Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCl.CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][OH:28])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C(N(CC)CC)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([CH:27]=[O:28])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Dichloromethane solution of DMSO (2.4 mL, 33.4 mmol) was added to dichloromethane solution of oxalyl chloride (1.5 mL, 16.7 mmol) at −76° C. for 30 minutes. After stirring for 30 minutes at −78° C., dichloromethane solution (15 mL) of 4-(hydroxymethyl)piperidine-1-carboxilic acid tert-butyl ester (3.00 g, 13.9 mmol) was added at −76° C. for 30 minutes. After stirring for 30 minutes at −76° C., triethylamine (9.7 mL) was added at −76° C. for 10 minutes. The mixture was stirred at −76° C. for 15 minutes and was stirred for 45 minutes after increasing the temperature to room temperature. The reaction was terminated by adding water. The reaction mixture was extracted with dichloromethane three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to obtain compound P33 (2.41 g, 11.3 mmol, 81%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([Cl:13])[N:3]=1.CC(C)([O-])C.[K+].[F:20][C:21]([F:31])([F:30])[O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1.O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:4]1[N:3]=[C:2]([NH:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][C:21]([F:20])([F:30])[F:31])=[CH:24][CH:25]=2)[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=1
Reactant: Clc1cc(N2CCCC2)cc(Cl)n1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)Oc1ccc(Nc2cc(N3CCCC3)cc(Cl)n2)cc1
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
To a solution of 2,6-dichloro-4-pyrrolidino-pyridine (1.0 g, 4.62 mmol) in toluene (6 mL) were added potassium tert-butoxide (0.1556 g, 1.38 mmol), palladium(II)acetate (26 mg, 0.115 mmol), BINAP (36 mg, 0.057 mmol) and 4-trifluoromethoxyphenylamine (246 mg, 1.38 mmol), in a 10 mL reaction vessel. This reaction mixture was subjected the microwave radiation, in which the microwave power was 250 W, to attain a reaction temperature of 150° C. After this reaction proceeded for 30 min, water (200 mL) was added to the reaction mixture and the reaction product was extracted with ethyl acetate. The organic layer was dried over sodium sulphate, filtered, and the filtrate concentrated under vacuum. The product was purified through column chromatography using 230-400 mesh silica gel to afford the desired compound as light brown solid (220 mg, yield 14%).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:6][O:5][C:4]([C:7]2[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=2[CH:9]([C:11]2[N:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[N:12]=2)Br)=[N:3]1.C([O-])([O-])=[O:27].[Na+].[Na+].O>CS(C)=O>[CH3:1][C:2]1([CH3:25])[CH2:6][O:5][C:4]([C:7]2[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=2[C:9]([C:11]2[N:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[N:12]=2)=[O:27])=[N:3]1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(OC)nc(C(Br)c2ccccc2C2=NC(C)(C)CO2)n1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(OC)nc(C(=O)c2ccccc2C2=NC(C)(C)CO2)n1
Reaction time: 3 h

Procedure:
A mixture of 1.2 g of 2-(2-(4,4-dimethyl-oxazolin-2-yl)-α-bromobenzyl)-4,6-dimethoxy-pyrimidine and 2 g of Na2CO3 in 30 ml of DMSO is heated with stirring at 50°-60° C. for 3 hrs. The mixture is poured into 150 ml of water and extracted with toluene. The toluene extract is washed twice with water (2×50 ml) separated and concentrated. The thus obtained gum is chromatographed with 800 ml of 80/20 hexane/ethyl acetate, 500 ml 70/30 hexane/ethyl acetate, 60/40 ml hexane/ethyl acetate (50 ml fractions) fractions 29 to 34 yielded the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.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>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1ccc(-c2ccccn2)cc1
Temperature: 90 °C

Procedure:
