Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][N:17]([CH3:35])[CH2:18][CH2:19][CH2:20][C:21]1[N:22]=[N+:23]([O-:34])[C:24]2[CH:33]=[C:32]3[C:28]([CH2:29][CH2:30][CH2:31]3)=[CH:27][C:25]=2[N:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[O-:34][N+:23]1[C:24]2[CH:33]=[C:32]3[C:28](=[CH:27][C:25]=2[N+:26]([O-:4])=[C:21]([CH2:20][CH2:19][CH2:18][N:17]([CH3:16])[CH3:35])[N:22]=1)[CH2:29][CH2:30][CH2:31]3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CN(C)CCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCCc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 41.1 %

Procedure:
H2O2 (70%, 0.65 mL, 13 mmol) was added dropwise to a stirred solution of TFAA (1.8 mL, 13 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 78 (353 mg, 1.3 mmol) and TFA (0.7 mL, 9.1 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 8 h, diluted with dilute aqueous NH3 solution (12 mL) and extracted with DCM (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 79 (154 mg, 41%) as a red solid: 1H NMR δ 8.30 (s, 1H, H-9), 8.26 (s, 1H, H-5), 3.25-3.09 (m, 6H, H-6, H-8, CH2), 2.75 (t, J=7.3 Hz, 2H, CH2), 2.70 [s, 6H, N(CH3)2], 2.29-2.14 (m, 4H, H-7, CH2); 13C NMR δ 155.2, 153.9, 150.8, 139.1, 133.9, 115.9, 113.9, 58.0, 44.3 (2), 33.4, 32.9, 27.9, 25.6, 21.7; HRMS (FAB+) calcd for C15H21N4O2 (MH+) m/z 289.1665, found 289.1669.
Reaction SMILES: Br[C:2]1[C:3]([CH3:15])=[C:4]([CH3:14])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[C:7](=[O:12])[C:6]=2[CH:13]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[O:29][CH2:28][CH2:27][NH:26][CH2:25]2)=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]2[O:29][CH2:28][CH2:27][N:26]([C:2]3[C:3]([CH3:15])=[C:4]([CH3:14])[C:5]4[O:9][C:8]([CH3:11])([CH3:10])[C:7](=[O:12])[C:6]=4[CH:13]=3)[CH2:25]2)=[CH:22][CH:23]=1
Reactant: Cc1c(Br)cc2c(c1C)OC(C)(C)C2=O
Reactant: COc1ccc(C2CNCCO2)cc1
Product: COc1ccc(C2CN(c3cc4c(c(C)c3C)OC(C)(C)C4=O)CCO2)cc1
Yield: 34.1 %

Procedure:
By using 5-bromo-2,2,6,7-tetramethyl-1-benzofuran-3(2H)-one (488 mg, 1.72 mmol) synthesized in Reference Example 18 and 2-(4-methoxyphenyl)morpholine (500 mg, 2.59 mmol), the reaction was carried out in the same manner as Reference Example 59 to synthesize 224 mg of the title compound (yield 34%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH3:16])=[O:14].[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1>>[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[C:3]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:20][CH:19]=1
Reactant: COC(=O)c1c(C)nc2ccccc2c1N
Reactant: BrCc1ccc(Br)cc1
Product: COC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)cc1

Procedure:
Methyl 4-(4-bromobenzylamino)-2-methylquinoline-3-carboxylate was synthesized by the same method as described for 1-(4-(4-bromobenzylamino-2-methylquinolin-3-yl)ethanone (Example 1, Intermediate 2c), starting from methyl 4-amino-2-methylquinoline-3-carboxylate and 4-bromobenzyl bromide. Melting point: 89° C.; MS(ES+): 385/387.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[N:19]=[CH:18][C:17]([O:20][CH:21]3[CH2:26][CH2:25][N:24]([C:27]#[N:28])[CH2:23][CH2:22]3)=[CH:16][CH:15]=1)[CH:9]=[CH:8]2)(=[O:4])=[O:3].[OH:29][NH:30][C:31](=N)[CH:32]([CH3:34])[CH3:33]>C1COCC1.[Cl-].[Zn+2].[Cl-]>[CH:32]([C:31]1[N:28]=[C:27]([N:24]2[CH2:25][CH2:26][CH:21]([O:20][C:17]3[CH:18]=[N:19][C:14]([N:10]4[C:11]5[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=5)[CH:8]=[CH:9]4)=[CH:15][CH:16]=3)[CH2:22][CH2:23]2)[O:29][N:30]=1)([CH3:34])[CH3:33]
Reactant: CC(C)C(=N)NO
Reactant: CS(=O)(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(C#N)CC3)cn2)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC(Oc3ccc(-n4ccc5cc(S(C)(=O)=O)ccc54)nc3)CC2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.5 %

