Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:10]([OH:12])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:33]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44]CC(C)C)[CH:39]=1)[CH:34]([CH3:36])[CH3:35]>C(Cl)Cl.C(Cl)(Cl)Cl.CN(C)C=O>[OH:44][C:40]1[CH:39]=[C:38]([O:37][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:43]=[CH:42][C:41]=1[C:10]([C:9]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:22])[CH:8]=1)=[O:12]
Reactant: CC(C)COc1cccc(OCC(C)C)c1
Reactant: CCOC(=O)CCc1cc(C(=O)O)ccc1OCCC(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCc1cc(C(=O)c2ccc(OCC(C)C)cc2O)ccc1OCCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
In 9 ml of methylene chloride is dissolved 0.90 g of 3-(3-ethoxy-3-oxopropyl)-4-isopentyloxybenzoic acid. At ambient temperature, 0.31 ml of oxalyl chloride and 20 μl of N,N-dimethylformamide are successively added and the mixture thus obtained is stirred at ambient temperature for one hour. Then, at 5-10° C., 0.78 g of aluminum chloride and 0.78 g of 1,3-diisobutoxybenzene are successively added. The mixture thus obtained is stirred first at the same temperature as above for 30 minutes and then at ambient temperature for 30 minutes. Further, 0.39 g of aluminum chloride is added at ambient temperature and stirred at the same temperature as above for 30 minutes. The reaction mixture is added to a mixture of chloroform and ice water and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; hexane:ethyl acetate=10:1) to obtain 0.67 g of ethyl 3-[5-(2-hydroxy-4-isobutoxybenzoyl)-2-isopentyloxyphenyl]propanoate as a light yellow oily product.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:30]=[CH:29][C:7]([CH2:8][CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[Li]CCCC.[CH:36]([C:39]1[CH:40]=[C:41]([CH:45]([CH3:49])[CH2:46][CH:47]=O)[CH:42]=[CH:43][CH:44]=1)([CH3:38])[CH3:37]>>[CH:36]([C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]([CH2:46][CH:47]=[CH:9][CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:30][CH:29]=2)[CH3:49])[CH:40]=1)([CH3:38])[CH3:37]
Reactant: COc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)c1cccc(C(C)CC=O)c1
Agent: [Br-]
Agent: [Li]CCCC
Product: COc1ccc(CC=CCC(C)c2cccc(C(C)C)c2)cc1
Yield: 25.8 %

Procedure:
Starting from p-methoxyphenethyltriphenylphosphonium bromide (1.20 g, 2.51 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 1.6 mL, 2.51 mmol, 1.0 equiv.) and 3-(3-isopropylphenyl)butanal (0.72 g, 3.77 mmol, 1.5 equiv.), 0.20 g (26%) of the title compound as a yellow oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 99:1).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:15]3[C:20]([C:21]=2I)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].[CH2:30]([OH:34])[CH2:31][C:32]#[CH:33].O>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:15]3[C:20]([C:21]=2[C:33]#[C:32][CH2:31][CH2:30][OH:34])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: C#CCCO
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(N)c3c2C(=O)NC3=O)c(I)c2ccccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: O
Solvent: CCNCC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(N)c3c2C(=O)NC3=O)c(C#CCCO)c2ccccc21
Temperature: 50 °C
Reaction time: 3.7 h
Yield: 86.6 %

Procedure:
3-Amino-6-[1-(tert-butoxycarbonyl)-3-iodoindol-2-yl]phtalimide (150 mg, 0.298 mmol) was dissolved in diethylamine (7.5 mL), and the solution was added with bis(triphenylphosphine)dichloropalladium (16.7 mg, 0.0234 mmol), copper iodide (11.4 mg, 0.0596 mmol) and 3-butyn-1-ol (0.226 mL, 2.98 mmol), followed by stirring at 50° C. for 3.7 hours under argon atmosphere. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/methanol=10/1) to obtain 3-amino-6-[1-(tert-butoxycarbonyl)-3-(4-hydroxy-1-butynyl)indol-2-yl]phtalimide (115 mg, yield 87%).
Reaction SMILES: [NH2:1][C:2]([C:18]1[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH3:29])=[C:23]2[C:19]=1[CH:20]=[CH:21][N:22]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([C:7]1[NH:11][C:10]2[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:9]=2[N:8]=1)[C:3]([F:6])([F:5])[F:4].[C:37](OCC)(=O)[CH:38]=[O:39].CO.[BH4-].[Na+]>ClCCCl>[C:16]([C:14]1[CH:13]=[CH:12][C:10]2[NH:11][C:7]([C:2]([C:18]3[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH3:29])=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([NH:1][CH2:37][CH2:38][OH:39])[C:3]([F:6])([F:5])[F:4])=[N:8][C:9]=2[CH:15]=1)#[N:17]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(N)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Reactant: CCOC(=O)C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(NCCO)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F