Pd(PPh3)4 (0.404 gm, 0.35 mmol) was added to a degassed solution of 4-cyanobenzene boronic acid (1.029 g, 7 mmol) and 2-bromopyridine (1.11 g, 7 mmol) in 75 mL acetonitrile. 0.4 M sodium carbonate solution (35 mL) was added to the reaction mixture and the resulting solution was refluxed at 90° C. under Ar for 24 hours (progress of reaction was monitored by TLC). The reaction mixture was cooled and aqueous layer was separated. The organic layer containing the product and spent catalyst was mixed with silica gel (15 g) and concentrated to dryness. The 4-(2-pyridyl)-benzonitrile was isolated by column chromatography (0.850 g, 68%). LCMS: MH+=181; 1H NMR (CDCl3) δ 8.85 (d, 1H), 8.7 (dd, 1H), 7.9 (dd, 1H), 7.75 (d, 2H), 7.7 (d, 2H), 7.4 (dd, 1H).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Br:20][C:21]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:22]=1[C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.[C:44]([O:48][C:49](=[O:60])[NH:50][CH2:51][C:52](=[O:59])[N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([O:48][C:49](=[O:60])[NH:50][CH2:51][C:52]([N:53]1[CH2:54][CH2:55][N:56]([C:23](=[O:25])[C:22]2[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:21]=2[Br:20])[CH2:57][CH2:58]1)=[O:59])([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCNCC1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Br)c(C(=O)N2CCN(C(=O)CNC(=O)OC(C)(C)C)CC2)c1
Temperature: 10 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
HOBt (125 mg, 0.93 mmol) and DIPEA (287 mg, 2.2 mmol) were added to a stirred solution of 2-bromo-5-methoxy-benzoic acid (171 mg, 0.74 mmol) in DMF (2.5 mL). The mixture was then cooled to 10° C. and EDCI.HCl (178 mg, 0.93 mmol) followed by (2-oxo-2-piperazin-1-yl-ethyl)-carbamic acid tert-butyl ester (200 mg, 0.82 mmol) were added. The reaction mixture was then stirred at room temperature overnight. Water was added, and the product was extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. Purification using column chromatography (silica gel (60-120 mesh) and 50% ethyl acetate in hexane as the eluent) afforded {2-[4-(2-Bromo-5-methoxy-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester in 97% yield. LC-MS purity: 97.79%
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:4]([Cl:16])[CH:3]=1.[Cl:17]P(Cl)(Cl)(Cl)Cl.ClCCCl.C(=O)([O-])[O-].[K+].[K+]>O.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[Cl:17])=[CH:9]\[N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:4]([Cl:16])[CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(Cn1cncn1)c1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCCl
Solvent: ClCCl
Product: Cl/C(=C/n1cncn1)c1ccc(Br)cc1Cl
Reaction time: 8 h
Yield: 37 %

Procedure:
A mixture of 20 parts of 1-(4-bromo-2-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone, 40 parts of pentachlorophosphorane and 300 parts of 1,2-dichloroethane was stirred and relfuxed overnight. 300 Parts of potassium carbonate and 650 parts of dichloromethane were added and water was added dropwise carefully till a volume of about 1500 parts. The aqueous phase was extracted with dichloromethane. The combined organic layers were washed with water, dried, filtered and evaporated. The residue was purified by reversed phase chromatography (HPLC) over LiChroprep RP 18 using a mixture of 75% of methanol containing 0.1% of N-(1-methylethyl)-2-propanamine and 25% of water containing 0.5% of ammonium acetate. The first fraction (E-isomer) was collected and the eluent was evaporated. The residue was crystallized from hexane at 0° C. The product was filtered off and dried in vacuo at 60° C., yielding 7.9 parts (37%) of (E)-1-[2-(4-bromo-2-chlorophenyl)-2 -chloroethenyl]-1H-1,2,4-triazole; mp. 84.0° C. (compound 44). The second fraction (Z-isomer) was collected and the eluent was evaporated. The residue was crystallized from hexane at 0° C. The product was filtered off and dried in vacuo at 60° C., yielding 0.36 parts of (Z)-1-[2-(4-bromo-2-chlorophenyl)-2-chloroethenyl]-1H-1,2,4-triazole; mp. 96.0° C. (compound 45).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH:3]1[OH:10].[H-].[Na+].[O:13]1[CH:15]([CH2:16][CH2:17][CH3:18])[CH2:14]1.OS(O)(=O)=O>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH:3]1[O:10][CH2:14][CH:15]([OH:13])[CH2:16][CH2:17][CH3:18]
