Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:42](=[CH:43][CH:44]=3)[CH2:41][C@:23]3([C:31]5[C:26](=[N:27][CH:28]=[CH:29][CH:30]=5)[N:25]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:24]3=[O:40])[CH2:22]4)=[O:17])[C:13](=[O:45])[C:12]([CH3:47])([CH3:46])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].I[CH3:51]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([N:18]([CH3:51])[C:19]3[CH:20]=[C:21]4[C:42](=[CH:43][CH:44]=3)[CH2:41][C@:23]3([C:31]5[C:26](=[N:27][CH:28]=[CH:29][CH:30]=5)[N:25]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:37])[CH3:38])[C:24]3=[O:40])[CH2:22]4)=[O:17])[C:13](=[O:45])[C:12]([CH3:47])([CH3:46])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CI
Reactant: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)N(COCC[Si](C)(C)C)c3ncccc32)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)CN1C(=O)C(C)(C)CC[C@H]1c1cc(F)cc(F)c1)c1ccc2c(c1)C[C@@]1(C2)C(=O)N(COCC[Si](C)(C)C)c2ncccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2-[(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-((2R)-2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]acetamide from Step A (47 mg, 0.07 mmol) in DMF (1 mL) at 0° C. was added NaH (11 mg of a 60% dispersion in oil, 0.28 mmol). After 15 min, iodomethane (30 mg, 0.21 mmol) was added and the mixture was allowed to warm to ambient temperature and was stirred for 1 h. The reaction mixture was quenched with H2O (5 mL) and the precipitate was isolated by filtration, washed with H2O, and dried in vacuo to provide the title compound. MS: m/z=675 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)(=[O:5])=[O:4].C([Li])CCC.[Cl:17]C(Cl)(Cl)C(Cl)(Cl)Cl.O>C1COCC1>[Cl:17][C:10]1[N:6]([S:3]([N:2]([CH3:11])[CH3:1])(=[O:4])=[O:5])[N:7]=[CH:8][CH:9]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CN(C)S(=O)(=O)n1cccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)S(=O)(=O)n1nccc1Cl
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
N,N-dimethyl-1H-pyrazole-1-sulfonamide (8.89 g, 50.8 mmol) was dissolved in anhydrous THF (250 mL). The solution was cooled at −78° C., a solution of n-butyl lithium (32.6 mL, 81.4 mmol, 2.5 M in hexane) was added dropwise, and then the mixture was stirred for 45 minutes. A solution of hexachloroethane (18.0 g, 76.3 mmol) in anhydrous THF (20 mL) was added dropwise at −78° C., and the reaction stirred for 1.5 hours. Water was added, and the mixture was extracted 5 times with dichloromethane. The combined organic phases were washed with brine and then dried over magnesium sulfate. After evaporation of the solvent, 5-chloro-N,N-dimethyl-1H-pyrazole-1-sulfonamide was obtained and used in the next step without further purification.