Procedure:
To a mixture of 4-((6-(5-(methylsulfonyl)-1H-indol-1-yl)pyridin-3 yl)oxy)piperidine-1-carbonitrile (intermediate-36) (0.110 g, 0.27 mmol) and N-hydroxy-isobutyramidine (0.05 g, 0.5 mmol) in anhydrous THF (15 mL), 1M solution of zinc chloride in THF (0.56 mL, 0.56 mmol) was added. The suspension was stirred at room temperature for 18 h. Solvent was concentrated in vacuo, the resulting crude was dissolved in 4N HCl in ethanol, water (1:1) and stirred at 60-70° C. for 2-3 h. The reaction was quenched by saturated NaHCO3 and the organic layer was separated and concentrated. The residue was purified by flash column chromatography to give 3-isopropyl-5-(4-((6-(5-(methylsulfonyl)-1H-indol-1-yl)pyridin-3-yl)oxy)piperidin-1-yl)-1,2,4-oxadiazole (0.041 g, 30%)
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][CH2:6][OH:7].C(N(CC)C(C)C)(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][CH2:6][O:7][S:20]([CH3:19])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOCC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCOCC(F)(F)F
Reaction time: 2 h

Procedure:
Combine 2-hydroxyethyl 2,2,2-trifluoroethyl ether (0.5 mmol) and N,N-diisopropylethylamine (1 mmol) in dichloromethane (20 mL). Cool in a ice-bath. Add dropwise, methanesulfonyl chloride (0.6 mmol). After 2 hours, extract with 1M hydrochloric acid solution and 5% sodium bicarbonate solution. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([CH2:22][OH:23])[C:9]=2[CH2:24][OH:25])[CH:5]=[CH:4][N:3]=1.O=C1[NH:31][C:30]2[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=2[O:28]1>>[OH:28][C:29]1[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=1[NH:31][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([CH2:22][OH:23])[C:9]=2[CH2:24][OH:25])[CH:5]=[CH:4][N:3]=1
Reactant: O=c1[nH]c2ccccc2o1
Reactant: COc1cc2cc(CO)c(CO)c(-c3ccnc(Br)c3)c2cc1OC
Product: COc1cc2cc(CO)c(CO)c(-c3ccnc(Nc4ccccc4O)c3)c2cc1OC

Procedure:
1-(2-Bromo-4-pyridyl)-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene and 2-oxobenzoxazolidine are treated in the same manner as Example 6-(2) to give 1-[2-(2-hydroxyphenyl)amino-4-pyridyl)-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene which is a hydrolysis product of 1-[2-(2-oxobenzoxazolidin-3-yl)-4-pyridyl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene and listed in Table 6.
Reaction SMILES: [CH2:1]([O:8]CCOC1C=C(C2OC(=O)NCC2)C=CC=1OC)C1C=CC=CC=1.[CH:27]1([O:32][C:33]2[CH:34]=[C:35]([CH:41]([OH:47])[C:42]([CH3:46])([CH3:45])[C:43]#[N:44])[CH:36]=[CH:37][C:38]=2[O:39][CH3:40])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([O:32][C:33]2[CH:34]=[C:35]([CH:41]3[O:47][C:1](=[O:8])[NH:44][CH2:43][C:42]3([CH3:45])[CH3:46])[CH:36]=[CH:37][C:38]=2[O:39][CH3:40])[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COc1ccc(C(O)C(C)(C)C#N)cc1OC1CCCC1
Reactant: COc1ccc(C2CCNC(=O)O2)cc1OCCOCc1ccccc1
Product: COc1ccc(C2OC(=O)NCC2(C)C)cc1OC1CCCC1
Yield: 54.3 %

Procedure:
According to the same procedure as in Example 1(2) to (3), using 3-(3-cyclopentyloxy-4-methoxyphenyl)-2,2-dimethyl-3-hydroxypropiononitrile instead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, the above-described compound (yield 54.3%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]#[CH:12])[CH:6]=[CH:7][CH:8]=1.[F:13][C:14]([F:27])([F:26])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=1I.C1C=CC=CC=1>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]#[C:12][C:16]2[CH:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=[CH:20][C:15]=2[C:14]([F:13])([F:26])[F:27])[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(C(F)(F)F)c(I)c1
Reactant: C#CC#Cc1cccc(OC)c1
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1cccc(C#CC#Cc2cc(C(F)(F)F)ccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 29.6 %