Procedure:
A solution of (±)-tert-butyl 4-(1-amino-1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (50 mg, 0.100 mmol) and ethyl glyoxylate (50% in toluene) (39.7 μL, 0.200 mmol) in DCE (1.00 mL) was stirred at room temperature. After 50 minutes MeOH (1 mL) was added followed by NaBH4 (11.36 mg, 0.300 mmol). After 30 minutes additional NaBH4 (4 mg, 0.106 mmol) was added. After 25 more minutes additional NaBH4 (40 mg, 1.06 mmol) was added. After 15 more minutes the reaction was quenched with water, extracted twice with EtOAc, dried with MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-80% EtOAc in heptanes) to provide the title compound. MS (ESI+) m/z 544.2 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=O)[O:27]C2C=CC=CC=2)=[C:21]([F:35])[CH:20]=1)#[N:2].[NH2:36][C:37]1[S:38][CH:39]=[CH:40][N:41]=1.C(N(CC)CC)C.O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:36][C:37]2[S:38][CH:39]=[CH:40][N:41]=2)=[O:27])=[C:21]([F:35])[CH:20]=1)#[N:2]
Reactant: Nc1nccs1
Reactant: COCCOc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)c(F)c3)c2cc1C#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)c2cc1C#N
Temperature: 90 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
Phenyl N-(4 (6-cyano-7-(2-methoxyethoxy)-4-quinolyl)oxy-2-fluorophenyl)carbamate (200 mg) and 2-aminothiazole (85 mg) were dissolved in 1 ml of dimethylformamide, and then 0.12 ml of triethylamine was added thereto and the mixture was heated and stirred at 90° C. for 2 hours. After cooling, water was added and the precipitated solid was filtered out and washed with ethyl acetate to obtain 110 mg of the title compound as light brown crystals (57% yield).
Reaction SMILES: [CH2:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16](=[O:19])[CH2:17][N:18]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)[CH3:2].[CH:22]([O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1)([CH3:24])[CH3:23].C(N(CC)CC)C.O>C1C=CC=CC=1>[CH2:1]([C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[O:15][C:16](=[O:19])/[C:17](=[CH:30]/[C:29]4[CH:32]=[CH:33][C:26]([O:25][CH:22]([CH3:24])[CH3:23])=[CH:27][CH:28]=4)/[N:18]=3)=[CH:12][CH:13]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Oc2ccc(C3=NCC(=O)O3)cc2)cc1
Reactant: CC(C)Oc1ccc(C=O)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCc1ccc(Oc2ccc(C3=N/C(=C\c4ccc(OC(C)C)cc4)C(=O)O3)cc2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A mixture of N-[4-(4-ethylphenoxy)benzoyl]glycine (200 mg, 0.668 mmol) prepared in Example 89 (89a) and acetic anhydride (0.38 mL, 4.03 mmol) was stirred at 80° C. for 20 minutes. Ethyl acetate was added to the reaction mixture, and then the mixture was cooled to room temperature. The solvent was evaporated, and then the residue was purified by silica gel column chromatography (hexane:ethyl acetate, 3:1, v/v) to give 2-[4-(4-ethylphenoxy)phenyl]-1,3-oxazol-5(4H)-one (120 mg, 0.427 mmol). All of this 2-[4-(4-ethylphenoxy)phenyl]-1,3-oxazol-5(4H)-one was dissolved in benzene (0.9 mL), and then 4-isopropoxybenzaldehyde (71 mg, 0.432 mmol) and triethylamine (24 μL, 0.172 nmol) were added thereto. The mixture was stirred at 90° C. for 2 hours. After the addition of water to the reaction solution, the mixture was extracted with a solvent mixture of hexane and ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated to give 181 mg of the title compound (brown oil, yield: 99%).
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=C1)=[S:2].[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>O1CCCC1>[NH2:3][C:1](=[S:2])[N:16]1[CH2:17][CH2:18][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:15]1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(N)=S)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
To a solution of thiocarbonyldiimidazole (2.1 g, 11.8 mmol) in tetrahydrofuran (30 mL) at room temperature, was added 1,1-dimethylethyl 1-piperazinecarboxylate (2 g, 10.75 mmol). The reaction mixture was stirred at room temperature for 2 h and then heated to 55° C. for additional 2 h. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure until approximately 20 mL of tetrahydrofuran remained. The residue was then treated with a 2 M solution of ammonia in methanol (10 mL) and stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure, and the residue was triturated with diethyl ether (25 mL) to give a white precipitate. The precipitate was filtered and dried to give 1.5 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[O:12])[NH:7]2.I[CH2:14][CH:15]([CH3:17])[CH3:16]>>[CH2:14]([CH:5]1[C:4]2[C:8](=[CH:9][CH:10]=[CH:11][C:3]=2[O:2][CH3:1])[NH:7][C:6]1=[O:12])[CH:15]([CH3:17])[CH3:16]
Reactant: COc1cccc2c1CC(=O)N2
Reactant: CC(C)CI
Product: COc1cccc2c1C(CC(C)C)C(=O)N2
Yield: 80 %

