]4)=[C:23]([O:33][CH3:34])[CH:22]=3)=[N:16][C:15]=2[CH2:35][OH:36])=[CH:12][CH:13]=1
Reactant: COC(=O)c1nc(/C=C/c2ccc(-n3cnc(C)c3)c(OC)c2)[nH]c1-c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/c2nc(CO)c(-c3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
LAH (18 mg) was added to a solution of methyl 5-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-1H-imidazole-4-carboxylate (50 mg) in THF (5 mL), and the reaction solution was stirred at room temperature for 1.5 hours. Ethyl acetate and brine were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate->ethyl acetate:methanol=5:1). The resulting solid was suspended in diethyl ether and collected by filtration to obtain 36 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([CH:9]3[CH2:11][CH:10]3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH2:18][O:19][CH:20]2[CH2:26][CH:25]3[N:27]([C:28]4[S:29][C:30]5[CH:36]=[C:35]([C:37]([O:39]CC)=[O:38])[CH:34]=[CH:33][C:31]=5[N:32]=4)[CH:22]([CH2:23][CH2:24]3)[CH2:21]2)[CH2:3][CH2:2]1.CO.O.[Li+].[OH-]>C1COCC1>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([CH:9]3[CH2:11][CH:10]3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH2:18][O:19][CH:20]2[CH2:26][CH:25]3[N:27]([C:28]4[S:29][C:30]5[CH:36]=[C:35]([C:37]([OH:39])=[O:38])[CH:34]=[CH:33][C:31]=5[N:32]=4)[CH:22]([CH2:23][CH2:24]3)[CH2:21]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1ccc2nc(N3C4CCC3CC(OCc3c(C5CC5c5ccccc5)noc3C3CC3)C4)sc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2nc(N3C4CCC3CC(OCc3c(C5CC5c5ccccc5)noc3C3CC3)C4)sc2c1

Procedure:
A suspension of ethyl 2-(3-((5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6-carboxylate (0.03 g, 0.05 mmol) in THF:MeOH:H2O=3:2:1 solution (0.6 mL) was treated with 6N LiOH (0.05 mL) at rt for 14 h. The volatiles were removed in vacuo, the residue diluted with water (1 mL), and 6N HCl was added to adjust pH to 2. The solids were collected by filtration and dried under vacuum to afford 2-(3-((5-cyclopropyl-3-(2-phenylcyclopropyl)isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octan-8-yl)benzo[d]thiazole-6 carboxylic acid as hydrochloride salt.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[C:7]([OH:9])=[O:8].C(N(CC)CC)C.[CH:17](O)([CH3:19])[CH3:18].[Cl-].[Na+]>CN(C)C=O.S(Cl)(Cl)=O>[CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[C:7]([O:9][CH:17]([CH3:19])[CH3:18])=[O:8]
Reactant: Cc1nnsc1C(=O)O
Reactant: CC(C)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nnsc1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.8 %

Procedure:
To 1.0 g (6.9 mmoles) of 4-methyl-1,2,3-thiadiazole-5-carboxylic acid were added 40 ml of thionyl chloride and 2 drops of dimethylformamide at room temperature, and the resulting mixture was refluxed with heating or 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and the excess thionyl chloride was distilled off and 7.0 ml of tetrahydrofuran was added to the residue. Then, 2.1 g (21 mmoles) of triethylamine and 0.83 g (13.8 mmoles) of isopropanol were added and the resulting mixture was stirred at room temperature for 18 hours, after which a saturated aqueous sodium chloride solution was added. The desired compound was extracted with ethyl acetate and the organic layer was washed successively with diluted hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (n-hexane:ethyl acetate=10:1) to obtain 1.0 g of the desired compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]2[C:12](=[N:15]O)[CH2:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1>CO.O1CCCC1.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]2[CH:12]([NH2:15])[CH2:13][O:14][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: COCCOc1cccc2c1C(=NO)CO2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COCCOc1cccc2c1C(N)CO2
Reaction time: 120 h
Yield: 109.9 %