Procedure:
430 mg of the thus-obtained 1-(3-methoxyphenyl)-1,3-butadiyne and 1200 mg of 2,5-bis(trifluoromethyl) iodobenzene were dissolved in 20 ml of triethylamine in an atmosphere of argon, and 21 mg of bis(triphenylphosphine) palladium (II) chloride and 6 mg of copper (I) chloride were rapidly added to the reaction mixture. After the solution had been stirring at room temperature for 13 hours, 30 ml of benzene were added thereto, and the precipitates produced were filtered off. After the solvent had been evaporated, the residue was neutralized by 1N hydrochloric acid and then subjected to extraction with 50 ml benzene three times. The organic layer was dried over magnesium sulfate, and the solvent was then evaporated. The residue was then purified by silica-gel column chromatography using hexane as an eluent to obtain 300 mg of 1-(3-methoxyphenyl)-4-[2,5-bis(trifluoromethyl)phenyl]-1,3-butadiyne. This compound was a slightly yellowish white crystal having a melting point of 37° C.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][N:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:20]([N:27]([C:35](=[O:37])[CH3:36])[C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:19][C@@H:18]2[CH3:38])=[O:16])=[CH:11][CH:10]=1)[CH3:8].C(O)C.[OH-].[Li+]>O1CCCC1>[C:35]([N:27]([C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C@H:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:17]([C:15]([C:12]2[CH:13]=[CH:14][C:9]([N:7]([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]([OH:39])=[O:2])=[CH:10][CH:11]=2)=[O:16])[C@@H:18]([CH3:38])[CH2:19]1)(=[O:37])[CH3:36]
Reactant: COC(=O)CCCN(C)c1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N(C)CCCC(=O)O)cc2)c2ccccc21
Temperature: 50 °C

Procedure:
(2S,4R)-4-[(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-methyl-amino]-butyric acid was prepared from (2S,4R)-4-[(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-methyl-amino]-butyric acid methyl ester was hydrolyzed to the acid by dissolving in tetrahydrofuran and ethanol and lithium hydroxide (1N) was added and heated 50° C. for 2 h. The mixture was cooled to room temperature, acidified to form a white precipitate. The solid was filtered to give to afford the product after HPLC purification.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[N:9]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]1.CN(CCN(C)C)C.[O:34]=[CH:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41]>C1COCC1>[C:40]([O:39][C:38]([NH:37][CH2:36][CH:35]([C:12]1([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10][N:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]1)[OH:34])=[O:44])([CH3:43])([CH3:42])[CH3:41]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(C)[N-]C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(C(O)CNC(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of LDA (prepared by adding n-butyllithium (20.0 mL, 49.3 mmol) to diisopropylamine (5.16 mg, 51.0 mmol) in THF (40 mL) at 0° C., stirred for 30 min) was added 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (4.00 g, 16.4 mmol) in TMEDA (15 mL, 99 mmol) drop-wise via syringe pump at −78° C. for 10 min. The mixture was stirred at the same temperature for 30 min, then tert-butyl (2-oxoethyl)carbamate (8.11 g, 51.0 mmol) in THF (20 mL) was added slowly by syringe pump for 15 min. The mixture was stirred at −78° C. for 30 min, quenched with saturated NH4Cl at −78° C., warmed up to rt and diluted with EtOAc (200 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed with brine, dried (MgSO4), and concentrated. The residue was purified by column chromatography (80 g, silical gel, MeOH/DCM, gradient 0-10%, monitor at 210 nm) to afford title compound. LC/MS: [(M+1)]+=403
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:21](=[O:22])[C:20]3[CH:24]=[CH:25][C:17]([Cl:16])=[CH:18][CH:19]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccc(Cl)cc1

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-4-chlorobenzamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 4-chlorobenzoyl chloride in a similar manner as described above to give a tan solid (69% yield). 1H-NMR (CDCl3): δ 8.89 (s, 1H), 7.71 (d, 2H), 7.60 (m, 1H), 7.40 (d, 2H), 7.23 (dd, 1H), 7.17 (dd, 1H), 6.36 (d, 1H), 5.30 (m, 1H), 2.69 (m, 2H), 2.29 (m, 1H), 1.96 (m, 3H); MS m/z 403 (M−1).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O.CC(O)=O>CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])/[CH:11]=[CH:17]/[C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[O:14][CH3:13])=[CH:6][CH:5]=1
Reactant: COc1ccccc1C=O
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccccc1/C=C/C(=O)c1ccc(Cl)cc1
Reaction time: 18 h
Yield: 96.8 %