Reaction SMILES: C(O[C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)(=O)C.CCCCCCC.S(=O)(=O)(O)O.[CH3:27][O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=1>C(O)C>[C:5]12([C:30]3[CH:31]=[C:32]([CH:36]=[CH:37][C:29]=3[O:28][CH3:27])[C:33]([OH:35])=[O:34])[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2
Reactant: CC(=O)OC12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: CCCCCCC
Solvent: CCO
Product: COc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 48 h

Procedure:
In a 100 ml three-necked flask, and under a nitrogen environment, are placed 1 g of 1-acetoxyadamantane and 50 ml of n-heptane. After dissolution, 0.25 g of concentrated sulfuric acid is added drop by drop at a temperature of approximately 22° C. and 0.783 g of 4-methoxybenzoic acid is poured in slowly. After leaving the mixture well agitated for 48 hours, 50 ml of denatured ethanol are added and the insoluble material is filtered Concentration of the filtrate volume to three quarters yields a solid white precipitate which is filtered with sintered glass. It is dried in a vacuum oven for 24 hours at 30° C. and 0.680 g of expected raw product was collected (Melting point: 245°-246° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[N:19]=[CH:20][N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:33]C1C=CC2C3N(CC(C)C)C(C)=NC=3C=NC=2C=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N+:15]([O-:33])=[CH:14][C:13]3[N:19]=[CH:20][N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Reactant: CC(C)Cn1cnc2cnc3ccc(OCc4ccccc4)cc3c21
Product: CC(C)Cn1cnc2c[n+]([O-])c3ccc(OCc4ccccc4)cc3c21

Procedure:
The general method described in Part B of Example 3 was followed using 8-benzyloxy-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (2.1 g, 6.3 mmol) in lieu of 7-benzyloxy-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline. After the work-up, 2.16 g of 8-benzyloxy-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c]quinoline were obtained as a white solid and used without purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N:10]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:21](Cl)=[O:22]>>[CH3:1][N:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N:10]=1)[C:21](=[O:22])[C:20]1[CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=[C:18]([C:17]([F:16])([F:31])[F:32])[CH:19]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ncccc1C
Product: Cc1cccnc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 55, from methyl-(3-methyl-[2,4]bipyridinyl-3′-yl)-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8) and using preparative HPLC for the chromatographic purification. Off-white solid (20%). MS (ESI): m/z=440.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5](=[N:7][OH:8])[NH2:6].[CH:13](OCC)(OCC)OCC.C(#N)C>FC(F)(F)C(O)=O.O>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[CH:13][O:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccc(C(N)=NO)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: Cc1ccc(-c2ncon2)cc1F
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A suitable vessel equipped with a mechanical stirrer under a N2 atmosphere was charged with 3-fluoro-N′-hydroxy-4-methylbenzimidamide (302.52 g, 1.79 mol), triethyl orthoformate (382.5 mL, 341.1 g, 2.3 mol) and acetonitrile (1512 mL). The reaction mixture was heated to 45° C. and trifluoroacetic acid (6.72 mL, 10.08 g, 87.6 mmol) was added at this temperature. The reaction mixture was heated at 60° C. for an additional 90 minutes, then cooled to room temperature. Water (3 L) was added dropwise over a period of 60 minutes. The slurry was cooled to 4° C. and stirred at this temperature for 30 minutes. The solid was filtered and dried in vacuum at 50° C. for 12 hours to give 3-(3-fluoro-4-methylphenyl)-1,2,4-oxadiazole as a white solid (306 g, 95.6%). HPLC indicated 99.8% chemical purity. 