Procedure:
A mixture of the above described 4-(2-methoxy-ethoxy)-benzofuran-3-one oxime (1.19 g, 5 mmol) in methanol (100 mL) and tetrahydrofuran (100 mL) with 10% palladium on carbon (1.42 g) was hydrogenated at 23° C. and atmospheric pressure for 5 days. Filtered the catalyst off, washed with tetrahydrofuran, evaporated the filtrate totally and dried in high vacuum to give the title compound as a red oil (1.15 g, 90%, ca. 90% purity, contains residual starting material); MS: m/e=193.1 (M−NH2+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](C2C=CC=C(S(C3C=C4C(=C(C)C=3)N=CC(C(N)=O)=C4NC3C=CC=C(OC)C=3)(=O)=O)C=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([S:48]([C:51]2[CH:52]=[C:53]3[C:58](=[C:59]([CH3:61])[CH:60]=2)[N:57]=[CH:56][C:55]([C:62]([NH2:64])=[O:63])=[C:54]3[NH:65][C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([O:72][CH3:73])[CH:67]=2)(=[O:50])=[O:49])=[CH:44][CH:43]=1>>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:42]2[CH:47]=[CH:46][C:45]([S:48]([C:51]3[CH:52]=[C:53]4[C:58](=[C:59]([CH3:61])[CH:60]=3)[N:57]=[CH:56][C:55]([C:62]([NH2:64])=[O:63])=[C:54]4[NH:65][C:66]3[CH:71]=[CH:70][CH:69]=[C:68]([O:72][CH3:73])[CH:67]=3)(=[O:50])=[O:49])=[CH:44][CH:43]=2)=[CH:5][CH:4]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4ccc(Br)cc4)cc23)c1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(-c5ccc(CO)cc5)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4ccc(-c5ccc(CO)cc5)cc4)cc23)c1
Temperature: 25 °C
Yield: 77 %

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 64, using Intermediate 63 (1.38 mmol) as substrate. The crude product was triturated in 15 mL of ethyl acetate for 10 min. After cooling to room temperature, the suspension was recovered by filtration and washed with ethyl acetate to give the title compound as a yellowish solid (591 mg, 77% for 3 steps). ES/MS calcd. for C31H28N3O5S+ 554.2. Found m/z=554.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[F:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[F:26])[CH2:9]/[C:10](/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:28]\[OH:29])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccc(Cl)cc2F)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(CC(c2ccc(Br)cc2)c2ccc(Cl)cc2F)=N/O)ccn1

Procedure:
In analogy to example 1, step 2, 3-(4-bromo-phenyl)-3-(4-chloro-2-fluoro-phenyl)-1-(2-methyl-pyridin-4-yl)-propan-1-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing 10% of the corresponding Z isomer as an off-white powder, MS (ESI+): m/z=448.9 [M+H]+.
Reaction SMILES: [C:1]([O:10]N1C(=O)CCC1=O)([O:3][CH2:4][CH2:5][Si:6]([CH3:9])([CH3:8])[CH3:7])=O.[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:27][NH:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:24])([CH3:21])([CH3:20])[CH3:19].C([O-])([O-])=O.[Na+].[Na+].O>C(Cl)Cl>[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:33][CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)[CH2:27][N:28]([CH2:29][CH2:30][CH2:31][CH3:32])[C:1]([O:3][CH2:4][CH2:5][Si:6]([CH3:7])([CH3:8])[CH3:9])=[O:10])=[O:24])([CH3:19])([CH3:20])[CH3:21]
Reactant: CCCCNC[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCN(C[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 106.5 %

