Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:33])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Br:32])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[Br:32][C:28]1[CH:27]=[C:26]([C:24]2[CH2:23][C:22](=[O:33])[NH:21][C:9]3[CH:10]=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[F:20])[CH:12]=[CH:13][C:8]=3[N:7]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1cccc(Br)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(Br)c2)=Nc2ccc(-c3ccccc3F)cc2N1

Procedure:
) The title compound was prepared from the above described {3-[3-(3-bromo-phenyl)-3-oxo-propionylamino]-2′-fluoro-biphenyl-4-yl}-carbamic acid tert-butyl ester (2.15 g, 4.076 mmol, 90% purity) and TFA (15 mL) according to general procedure I step 2. Obtained as a light yellow solid (1.25 g, 75%). MS (ISP) 409.0 [(M+H)+] and 411.0 [(M+2+H)+].
Reaction SMILES: [O:1]=[C:2]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:3]([CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]1[C:20]#[N:21])C(OC)=O.[OH-].[Li+].Cl>CO>[C:20]([CH:9]1[C:10]2[C:15](=[CH:14][C:13]([O:18][CH3:19])=[CH:12][CH:11]=2)[CH2:16][CH2:17][CH:8]1[CH2:3][C:2](=[O:1])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)#[N:21]
Reactant: COC(=O)C(C(=O)Cc1ccccc1)C1CCc2cc(OC)ccc2C1C#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1)CCC(CC(=O)Cc1ccccc1)C2C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 3-oxo-4-phenyl-2-(1-cyano-6-methoxy-1,2,3,4-tetrahydronaphth-2-yl)-butyrate (4.63 g, 12 mmol), from Step 1, was dissolved in 100 mL of methanol and lithium hydroxide (77 mL of a 1.0M solution) was added. The reaction mixture was stirred overnight at ambient temperature and then acidified with 1N aqueous hydrochloric acid solution and extracted with diethyl ether. The ether extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The basic ether extract yielded 2.76 (70% yield) of the title compound; MS DCl--NH3M/Z: 337 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[C:16]1(=[O:20])[CH2:19][CH2:18][CH2:17]1>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:16]1([OH:20])[CH2:19][CH2:18][CH2:17]1
Reactant: O=C1CCC1
Reactant: Brc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1(c2ccncc2Br)CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.7 %

Procedure:
3-Bromopyridine (1 g, 6.3 mmol) was added in a dropwise fashion to a stirred, −78° C. solution of lithium diisopropylamide (1.8 M commercial solution; 3.7 mL, 6.7 mmol) in THF (16 mL). After 10 minutes, cyclobutanone (0.52 mL, 7.0 mmol) was added dropwise and stirring was continued for 1 hour at −78° C., prior to warming to ambient temperature. After stirring for a further 30 minutes, the reaction was quenched by addition of saturated aqueous NH4Cl (10 mL) and the mixture partitioned between EtOAc (100 mL) and water (100 mL). The organic fraction was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting crude product was purified by flash column chromatography on silica (eluent 50% EOAc/isohexane) to afford 1-(3-bromopyridin-4-yl)cyclobutanol as an off-white solid (412 mg). m/z (ES+) 228/230 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=O)[CH:8]=[CH:7]2.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][NH2:22]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([F:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9](/[CH:12]=[N:22]/[NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=1)[CH:8]=[CH:7]2
Reactant: O=Cc1ccc2cc(F)cc(Br)c2n1
Reactant: NNc1ccccn1
Solvent: CCO
Product: Fc1cc(Br)c2nc(/C=N/Nc3ccccn3)ccc2c1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
8-Bromo-6-fluoroquinoline-2-carbaldehyde (100 mg, 0.39 mmol) and 1-(pyridin-2-yl)hydrazine (43 mg, 0.39 mmol) were dissolved in 15 mL of absolute EtOH, and heated to reflux for 2 hours, at which time all starting material had been consumed. The reaction was then cooled to ambient temperature, and the yellow/orange product was collected by filtration (wash EtOH), affording (100 mg, 73.6% yield) as a yellow solid. MS APCI (+) m/z 345.1 and 347 (M+1 of each Br isotope) detected.
Reaction SMILES: Cl.CO[C:4]([C:6]1[N:7]([NH2:12])[CH:8]=[CH:9][C:10]=1[Cl:11])=[O:5].FC(F)(F)C(O)=O.[CH2:20]([N:22](CC)CC)[CH3:21]>C(#N)C>[Cl:11][C:10]1[CH:9]=[CH:8][N:7]2[C:6]=1[C:4](=[O:5])[NH:22][C:20]([CH3:21])=[N:12]2
Reactant: CCN(CC)CC
Reactant: COC(=O)c1c(Cl)ccn1N
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cc1nn2ccc(Cl)c2c(=O)[nH]1
Temperature: 85 °C
Reaction time: 0.33 h
Yield: 80.2 %