1H-NMR (CDCl3, 400 MHz) δ8.67 (s, 1H), 7.71 (m, 2H), 7.23 (t, J=8 HZ, 1H), 2.28 (s, 3H); 13C-NMR (CDCl3, 400 MHz) δ166.9447, 164.7258, 162.5473, 160.1066, 132.0480, 132.0077, 128.5987, 122.9910, 122.9507, 114.2568, 114.0147, 14.6902. 19F-NMR (CDCl3, 400 MHz) δ−115.94, −115.96.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[N:18]2[N:19]=[C:20]([C:22]3([CH2:40][C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[CH:39]=[CH:38][C:25]4[CH2:26][CH2:27][N:28](CCS(=O)(=O)NC)[CH2:29][CH2:30][C:24]=4[CH2:23]3)[N:21]=[C:17]2[CH:16]=[CH:15][CH:14]=1.ClCC(N(C)C)=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:11])([F:12])[F:10])=[CH:5][C:4]=1[C:13]1[N:18]2[N:19]=[C:20]([C:22]3([CH2:40][C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[CH:39]=[CH:38][C:25]4[CH2:26][CH2:27][NH:28][CH2:29][CH2:30][C:24]=4[CH2:23]3)[N:21]=[C:17]2[CH:16]=[CH:15][CH:14]=1
Reactant: CNS(=O)(=O)CCN1CCC2=C(CC1)CC(CC(=O)N(C)C)(c1nc3cccc(-c4cc(C(F)(F)F)ccc4OC)n3n1)C=C2
Agent: CN(C)C(=O)CCl
Product: COc1ccc(C(F)(F)F)cc1-c1cccc2nc(C3(CC(=O)N(C)C)C=CC4=C(CCNCC4)C3)nn12
Yield: 29 %

Procedure:
2-(7-[5-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(2-methylsulfamyl-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-N,N-dimethyl-acetamide was prepared from [5-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl-amino]-1,2,4,5-tetrahydro-3-benzazepin-7-yl)-amine (0.118 g, 0.26 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.047 g, 0.387 mmol) in a manner analogous to Example 235. Product was isolated as a foam (0.041 g, 29%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.91 (s, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.57-7.52 (m, 2H), 7.39 (s, 1H), 7.33-7.29 (m, 1H), 7.21 (d, J=8.8 Hz, 1H), 7.06-6.98 (m, 2H), 6.91 (s, 1H), 4.67-4.56 (m, 4H), 3.89 (s, 3H), 3.21 (s, 2H), 3.17-3.09 (m, 4H), 2.99 (s, 6H). MS=539 (MH)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.[C:16]1([S:22]([CH2:24][CH2:25][CH2:26][CH2:27]Br)=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([S:22]([CH2:24][CH2:25][CH2:26][CH2:27][O:1][C:2]2[C:3]([CH3:15])=[CH:4][C:5]3[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:12])([CH3:13])[C:6]=3[CH:14]=2)=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc2c(cc1O)C(C)(C)OC(=O)N2
Reactant: O=S(CCCCBr)c1ccccc1
Product: Cc1cc2c(cc1OCCCCS(=O)c1ccccc1)C(C)(C)OC(=O)N2

Procedure:
Prepared analogously to Example 4 from 6-hydroxy-4,4,7-trimethyl-4H-3,1-benzoxazin-2-one and 4-phenylsulfinylbutylbromide.
Reaction SMILES: [N:1]1([NH:7][C:8]([NH:10][C:11]2[C:16]3[C:17](=[O:34])[C:18]4[C:19](=[N:20][NH:21][C:22]=4[C:23]4[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29]([OH:31])=O)=[CH:25][CH:24]=4)[C:15]=3[CH:14]=[CH:13][CH:12]=2)=[O:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:35][CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][O:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][NH:53][C:54]([CH2:56][CH2:57][C@H:58]([NH:66][C:67]([C:69]1[CH:74]=[CH:73][C:72]([NH:75][CH3:76])=[CH:71][CH:70]=1)=[O:68])[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])=[O:55].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:76][NH:75][C:72]1[CH:73]=[CH:74][C:69]([C:67]([NH:66][C@@H:58]([CH2:57][CH2:56][C:54](=[O:55])[NH:53][CH2:52][CH2:51][O:50][CH2:49][CH2:48][O:47][CH2:46][CH2:45][O:44][CH2:43][CH2:42][O:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][NH:35][C:29](=[O:31])[CH2:28][O:27][C:26]2[CH:32]=[CH:33][C:23]([C:22]3[NH:21][N:20]=[C:19]4[C:15]5[CH:14]=[CH:13][CH:12]=[C:11]([NH:10][C:8](=[O:9])[NH:7][N:1]6[CH2:6][CH2:5][O:4][CH2:3][CH2:2]6)[C:16]=5[C:17](=[O:34])[C:18]=34)=[CH:24][CH:25]=2)[C:59]([O:61][C:62]([CH3:65])([CH3:63])[CH3:64])=[O:60])=[O:68])=[CH:70][CH:71]=1