Reactant: CCCC1CO1
Reactant: CC1CCCC(C)(C)C1O
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCC(O)COC1C(C)CCCC1(C)C
Yield: 75 %

Procedure:
A mixture of 2.0 g of 2,6,6-trimethyl-cyclohexanol and 0.354 g of sodium hydride was heated for 24 hours at 80° in 10 ml of anhydrous toluene. 1.2 G of 1,2-epoxy-pentane were then added to the thus obtained solution and heating at 80° was maintained for 24 additional hours. After cooling, the reaction mixture was poured onto crushed iced, acidified with diluted H2SO4, whereupon the organic phase was washed with brine until neutrality. After evaporation of the volatile parts and distillation of the residue in a a bulb apparatus (bath temperature: 140°/7 Pa), the desired product was obtained in yield of about 75%. An analytical sample was purified by preparative gas chromatography.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])(O)[CH2:14][CH2:13]1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[CH2:1]([O:8][CH2:9][C:10]([N:12]1[CH2:13][CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[CH2:16][CH2:17]1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(COCc1ccccc1)N1CCC(O)(c2ccc(Cl)cc2Cl)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C(COCc1ccccc1)N1CC=C(c2ccc(Cl)cc2Cl)CC1
Yield: 27.8 %

Procedure:
A solution of 2-benzyloxy-1-[4-(2,4-dichloro-phenyl)-4-hydroxy-piperidin-1-yl]-ethanone (0.035 g, 0.09 mmol) in trifluoroacetic acid (1 mL) was stirred at RT for 48 h. Ethyl acetate (2 mL) and saturated aqueous sodium bicarbonate (2 mL) were added and the layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The isolated residue was chromatographed on silica gel using dichloromethane/ethyl acetate to 100% to 90% dichloromethane in a gradient fashion, to give the title compound as a gum (0.0094 g, 28%).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:9]([SH:12])=[N:10][N:11]=2)=[CH:3][CH:2]=1.CI.[C:28](=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:9]([S:12][CH3:28])=[N:10][N:11]=2)=[CH:3][CH:2]=1
Reactant: Fc1ccccc1-n1c(S)nnc1-c1ccc(-c2ccccc2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CI
Product: CSc1nnc(-c2ccc(-c3ccccc3)cc2)n1-c1ccccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.5 %

Procedure:
5-Biphenyl-4-yl-4-(2-fluorophenyl)-4H-1,2,4-triazole-3-thiol (2.7 g) was dissolved in acetonitrile (50 ml), followed by addition of methyl iodide (0.967 ml) and potassium carbonate (1.07 g), and stirred at ambient temperature for 3 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with saturated aqueous saline and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resulting solid was recrystallized from a mixture solvent of acetonitrile and ethyl acetate, to afford the entitled compound 3-biphenyl-4-yl-4-(2-fluorophenyl)-5-methylsulfanyl-4H-1,2,4-triazole as pale yellow crystal (2.03 g, 72%). The physico-chemical values are as follows.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]([OH:22])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:5]=[CH:4][C:3]=1[C:23]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH:37]([OH:49])[CH2:38][O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[CH:31][C:30]=2[OH:50])[N:26]=[C:25]([C:51]2[CH:56]=[CH:55][C:54]([S:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[CH:53][CH:52]=2)[N:24]=1.ClC1C=C(C=CC=1)C(OO)=[O:69].CCCCCCC.C(OCC)(=O)C>C(Cl)(Cl)Cl>[C:58]1([S:57]([C:54]2[CH:53]=[CH:52][C:51]([C:25]3[N:26]=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH:37]([OH:49])[CH2:38][O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[CH:31][C:30]=4[OH:50])[N:28]=[C:23]([C:3]4[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH:10]([OH:22])[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:7][C:2]=4[OH:1])[N:24]=3)=[CH:56][CH:55]=2)=[O:69])[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCCCCOCC(O)COc1ccc(-c2nc(-c3ccc(Sc4ccccc4)cc3)nc(-c3ccc(OCC(O)COCCCCCCCCC)cc3O)n2)c(O)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCOCC(O)COc1ccc(-c2nc(-c3ccc(S(=O)c4ccccc4)cc3)nc(-c3ccc(OCC(O)COCCCCCCCCC)cc3O)n2)c(O)c1

