Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[CH3:23][N:24]1[CH:28]=[C:27]([NH2:29])[C:26]([CH3:30])=[N:25]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)=[N:7][C:2]([NH:29][C:27]2[C:26]([CH3:30])=[N:25][N:24]([CH3:23])[CH:28]=2)=[N:3][CH:4]=1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reactant: Cc1nn(C)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1nn(C)cc1Nc1ncc(Cl)c(CCc2ccccc2C2(C(N)=O)CC2)n1
Temperature: 120 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
A mixture of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.100 g, 0.297 mmol), 1,3-dimethyl-1H-pyrazol-4-amine (0.070 g, 0.63 mmol) and p-toluenesulfonic acid monohydrate (0.006 g, 0.032 mmol) in 1,4-dioxane (1.0 mL) was stirred in the microwave at 120° C. for 2 hours. Additional 1,4-dioxane (1.5 mL) was added and the reaction mixture was stirred in the microwave at 120° C. for a further 4 hours. The reaction mixture was adsorbed onto SiO2 and purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 15-100% EtOAc in petroleum benzine 40-60° C.). Fractions containing suspected product were combined and adsorbed onto silica and purified by column chromatography (Biotage Isolera, 12 g SiO2, 0-5% MeOH in DCM) to give the title compound 26 as a pale yellow solid (0.030 g, 25%). LCMS-D: rt 3.24 min; m/z 411 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[CH:7][C:6]=1[C:21]1[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=1.O.[NH2:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1.[H-].[Na+]>CC(N(C)C)=O>[F:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:28][C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[C:6]([C:21]2[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=2)[CH:7]=1)=[O:20]
Reactant: Cn1nccc1-c1cc(NC(=O)c2cccc(F)c2)ccc1OCCBr
Reactant: Nc1nnn[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1nccc1-c1cc(NC(=O)c2cccc(F)c2)ccc1OCCNc1nnn[nH]1
Reaction time: 2 h
Yield: 20.3 %

Procedure:
To a solution of N-(4-(2-bromoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-fluorobenzamide (61.0 mg, 0.146 mmol) and 5-amino-1H-tetrazole monohydrate (42.5 mg, 0.500 mmol) in DMA (4 mL) was added NaH (30 mg, 60% dispersion in mineral oil) and the reaction was stirred for two hours. The resulting material was purified by HPLC. The product was dried under reduced pressure to afford the title compound as a white solid (12.5 mg, 20%). LCMS m/z (%)=423 (M+H, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]3[C:14]4[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=4[NH:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.[CH3:22][CH2:23][CH2:24]Br>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[N:7]3[C:14]4[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=4[N:12]([CH2:22][CH2:23][CH3:24])[C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1c2ccc(Cl)cc2nc2[nH]c3cc(Cl)c(Cl)cc3n12
Reactant: CCCBr
Product: CCCn1c2cc(Cl)c(Cl)cc2n2c(=O)c3ccc(Cl)cc3nc12

Procedure:
3,8,9-Trichloro-6-(n-propyl)benzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 3,8,9-trichlorobenzimidazo[2,1-b]-quinazolin-12(6H)one and n-propyl bromide.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9].[CH2:21]([C:28]1[C:33]([I:34])=[CH:32][CH:31]=[C:30]([N:35]2[CH2:39][C@H:38]([O:40][CH3:41])[C@@H:37]([OH:42])[CH2:36]2)[N:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:21]([C:28]1[C:33]([I:34])=[CH:32][CH:31]=[C:30]([N:35]2[CH2:39][C@H:38]([O:40][CH3:41])[C@@H:37]([O:42][S:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=3)(=[O:18])=[O:19])[CH2:36]2)[N:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@@H]1OS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100.6 %