Reactant: CNc1ccc(C(=O)N[C@@H](CCC(=O)NCCOCCOCCOCCOCCOCCN)C(=O)OC(C)(C)C)cc1
Reactant: O=C(O)COc1ccc(-c2[nH]nc3c2C(=O)c2c(NC(=O)NN4CCOCC4)cccc2-3)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1ccc(C(=O)N[C@@H](CCC(=O)NCCOCCOCCOCCOCCOCCNC(=O)COc2ccc(-c3[nH]nc4c3C(=O)c3c(NC(=O)NN5CCOCC5)cccc3-4)cc2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 25 (0.60 g, 1 mmol) and compound 26 (0.46 g, 1 mmol) were dissolved in 10 ml DMF and HBTU (0.7 g, 1.8 mmol) was added as a solid followed by DIEA (1.0 ml, 5.7 mmol). The reaction mixture was stirred at room temperature overnight, diluted with EtOAc and the organic phase washed with 0.5N NaOH, brine, dried over MgSO4, filtered and concentrated to an oil. This oil was purified by flash silica chromatography (10 to 20% MeOH/EtOAc) to give a yellow foam (0.65 g, 0.62 mmol, 62%, compound 28).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]3[NH:20][CH:21]=[N:22][C:23](=[O:24])[C:17]3=[CH:16][N:15]=2)=[N:6]1.Cl[C:30]1C(C(OC)=O)=CN=C(C2C3C(=NC=CC=3)N(CC3C=CC=CC=3F)N=2)N=1.Cl.C(N)(=N)C.C(N(CC)CC)C>>[F:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]3[NH:20][C:21]([CH3:30])=[N:22][C:23](=[O:24])[C:17]3=[CH:16][N:15]=2)=[N:6]1
Reactant: COC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1Cl
Reactant: O=c1nc[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc12
Agent: CC(=N)N
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1nc(=O)c2cnc(-c3nn(Cc4ccccc4F)c4ncccc34)nc2[nH]1

Procedure:
In analogy to the preparation process for 7-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimido[4,5-d]pyrimidin-4(1H)-one (example 152), proceeding from 100 mg (0.25 mmol) of methyl 4-chloro-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-5-carboxylate (example 106A), 47.5 mg (0.50 mmol) of acetamidine hydrochloride and 175 μl (1.26 mmol) of triethylamine, 32 mg (31% of theory) of the target compound were obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH:21]3[CH2:24][CH2:23][CH2:22]3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH:21]1([C:17]2[CH:18]=[C:19]([CH3:20])[C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:15][CH:16]=2)[CH2:22][CH2:23][CH2:24]1
Reactant: Cc1cc(C2CCC2)cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(C2CCC2)cnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
To a mixture of 4-(5-bromo-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (4.8 g), bis(tricyclohexylphosphine)palladium (II) dichloride (515 mg), tripotassium phosphate (16 g) and cyclobutylboronic acid (2.6 g) were added toluene (39 mL) and water (2 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(5-cyclobutyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (560 mg). 4-(5-cyclobutyl-3-methylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (560 mg) was dissolved in chloroform (1.5 mL), 4N hydrogen chloride/ethyl acetate (1.5 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1N aqueous sodium hydroxide solution (8 mL), and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated to give the title compound (350 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>C1(C)C=CC=CC=1.O>[Cl:12][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[N:7][CH:6]=1
Reactant: Cc1ccc(CO)cn1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(CCl)cn1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
