Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:24])[C:11]3[C:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)=[N:15][N:14]([CH3:23])[C:12]=3[N:13]=2)=[C:4]([O:25][CH2:26][CH3:27])[CH:3]=1.Cl.[CH3:29][N:30]([CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[C:31](=[O:40])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH:17]1([C:16]2[C:11]3[C:10](=[O:24])[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:44]5[CH2:43][CH2:42][CH:41]([N:30]([CH3:29])[C:31](=[O:40])[O:32][CH2:33][C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=6)[CH2:46][CH2:45]5)=[CH:3][C:4]=4[O:25][CH2:26][CH3:27])=[N:13][C:12]=3[N:14]([CH3:23])[N:15]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CN(C(=O)OCc1ccccc1)C1CCNCC1
Reactant: CCOc1cc(Br)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Agent: Cl
Product: CCOc1cc(N2CCC(N(C)C(=O)OCc3ccccc3)CC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Yield: 77 %

Procedure:
The same reaction procedure as in Example 27 was performed, except that the compound obtained in Example 85 was used in place of the compound obtained in Example 26, and benzyl methyl(4-piperidinyl)carbamate hydrochloride was used in place of N-methylpiperazine. In this manner, 234 mg (77%) of the captioned compound was obtained.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:17]=2[O:24][CH3:25])=[O:13])[C:9]([OH:26])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:27][N:28]([CH3:36])[C:29]1[CH:34]=[CH:33][C:32]([SH:35])=[CH:31][CH:30]=1.C(N(CC)CC)C>>[CH3:25][O:24][C:17]1[C:18]([O:22][CH3:23])=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][NH:14][C:12]([C:10]1[C:9]([OH:26])=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([S:35][C:32]2[CH:33]=[CH:34][C:29]([N:28]([CH3:36])[CH3:27])=[CH:30][CH:31]=2)[N:11]=1)=[O:13]
Reactant: COc1cccc(CNC(=O)c2nc(Br)c3cccnc3c2O)c1OC
Reactant: CN(C)c1ccc(S)cc1
Solvent: CCN(CC)CC
Product: COc1cccc(CNC(=O)c2nc(Sc3ccc(N(C)C)cc3)c3cccnc3c2O)c1OC
Temperature: 135 °C

Procedure:
Into a pressure reactor was placed 5-bromo-N-(2,3-dimethoxybenzyl)-8-hydroxy-1,6-naphthyridine-7-carboxamide (0.1 g, 0.24 mmol), 4-(dimethylamino)benzenethiol (0.147 g, 0.96 mmol) and triethylamine (0.363 g, 0.5 mL, 3.59 mmol). The vessel was purged with nitrogen gas, sealed and heated to 135° C. for 18 hours, after which time it was cooled and the excess triethylamine removed in vacuo. The residue was partitioned between EtOAc/water and extracted. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and the solvent removed. The resulting glass was triturated with diethyl ether and filtered to yield N-(2,3-dimethoxybenzyl)-5-{[4-(dimethylamino)phenyl]thio}-8-hydroxy-1,6-naphthyridine-7-carboxamide as a solid.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>C(#N)C>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:28]3[CH2:29][CH2:30][CH:25]([C:23](=[O:24])[C:20]4[CH:19]=[CH:18][C:17]([F:16])=[CH:22][CH:21]=4)[CH2:26][CH2:27]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCCC1CC1)c1ccc(N2CCC(C(=O)c3ccc(F)cc3)CC2)nn1
Yield: 85 %