Procedure:
300 mg of 4-dimethylaminopyridine, 10 ml of triethylamine and 9.7 g of 3-nitrobenzenesulfonyl chloride were added to a solution of 10.0 g of 2-benzyl-3-iodo-6-[(3S,4S)-3-hydroxy-4-methoxypyrrolidine-1-yl]pyridine obtained in the same manner as in Example 10-c in 150 ml of ethyl acetate, followed by stirring at room temperature for 3 days. The reaction solution was first filtered through 50 g of silica gel, and washed with ethyl acetate. Further, the filtrate was filtered through 50 g of NH-silica gel and washed with ethyl acetate. The filtrate was concentrated, to give 14.6 g of the target compound.
Reaction SMILES: Br[C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][N:5]([CH2:7][CH3:8])[CH:6]=1.[CH2:13]([Zn]CC)[CH3:14].O.Cl>O1CCOCC1>[CH2:7]([N:5]1[CH:6]=[C:2]([CH2:13][CH3:14])[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4]1)[CH3:8]
Reactant: CC[Zn]CC
Reactant: CCn1cc(Br)c(C(=O)OC)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCc1cn(CC)nc1C(=O)OC
Temperature: 75 °C
Yield: 43.9 %

Procedure:
Methyl 4-bromo-1-ethyl-1H-pyrazole-3-carboxylate (2.5 g, 11.4 mmol) was dissolved in anhydrous dioxane (90 mL). A solution of diethyl zinc (10.4 mL, 11.4 mmol, 1.1 M in toluene) was added dropwise, and then was added (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (125 mg, 171 μmol). The mixture was heated at 75° C. overnight, and water plus 1 N HCl were added. The mixture was extracted 3 times with ethyl acetate, and the combined organic phases were washed with brine and dried over sodium sulfate. After evaporation, the residue was dissolved in DCM and purified on silica gel using 0-30% hexane/ethyl acetate to afford methyl 1,4-diethyl-1H-pyrazole-3-carboxylate (912 mg, 48% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2([CH3:21])[CH2:16][C:15]([C:17]([F:20])([F:19])[F:18])=[N:14][NH:13]2)=[S:11])=[CH:5][C:4]=1[C:22]([F:25])([F:24])[F:23])#[N:2].C([O-])([O-])=O.[K+].[K+].[CH3:32][C:33](C)=O>>[CH2:32]([S:11][C:10]([C:12]1([CH3:21])[CH2:16][C:15]([C:17]([F:18])([F:19])[F:20])=[N:14][NH:13]1)=[N:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:22]([F:25])([F:24])[F:23])[CH:5]=1)[CH3:33]
Reactant: CC1(C(=S)Nc2ccc(C#N)c(C(F)(F)F)c2)CC(C(F)(F)F)=NN1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCSC(=Nc1ccc(C#N)c(C(F)(F)F)c1)C1(C)CC(C(F)(F)F)=NN1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
3-Methyl-5-trifluoromethyl-3,4-dihydro-2H-pyrazole-3-carbothioic acid (4-cyano-3-trifluoromethyl-phenyl)-amide (10 mmoL), K2CO3 (15 mmoL) in acetone was treated with Etl (10 mmoL) at room temperature. The reaction was slightly heated and stirred at 50° C. for 1 hr. The solid was filtrated and the filtrate was concentrated to give the crude product as a brown oil, which was then purified by silica gel column chromatography using hexanes and ethyl acetate as eluent to afford the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][O:12][CH2:11][CH:10]2[OH:14])[CH:6]=[CH:7][CH:8]=1.[Cr](Cl)(O)(=O)=O.N1C=CC=CC=1.ClCCl>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][O:12][CH2:11][C:10]2=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2COCC2O)c1
Agent: O=[Cr](=O)(O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(C2COCC2=O)c1
Reaction time: 3 h
Yield: 55.3 %