Procedure:
Solid Teoc-OSu (390 mg, 1.5 mmol) was added to a vigorously stirred 2-phase mixture of (2S)-2-(tert-butoxycarbonylamino)-1-butylamino-3-cyclohexylpropane (312.8 mg, 1.0 mmol), Na2CO3 (525 mg, 5.0 mmol), H2O (5.0 mL), and CH2Cl2 (25.0 mL). The mixture was stirred for 90 min at rt and the reaction was taken up in CH2Cl2 (50 mL), washed with brine (3×10 mL), dried over Na2SO4, decanted, and stripped to give a clear oil. This oil was separated on a 4 g SiO2 column to give crude (2S)-2-(tert-butoxycarbonylamino)-1-(N-butyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)-3-cyclohexylpropane (486.5 mg, 106%) as a clear oil (quant). MS ESI+ve m/z 479 (M+Na). The crude product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([OH:18])=O)=[CH:10][CH:9]=1.S(Cl)([Cl:21])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([Cl:21])=[O:18])=[CH:10][CH:9]=1
Reactant: O=C(O)CCc1ccc(-c2ccccc2Cl)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CCc1ccc(-c2ccccc2Cl)cc1
Temperature: 60 °C

Procedure:
β-(2'-chloro-4-biphenylyl)propionic acid (26 g.) is treated with thionyl chloride (18 g.) at 0°-5°C. After 10 mins the temperature is raised to 60°C for 30 mins, then the residue is distilled at 0.05 mm to give β-(2'-chloro-4-biphenylyl)propionyl chloride.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[O:7][CH:8]=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[CH2:1]([N:5]([C:6]1[O:7][CH:8]=[C:9]([CH3:11])[N:10]=1)[C:12](=[O:14])[CH3:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1nc(C)co1
Reactant: CC(=O)OC(C)=O
Product: CCCCN(C(C)=O)c1nc(C)co1
Yield: 75.4 %

Procedure:
The procedure of Example 17 was followed using 15.0 g. (0.0974 m) of 2-butylamino-4-methyl oxazole and 25 c.c. of acetic anhydride. B.p. = 58°-60° C/0.1 mm. wt. = 14.4 g. yield = 75.4%.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:29]([CH3:31])[CH3:30]>>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH:29]([CH3:31])[CH3:30])[CH2:21][CH2:20]1
Reactant: CC(C)I
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCN(C(C)C)CC3)c2n1

Procedure:
Prepared similarly to Example 82 from 2-(butyloxy)-8-(methyloxy)-9-[4-(4-piperidinyl)butyl]-9H-purin-6-amine and 2-iodopropane.
Reaction SMILES: Br.[CH3:2][C:3]1([CH3:9])[CH2:7][NH:6][C:5](=[NH:8])[NH:4]1.[C:10](OCC)(=[O:17])[CH2:11][C:12](OCC)=[O:13].C[O-].[Na+]>>[OH:17][C:10]1[N:8]=[C:5]2[NH:4][C:3]([CH3:9])([CH3:2])[CH2:7][N:6]2[C:12](=[O:13])[CH:11]=1
Reactant: CC1(C)CNC(=N)N1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Br
Agent: C[O-]
Agent: [Na+]
Product: CC1(C)Cn2c(nc(O)cc2=O)N1

Procedure:
The process is carried out according to the procedure described in stage g of Example 1, using 5 g of 4,4-dimethylimidazolidin-2-ylideneamine hydrobromide, 4 ml of diethyl malonate and 2.8 g of sodium methoxide. 4.5 g of 7-hydroxy-2,2-dimethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one are thus obtained in the form of a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].[S:6](Cl)([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7]>N1C=CC=CC=1.O>[S:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCCl)cc1
Reaction time: 16 h