Procedure:
A mixture of 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.500 g, 2.22 mmol), (4-fluorophenyl)piperidin-4-ylmethanone (0.620 g, 2.55 mmol) and triethylamine (0.7 mL, 5 mmol) in acetonitrile (20 mL) was heated to reflux overnight. The solvent was removed in vacuo. The residue was diluted with water, then extracted with ethyl acetate. The residue obtained upon the evaporation of solvent was purified by column chromatography. The title compound was obtained as a white solid in 85% yield (0.270 g). 1H NMR (300 MHz, CDCl3) δ 8.26 (d, J=9.0 Hz, 1H), 8.02-7.93 (m, 2H), 7.65 (d, J=9.0 Hz, 1H), 7.2-7.11 (m, 2H), 6.98 (d, J=9.0 Hz, 1H), 4.55-4.44 (m, 2H), 3.63-3.49 (m, 3H), 3.32-3.19 (m, 2H), 2.5-1.8 (m, 2H), 1.7-1.44 (m, 4H), 0.8-0.67 (m, 1H), 0.52-0.41 (m, 2H), 0.15-0.07 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 200.1, 167.5, 164.1, 163.2, 161.4, 159.9, 158.9, 151.8, 144.6, 132.0, 131.0, 130.9, 129.4, 128.0, 126.9, 116.1, 115.8, 112.2, 44.5, 43.1, 40.0, 39.6, 34.5, 34.3, 27.9, 8.64, 8.6, 4.2. MS (ES+) m/z 397 (M+1).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:26])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH:15]1[C:24]2[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1)[CH3:3].CCN(C(C)C)C(C)C.Cl[C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38]>C(Cl)Cl>[CH2:40]([O:39][C:37]([N:16]1[CH2:17][CH2:18][C:19]2[C:24](=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH:15]1[C:9]1[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[O:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:26])=[O:38])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1NCCc2cc(F)ccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(Cl)cc1C1c2ccc(F)cc2CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an-ice cooled solution of (±)-[4-chloro-2-(6-fluoro-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (900 mg, 2.25 mmol, 1.0 eq.) and DIPEA (1.16 mL, 6.75 mmol, 3.0 eq.) in DCM (30 mL), benzyl chloroformate (0.43 mL, 2.92 mmol, 1.3 eq.) was added dropwise. Upon completion of the addition, the cooling bath was removed and the solution was stirred at r.t. for 3 hours. The reaction was quenched with 1M aq. citric acid soln. (25 mL). The layers were separated. The aq. phase was extracted with DCM (3×50 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash master (column: 50 g, flow: 40 mL/min, Heptane+10% EtOAc to Heptane+50% EtOAc) to yield the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24]([OH:26])=O)[CH2:9]2)=[O:7])[CH2:3]1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[C:35](=[N:37]O)[NH2:36]>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[C:35]1[N:37]=[C:24]([CH:10]2[CH2:11][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=3)[CH2:13][N:8]([C:6]([N:4]3[CH2:5][CH:2]([OH:1])[CH2:3]3)=[O:7])[CH2:9]2)[O:26][N:36]=1
Reactant: NC(=NO)c1cc(F)ccc1F
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Product: O=C(N1CC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cc(F)ccc3F)no2)C1

Procedure:
90.0 mg (0.242 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 45.7 (0.266 mmol) of 2,5-difluoro-N′-hydroxybenzenecarboximidamide (Example 74A) were reacted according to the General Method 1. Yield: 42.9 mg (34% of theory).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][S:23](=[O:26])[CH2:22][CH2:21]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[N:7]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[O:26]=[S:23]1[CH2:24][CH2:25][N:20]([C:4]2[C:5]3[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]4[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=4)[C:6]=3[N:7]=[C:2]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:3]=2)[CH2:21][CH2:22]1
Reactant: O=S1CCN(c2nc(Cl)nc3c(NCc4cccnc4)ncnc23)CC1
Reactant: C1CNCCN1
Product: O=S1CCN(c2nc(N3CCNCC3)nc3c(NCc4cccnc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 118 from 2-chloro-4-(1-oxido-thiomorpholino)-8-(3-picolylamino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 227°-229° C.) and piperazine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[C:18](=[O:19])[CH:17]=[CH:16][N:15]([C:20]3[CH:21]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:23]=[CH:24][CH:25]=3)[N:14]=2)=[CH:11][CH:10]=[N:9]1.[CH3:30]I.[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[C:18](=[O:19])[CH:17]=[CH:16][N:15]([C:20]3[CH:21]=[C:22]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])[CH:23]=[CH:24][CH:25]=3)[N:14]=2)=[CH:11][CH:10]=[N:9]1
Reactant: CI
Reactant: CC(=O)Nc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3F)n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3F)n2)c1