Procedure:
3-Isobutyl-4-methoxy-1,3-dihydro-indol-2-one is prepared from 4-methoxyoxindole (3.1 mmol) and 1-iodo-2-methylpropane (3.1 mmol) substantially as described above for Epoxide 1 and Epoxide 2. The compound is purified by flash chromatography (SiO2, 25% ethyl acetate:hexane) to obtain 180 mg (27%) of the desired compound. MS (ESI+) 220.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9](O)=O.[CH:13]1([NH2:16])[CH2:15][CH2:14]1>>[CH:13]1([NH:16][CH2:9][CH2:8][O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:12])[CH2:15][CH2:14]1
Reactant: Cc1ccccc1OCC(=O)O
Reactant: NC1CC1
Product: Cc1ccccc1OCCNC1CC1

Procedure:
Synthesized according to typical procedures C and D from o-tolyloxyacetic acid and cyclopropylamine.
Reaction SMILES: [CH2:1]1[O:3][C@@H:2]1[CH2:4][OH:5].[NH2:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[NH:13][C:14]2=[O:17])=[CH:9][CH:8]=1>C(O)C>[OH:3][C@H:2]([CH2:4][OH:5])[CH2:1][NH:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:25])[F:26])[NH:13][C:14]2=[O:17])=[CH:9][CH:8]=1
Reactant: OC[C@@H]1CO1
Reactant: Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Solvent: CCO
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(NC[C@H](O)CO)cc12
Yield: 63 %

Procedure:
(R)-Glycidol (78.3 μl, 1.18 mmol) was added to an ethanol solution (4 ml) that contained the 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in step C of Example 1-1, and the obtained mixture was stirred under heating to reflux for 3 days. Thereafter, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=20:1), so as to obtain 7-((S)-2,3-dihydroxypropylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (281.9 mg; yield: 63%) in the form of a pale yellow amorphous substance.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[S:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[NH:15]1[CH2:20][CH2:19][C:18]2([CH2:29][CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:21]2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:20][CH2:19][C:18]4([CH2:29][CH2:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[O:21]4)[CH2:17][CH2:16]3)=[CH:7][CH:6]=2)[S:12][N:11]=1
Reactant: c1ccc2c(c1)CCC1(CCNCC1)O2
Reactant: Cc1nsc(-c2ccc(Cl)nn2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nsc(-c2ccc(N3CCC4(CCc5ccccc5O4)CC3)nn2)n1

