Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[N:5]([CH3:24])[C:4]1=[O:25])[CH3:2].C([C@H]1N(C(=O)C2C=CC(O)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[N:5]([CH3:24])[C:4]1=[O:25])[CH3:2]
Reactant: CC[C@@H]1C(=O)N(C)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Agent: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(O)cc1
Product: CC[C@@H]1C(=O)N(C)c2ccc(F)cc2N1C(=O)c1ccc(O)cc1
Yield: 71 %

Procedure:
(3R)-3-Ethyl-6-fluoro-4-(4-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-hydroxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3R)-3-ethyl-6-fluoro-4-(4-hydroxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (71%). [α]D25=−290° (c=0.0095 G/ML, CHCl3); MS (ESI) m/z 329 ([M+H]+); MS (ESI) m/z 327 ([M−H]−); HRMS: calcd for C18H17FN2O3, 328.1223; found (ESI_FT), 329.12887.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][C:24]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: Nc1ccccn1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)Nc1ccccn1
Yield: 21.1 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (1.73 g, 0.014 mole) was added slowly to a stirred and chilled (10°-15° C.) suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.7 g, 0.013 mole) in 50 ml of dry dimethylformamide. The reaction mixture was heated between 60°-90° C. for 5 hours. The solution of the acyl chloride was added dropwise under a nitrogen atmosphere to a stirred, chilled (10°-15° C.) solution of 2-aminopyridine (1.77 g, 0.019 mole), and triethylamine (1.90 g, 0.019 mole) in 75 ml of dry dimethylformamide. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water, diluted with water to the cloud point, and seeded. The crystalline solid was collected by filtration, washed with water, and dried under high vacuum at 70° C. for 2 hours, then at 60° C. overnight to give 1.0 g (20%) of crystals, mp 190°-191° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11]C)=[O:10])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[OH-].[K+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: COC(=O)C(C)(C)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C(=O)O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
In 200 ml of methanol was dissolved 75.5 g of methyl 2-(4-chloro-3-nitrophenyl)-2-methylpropionate. Under ice cooling, 70 ml of an aqueous solution of 49.3 g of potassium hydroxide was added dropwise and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. To the residue were added water and n-hexane to separate the mixture into layers. Concentrated hydrochloric acid was added to the aqueous layer to adjust its pH to 2 or less, followed by extraction with ethyl acetate. The ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 53.1 g of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:5](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[N:6][CH:7]=[CH:8][C:9]=1[Cl:10].C(N(CC)CC)C>O1CCOCC1>[Cl:10][C:9]1[C:4]2[CH2:3][CH2:2][NH:1][CH:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:5]=2[N:6]=[CH:7][CH:8]=1
Reactant: COC(=O)/C=C/c1nccc(Cl)c1CCN
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)CC1NCCc2c(Cl)ccnc21
Yield: 85.9 %

Procedure:
94-5. A yellow solution of (E)-methyl 3-(3-(2-aminoethyl)-4-chloropyridin-2-yl)acrylate (530 mg, 1.49 mmol) and triethylamine (1.04 mL, 7.47 mmol) in dioxane (10 mL) was stirred at 50° C. for 1 h. The solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera One, eluent: gradient from 2% MeOH in DCM to 20% MeOH in DCM in 14 min) to yield the title compound as a clear oil (308 mg). UPLC-MS: MS 241.1 (M+H+); UPLC rt 0.43 min.
Reaction SMILES: [CH3:1][CH:2](O)[CH2:3][NH:4][C:5]([NH:13][C:14]#[N:15])=[N:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][CH:2]1[N:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:5](=[N:13][C:14]#[N:15])[NH:4][CH2:3]1
Reactant: CC(O)CNC(=Nc1ccncc1)NC#N
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1CNC(=NC#N)N1c1ccncc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of N-(2-methyl-2-hydroxyethyl)-N′-cyano-N″-4-pyridylguanidine (0.5 g, 2.2 mmol) and triphenylphosphine (1.2 g, 4.5 mmol) in THF (20 mL) at 0° C. under nitrogen was added diisopropyl azodicarboxylate (0.92 g, 4.5 mmol) dissolved in THF (10 mL) dropwise over 15 minutes. The resulting mixture was stirred at 0° C. for another 2 hours and then warmed to room temperature for 60 hours. After the reaction was complete, the mixture was concentrated and purified by chromatography on silica gel using ethyl acetate as eluant to remove triphenylphosphine and triphenylphosphine oxide followed by clution with a mixture of dichloromethane and methanol (7:1) to afford the product (i.e., Compound 12) as a white solid (0.23 g, 50%).
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[S:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31]>>[CH3:1][N:2]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[C:29]2[S:25][C:26](=[O:31])[NH:27][C:28]2=[O:30])=[CH:19][CH:18]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CN(CCCCOc1ccc(C=O)cc1)c1nc2ccccc2o1
Reactant: O=C1CSC(=O)N1
Product: CN(CCCCOc1ccc(C=C2SC(=O)NC2=O)cc1)c1nc2ccccc2o1