Procedure:
The product was obtained starting from N-(3-{3-[2-(2-Fluoro-phenyl)-2H-pyrazol-3-yl]-4-oxo-4H-pyridazin-1-yl}-phenyl)-acetamide (example 292) and methyl iodide in presence of sodium hydride in DMF at room temperature over night. MS: M=404.4 (M+H)+
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][C@H:5]1[C:23](=[O:24])[O:22][C@H:7]2[CH2:8][C@:9]3([CH3:21])[O:11][C@H:10]3[C@@H:12]3[O:14][C@@H:13]3[C:15]3[C:19](=[O:20])[O:18][C@@H:17]([C@H:6]12)[CH:16]=3>CC(C)=O>[CH3:1][N:2]([CH3:3])[CH:13]1[C:15]2=[CH:16][CH:17]([O:18][C:19]2=[O:20])[CH:6]2[CH:7]([O:22][C:23](=[O:24])[CH:5]2[CH3:4])[CH2:8][C:9]2([CH3:21])[CH:10]([O:11]2)[CH:12]1[OH:14]
Reactant: CNC
Reactant: C[C@H]1C(=O)O[C@H]2C[C@]3(C)O[C@H]3[C@@H]3O[C@@H]3C3=C[C@@H](OC3=O)[C@@H]21
Solvent: CC(C)=O
Product: CC1C(=O)OC2CC3(C)OC3C(O)C(N(C)C)C3=CC(OC3=O)C21
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
A solution of dimethylamine (500 μmol, 250 μl, 2M in THF) is added to a solution of dihydromikanolide (100 μmol, 29 mg) in acetone (1 ml). The reaction mass is stirred for 2 hours at ambient temperature then the solvent is eliminated by evaporation under reduced pressure. The residue is taken up in ether, filtered and dried under vacuum. 25 mg of product is obtained in the form of a white powder.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]2[C:21]3[CH:22]=[CH:23][C:24]([NH2:28])=[CH:25][C:26]=3[CH2:27][C@H:16]12)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>ClCCl>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]2[C:21]3[CH:22]=[CH:23][C:24]([NH:28][C:1](=[O:3])[CH3:2])=[CH:25][C:26]=3[CH2:27][C@H:16]12)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]2c3ccc(N)cc3C[C@@H]21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc2c(c1)C[C@H]1[C@@H]2CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetic anhydride (50 μL) is added to a solution of cis-7-amino-2,3,4,4a,9,9a-hexahydro-indeno[2,1-b]pyridine-1-carboxylic acid tert-butyl ester (140 mg) and triethylamine (70 μL) in dichloromethane (3 mL) at room temperature. The solution is stirred for 1 h at room temperature and then aqueous NaHCO3 solution is added. The mixture is stirred vigorously for 20 min and then extracted with dichloromethane. The combined extract is concentrated and the residue is chromatographed (cyclohexane/ethyl acetate 7:3→1:9) to give the title compound. Yield: 100 mg (62% of theory); LC (method 1): tR=3.60 min.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:10][O:9][C:7]([C:4]1[S:3][C:2]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][OH:11])[CH2:15][CH2:16]2)=[N:6][CH:5]=1)=[O:8]
Reactant: OCCN1CCNCC1
Reactant: COC(=O)c1cnc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cnc(N2CCN(CCO)CC2)s1
Temperature: 80 °C
Yield: 68.2 %

Procedure:
To a solution of methyl 2-bromothiazole-5-carboxylate 1 (222 mg, 1.00 mmol) in acetonitrile (20 mL) were added N-(2-hydroxyethyl)piperazine 14c (156 mg, 1.20 mmol) and potassium carbonate (152 mg, 1.10 mmol) under a N2 atmosphere. The reaction mixture was heated to reflux at 80° C. for 10 h. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using silica gel to give the compound 15c (185 mg, 68.2%).
Reaction SMILES: C(OC([NH:8][C:9]1[C:14]([F:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([F:23])[CH:17]=2)[N:12]=[C:11]([C:24]([O:26][CH3:27])=[O:25])[C:10]=1[CH:28]=[CH2:29])=O)(C)(C)C.FC(F)(F)C(O)=O>ClC(Cl)C>[NH2:8][C:9]1[C:14]([F:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([F:23])[CH:17]=2)[N:12]=[C:11]([C:24]([O:26][CH3:27])=[O:25])[C:10]=1[CH:28]=[CH2:29]
Reactant: C=Cc1c(C(=O)OC)nc(-c2ccc(Cl)c(F)c2)c(F)c1NC(=O)OC(C)(C)C
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: C=Cc1c(C(=O)OC)nc(-c2ccc(Cl)c(F)c2)c(F)c1N
Reaction time: 4 h
Yield: 95.5 %