To a solution of (6-methyl-3-pyridyl)-methanol (50 g, 0.506 mol) in toluene (500 ml) and water (9 ml) at 35° C. under nitrogen was added thionyl chloride (66.9 ml, 1.06 mol) dropwise After stirring at 35° C. overnight 300 ml was distilled off under vacuum and rediluted with toluene (250 ml) and water (10 ml) to give a solution of 5-chloromethyl-2-methyl-pyridine (J. Med. Chem, 2004, 47(11), 4787). The mixture was then heated to 40° C. and morpholine (112.2 ml, 1.29 mol) added and the slurry heated to 80° C. for 3 hrs. After cooling to room temperature saturated sodium carbonate solution (150 ml) was added and the aqueous phase separated and extracted with toluene (200 ml). The combined organic layer was washed with brine and concentrated. The oil was dissolved in iso-octane (300 ml) at 40° C. then cooled to −5° C. overnight. Two crops were obtained which gave 53.65 g, 72% yield of 4-[(6-methylpyridin-3-yl)methyl]morpholine as a beige solid. 1H NMR (400 MHz; CDCl3): δ 8.4 (d, J=1.72 Hz, 1H), 7.54 (dd, J=2.1, 7.91 Hz, 1H), 7.1 (d, J=7.92 Hz, 1H), 3.68 (apparent t, J=4.6, 9.28 Hz, 4H), 3.4 (s, 2H), 2.5 (s, 3H), 2.4 (apparent t, J=4.5, 8.93 Hz, 4H); 13C NMR: (100 MHz, CDCl3): δ 157.3, 149.8, 137.2, 129.9, 122.9, 66.9, 60.3, 53.5, 24.1 ppm; MS (ESI) m/z 193 [M+1]+; Melting point: 51-52° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:38])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([Br:31])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:32]([O:34]CC)=[O:33])=[N:20][C:19]=2[CH3:37])[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].O>O1CCCC1.CO>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:38])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([Br:31])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:32]([OH:34])=[O:33])=[N:20][C:19]=2[CH3:37])[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(C)c(-c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(Br)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1nc(C(=O)O)c2[nH]c3cc(Br)ccc3c2c1-c1cccc(NC(=O)OCc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.9 %

Procedure:
A mixture of ethyl 4-(3-(((benzyloxy)carbonyl)amino)-2-methylphenyl)-7-bromo-3-methyl-9H-pyrido[3,4-b]indole-1-carboxylate (1.36 g, 2.38 mmol) and lithium hydroxide, monohydrate (0.399 g, 9.50 mmol) in tetrahydrofuran (30 mL), methanol (10 mL), and water (12 mL) was stirred at room temperature for 4 h. The solvent was removed under reduced pressure, and the residue was suspended in water (˜20 mL) and 1N aqueous hydrochloric acid (9.5 mL). The pH was adjusted to 5 with 1N aqueous sodium hydroxide, and the suspension was stirred for 60 min. The solid was collected by vacuum filtration, washed with water, and dried overnight to give 4-(3-(((benzyloxy)carbonyl)amino)-2-methylphenyl)-7-bromo-3-methyl-9H-pyrido[3,4-b]indole-1-carboxylic acid (1.10 g, 2.02 mmol, 85% yield) as a yellow solid. LC/MS M+1=544.3 and 546.3.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CO>C(#N)C.ClCCl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1ccnc2ccc(I)cc12
Solvent: CO
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc3ccc(I)cc23)CC1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
The mixture of 4-chloro-6-iodo-quinoline (217.5 mg, 1 mmol, prepared by similar procedure to example 1e), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (150 mg, 0.75 mmol), and 1-tert-butyl-2,2,4,4-pentakis(dimethylamino)-2λ5, 4λ5-catenadi(phosphazene) in tetrahdyrofuran (2M, 0.75 ml, 1.5 mmol) in acetonitrile (3.5 ml) was stirred at 100° C. for 30 min in microwave instrument (Personal Chemistry). After cooling the reaction, the solvent was evaporated, followed by addition of water, some of sodium carbonate saturated solution. The resulting solution was extracted with dimethylene chloride three times. The combined organic layer was dried over the brain, sodium sulfate, then evaporated to give a reddish gel. Flash chromatography (Merck silica gel 60, 230-400 mesh, 0%-3% methanol in dichloromethane for 30 min) afforded 4-(6-iodo-quinolin-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (262.5 mg, 77%) as A light yellow solid. LC-MS m/e 455 (MH+).