Procedure:
The title compound (m.p. 168° C.) was prepared from 4-[4-(N-methyl-N-(2-benzoxazolyl)amino)butoxy]benzal dehyde (3.5 g) and 2,4-thiazolidinedione (1.4 g) by a similar procedure to that described in Example 4.
Reaction SMILES: C(OC(N1CCC(C(O[C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)CC)CC1)=O)C1C=CC=CC=1.[C:44]([O:48][C:49]([N:51]1[CH2:57][CH2:56][CH2:55][CH:54]([CH:58]([OH:60])[CH3:59])[CH2:53][CH2:52]1)=[O:50])([CH3:47])([CH3:46])[CH3:45].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1.CCOC(C)=O>[C:44]([O:48][C:49]([N:51]1[CH2:57][CH2:56][CH2:55][CH:54]([CH:58]([O:60][C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)[CH3:59])[CH2:53][CH2:52]1)=[O:50])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(O)C1CCCN(C(=O)OC(C)(C)C)CC1
Reactant: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)C4CCCN(C(=O)OC(C)(C)C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.3 %

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (267 mg, 0.82 mmol), 4-(1-hydroxyethyl)azepane-1-carboxylic acid tertbutyl ester (300 mg, 1.23 mmol) and triphenylphosphine (365 mg, 1.39 mmol) in dioxane (3 mL) was added dropwise DIAD (273 ul, 1.39 mmol) and the reaction mixture was stirred at RT for 2 h. The mixture was then diluted with EtOAc and washed with aq. NaOH (1N). The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were then washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in DCM followed by Si-PCC, gradient 0-10% MeOH in EtOAc) affording the title compound as a colorless oil (60 mg, 15%). LCMS: RT 4.08 min [M+H]+ 551.2
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.C(N(CC)CC)C.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>O1CCCC1.O>[OH:6][CH:4]1[CH2:5][N:2]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1
Reactant: OC1CNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC(O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
To a solution of azetidin-3-ol hydrochloride in tetrahydrofuran (90 mL) and water (10 mL) was added triethylamine (15 mL, 0.106 mol) followed by slow addition of benzyl chloroformate (8.0 mL, 0.056 mol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours then partitioned with water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by flash chromatography (SiO2, 25-50% ethyl acetate in hexanes) to afford phenylmethyl 3-hydroxyazetidine-1-carboxylate (3.56 g, 33% yield) as a clear and colorless oil. 1H NMR (400 MHz, CDCl3): 7.36-7.31 (m, 5H), 5.09 (s, 2H), 4.64-4.57 (m, 1H), 4.22 (dd, 2H), 3.88 (dd, 2H), 2.61 (d, 1H, J=4.0 Hz). MS (EI) for C11H13NO3: 208 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]Cl)=[CH:4][CH:3]=1.[O:10]([CH2:17][CH:18]1[O:22][C:21](=[O:23])[NH:20][CH2:19]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][N:20]2[CH2:19][CH:18]([CH2:17][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:22][C:21]2=[O:23])=[CH:4][CH:3]=1
Reactant: O=C1NCC(COc2ccccc2)O1
Reactant: ClSc1ccc(Cl)cc1
Product: O=C1OC(COc2ccccc2)CN1Sc1ccc(Cl)cc1
Yield: 33 %