Procedure:
Methyl 4-(tert-butoxycarbonylamino)-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-vinylpicolinate (0.966 g, 2.274 mmol) was dissolved in dichloroethane (11 mL) and trifluoroacetic acid (3.50 mL, 45.5 mmol) was added. After 4 h at room temperature, the reaction mixture was concentrated under vacuum then coevaporated with additional dichloroethane twice more. The residue was purified by flash chromatography (SiO2, eluting with 7-60% ethyl acetate in hexanes) to provide the title compound as a white solid (0.705 g, 95%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=1.C([Li])(C)(C)C.[CH3:19][C:20]12[CH:29]([CH:30]=[O:31])[CH2:28][CH2:27][CH:26]=[C:25]1[CH2:24][C:23]1([S:35][CH2:34][CH2:33][S:32]1)[CH2:22][CH2:21]2>CCOCC>[CH3:19][C:20]12[CH:29]([CH:30]([C:2]3[CH:3]=[C:4]([O:12][CH3:13])[C:5]([O:10][CH3:11])=[C:6]([O:8][CH3:9])[CH:7]=3)[OH:31])[CH2:28][CH2:27][CH:26]=[C:25]1[CH2:24][C:23]1([S:32][CH2:33][CH2:34][S:35]1)[CH2:22][CH2:21]2
Reactant: CC12CCC3(CC1=CCCC2C=O)SCCS3
Reactant: COc1cc(Br)cc(OC)c1OC
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: COc1cc(C(O)C2CCC=C3CC4(CCC32C)SCCS4)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 73.1 %

Procedure:
A solution 5-bromo-1,2,3-trimethoxy-benzene (276 mg, 1.12 mmol) dissolved in 6 mL anhydrous ether is cooled to −78° C. and tert-butyllithium (1.7 M in pentane, 1.32 mL, 2.24 mmol) is added. The mixture was stirred at −78° C. for 15 minutes, then at room temperature for 3 hours. Aldehyde 241 (100 mg, 0.373 mmol) was added dropwise over 10 minutes in 10 mL ether at −30° C. The mixture was stirred for 0.5 hours and the reaction quenched with dropwise addition of saturated aqueous NH4+Cl−. The phases were separated and the aqueous phase was extracted with ether (4×10 mL). The pooled organic extracts were washed with saturated aqueous NaHCO3, brine, dried (MgSO4), filtered and concentrated under vacuum. The residue was purified by flash chromatography over silica gel (25% ethyl acetate-hexanes) to yield 243 (119 mg, 73%).
Reaction SMILES: [C:1]([C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)#[N:2].C([O-])(=O)C.[K+].CC1(C)C(C)(C)OB([C:42]2[CH:43]=[C:44]3[C:48](=[CH:49][CH:50]=2)[C:47](=[O:51])[NH:46][CH2:45]3)O1>C(#N)C.O>[C:1]([C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:42]2[CH:43]=[C:44]3[C:48](=[CH:49][CH:50]=2)[C:47](=[O:51])[NH:46][CH2:45]3)=[CH:7][CH:6]=1)#[N:2]
Reactant: CC1(C)OB(c2ccc3c(c2)CNC3=O)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(I)cc2)CCOCC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@H](C#N)Cc2ccc(-c3ccc4c(c3)CNC4=O)cc2)CCOCC1
Temperature: 90 °C
Yield: 60.9 %