Procedure:
KOH (1.415 g, 25.2 mmol) was added to a solution of 1-(4-chlorophenyl)ethanone (3.9 g, 25.2 mmol) and 2-methoxybenzaldehyde (3.43 g, 25.2 mmol) in methanol (100 ml) at RT and the solution was stirred for 18 hours. The solution was concentrated under reduced pressure until a precipitate was formed. AcOH (1.444 ml, 25.2 mmol) was added and the mixture was cooled down to 0° C.-5° C. The mixture was stirred for 1 hour and the light yellow precipitate was separated by filtration and washed with cold methanol to afford 6.72 g (24.39 mmol, 97% yield) of the title compound. LCMS: (M+H)=273; tR=1.28 min (LC-MS 3). 1H-NMR (d6-DMSO, 600 MHz) δ ppm 8.12 (d, 2H) 8.04 (d, 1H) 7.98 (d, 1H) 7.86 (d, 1H) 7.62 (d, 2H) 7.45 (t, 1H) 7.10 (d, 1H) 7.02 (t, 1H) 3.88 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21](Cl)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][N:25]1[C:29]2[CH:30]=[C:31]([NH2:34])[CH:32]=[CH:33][C:28]=2[N:27]=[CH:26]1>CCCCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([NH:34][C:31]4[CH:32]=[CH:33][C:28]5[N:27]=[CH:26][N:25]([CH3:24])[C:29]=5[CH:30]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Reactant: Cn1cnc2ccc(N)cc21
Solvent: CCCCO
Product: Cn1cnc2ccc(Nc3ncnc4[nH]c(C5=CCN(C(=O)OC(C)(C)C)CC5)cc34)cc21
Temperature: 120 °C

Procedure:
A mixture of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (134 mg, 0.400 mmol) and 3-methyl-3H-benzoimidazol-5-ylamine (70.6 mg, 0.480 mmol) in n-BuOH (3 mL) in a sealed tube was heated at 120° C. for 17 h and concentrated in vacuo to obtain a brown solid that was purified using the mass-directed purification system to yield the title compound as beige solid. 1H NMR (CD3OD, 400 MHz): δ=1.52 (s, 9H), 2.57 (brs, 2H), 3.68 (brs, 2H), 3.93 (s, 3H), 4.12 (brs, 2H), 6.31 (brs, 1H), 6.65 (brs, 1H), 7.46 (dd, 1H, J=2.0 & 8.4 Hz), 7.66 (d, 1H, J=8.8 Hz), 8.14-8.15 (m, 2H), 8.23 (s, 1H), 8.24 (brs, 1H). MS (ES+): m/z 464.12 (100) [MH+]. HPLC: tR=2.18 min (ZQ2000, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:14])=O>CN(C=O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(O)c1cccnc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccnc1Cl

Procedure:
A mixture of 2-chloronicotinic acid (2-chloro-3-pyridylcarboxylic acid, 4.0 g, 25.4 mmol), oxalyl chloride (2.28 ml, 26.65 mmol) and two drops of DMF are stirred in chloroform (60 ml) for 30 minutes and subsequently refluxed for 45 minutes. The volatiles are distilled under reduced pressure to give crude 2-chloronicotinoyl chloride. This crude product is added to a mixture of diethyl malonate (3.85 ml, 25.38 mmol), magnesium chloride (2.4 g, 25.38 mmol) and triethylamine (7 ml, 50.77 mmol) in acetonitrile (25 ml) with cooling, such that the temperature does not rise above 15° C. After stirring for 24 hours the reaction mixture is diluted with ether and washed repeatedly with 1 M hydrochloric acid and brine. Drying of the organic phase over magnesium sulfate, filtering and evaporation of the solvents gives crude diethyl 2-(2-chloronicotinoyl)-malonate. This crude product is dissolved in DMSO (40 ml) and water (3 ml), and is heated at 140-150° C. for four hours. The mixture is poured onto crushed ice and the product is extracted using ether. Filtering of the ether phase over a pad of silicagel gives 3-acetyl-2-chloropyridine as a yellow oil; 1H-NMR (CDCl3, 300 MHz): 8.50 (dd, 1H); 7.91 (dd, 1H); 7.34 (ddd, 1H); 2.71 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[NH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:13][N:14]=2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1.CO>CN(C=O)C>[N:33]1[CH:34]=[CH:35][CH:36]=[C:31]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:12]3[NH:11][C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:1])[F:23])[CH:4]=4)=[N:14][N:13]=3)=[CH:16][CH:17]=2)[CH:32]=1
Reactant: Brc1cccnc1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CO
Product: FC(F)(F)c1cccc(Nc2nnc(-c3ccc(Oc4cccnc4)cc3)[nH]2)c1
Yield: 18.2 %