Procedure:
A mixture of 1-amino-3-chloro-1H-pyrrole-2-carboxylic acid methyl ester, hydrochloride salt (11.0 g, 52.1 mmol) and trifluoroacetic acid (6.0 mL, 77.9 mmol) in acetonitrile (230 mL) was heated at 85° C. overnight. The reaction mixture was concentrated and treated with fresh acetonitrile (200 mL) and triethylamine (22.0 mL, 157.8 mmol). The reaction mixture was heated at 85° C. overnight and concentrated to small volume and diluted with water (100 mL). The mixture was then stirred at rt for 20 min. The precipitate was collected, washed with water and dried to give the title compound as a brown solid (7.67 g, 80%): 1H NMR (CD3OD): δ 7.28 (s, 1H), 6.42 (s, 1H), 2.20 (s, 3H); MS (ESI+) 184.02, 186.10 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)([CH:11]([CH3:13])[CH3:12])[C:9]#[N:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:22].[OH-].[NH4+]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)([CH:11]([CH3:13])[CH3:12])[C:9]([NH2:10])=[O:22])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: CC(C)C(C#N)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)C(C(N)=O)(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
2,2-Bis-(4-fluoro-phenyl)-3-methyl-butyronitrile (2.21 g) was suspended in acetic acid (2 ml) and conc. sulphuric acid (2 ml) and heated to 130° C. for 1.5 hrs. The reaction mixture was poured onto ice/water and the pH adjusted to 9 with aq. ammonium hydroxide. The mixture was extracted with dichloromethane (3×), washed with water (2×) and brine, dried (MgSO4), filtered and concentrated. The product was taken up in dichloromethane and triturated with cold hexane to precipitate the title compound (50%; M.p. 142.3–147.0° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6](Cl)[C:3]=1[CH:4]=O.[NH2:12][NH2:13]>O1CCOCC1>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]2[C:3]=1[CH:4]=[N:12][NH:13]2
Reactant: NN
Reactant: O=Cc1c(Cl)cc(Cl)cc1Cl
Solvent: C1COCCO1
Product: Clc1cc(Cl)c2cn[nH]c2c1
Temperature: 160 °C
Yield: 38.6 %

Procedure:
In a microwave vial 2,4,6-trichlorobenzaldehyde (4.0 g, 19.1 mmol) was dissolved in 1,4-dioxane (8 mL) and hydrazine (7.2 mL, 229 mmol) was added. The vial was sealed and heated under microwave irradiation at 160° C. for 30 min. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 50% to 100% EtOAc/heptane to provide 1.38 g (38%) of 4,6-dichloro-1H-indazole as a white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.14 (s, 1H), 7.44 (s, 1H), 7.20 (d, J=1.5 Hz, 15H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1.[CH3:21][C:22]1[N:23]=[CH:24][S:25][C:26]=1[CH:27]=[CH2:28].C(N(C(C)C)C(C)C)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:21][C:22]1[N:23]=[CH:24][S:25][C:26]=1/[CH:27]=[CH:28]/[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:3]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Reactant: C=Cc1scnc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ncsc1/C=C/c1nn(COCC[Si](C)(C)C)c2cc(C=O)ccc12
Temperature: 90 °C
Reaction time: 24 h
Yield: 44.2 %