Procedure:
A mixture of (S)-tert-butyl 4-(1-cyano-2-(4-iodophenyl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 15, step (i), 260 mg), potassium acetate (153 mg) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (162 mg) in acetonitrile (10 mL) and water (5 mL) under a nitrogen atmosphere, was treated with 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (10 mg) and the mixture stirred and heated at 90° C. for 18 h. The reaction mixture was cooled to room temperature and diluted with water. The products were extracted into ethyl acetate (2×100 mL) and the combined extracts dried over magnesium sulphate and concentrated to dryness. The residue was purified by chromatography on silica eluting with ethyl acetate to afford the sub-titled compound (160 mg).
Reaction SMILES: [CH:1]([N:4]([CH:25]([CH3:27])[CH3:26])[C:5](=[O:24])[CH:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:23])([F:22])[F:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2]>C(O)C.[Pd]>[CH:25]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:24])[CH2:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:22])([F:23])[F:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:27])[CH3:26]
Reactant: CC(C)N(C(=O)C=C(c1ccccc1)c1ccccc1C(F)(F)F)C(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)N(C(=O)CC(c1ccccc1)c1ccccc1C(F)(F)F)C(C)C

Procedure:
A solution of N,N-diisopropyl-3-(2-trifluoromethylphenyl)-3-phenylpropenamide (2.95 g, 8.1 mmol) in ethanol (50 mL) was hydrogenated over Pd/C (10%, 300 mg) at normal pressure for 24 h. The catalyst was filtered off, the solvent partly evaporated and the product collected after crystallisation. Yield 1.78 g (60%). 1H NMR (CDCl3-d) δ1.16 (m, 6H), 1.30 (m, 6H), 2.86 (dd, 1H), 3.11 (dd, 1H), 3.41 (m, 1H), 4.03 (m, 1H), 5.12 (m,1H) and 7.10-7.78 (m, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[C:20]3[O:21][C:22]4[C:27]([C:19]=3[CH:18]=[CH:17][CH:16]=2)=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=4)[CH:10]=1.C(OCCO)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[C:20]3[O:21][C:22]4[C:27]([C:19]=3[CH:18]=[CH:17][CH:16]=2)=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=4)[CH:10]=1
Reactant: Cc1ccc2c(n1)oc1c(-c3cc(-c4ccc(F)cc4F)ccn3)cccc12
Solvent: CN(C)C=O
Solvent: CCOCCO
Product: Cc1ccc2c(n1)oc1c(-c3cc(-c4ccccc4F)ccn3)cccc12
Temperature: 130 °C

Procedure:
To a 250 mL flask added iridium complex (2.348 g, 3.29 mmol), 8-(4-(2,4-difluorophenyl)pyridin-2-yl)-2-methylbenzofuro[2,3-b]pyridine (2.45 g, 6.58 mmol), 2-ethoxyethanol (60 mL), DMF (60 mL). The mixture was heated in an oil bath at 130° C. overnight under N2 and allowed to cool and evaporated the solvents to leave a red/orange solid which was further purified by silica gel column to give orange solid 1.7 g (61% yield) desired product which was confirmed by LC-MS.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([OH:16])[C:9]([C:13]([OH:15])=[O:14])=[CH:10]2)=[CH:5][CH:4]=1)=O.C(O)(=O)C.[CH3:21][CH:22]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[CH3:23].C([BH3-])#N.[Na+].Cl>CO>[OH:16][C:8]1[C:9]([C:13]([OH:15])=[O:14])=[CH:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]([CH2:1][NH:28][C:27]1[CH:29]=[CH:30][C:24]([CH:22]([CH3:23])[CH3:21])=[CH:25][CH:26]=1)[CH:12]=2
Reactant: O=Cc1ccc2cc(O)c(C(=O)O)cc2c1
Reactant: CC(C)c1ccc(N)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)c1ccc(NCc2ccc3cc(O)c(C(=O)O)cc3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
7-Formyl-3-hydroxynaphthalene-2-carboxylic acid (40 mg, 0.19 mmol) (example 342) was suspended in methanol (300 μL). Acetic acid (16 μL, 17 mg, 0.28 mmol) and 4-(2-propyl)aniline (40 μL, 40 mg, 0.30 mmol) were added consecutively, and the resulting mixture was stirred vigorously at room temperature for 2 hours. Sodium cyanoborohydride (1.0 M in tetrahydrofuran, 300 μL, 0.3 mmol) was added, and the stirring was continued for another 17 hours. The reaction mixture was poured into 6 N hydrochloric acid (aq.) (6 mL), and the precipitate was filtered off and rinsed with water (3×2 mL) to yield the title compound (40 mg) as its hydrochloride salt. No further purification was necessary.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3=[N:16][CH:17]=[CH:18][C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)=[C:14]3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[CH:29]1([CH2:28][O:27][C:21]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=2[C:19]2[CH:18]=[CH:17][N:16]=[C:15]3[C:11]([C:9]([NH:8][C@H:5]4[CH2:6][CH2:7][C@H:2]([NH:1][C:33](=[O:36])[CH2:34][CH3:35])[CH2:3][CH2:4]4)=[O:10])=[C:12]([CH3:32])[NH:13][C:14]=23)[CH2:30][CH2:31]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (example D.f5) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[CH3:13][C:14](=O)[CH2:15][CH2:16][C:17](=O)[CH3:18]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]2[CH3:13])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C)n1-c1ccc(Br)c(C(F)(F)F)c1
Reaction time: 2 h
Yield: 97.7 %