Procedure:
The object product (74 mg, 44%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-thiadiazol-5-yl)pyridazine (95 mg), 3,4-dihydrospiro[chromene-2,4′-piperidine] hydrochloride (105 mg) and potassium carbonate (138 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[C:9]2[CH3:15])=[CH:4][CH:3]=1>C(Cl)Cl.[Mn]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([CH:13]=[O:14])[N:10]=[C:9]2[CH3:15])=[CH:6][CH:7]=1
Reactant: Cc1nc(CO)cn1-c1ccc(F)cc1
Agent: [Mn]
Solvent: ClCCl
Product: Cc1nc(C=O)cn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
[1-(4-Fluoro-phenyl)-2-methyl-1H-imidazol-4-yl]-methanol (7.16 g, 34.7 mmol) was dissolved in 2.3 L methylene chloride. Mangan (IV) oxid (26.8 g, 278 mmol) was added and the reaction mixture was stirred at room temperature for 3 days. The suspension was filtered through a dicalite speed plus pad and washed with 1 L methylene chloride. The solvents were evaporated and the desired compound was obtained as a white solid (5.87 g, 83%), MS: m/e=205.1 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:22]([O:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OCCCSc1cccc2nccn12
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCCCSc1cccc2nccn12)c1ccccc1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
To a solution of 5-[3-(hydroxy)propylthio]imidazo[1,2-a]pyridine (1.00 g, 4.80 moles) and triethylamine (0.80 ml, 5.74 moles) in methylene chloride (25 ml) was added benzoyl chloride (1.10 ml, 11.6 moles) with stirring at room temperature and the mixture was further stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous 1N sodium hydroxide solution and dried. After the solvent was distilled off, the residue was purified by column chromatography [eluent: hexane/acetone (1:1)] to obtain 1.32 g of the desired product (88.1%, white solid).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.O.[NH2:11][NH2:12].[OH-].[K+]>>[NH:11]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1)[NH2:12]
Reactant: OCc1ccc(Cl)nc1
Reactant: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NNc1ccc(CO)cn1
Temperature: 150 °C
Reaction time: 5 h

Procedure:
220.0 g (1.5 mol) (6-chloropyridin-3-yl)methanol [Evans et al., Organic Letters 2001, 19, 3009-3012] are initially introduced into 746 ml (767.1 g, 15.3 mol) hydrazine hydrate and the mixture is stirred at a bath temperature of 150° C. for 5 h. The reaction mixture is concentrated in vacuo, the residue is taken up in 500 ml water and 86.0 g (1.5 mol) potassium hydroxide are added. The mixture is stirred for 15 min, the water is then removed almost completely on a rotary evaporator and the residues of water are distilled off azeotropically with toluene several times. The oily residue is stirred in ethanol, the mixture is cooled to approx. 10° C., the potassium chloride which has precipitated out is filtered off, the filtrate is concentrated, diethyl ether is added to the residue and the mixture is stirred. Finally, the product is filtered off, the residue on the filter is washed with diethyl ether and the crystals are dried in vacuo.
Reaction SMILES: N[C:2]1[C:11]([CH3:12])=[CH:10][C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:14][B-](F)(F)F.N#[O+].C1C(Cl)=CC=C(Cl)C=1>C(Cl)Cl>[F:14][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: F[B-](F)(F)F
Reactant: COC(=O)c1cc(F)cc(C)c1N
Agent: N#[O+]
Solvent: ClCCl
Solvent: Clc1ccc(Cl)cc1
Product: COC(=O)c1cc(F)cc(C)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (E3) (1.0 eq.) in dry DCM (0.4 M) at 0° C. was added nitrosonium tetrafluoroborate (1.3 eq.) portionwise. After 1 h at 0° C. dry dichlorobenzene (120 eq.) was added and the reaction was slowly heated to 160° C. while DCM was distilled off. After 3 hrs, the mixture was cooled to RT, EtOAc was added and the organic phase was washed with brine (2×). After drying over MgSO4, the solvents were removed under reduced pressure. The crude was purified by flash chromatography using 1-10% EtOAc/petroleum ether to yield (E4) as a yellow oil. 1H NMR (400 MHz, CDCl3, 300K) δ 7.42 (1H, m), 7.06 (1H, m), 3.92 (3H, s), 2.30 (3H, d, J=2.3 Hz).
Reaction SMILES: CCN(C(C)C)C(C)C.FC1C(C)=NC2C(N=1)=C([C:21]1[NH:29][C:28]3[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=3[CH:22]=1)C=CC=2.CC1(N)CCCC1>CS(C)=O>[NH:29]1[C:28]2[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=2[CH:22]=[CH:21]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Agent: CC1(N)CCCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCCc2[nH]ccc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Prepared according to Example 127, using DIPEA (141 μl, 0.803 mmol), 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 40 mg, 0.135 mmol), 1-methylcyclopentanamine (40.2 mg, 0.405 mmol, Sigma Aldrich), and DMSO (1.4 mL) and stirring at 80° C. for 2 h. Purification by high throughput parallel purification (Rilas Technologies, Woburn, Mass.) provided 2-(2-methyl-3-(1-methylcyclopentyl)amino)-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one. 1H NMR (DMSO-d6) δ: 12.21 (s, 1H), 7.83-7.91 (m, 1H), 7.53-7.61 (m, 1H), 7.30-7.39 (m, 1H), 7.07 (s, 1H), 6.95 (s, 1H), 6.18 (s, 1H), 3.40-3.48 (m, 2H), 2.85-2.94 (m, 2H), 2.55 (s, 3H), 2.37-2.48 (m, 2H), 1.67-1.85 (m, 6H), 1.64 (s, 3H). m/z (ESI, +ve) 376.1 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[N:25]=[C:24](Cl)[C:23]([C:27]#[N:28])=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CC(O)C.CO>[NH2:19][C:20]1[N:25]=[C:24]([NH:18][CH:16]([C:8]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH3:17])[C:23]([C:27]#[N:28])=[CH:22][N:21]=1
Reactant: CC(N)c1nc2cccnc2n1-c1ccccc1
Reactant: N#Cc1cnc(N)nc1Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(Nc1nc(N)ncc1C#N)c1nc2cccnc2n1-c1ccccc1
Temperature: 90 °C
Yield: 45.5 %