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][C:14]([C:22]([CH3:25])([CH3:24])[CH3:23])=[N:13]2)=[CH:8][CH:7]=1.C1COCC1.[OH-].[Li+].Cl>O.CO>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]([C:22]([CH3:25])([CH3:24])[CH3:23])=[N:13]2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc(-c2nnco2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(C(=O)O)n(-c2ccc(-c3nnco3)cc2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
A solution of ethyl 1-(4-(1,3,4-oxadiazol-2-yl)phenyl)-3-tert-butyl-1H-pyrazole-5-carboxylate (440 mg, 1.29 mmol) in a mixture comprised of THF (3 mL), methanol (1 mL) and water (1 mL) was cooled to 0° C. and treated with lithium hydroxide (62 mg, 2.59 mmol). The reaction mixture was stirred 3 h at 0° C. and was then allowed to warm to RT over 4 h. Water (15 mL) was added and the mixture was extracted with ether (2×10 mL). The aqueous portion was acidified by addition of 1 M aq HCl (2.5 mL, 2.5 mmol) and was extracted with EtOAc (3×20 mL). The organics were dried (Na2SO4) and concentrated in vacuo to provide 1-(4-(1,3,4-oxadiazol-2-yl)phenyl)-3-tert-butyl-1H-pyrazole-5-carboxylic acid (355 mg, 88% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.35 (br s, 1 H), 9.40 (d, J=3.4 Hz, 1 H), 8.11 (m, 2 H), 7.69 (m, 2 H), 7.01 (d, J=3.2 Hz, 1 H), 1.32 (s, 9 H); MS (ESI) m/z: 313.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.C([Li])CCC.[C:14]([C:16]1[C:17]([CH3:25])=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([OH:21])=[O:20])#N.[Li].Cl.CC[O:30]CC>CCCCCC.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:14]([C:16]2[C:17]([CH3:25])=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]([OH:21])=[O:20])=[O:30])=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: Clc1ccc(Br)cc1
Reactant: Cc1c(C#N)cccc1C(=O)O
Agent: Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
A solution of 68 g of p-chlorobromobenzene in 150 cc of ether was added under an inert atmosphere to 250 cc of a solution of 1.4 N butyl lithium in hexane cooled to -20° C. and after stirring for 2 hours, the temperature was allowed to rise to room temperature. A solution of 28.6 g of 3-cyano-2-methylbenzoic acid in 300 cc of tetrahydrofuran was added to the solution of the lithium compound cooled to -60° C. and then the temperature was allowed to return to room temperature and remain there overnight. The reaction mixture was added to a water-ice mixture and made acidic by addition of hydrochloric acid. The mixture was heated at 70°-80° C. for 3 hours and the tetrahydrofuran was distilled off. After cooling, the mixture was extracted with ether and the ether phase was washed with water, dried over magnesium sulfate and concentrated. The residue was empasted with isopropyl ether, vacuum filtered and dried. The residue was crystallized from methanol, and dissolved in methanol and treated with activated carbon, concentrated and allowed to crystallize to obtain 10.3 g of 3-p-chlorobenzoyl-2-methyl-benzoic acid melting at 206° C. A second crop of 4.3 g of product was obtained by crystallization of the mother liquors.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][NH:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[O:16])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>C(OCC)(=O)C>[C:31]([N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:13][NH:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])[CH2:12][CH2:11]1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccccc1C(=O)NCC1(c2ccccc2)CCNCC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CCN(C(C)=O)CC1

Procedure:
A solution of 0.1 g (0.31 mmol) of 4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)piperidine (Example 2), 0.025 mL of pyridine (0.31 mmole) in 2 mL of acetic anhydride was mixed for 18 hr. The reaction was diluted with ethyl acetate and washed with saturated NaHCO3. The organic fraction was dried over MgSO4 and the filtrate was concentrated. The residue was purified by chromatography (silica, ethyl acetate) to give the title compound.