Procedure:
A degassed mixture of 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (70 mg, 0.17 mmol), 4-methyl-5-vinylthiazole (44 mg, 0.35 mmol), N-ethyl-N-isopropylpropan-2-amine (DIPEA, 45 mg, 0.35 mmol), Pd(OAc)2 (3.9 mg, 0.017 mmol) and P(o-MeC6H4)3 (16 mg, 0.052 mmol) in anhydrous MeCN (2 mL) were heated with stirring in a sealed tube under Ar at 90° C. for 1 d. The crude mixture was later concentrated under reduced pressure and purified by prepTLC (SiO2 5:1 hexanes/EtOAc) to provide the title compound (30 mg, 43%): 1H NMR (400 MHz, CDCl3) δ ppm 10.17 (s, 1H), 8.64 (s, 1H), 8.12 (s, 1H), 8.06 (d, J=8.28 Hz, 1H), 7.83 (d, 1H), 7.64 (d, J=16.06 Hz, 1H), 7.12 (d, J16.31 Hz, 1H), 5.82 (s, 2H), 3.62 (t, J=8.28 Hz, 2H), 2.62 (s, 3H), 0.92 (t, J=8.28 Hz, 2H), −0.05 (s, 9H); MS ESI 400.2 [M+H]+, calcd for [C20H25N3O2SSi+H]+ 400.6.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[F:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[C:10]([CH3:18])([CH3:17])[NH:9]2.[CH:19]([N:22]([CH:25]([CH3:27])C)CC)([CH3:21])C.C1COCC1>C1(C)C=CC=CC=1>[F:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[C:10]([CH3:18])([CH3:17])[N:9]2[C:1]([N:22]1[CH2:19][CH2:21][CH2:27][CH2:25]1)=[O:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)Cl
Reactant: CC1(C)Nc2cc(F)ccc2NC1=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)C(=O)Nc2ccc(F)cc2N1C(=O)N1CCCC1
Reaction time: 0.75 h

Procedure:
Phosgene in toluene (1.2M, 12.9 ml) is added to a mixture of 6-fluoro-1,2,3,4-tetrahydro-3,3-dimethylquinoxalin-2-one (IV, EXAMPLE 8, 1.001 g) and diisopropylethylamine (0.94 ml), and THF (10 ml) at 0°. After 45 min the reaction is allowed to warm to 20°-25°. After stirring for 3 hr, the reaction is again cooled to 0° and additional phosgene (4.2 ml) is added. The ice bath is removed and the reaction is stirred for 100 min, after which the excess phosgene and solvents are removed via a water aspirator. The mixture is then stirred with THF (10 ml) and of pyrrolidine (0.90 ml) are added. After stirring overnight, the reaction is concentrated mid the residue chromatographed on silica gel eluting with methanol/methylene chloride (2/98). The appropriate fractions are pooled and concentrated to give the title compound; MS (m/z) at 291; IR (mineral oil) 1681, 1660, 1396 and 1163 cm-1 ; NMR (CDCl3) 1.4-2.0, 3.15, 3.6, 6.43, 6.65, 6.76 and 8.32 δ.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[C:14]([CH:15]=[O:16])=[C:13]([Cl:17])[N:12]=[C:11]1[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[C:14]([CH2:15][OH:16])=[C:13]([Cl:17])[N:12]=[C:11]1[C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1c(Cl)nc(-c2ccc([N+](=O)[O-])cc2)n1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(-c2nc(Cl)c(CO)n2Cc2ccccc2)cc1
Reaction time: 2 h