Procedure:
4-(5-{[3-(trifluromethyl)phenyl]amino}-4H-1,2,4-triazol-3-yl)phenol (100 mg, 0.31 mmol) was dissolved in 2 mL of anhydrous DMF in 2-5 mL microwave vial (Personal Chemistry). Solid Cs2CO3 (203.4 mg, 0.62 mmol) was added, followed by 3-bromopyridine (74.0 mg, 0.468 mmol). The vial was capped and microwaved at 250° C. for 30 min. Then ca. 1 mL of MeOH was added to dissolve the formed suspension. The resulting reddish-brown solution was filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetontrile/water system with 0.01% of TFA. The fractions, containing the product, were collected and partitioned between EtOAc and saturated aqueous NaHCO3. Ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title compound as a yellow solid (22.4 mg).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([CH3:34])([CH3:33])[CH2:5][N:6]1[C:18]([CH3:20])([CH3:19])[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH:7]1[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([O:31]C)=[O:30])=[CH:23][CH:22]=1>CO.O>[F:3][C:4]([CH3:34])([CH3:33])[CH2:5][N:6]1[C:18]([CH3:20])([CH3:19])[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH:7]1[C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30])=[CH:23][CH:22]=1
Reactant: COC(=O)/C=C/c1ccc(C2c3[nH]c4ccccc4c3CC(C)(C)N2CC(C)(C)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(F)CN1C(c2ccc(/C=C/C(=O)O)cc2)c2[nH]c3ccccc3c2CC1(C)C
Temperature: 22 °C
Reaction time: 40 h
Yield: 74.3 %

Procedure:
2M Sodium hydroxide solution (0.782 ml, 1.56 mmol) was added to a solution of (E)-methyl 3-(4-(2-(2-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (isomer 1) (68 mg, 0.16 mmol) in methanol (5 ml) THF (5.00 ml) and water (5.00 ml) and the mixture stirred for 40 hours at 22° C. The mixture was concentrated to a volume such that all of the organic solvent had been removed and was acidified to pH6 with 2M HCl. Concentrated aqueous ammonia (2 drops) was added, followed by methanol (˜2 ml), giving a pale yellow solution. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title product (isomer 1) (50.0 mg, 76%) as a yellow solid. 1H NMR (500 MHz, DMSO, 30° C.) δ 0.93 (3H, s), 1.19 (3H, d), 1.23 (3H, s), 1.51 (3H, d), 2.56-2.64 (2H, m), 2.75 (1H, d), 3.04 (1H, dd), 5.06 (1H, s), 6.40 (1H d), 7.03 (1H, ddd), 7.09-7.15 (2H, m), 7.35 (1H, dd), 7.44-7.51 (5H, m), 10.87 (1H, s), CO2H not observed. m/z: ES+ [M+H]+ 421. *Stereochemistry inferred to be (R) at the undefined centre by analogy with other examples.
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:11][C:12](C=O)=[C:13]([CH3:14])[C:6]=2[C:5]1=[O:17].N1CCCCC1>C(O)C>[OH:1][CH:2]([CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:11][CH:12]=[C:13]([CH3:14])[C:6]=2[C:5]1=[O:17]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CCC2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c[nH]c2c1C(=O)N(CC(O)CN1CCOCC1)CCC2
Temperature: 25 °C
Yield: 87.3 %

Procedure:
(S)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 78f (50 mg, 0.149 mmol) was dissolved in 261 μl of ethanol under stirring, and added with 5-fluoro-1,3-dihyrdro-indole-2-one (20.28 mg, 0.134 mmol) and piperidine (7.3 μl, 0.074 mmol) to the solution at room temperature. Upon the completion of the addition, the reaction mixture was stirred for 2 hours in dark at 80° C. in an oil bath. After thin lay chromatography showed the disappearance of starting materials, the reaction was stopped, and the oil bath was removed. The reaction system was cooled to room temperature, the reaction solution was filtered and the filter cake was dried to obtain the title compound (S,Z)-2-(5-fluoro-2-oxoindolin-3-ylidene)methyl)-5-(2-hydroxy-3-morpholinopropyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 78(40 mg, yield 57%) as a yellow solid.