Procedure:
In 50 mL of toluene, 3.6 g (15 mmol) of 4-bromo-3-(trifluoromethyl)aniline was dissolved, and 2.06 g (18 mmol) of 2,5-hexanedione and 54 mg (0.28 mmol) of p-toluenesulfonic acid-hydrate were added thereto and the mixture solution was refluxed with stirring for two hours. The reaction solution was partitioned between a saturated sodium bicarbonate solution and ethyl acetate and the organic layer was washed with a saturated sodium chloride solution and concentrated under reduced pressure. The obtained residue was purified by a silica gel column (n-hexane:ethyl acetate=9:1) to obtain 4.66 g (97%) of a target product as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[N+:12]([O-])([O-:14])=[O:13].[K+].N>OS(O)(=O)=O>[N+:12]([C:10]1[CH:9]=[CH:8][C:3]2[CH2:4][CH2:5][CH2:6][CH2:7][NH:1][C:2]=2[CH:11]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])[O-]
Reactant: c1ccc2c(c1)CCCCN2
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1ccc2c(c1)NCCCC2
Reaction time: 0.67 h
Yield: 52 %

Procedure:
At −10° C., 2,3,4,5-tetrahydro-1H-benzo[b]azepine (1.9 g, 13 mmol) was added dropwise to a solution of KNO3 (3 g, 30 mmol) in H2SO4 (50 mL). The mixture was stirred for 40 min, poured over crushed ice, basified with aq. ammonia to pH 13, and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4 and concentrated to give 8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine as a black solid (1.3 g, 51%), which was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:9]([NH:12][CH:13]([CH3:15])[CH3:14])([CH3:11])[CH3:10].C(O)C.Cl>O>[CH:9]([N:12]([CH:13]([CH3:15])[CH3:14])[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])([CH3:11])[CH3:10]
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)CCBr
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCN(C(C)C)C(C)C
Temperature: 25 °C

Procedure:
Ethyl 3-diisopropylaminopropionate may be obtained in the following manner: ethyl 3-bromopropionate (18.1 g) is introduced dropwise in the course of 30 minutes into a solution of diisopropylamine (28.5 cc) and ethanol (40 cc) maintained at a temperature of 25° C. The suspension obtained is heated to reflux for 4 hours. After being cooled, the reaction mixture is taken up with water (100 cc) and 4N aqueous hydrochloric acid solution (70 cc). After the mixture is washed with ethyl ether (100 cc), it is alkalinized to a pH in the region of 9 with 4N aqueous sodium hydroxide solution. The oil formed is extracted with methylene chloride (3×150 cc). After being washed with water (2×100 cc) and dried, the methylene chloride solution obtained is concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. Ethyl 3-diisopropylaminopropionate (11.6 g) is thereby obtained in the form of an oil, which is employed in the crude state in the subsequent syntheses.