Procedure:
Following the general procedure of Example 7, 1.55 g (1.76 mmol) of 2,4-bis-[2-hydroxy-4-(2-hydroxy-3-nonyloxypropoxy)phenyl]-6-[4-(phenylthio)phenyl]-s-triazine are dissolved in 30 mL of chloroform. To the stirred solution at room temperature are added 0.606 g (1.76 mmol) of m-chloroperoxybenzoic acid (50-60%) all at once. After several minutes, the chloroform is removed under reduced pressure and the residue is redissolved in ethyl acetate. The solution is then washed five times with saturated sodium bicarbonate solution, once with water and once with brine and finally dried over anhydrous magnesium sulfate. The solvent is removed to give a yellow oil which is subjected to medium pressure liquid chromatography with 1:3 heptane:ethyl acetate. The title compound is isolated as a yellow glassy solid in a yield of 0.43 g (27%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11](=[NH:14])[NH:12][NH2:13])=[N:9][N:8]([CH2:15][C:16]3[C:21]([F:22])=[CH:20][CH:19]=[C:18]([F:23])[C:17]=3[F:24])[C:5]2=[N:6][CH:7]=1.[CH3:25][C:26]([CH3:37])([C:31](=O)[C:32](OC)=[O:33])[C:27]([O:29][CH3:30])=[O:28]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[N:13][C:31]([C:26]([CH3:37])([CH3:25])[C:27]([O:29][CH3:30])=[O:28])=[C:32]([OH:33])[N:14]=3)=[N:9][N:8]([CH2:15][C:16]3[C:21]([F:22])=[CH:20][CH:19]=[C:18]([F:23])[C:17]=3[F:24])[C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)C(=O)C(C)(C)C(=O)OC
Reactant: N=C(NN)c1nn(Cc2c(F)ccc(F)c2F)c2ncc(F)cc12
Solvent: CCO
Product: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3c(F)ccc(F)c3F)c3ncc(F)cc23)nc1O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
6.85 g (20.271 mmol) of the compound from Example 81A were dissolved in 300 ml of ethanol, 7.629 g (40.542 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate (described in J. Am. Chem. Soc. 124(14), 3680-3691; 2002) were added and the mixture was stirred at 50° C. overnight. After cooling, a precipitate was filtered off and washed with ethanol. The filtrate was concentrated and then purified by preparative HPLC (methanol:water-75:25). This gave 3.30 g (33% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:30]=[CH:29][C:18]([O:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][N:21]=2)=[CH:17][CH:16]=1)[CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=[N:41][C:39]=2C=1.CCN(C(C)C)C(C)C.Cl.CN.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][CH:11]([CH3:12])[CH3:13])[CH2:14][C:15]1[CH:30]=[CH:29][C:18]([O:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](=[O:26])[NH:41][CH3:39])=[CH:22][N:21]=2)=[CH:17][CH:16]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC(C)CCN(Cc1ccc(Oc2ccc(C(=O)O)cn2)cc1)C(=O)OC(C)(C)C
Agent: CN
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1ccc(Oc2ccc(CN(CCC(C)C)C(=O)OC(C)(C)C)cc2)nc1
Reaction time: 72 h
Yield: 62.6 %

Procedure:
Combine 6-(4-{[tert-Butoxycarbonyl-(3-methyl-butyl)-amino]-methyl}-phenoxy)-nicotinic acid (0.090 g, 0.21 mmol), CH2Cl2 (5 mL), EDC (0.048 g, 0.25 mmol), HOBt (0.034 g, 0.25 mmol), Hunig's Base (92 uL, 0.53 mmol), and Methylamine Hydrochloride (0.014 g, 0.21 mmol) in a 7 mL reaction vial. After reactions shake for 72 hours, add 10% Citric acid, followed by 10% NaHCO3, and then add the organic mixture to a Celite column. Elute with CH2Cl2, concentrate, and flash chromatograph using 2:1 Ethyl acetate:Hexanes eluent to afford 56.2 mg (63% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 0.9 (6H, d), 1.3-1.6 (12H, m), 3.0 (3H, s), 3.1-3.3 (2H, m), 4.3-4.5 (2H, m), 6.3 (1H, br s), 6.9 (1H, d), 7.1 (2H, d), 7.2-7.4 (2H, m), 8.1 (1H, d), 8.5 (1H, s); MS m/z 328 (M−100, Boc).