Procedure:
Sodium borohydride (1.1 g, 29 mmole) was added in three portions to a stirred mixture of crude 1-benzyl-4-chloro-5-formyl-2-(4-nitrophenyl)imidazole (54.2 g, 88 mmole) in methanol (250 ml) at room temperature. After two hours, more sodium borohydride (0.51 g, 15 mmol) was added, the mixture was stirred for 30 minutes and the methanol was evaporated. The residue was mixed with water (250 ml) and extracted with methylene chloride (200 ml, 3×50 ml). The combined organic solutions were washed with water (2×50 ml) and dried (NaSO4) overnight.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:4])[CH2:2]C.[C:14]1([NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20]>ClC1C=CC=CC=1>[CH3:2][C:1]12[NH:21][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:20]1[C:7](=[O:9])[C:6]1[C:5]2=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:1]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:4])[CH3:2].[C:14]1([NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20]
Reactant: CCC(=O)c1ccccc1C(=O)O
Agent: Nc1ccccc1N
Solvent: Clc1ccccc1
Product: CC(=O)c1ccccc1C(=O)O
Product: CC12Nc3ccccc3N1C(=O)c1ccccc12

Procedure:
17.8 Parts of o-propionyl-benzoic acid and 11 parts of o-phenylenediamine are heated for 1 hour in 200 parts of chlorobenzene while distilling off water and chlorobenzene. The excess chlorobenzene is then removed in vacuo and the residue is distilled under high vacuum. The destillate solidifies and is recrystallised from a little ethyl acetate. The pure 4b-ethyl-4b,5-dihydro-11H-benzo[4,5]imidazo[2,1-a]isoindol-11-one of the formula ##STR30## melts at 134°. 4b-methyl-4b,5-dihydro-11H-benzo[4,5]imidazo[2,1-a]isoindol-11-one (M.P. 182.5°) is produced in an analogous manner from o-acetylbenzoic acid and o-phenylenediamine.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[C:11]1[N:16]=[C:15](Cl)[C:14]([F:18])=[CH:13][N:12]=1>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:11]2[N:16]=[C:15]([NH:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[C:14]([F:18])=[CH:13][N:12]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Product: N#Cc1ccc(Nc2ncc(F)c(Nc3ccc(C#N)cc3)n2)cc1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-4-pyrimidineamine, 4-aminobenzonitrile and 2,4-dichloro-5-fluoropyrimidine gave N2,N4-bis(4-cyanophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 7.26 (d, J=8.7 Hz, 2H), 7.36 (d, J=9.0 Hz, 2H), 7.43 (d, J=8.7 Hz, 2H), 7.60 (d, J=8.7 Hz, 2H), 7.86 (d, J=3.6 Hz, 1H), 9.49 (br, 1H, NH), 9.51 (br, 1H, NH); 19F NMR (282 MHz, DMSO-d6): δ −161.48; LC: 27.15 min.; 100%; MS (m/e): 331.00 (MH+).
Reaction SMILES: [CH2:1]([S:3]([C:5]1[CH:12]=[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:10]=[C:9]([CH3:19])[C:6]=1[C:7]#[N:8])=[O:4])[CH3:2].[OH-:20].[Na+]>C(O)C.O>[CH2:1]([S:3]([C:5]1[CH:12]=[C:11]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[CH:10]=[C:9]([CH3:19])[C:6]=1[C:7]([NH2:8])=[O:20])=[O:4])[CH3:2]
Reactant: CCS(=O)c1cc(N2CCOCC2)cc(C)c1C#N
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCS(=O)c1cc(N2CCOCC2)cc(C)c1C(N)=O
Temperature: 80 °C
Yield: 36 %