Procedure:
A mixture of 1-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)ethylamine (68 mg, 0.29 mmol), 2-amino-4-chloropyrimidine-5-carbonitrile (44 mg, 0.29 mmol) and DIPEA (147 μL, 0.86 mmol) in IPA (1 mL) was heated at 90° C. in a sealed vial for 18 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 50-100% EtOAc in cyclohexane) followed by trituration from EtOAc to afford 365 as an off-white solid (47 mg, 46%). LCMS (Method K): RT 2.58 min [M+H]+ 357.09. 1H NMR (DMSO-d6, 400 MHz): δ 8.25 (1H, dd, J=4.76, 1.48 Hz), 8.14 (1H, dd, J=7.98, 1.47 Hz), 8.09 (1H, s), 7.72 (1H, d, J=7.41 Hz), 7.55-7.43 (5H, m), 7.32 (1H, dd, J=7.99, 4.77 Hz), 7.16-6.68 (2H, m), 5.55 (1H, m), 1.49 (3H, d, J=6.81 Hz)
Reaction SMILES: [Na].[CH3:2][N:3]([CH3:25])[C:4]1[N:8]=[C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=2)[CH3:10])[O:6][N:5]=1.Cl>CO>[CH3:25][N:3]([CH3:2])[C:4]1[N:8]=[C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([OH:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=2)[CH3:10])[O:6][N:5]=1
Reactant: CC(c1cccc(C(=O)c2ccccc2)c1)c1nc(N(C)C)no1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CC(c1cccc(C(O)c2ccccc2)c1)c1nc(N(C)C)no1
Yield: 103.1 %

Procedure:
To sodium brohydride suspended (0.177 g, 4.7 mmol) in methanol (15 ml) under cooling with ice was slowly added dropwise 3-dimethylamino-5-(1-(3-benzoylphenyl)ethyl)-1,2,4-oxadiazole (1.45 g, 4.5 mmol) in methanol (15 ml). After the mixture was stirred under cooling with ice for 1 h, 1N-HCl was added to the mixture, then the mixture was adjusted at pH 6. The mixture was evaporated under reduced pressure to a residue, which was extracted with dichloromethane. The extracts were washed with saturated NaCl aq., dried with anhydrous magnesium sulfate, and evaporated under reduced pressure to a residue, which was chromatographed to afford 3-dimethylamino-5-(1-(3-(α-hydroxybenzyl)phenyl)ethyl)-1,2,4-oxadiazole (1.50 g, 99% yield) as oily substance: NMR(CDCl3)δ 1.45(d, 3H), 2.27(d, 1H), 3.00(s, 6H), 4.20(q, 1H), 5.80(d, 1H), 7.20-7.45(m, 9H) ppm; IR(neat) 3375, 1600, 1405 cm-1.