Procedure:
Analogously to Example 4, 33% yield of 3-(4-chlorophenylthio)-5-phenoxymethyloxazolidin-2-one with a melting point of 98° to 101° C. was obtained from 4-chlorophenylsulphenyl chloride and 5-phenoxymethyloxazolidin-2-one.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:39]=[CH:38][CH:37]=[CH:36][C:19]=3[CH:20](O)[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27]CC4C=CC=CC=4)[CH:22]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O.[H][H]>C(OCC)(=O)C.CO.[Pd]>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:39]=[CH:38][CH:37]=[CH:36][C:19]=3[CH2:20][C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(c1cccc(OCc2ccccc2)c1)c1ccccc1-c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1cccc(Cc2ccccc2-c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Yield: 29.1 %

Procedure:
A solution of 2-(4,5-diphenyl-2-oxazolyl)-3'-benzyloxybenzhydrol (650 mg) in ethyl acetate (3 ml), methanol (3 ml), and 10% hydrogen chloride in methanol (0.3 ml) was stirred in the presence of 10% palladium on carbon--water (50/50 wt. % ) (400 mg) and hydrogen at atmospheric pressure at room temperature for 10 hours. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was chromatographed (toluene--ethyl acetate) over silica gel to afford 3-[[2-(4,5-diphenyl-2-oxazolyl)phenyl]methyl]phenol (150 mg) as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:21][NH2:22])[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH:23](OCC)(OCC)OCC>>[Br:1][C:2]1[N:3]2[CH:23]=[N:22][N:21]=[C:4]2[C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)nc2NN)CC1
Reactant: CCOC(OCC)OCC
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)n3cnnc23)CC1
Temperature: 130 °C
Yield: 69 %

Procedure:
A 50 mL round bottom flask was charged with tert-butyl 4-(5-bromo-3-hydrazinylpyrazin-2-yl)piperazine-1-carboxylate (5.8 g, 20 mmol) and triethyl orthoformate (60 mL). The resulting solution was heated at 130° C. for 3 h. TLC indicated a complete conversion. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel with 2% methanol in dichloromethane, to afford 5.3 g (69%) of the product as a yellow solid. MS m/z: 383 (M+H+).
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([S:14]([OH:17])(=[O:16])=O)[CH:12]=2)[NH:7][C:6]1=[O:18])[CH3:3].[CH3:19][O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24]C=1N.CS(O)(=O)=O>C(O)C>[CH3:19][O:20][C:21](=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[NH:2][CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([S:14](=[O:16])(=[O:17])[NH:7][CH:8]([CH3:13])[CH3:9])[CH:12]=2)[NH:7][C:6]1=[O:18]
Reactant: COC(=O)c1ccccc1N
Reactant: CN(C)C=C1C(=O)Nc2ccc(S(=O)(=O)O)cc21
Agent: CS(=O)(=O)O
Solvent: CCO
Product: COC(=O)c1ccccc1NC=C1C(=O)Nc2ccc(S(=O)(=O)NC(C)C)cc21
Temperature: 150 °C