Procedure:
To a stirred solution of 2-(ethylsulfinyl)-6-methyl-4-morpholin-4-yl-benzonitrile (0.78 g, 2.81 mmol) in ethanol (8.5 ml) is added a 5M solution of sodium hydroxide (8.5 ml) and the mixture is heated at 80° C. for 16 h. After completion of the reaction (monitored by TLC) the reaction mixture is concentrated to get a residue, which is diluted with water (10 ml) and extracted with ethyl acetate (3×30 ml). The combined organic layers are washed with water (10 ml), brine (10 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product which is purified by column chromatography (alumina, 5% methanol/dichloromethane) to yield 2-(ethylsulfinyl)-6-methyl-4-morpholin-4-yl-benzamide (0.30 g, 1.01 mmol, 36%).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=CC(C(O)=O)=C[CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:35](Cl)(=[O:40])[C:36](C)([CH3:38])[CH3:37].[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>C(Cl)Cl>[CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([C:19]3[CH:20]=[CH:38][C:36]([C:35]([N:46]4[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]4)=[O:40])=[CH:37][CH:27]=3)=[O:18])[CH2:15][CH2:16]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N3CCN(C)CC3)cc2)CC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
4-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid (1.2 g) was dissolved in methylene chloride (40 ml) and then, triethylamine (0.6 ml) was added and cooled. Pivaloyl chloride (0.46 ml) was added slowly to the solution at 0~5° C. and the mixture was stirred at 5° C. for 2 hours. With the addition of triethylamine (0.6 ml) and 1-methylpiperazine (0.38 g), the reaction mixture was stirred at 5° C. for 2 hours and heated slowly to 20° C. and stirred for 30 minutes. The reaction mixture was washed with water and aqueous sodium bicarbonate and the solvent was concentrated under reduced pressure. The concentrated residue was crystallized by treatment with hexane and ether, and further recrystallized using ethyl acetate and isopropyl ether. The recrystallized product was filtered and dried to give 1.15 g (yield: 78%) of the desired compound as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1)[CH:6]=[C:5]2[CH2:22][CH2:23][CH2:24][C:25]([O:27]CC1C=CC=CC=1)=[O:26].O1CCOCC1.O>CO.[Pd]>[NH2:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[C:5]([CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:6]1)=[O:21]
Reactant: O=C(CCCc1cn(C(=O)c2cccc([N+](=O)[O-])c2)c2ccc(Cl)cc12)OCc1ccccc1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: Nc1cccc(C(=O)n2cc(CCCC(=O)O)c3cc(Cl)ccc32)c1
Temperature: 20 °C
Reaction time: 4 h
Yield: 75.2 %

Procedure:
To a solution of benzyl 4-[5-chloro-1-(3-nitrobenzoyl)indol-3-yl]butyrate (1.3 g) in a mixture of methanol (35 ml), 1,4-dioxane (35 ml) and water (5 ml) was added 10% palladium on activated carbon (400 mg), and the mixture was stirred under hydrogen atmosphere (3 atm) at 20° C. for 4 hours. The catalyst was filtered off and the filtrate was evaporated. The residue was chromatographed on silica gel (40 g) eluting with 2% methanol in chloroform to give 4-[1-(3-aminobenzoyl)-5-chloroindol-3-yl]butyric acid (731 mg) as pale yellow crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@H:9]([C:11]([NH:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15])=[O:12])[CH3:10].C(N(CC)CC)C.[OH:26][C:27]1[C:28]([C:33](OC)=[O:34])=[N:29][CH:30]=[CH:31][N:32]=1>CS(C)=O>[O:26]=[C:27]1[NH:32][CH:31]=[CH:30][N:29]=[C:28]1[C:33]([NH:8][C@@H:9]([CH3:10])[C:11]([NH:13][C@@H:14]([CH3:15])[C:16]([OH:18])=[O:17])=[O:12])=[O:34]
Reactant: COC(=O)c1nccnc1O
Reactant: C[C@H](N)C(=O)N[C@@H](C)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@H](NC(=O)[C@H](C)NC(=O)c1ncc[nH]c1=O)C(=O)O
Temperature: 40 °C
Reaction time: 17 h
Yield: 8.1 %

Procedure:
In 5 mL of dimethyl sulfoxide is dissolved 0.42 g of L-alanyl-L-alanine trifluoroacetate. Then, 1.07 mL of triethylamine and 0.71 g of methyl 3-hydroxy-2-pyrazinecarboxylate are successively added to the solution, which is then stirred at 40° C. for 17 hours. The solvent is distilled off under reduced pressure, and 2 mL of water was added to the residue thus obtained. The deposited product is collected by filtration and purified by column chromatography [eluent: chloroform:methanol=30:1) to obtain 0.035 g of (2S)-2-[((2S)-2-{[(3-oxo-3,4-dihydro-2-pyrazinyl) carbonyl]amino}-propanoyl)amino]propanoic acid.
Reaction SMILES: C([N:8]([CH2:26][CH2:27][C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH2:9][CH2:10][CH:11]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)C1C=CC=CC=1.C([O-])=O.[NH4+].CO>C(Cl)Cl.[Pd]>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:11]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:10][CH2:9][NH:8][CH2:26][CH2:27][C:28]2[N:29]=[CH:30][CH:31]=[CH:32][N:33]=2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(C(CCN(CCc2ncccn2)Cc2ccccc2)c2ccc(F)cc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: Fc1ccc(C(CCNCCc2ncccn2)c2ccc(F)cc2)cc1
Temperature: 50 °C