Procedure:
Combine 4-(3-methoxy-phenyl)-tetrahydro-furan-3-ol (10.58 g, 54.0 mmol), pyridine chlorochromate (35.22 g, 163.0 mmol), silica gel (35.0 g), and dichloromethane (200 mL), stir at room temperature. After 3 hours, add ether and filter off the silica gel through a plug of Silica using 50% ethyl acetate/hexanes eluent. Concentrate and flash chromatograph with 10% to 40% ethyl acetate/hexanes to yield the titled compound (5.74 g, 55%) as a clear oil. TLC Rf=0.23 in 3:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.30 (m, 1H), 6.85 (m, 3H), 4.68 (t, 1H, J=9.0 Hz), 4.31 (t, 1H, J=8.8 Hz), 4.19 (d, 1H, J=17.2 Hz), 4.08 (d, 1H, J=17.2 Hz), 3.84 (s, 3H), 3.70 (t, 1H, J=8.1 Hz).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])N)=[CH:5][CH:4]=1.[CH3:20][CH2:21][O:22][C:23]([CH2:25][CH:26]1[C:31](=O)[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:24]>>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:27]3[CH:26]([CH2:25][C:23]([O:22][CH2:21][CH3:20])=[O:24])[CH2:31][CH2:30][CH2:29][C:28]=3[C:15]3[C:10]2=[C:11]([Cl:17])[CH:12]=[C:13]([Cl:16])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1c(Cl)cc(Cl)cc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(2,4-dichlorophenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound is prepared.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:26])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[C:16]([NH:18][CH3:19])[C:15]([F:20])=[CH:14][C:13]=1[F:21])[CH:9]=[C:8]([C:22]([OH:24])=[O:23])[C:7]2=[O:25].[CH3:28][NH2:29]>N1C=CC=CC=1>[CH3:9][NH2:10].[Cl:1][C:2]1[C:3]([NH:29][CH3:28])=[C:4]([F:26])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[C:16]([NH:18][CH3:19])[C:15]([F:20])=[CH:14][C:13]=1[F:21])[CH:9]=[C:8]([C:22]([OH:24])=[O:23])[C:7]2=[O:25]
Reactant: CNc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN
Solvent: c1ccncc1
Product: CNc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NC)c(Cl)c32)c(F)cc1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
8-Chloro-6,7-difluoro-1-(2,4-difluoro-5-methylaminophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (200 mg) and a 40% aqueous solution (220 mg) of methylamine were added to pyridine (600 mg), and the mixture was stirred at room temperature for 5 hours. After the solvent was distilled off under reduced pressure, ethanol (1 ml) was added to the residue, and the mixture was stirred for 30 minutes. Deposits were collected by filtration and washed successively with ethanol and diisopropyl ether to obtain the title compound (92 mg) as a colorless powder.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]3[CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.C(O)(=O)C.[Pd]>[C:22]1([CH:15]2[CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3[C:11]3([CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[O:14]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: c1ccc(CN2CCC3(CC2)OC(c2ccccc2)C2CCCCN23)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: c1ccc(C2OC3(CCNCC3)N3CCCCC23)cc1

Procedure:
A solution of 11 g of hexahydro-1'-benzyl-1-phenylspiro[3H-oxazolo[3,4-a]pyridine-3,4'-piperidine] in 95 ml of methanol and 5 ml of acetic acid is mixed with 1 g of 20% palladium on carbon and subjected to hydrogen pressure of about 50 p.s.i. After the theoretical amount of hydrogen is consumed, the reaction is stopped and the filtered solution is evaporated to dryness in vacuo. The residue is dissolved in methylene dichloride and stirred with excess dilute ammonium hydroxide solution to convert the acetate salt of hexahydro-1-phenylspiro[3H-oxazolo[3,4-a]pyridine-3,4'-piperidine] to the free base. The organic layer containing the aforementioned free base is separated, washed with a saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue is recrystallized from ethyl acetate or methanol-water to obtain the pure free base of hexahydro-1-phenylspiro[3H-oxazolo[3,4-a]pyridine-3,4'-piperidine]; mp 169°-171° C.; yield 7 g.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28]O)[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]1(=[O:36])[NH:34][C:33](=[O:35])[CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][N:34]3[C:30](=[O:36])[CH2:31][CH2:32][C:33]3=[O:35])[N:27]=2)[CH2:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CO)cs2)C1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(=O)N1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OC1CN(c2nc(CN3C(=O)CCC3=O)cs2)C1)(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 100.3 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-hydroxymethyl-1,3-thiazol-2-yl)azetidine (1.50 g, 3.53 mmol) (obtained as described in Reference Example 2(2)) in tetrahydrofuran (75 ml) were added succinimide (525 mg, 5.30 mmol), triphenylphosphine (1.39 g, 5.30 mmol) and 40% diethyl azodicarboxylate in toluene solution (2.03 ml, 5.30 mmol) in an ice bath under an atmosphere of nitrogen. The mixture was stirred in an ice bath for 4 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-succinimidomethyl-1,3-thiazol-2-yl)azetidine (1.79 g, yield 100%) as pale yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:21])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1.[I-:22].[Na+].O>CC(=O)CC>[I:22][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:21])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1
Reactant: O=C(CCCCc1ccccc1)c1ccc(CCBr)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: O=C(CCCCc1ccccc1)c1ccc(CCI)cc1
Yield: 83.2 %