Procedure:
A solution of 3-chloro-1-propanol (1.88 g, 20 mmole) in 20 ml of pyridine was treated at 0° with tosyl chloride (7.6 g, 40 mmole). The solution was warmed to 23°, and stirred 16 hours. The reaction was diluted with 100 mL of H2O and stirred for 90 minutes, and extracted with Et2O. The extracts were washed with 1N HCl, dried, and the solvents thoroughly removed, and gave the titled product, 2.3 g (46%). MS (ESI) 188 (MH+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:19][C:18]([N:20]3[CH2:23][C:22]4([CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]4)[CH2:21]3)=[N:17][N:16]=2)=[C:11]([F:36])[C:10]=1[F:37])C1C=CC=CC=1.CCOC(C)=O.C(Cl)Cl>CO.C(Cl)Cl.CO.[Pd]>[F:36][C:11]1[C:10]([F:37])=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[C:15]1[S:19][C:18]([N:20]2[CH2:23][C:22]3([CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]3)[CH2:21]2)=[N:17][N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(-c3ccc(OCc4ccccc4)c(F)c3F)s1)C2
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1nnc(-c3ccc(O)c(F)c3F)s1)C2
Yield: 33.5 %

Procedure:
A suspension of tert-butyl 2-(5-(4-(benzyloxy)-2,3-difluorophenyl)-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (169 mg, 0.32 mmol) in a 1:3 mixture of MeOH:EtOAc (12 mL) was added to a nitrogen flushed flask containing 10% Pd/C (17 mg). The reaction mixture was placed under hydrogen atmosphere (50 psi) on a Parr shaker for 18 hours. Additional 10% Pd/C (169 mg) was added and the reaction was re-subjected to hydrogenation at 50 psi using a Parr shaker for a further 5 days. The reaction mixture was placed under an inert atmosphere (nitrogen), diluted with 10% MeOH/DCM (50 mL), filtered through celite, and rinsed with DCM. The filtrate was concentrated in vacuo to afford a pale brown solid which was re-dissolved in a 1:1 mixture MeOH:DCM (8 mL) and re-subjected to hydrogenation for 4 days at 50 psi using a Parr shaker and 10% Pd/C (169 mg) as the catalyst. The reaction mixture was diluted with 10% MeOH/DCM (50 mL), filtered through celite, and rinsed with DCM. The filtrate was concentrated in vacuo to afford the crude product as a slightly off-white solid. The crude material was purified by flash chromatography using a 12 g silica cartridge running a MeOH/DCM gradient to afford the title compound as an off-white solid (47 mg, 34% yield). LC-MS: Rt 1.27 min; MS m/z 439.3 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 7.65 (td, J=8.5, 2.2 Hz, 1H), 6.92 (td, J=8.5, 1.9 Hz, 1H), 3.87 (s, 4H), 3.20-3.31 (m, 4H), 1.67-1.78 (m, 4H), 1.40 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:14][CH2:13][C:12]3[C:11]([C:15](=[O:28])[CH:16]([C:26]#[N:27])[C:17]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:18])=[N:10][N:9]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:8]=3[C:6]=2[CH:7]=1.[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1>O1CCCC1>[C:38]([CH2:37][CH2:36][C:35]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:14][CH2:13][C:12]3[C:11]([C:15](=[O:28])[CH:16]([C:26]#[N:27])[C:17]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:18])=[N:10][N:9]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:8]=3[C:6]=2[CH:7]=1)=[O:41])([OH:40])=[O:39]
Reactant: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1CSc1ccc(N)cc1-2
Reactant: O=C1CCC(=O)O1
Solvent: C1CCOC1
Product: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1CSc1ccc(NC(=O)CCC(=O)O)cc1-2
Temperature: 0 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
3-(8-amino-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide (1.1 g) dissolved in anhydrous tetrahydrofuran (23 ml) is reacted with succinic anhydride (0.71 g) at the reflux temperature under stirring for 3 hours. After cooling the reaction mixture is diluted with ice water. The precipitate is filtered and washed with water. Crystallization from CHCl3 /methanol yields 0.9 g of 3-[8-(3-carboxy-propanoylamino)-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl]-2-cyano-3-oxo-N-phenylpropanamide, m.p. 230°-233° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[C:16]2[C:17](=[O:23])[N:18]([CH3:22])[CH2:19][CH2:20][O:21][C:15]=2[CH:14]=[CH:13][CH:12]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:10][C:11]2[C:16]3[C:17](=[O:23])[N:18]([CH3:22])[CH2:19][CH2:20][O:21][C:15]=3[CH:14]=[CH:13][CH:12]=2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: CN1CCOc2cccc(N)c2C1=O
Reactant: Clc1cc(I)c(Cl)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CN1CCOc2cccc(Nc3cc(Cl)ncc3Cl)c2C1=O
Temperature: 100 °C
Yield: 47.8 %