Procedure:
To a mixture of N-benzyl-3,3-bis(4-fluorophenyl)-N-(2-(pyrimidin-2-yl)ethyl)propan-1-amine (1.23 g, 2.77 mmol), ammonium formate (0.985 g, 15.6 mmol), and palladium (10% wt on carbon) (0.382 g, 3.59 mmol) was added MeOH (10 mL). The reaction mixture was heated to 50° C. for 1 h, diluted with DCM, filtered and partially concentrated, diluted with EtOAc, washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 5% to 10% MeOH (2 M NH3) in DCM) gave 3,3-bis(4-fluorophenyl)-N-(2-(pyrimidin-2-yl)ethyl)propan-1-amine.
Reaction SMILES: [CH3:1][C:2]1[S:10][C:9]2[CH:8]([OH:11])[CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=1.[C:12]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](F)=[CH:16][CH:15]=1)#[N:13]>>[C:12]([C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([O:11][CH:8]2[CH2:7][NH:6][CH2:5][C:4]3[CH:3]=[C:2]([CH3:1])[S:10][C:9]2=3)=[CH:16][CH:15]=1)#[N:13]
Reactant: Cc1cc2c(s1)C(O)CNC2
Reactant: N#Cc1ccc(F)c2ccccc12
Product: Cc1cc2c(s1)C(Oc1ccc(C#N)c3ccccc13)CNC2

Procedure:
The same method as in Example 1 was conducted using 2-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 30) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-cyano-1-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[C:12]([O:16][C:17]([N:19]1[C@@H:23]([CH3:24])[CH2:22]OS1(=O)=O)=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17](=[O:18])[NH:19][C@@H:23]([CH3:22])[CH2:24][N:8]1[C:9]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: C[C@H]1COS(=O)(=O)N1C(=O)OC(C)(C)C
Reactant: N#Cc1ccc2[nH]ccc2c1
Product: C[C@@H](Cn1ccc2cc(C#N)ccc21)NC(=O)OC(C)(C)C

Procedure:
This compound was obtained according to example 4, step A1 from 5-cyanoindole (500 mg) and (S)-4-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester IV (1.0 g). Yield: 1.09 g, yellow solid.
Reaction SMILES: CON(C)[C:4](=[O:48])[CH2:5][CH2:6][C@H:7]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C@@H:10]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]3[O:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:27]=3[CH:37]=2)[CH2:9][N:8]1[S:38]([C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1)(=[O:40])=[O:39].[CH3:50][Mg]Br>>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C@@H:11]2[C@@H:10]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]4[O:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:27]=4[CH:37]=3)[CH2:9][N:8]([S:38]([C:41]3[CH:42]=[CH:43][C:44]([CH3:47])=[CH:45][CH:46]=3)(=[O:40])=[O:39])[C@@H:7]([CH2:6][CH2:5][C:4](=[O:48])[CH3:50])[CH2:12]2)=[CH:18][CH:17]=1
Reactant: C[Mg]Br
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CCC(=O)N(C)OC)C[C@@H]3c3ccc(OC)cc3)cc21
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CCC(C)=O)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
Similar to example 29b, 1.68 g of N-methoxy-3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-N-methyl-propionamide in the presence of methyl magnesium bromide are used to afford the title compound after flash chromatography (SiO2 60 F) as a colourless oil. Rf=0.23 (EtOAc-heptane 1:1); Rt=5.25.