Procedure:
A solution of 1-[4-(2-bromoethyl)phenyl]-5-phenylpentan-1-one (18.2 g) and sodium iodide (9.5 g) in 2-butanone (180 ml) was stirred at 60° C. for 3.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and the solvent was distilled away under reduced pressure to give a brown oily substance (19.2 g). The obtained brown oily substance was purified by silica gel column chromatography (eluent; hexane: ethyl acetate=20:1) to give 1-[4-(2-iodoethyl)phenyl]-5-phenylpentan-1-one (17.2 g) as a yellow oily substance.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH3:21][CH:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][NH2:30])[CH2:24][CH2:23]1.[BH4-].[Na+]>CO>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:30][CH2:29][CH2:28][CH:25]2[CH2:26][CH2:27][CH:22]([CH3:21])[CH2:23][CH2:24]2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: CC1CCC(CCN)CC1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCC2CCC(C)CC2)ccc1Oc1ccc(C(N)=O)cn1
Reaction time: 8 h
Yield: 65.7 %

Procedure:
Place 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.100 g, 0.367 mmol), 2-(4-methylcyclohexyl)ethylamine (0.0571 g, 0.404 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.6 mL), cap and stir overnight. Add NaBH4 (ca. 3-5 eq in two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 5 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 10 g ISCO® column with 6% to 15% (2.0 M NH3 in methanol) in ethyl acetate to give 6-(2-methoxy-4-{[2-(4-methylcyclohexyl)ethylamino]methyl}phenoxy)nicotinamide (0.0958 g, 65.6%). Dissolve the compound in dichloromethane (2.5 mL) and add 1 equivalent of 0.50 M methanesulfonic acid in dichloromethane. Stir the solution for a short time before concentrating to afford the title compound: TOF MS ES+ 398.2 (M+H)+, HRMS calcd for C23H32N3O3 398.2444 (M+H)+, found 398.2440, time 0.52 min; Anal. Calcd for C23H31N3O3.0.5H2O: C, 57.35; H, 7.22; N, 8.36. Found: C, 57.33; H, 6.94; N, 8.34.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N)=[CH:4][CH:3]=1.COC(OC)CCCNC.ClC1C=[C:23]2[C:27](=CC=1)NC=[C:24]2[CH2:30][CH2:31][NH:32][CH3:33].C=O>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:8][C:23]1[CH2:27][N:32]([CH3:33])[CH2:31][CH2:30][C:24]2=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CNCCc1c[nH]c2ccc(Cl)cc12
Agent: C=O
Agent: CNCCCC(OC)OC
Product: CN1CCc2c([nH]c3ccc(Cl)cc23)C1

Procedure:
Method for the synthesis of compound 6[6-chloro-2-methyl-9-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole]: (4-chlorophenyl)hydrazine is reacted with 4,4-dimethoxy-N-methylbutan-1-amine (Phytochemistry 1985, 24 (8), 1653-1656) to generate 2-(5-chloro-1H-indol-3-yl)-N-methylethanamine which upon treatment with formaldehyde, under standard Pictet Spingler reaction conditions (U.S. Pat. No. 2,642,438) gives 6-chloro-2-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. The further reaction of this unsubstituted β-carboline with 2-(trifluoromethyl)-5-vinylpyridine gives the desired compound [6-chloro-2-methyl-9-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole], compound 6. After the successful synthesis of the compound, purification can be achieved using standard normal phase or reverse phase methods.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:2]1.[C:16]1([CH2:22][C:23](O)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C1COCC1>[C:16]1([CH2:22][C:23]([NH:15][C:12]2[S:13][CH:14]=[C:10]([C:3]3[C:4]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[NH:1][CH:2]=3)[N:11]=2)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1nc(-c2c[nH]c3ncccc23)cs1
Reactant: O=C(O)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)Nc1nc(-c2c[nH]c3ncccc23)cs1
Temperature: 160 °C