Procedure:
2,5-Dichloro-4-iodopyridine (0.2 g, 0.73 mmol), 6-amino-4-methyl-2,3-dihydro-1,4-benzoxazepin-5-one (0.140 g, 0.73 mmol), palladium(II) acetate (6.56 mg, 0.03 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0.025 g, 0.04 mmol) and cesium carbonate (0.476 g, 1.46 mmol) were suspended in dioxane (5 mL). The mixture was heated at 100° C. for 30 minutes in a microwave reactor and then allowed to cool to room temperature. The mixture was loaded onto an SCX column and the product eluted first with MeOH and then with a 7M solution of NH3 in MeOH. Fractions containing product were combined and evaporated. The residue was purified by chromatography on silica, eluting with a gradient of 0-5% MeOH in CH2Cl2. Fractions containing product were combined and evaporated to afford 6-[(2,5-dichloropyridin-4-yl)amino]-4-methyl-2,3-dihydro-1,4-benzoxazepin-5-one (0.118 g, 48% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 3.10 (3H, s), 3.55 (2H, t), 4.34 (2H, t), 6.88-6.91 (1H, m), 7.13 (1H, s), 7.36-7.39 (1H, m), 7.50 (1H, t), 8.26 (1H, s), 9.31 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+ =337.96 and 339.99 and 341.96.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:38][CH3:39])=[CH:4][C:5](OC2C=CC(F)=CC=2F)=[C:6](C2C3C=CN(S(C4C=CC(C)=CC=4)(=O)=O)C=3C(=O)N(C)C=2)[CH:7]=1.C([O-])([O-])OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1.C(OCC)(=O)C>[N:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:38][CH:39]=1
Reactant: CNc1cc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3c2ccn3S(=O)(=O)c2ccc(C)cc2)cc1N
Agent: CCOC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc2[nH]cnc2c1

Procedure:
A suspension of 4-[5-amino-2-(2,4-difluorophenoxy)-4-(methylamino)phenyl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (0.045 g, 0.082 mmol) in tetrahydrofuran (0.80 mL) was treated with ethyl orthoformate (0.041 mL, 0.245 mmol) and p-toluenesulfonic acid monohydrate (1.6 mg, 8.2 μmol) and at 50° C. for 1 h. The reaction mixture was concentrated to give a residue. This residue was diluted with ethyl acetate (30 mL), washed with saturated sodium bicarbonate solution (20 mL), dried with sodium sulfate, filtered, and concentrated to give the intermediate benzimidazole which was used immediately without further purification. The intermediate benzimidazole was dissolved in ethanol (1.00 mL), treated with 1.0 M sodium hydroxide in water (0.327 mL, 0.327 mmol), and heated at 80° C. for 1 h. The reaction mixture was purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (19.5 mg, 59%). 1H NMR (300 MHz, DMSO-d6) δ 11.97 (br s, 1H), 8.19 (s, 1H), 7.68 (s, 1H), 7.40-7.28 (m, 1H), 7.26-7.21 (m, 2H), 7.17 (s, 1H), 7.08-6.88 (m, 2H), 6.24-6.10 (m, 1H), 3.77 (s, 3H), 3.52 (s, 3H); LCMS calculated for C22H17F2N4O2 (M+H)+: m/z=407.1. found: 407.1.