Procedure:
A mixture of rpm282 (0.260 g, 0.841 mmol) methyl-2-aminobenzoate (0.139 g, 0.925 mmol, 1.2 eq) and methansulfonic acid (0.088 g, 0.925 mmol, 1.1 eq) in ethanol (5 mL) was heated in the microwave at 150° C. for 5 min. The reaction mixture was cooled to 0° C., and the orange precipitate was collected by filtration and dried, to give pure rpm335 (0.207 g, 0.498 mmol, 59%). MS (API-ES): m/z 416 (M+H)+; HRMS (API-ES) m/z Found: 416.1276 (M+H)+.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])=[O:9])=[CH:6][N:5]=1)[NH2:3].C([O:20][CH:21]=[C:22]([C:28](OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])C.C(=O)([O-])[O-].[K+:37].[K+]>O.C(O)C>[CH2:26]([O:25][C:23]([C:22]1[CH:28]=[N:3][N:2]([C:4]2[CH:17]=[CH:16][C:7]([C:8](=[O:9])[NH:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:6][N:5]=2)[C:21]=1[O-:20])=[O:24])[CH3:27].[K+:37]
Reactant: COCCCNC(=O)c1ccc(NN)nc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnn(-c2ccc(C(=O)NCCCOC)cn2)c1[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
A mixture of 6-hydrazinyl-N-(3-methoxypropyl)nicotinamide hydrochloride (7.5 g, 28.8 mmol), diethyl 2-(ethoxymethylene)malonate (14 mL, 69 mmol), and potassium carbonate (9.94 g, 71.9 mmol) in water (150 mL) and ethanol (25 mL) and stirred at 25° C. for 3 h and then at 60° C. for 18 h. The mixture was cooled to 20° C. to give a precipitate which was collected by filtration and washed with water to give the title compound (8.14 g, 73.2% yield) as a yellow solid. MS m/z 349 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (t, J=7.1 Hz, 3 H) 1.77 (quin, J=6.7 Hz, 2 H) 3.25 (s, 3 H) 3.27-3.34 (m, 2 H) 3.38 (t, J=6.3 Hz, 2 H) 4.02 (q, J=7.1 Hz, 2 H) 7.52 (s, 1 H) 8.10 (dd, J=8.8, 2.5 Hz, 1 H) 8.42 (dd, J=8.8, 0.5 Hz, 1 H) 8.48 (t, J=5.6 Hz, 1 H) 8.78 (dd, J=2.4, 0.6 Hz, 1 H).
Reaction SMILES: [OH:1][C:2]1[C:19]([NH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35](OC)=[O:36].O>CN(C=O)C>[O:36]=[C:35]1[CH2:34][O:1][C:2]2[C:19](=[CH:18][C:5]3[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=3[CH:3]=2)[N:20]1[CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)c(NC3CCOCC3)cc2CC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)N(C1CCOCC1)C(=O)CO3
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 215 mg of t-butyl 7-hydroxy-8-(tetrahydro-2H-pyran-4-ylamino)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in 4 ml of DMF were added 98 mg of potassium carbonate and 0.062 ml of methyl bromoacetate, followed by stirring at room temperature for 6 hours. To the reaction mixture was added water, followed by extraction with EtOAc twice. The combined organic layer was washed with saturated brine three times, dried over anhydrous sodium sulfate, and then filtered, and the solvent was evaporated under reduced pressure. To a solution of 259 mg of the resulting residue in 7 ml of EtOH was added 1.2 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at 50° C. overnight. Further, 1.2 ml of a 1 M aqueous hydrochloric acid solution was added thereto under ice-cooling, followed by extraction with chloroform twice, and the combined organic layer was dried over anhydrous sodium sulfate and then filtered. The solvent was evaporated under reduced pressure. To a solution of 239 mg of the resulting residue in 4 ml of DMF were added 120 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 84 mg of HOBt at room temperature, followed by stirring at room temperature overnight. Water was added thereto, followed by extraction with EtOAc twice. The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 153 mg of t-butyl 3-oxo-4-(tetrahydro-2H-pyran-4-yl)-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate as a white solid.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]#[N:12])[CH2:7][CH2:6]2)[O:4]CC1.Cl>CC(C)=O>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([C:11]#[N:12])[CH2:7][CH2:6]1
Reactant: N#CC1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: N#CC1CCC(=O)CC1