Reaction SMILES: [CH2:1]1[C:13]2[C:12]3[CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3][N:2]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[H-].[Na+].I[CH3:28].[NH4+].[Cl-]>CN(C=O)C>[CH3:28][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:12]=2[C:13]2[CH2:1][N:2]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3][CH2:4][C:5]1=2
Reactant: COC(=O)c1ccc2[nH]c3c(c2c1)CN(C(=O)OC(C)(C)C)CC3
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)c1c(n2C)CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
A solution of 2-tert-butyl 8-methyl 3,4-dihydro-1H-pyrido[4,3-b]indole-2,8(5H)-dicarboxylate (17 in Scheme 1(i), 1.0 g, 3.0 mmol) in DMF (6.0 mL) was added to a cold solution (ice bath) of NaH (60%, 121 mg, 3.0 mmol) in DMF (3 mL). After stirring at 0° C. under N2 atmosphere for 30 min, iodomethane (210 μL, 471 mg, 3.3 mmol) was added dropwise. The reaction mixture was then allowed to warm up to room temperature overnight, cooled down to 0° C. and poured into saturated NH4Cl solution (20 mL). The resulting brown precipitate was filtered, dried and chromatographed (neat DCM→2% MeOH/DCM) to provide, upon trituration with ethyl ether, 2-tert-butyl 8-methyl 5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2,8(5H)-dicarboxylate (18 in Scheme 1(i), 0.82 g, 79%). 1H NMR (CD3OD, 300 MHz) 8.13 (s, 1H), 7.82 (dd, J=8.8, 1.7 Hz, 1H), 7.38 (d, J=8.5 Hz, 1H), 4.64 (br s, 2H), 3.90 (s, 3H), 3.84 (t, J=5.6 Hz, 2H), 3.69 (s, 3H), 2.86 (t, J=5.6 Hz, 2H), 1.52 (s, 9H) ppm; MS (ES) 345 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][N:24]=3)=[O:22])=[C:16]([F:31])[CH:15]=2)[CH2:9]1)=O)(C)(C)C.[ClH:32].O1CCOCC1>C1COCC1>[ClH:32].[C:29]([C:27]1[CH:26]=[CH:25][N:24]=[C:23]([C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([C@@H:10]3[O:11][CH2:12][CH2:13][NH:8][CH2:9]3)=[CH:15][C:16]=2[F:31])=[O:22])[CH:28]=1)#[N:30]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cc(C#N)ccn3)c(F)c2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: N#Cc1ccnc(C(=O)Nc2ccc([C@H]3CNCCO3)cc2F)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
To a solution of (S)-2-{4-[(4-Cyano-pyridine-2-carbonyl)-amino]-3-fluoro-phenyl}-morpholine-4-carboxylic acid tert-butyl ester (73 mg, 171 μmol, Eq: 1.00) in THF (3 ml) was added 4M−HCl in dioxane (0.642 ml, 2.52 mmol, Eq: 15). The reaction mixture was stirred at 60° C. for 5 h. To the cooled mixture was then added ethyl acetate and the suspension was filtered off and dried under high vacuo to give the target compound as a white solid (53 mg, 85%). MS (ISP): 325.2 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH2:11]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[OH:22])[CH:17]=[O:18])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:22][C:21]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=2[O:13][CH2:11][CH3:12])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: CCOc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)ccc1Oc1cc(Cl)ccc1C#N
Yield: 85.4 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.40 g, 2.6 mmol), 3-ethoxy-4-hydroxybenzaldehyde (0.43 g, 2.6 mmol) and cesium carbonate (0.84 g, 2.6 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 20 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water (1×), 10% sodium carbonate solution (1×), 0.5N sodium hydroxide solution (1×), water (1×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(2-ethoxy-4-formylphenoxy)benzonitrile (0.67 g, 86%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([C:27]([C:29]2[C:30]([CH3:36])=[C:31]([CH:34]=O)[NH:32][CH:33]=2)=[O:28])[CH2:21]1>C(O)C.N1CCCCC1>[CH3:26][C@H:24]1[NH:25][C@@H:20]([CH3:19])[CH2:21][N:22]([C:27]([C:29]2[C:30]([CH3:36])=[C:31]([CH:34]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[NH:13][C:12]3=[O:18])[NH:32][CH:33]=2)=[O:28])[CH2:23]1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Reactant: Cc1c(C(=O)N2C[C@@H](C)N[C@@H](C)C2)c[nH]c1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]cc(C(=O)N4C[C@@H](C)N[C@@H](C)C4)c2C)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.9 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-{4-((cis)-3,5-dimethyl-piperazine-1-carbonyl]-3-methyl-1H-pyrrol-2-ylmethylene}-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (74 mg, 63%).