Procedure:
4-(1H-Pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-ylamine (216 mg, 1.0 mmol), phenylacetic acid (150 mg, 1.10 mmol) and N-(1-methanesulfonyl)benzotriazole (220 mg, 1.10 mmol) were placed in a microwave reaction vessel (Personal Chemistry, Uppsala, Sweden). THF (2 mL) was added followed by triethylamine (0.5 mL, 3.59 mmol) and the mixture heated in the sealed tube at 160° C. for 10 minutes. Upon cooling to room temperature the reaction was concentrated to 1 mL, and then acetonitrile was added (4 mL) and the product 2-Phenyl-N-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-yl]-acetamide precipitated, was filtered, washed with acetonitrile and dried. (150 mg, 45%). 1H NMR (500 MHz, DMSO-d6) 12.39 (1H, s), 11.83 (s,1H), 8.50 (1H, d, J=7.91 Hz), 8.27 (m,1H), 7.84 (1H, d, J=2.48 Hz), 7.36-7.15 (7H, m), 3.81 (2H, s). LC-MS Rt=2.8 min, [M+H]+=335.0, [M−H]−=333.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[CH3:27][NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:28]([CH3:27])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: CNCc1ccccn1
Product: CN(Cc1ccccn1)C(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
40 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to N-methyl-1-(pyridin-2-yl)methanamine via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-methyl-N4-(pyridin-2-ylmethyl)terephthalamide. MS (Q1) 491 (M)+.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[C:12]1[S:16][C:15]2[CH:17]=[C:18]([OH:21])[CH:19]=[CH:20][C:14]=2[C:13]=1[O:22][C:23]1[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([O:33]C)=[O:32])=[CH:25][CH:24]=1)([F:4])[CH3:3]>C1COCC1.O>[F:1][C:2]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[C:12]1[S:16][C:15]2[CH:17]=[C:18]([OH:21])[CH:19]=[CH:20][C:14]=2[C:13]=1[O:22][C:23]1[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32])=[CH:25][CH:24]=1)([F:4])[CH3:3]
Reactant: COC(=O)/C=C/c1ccc(Oc2c(-c3ccc(F)cc3C(C)(F)F)sc3cc(O)ccc23)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(F)(F)c1cc(F)ccc1-c1sc2cc(O)ccc2c1Oc1ccc(/C=C/C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.9 %

Procedure:
To a solution of (E)-methyl 3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (1.4 g, 2.89) in THF (5 mL) and water (3 mL) was added 56% LiOH monohydrate (371 mg, 8.67 mmol). The resulting mixture was stirred at room temperature for 18 h after which time the reaction was concentrated in vacuo to remove THF and the resulting solution was diluted with water and acidified by addition of HCl (1N aq.), causing a precipitate to crash out. The resulting precipitate was filtered to give (E)-3-(4-((2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid as a white solid which was not purified further (980 mg, 2.021 mmol, 69.9% yield). 1H NMR (400 MHz, CD3OD) δ ppm=1.80 (t, J=18.44 Hz, 3 H), 6.23 (d, J=16.17 Hz, 1 H), 6.71-6.81 (m, 3 H), 7.03 (td, J=8.21, 2.78 Hz, 1 H), 7.08-7.14 (m, 2 H), 7.22-7.32 (m, 2 H), 7.37 (d, J=8.59 Hz, 2 H), 7.47 (d, J=16.17 Hz, 1 H), LC/MS (m/z, M−H): 468.9.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]([NH:11][NH2:12])=[CH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:3][CH2:2]1.O=P(Cl)(Cl)Cl.O.[CH3:22]N(C=O)C>>[CH:1]1([CH2:4][N:5]2[C:10]3=[N:11][NH:12][CH:22]=[C:9]3[C:8](=[O:13])[N:7]([CH3:14])[C:6]2=[O:15])[CH2:2][CH2:3]1
Reactant: CN(C)C=O
Reactant: Cn1c(=O)cc(NN)n(CC2CC2)c1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cn1c(=O)c2c[nH]nc2n(CC2CC2)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(Cyclopropylmethyl)-6-hydrazino-3-methylpyrimidine-2,4(1H,3H)-dione (5 g) was dissolved in DMF (5 mL) followed by addition of POCl3 (4 mL) dropwise at 0° C. The reaction was warmed to 80 C. for 3 h, followed by stirring at RT overnight. The solution was added to 200 mL of water and filtered to give about 5 g of yellow solids. Proton NMR was sufficient to carry on to next step.