Procedure:
A solution of 1,4-dioxaspiro[4,5]decane-8-carbonitrile (15.86 g, 94.8 mmol) (prepared according to the procedure in Lucija Peterlin-Masic, Andreja Jurca, Petra Marrinko, Anita Jancar and Danijel Kikelj, Tetrahedron 2002, 58, 1557-1563), in a mixture of aqueous hydrochloric acid (2 N, 60 mL) and acetone (100 mL) was refluxed overnight. The acetone was removed by evaporation. The aqueous phase was extracted with ethyl acetate three times. The combined organic extracts were washed with water one time and then dried over magnesium sulfate. The solution was filtered and concentrated to yield 4-oxo-cyclohexanecarbonitrile as a colorless oil, which was used in the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:13]([O:20][CH3:21])=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[N:7]([CH2:22][CH2:23][CH2:24][CH2:25]O)[C:6]=2[C:5]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:12]4[C:13]([O:20][CH3:21])=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=4)[CH2:25][CH2:24][CH2:23][CH2:22][N:7]3[C:6]=2[C:5]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(OC)nc3OC)n(CCCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccncc1
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(OC)nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.4 %

Procedure:
To a solution of 4-[4-chloro-2-[(2,6-dimethoxypyridin-3-yl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butan-1-ol (Reference Example 44; 80 mg, 0.18 mmol) in pyridine (1.8 mL) was added methanesulfonyl chloride (0.070 mL, 0.89 mmol) dropwise at 0° C. The mixture was warmed to room temperature and stirred for 16 hr. Aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The resulting crude mesylate was dissolved in N,N-dimethylformamide (3.6 mL) and potassium carbonate (123 mg, 0.89 mmol) was added. The mixture was stirred at 80° C. for 16 hr. Water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 5-20% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give a solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound (15 mg, 0.035 mmol, 19%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][CH:14]1[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]1)[CH2:5]2.[CH3:22][N:23](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[Cl:11][C:9]1[CH:10]=[C:2]([C:22]#[N:23])[CH:3]=[C:4]2[C:8]=1[C:7](=[O:12])[N:6]([CH2:13][CH:14]1[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]1)[CH2:5]2
Reactant: O=C1c2c(Cl)cc(Br)cc2CN1CC1CCC(F)(F)CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cc(Cl)c2c(c1)CN(CC1CCC(F)(F)CC1)C2=O
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
5-bromo-7-chloro-2-[(4,4-difluorocyclohexyl)methyl]isoindolin-1-one (1.14 g, 3.01 mmol) was set stirring in DMF (10 mL) under argon and Zn(CN)2 (389 mg, 3.31 mmol) and Pd(PPh3)4 (347 mg, 0.3 mmol) were added. The reaction was stirred at 80° C. for 1.5 hours. The reaction was partitioned between ethyl acetate and water and the organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the product was purified by column chromatography (40% EtOAc/Hexanes) to afford the title compound as a yellow foam (60 mg, 80%). 1H NMR (300 MHz, CDCl3): 7.72 (s, 1H), 7.65 (s, 1H), 4.45 (s, 2H), 3.53 (d, 2H), 2.11-2.15 (m, 2H), 1.66-1.91 (m, 5H), 1.41-1.50 (m, 2H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9](COCC[Si](C)(C)C)[N:8]=1.C(Cl)Cl.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[S:5][C:6]=1[C:7]1[NH:11][CH:10]=[N:9][N:8]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2sc(-c3ccncc3)cc2Br)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Brc1cc(-c2ccncc2)sc1-c1nnc[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 322.6 %

Procedure:
4-[4-Bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-thienyl]pyridine (111.0 mg, 0.224 mmol) was dissolved in methylene chloride (3.0 mL, 47 mmol). Trifluoroacetic acid (3.0 mL, 39 mmol) was added and the solution was stirred at rt overnight. After the reaction was completed saturated NaHCO3 (1 mL) was added and the reaction was stirred at rt for 20 min. EtOAc (5 mL) was added, the organic layer was separated, washed with brine, dried over MgSO4, filtered, concentrated and the obtained residue was purified by column chromatography (SiO2, elution with 2-20% MeOH in DCM) to give the title compound as a yellow solid (222 mg, 54%). LCMS: (FA) ES+ , 307, 309. 1H NMR (400 MHz, d6-DMSO)) δ: 14.5 (s, br, 1H), 8.70-8.72 (dd, J=1.5 Hz, 2H), 8.10 (s, 1H), 7.90-7.94 (dd, J=1.5 Hz, 2H)