Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.CS(O[CH2:21][C:22]1([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH2:24][CH2:23]1)(=O)=O.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:21][C:22]3([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH2:24][CH2:23]3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CS(=O)(=O)OCC1(c2ccncc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: Cc1ccc2c(c1)c1c(n2CC2(c3ccncc3)CC2)CCN(C)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 12.2 %

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (183 mg, 0.917 mmol), tetra n-butyl ammonium bromide (14 mg, 0.045 mmol), and (1-(pyridin-4-yl)cyclopropyl)methyl methanesulfonate (250 mg, 1.10 mmol) were taken into 50% NaOH (6 mL). The reaction mixture was stirred overnight at 100° C. Reaction was monitored by TLC and LCMS. After completion of the reaction, reaction mixture was extracted with EtOAc and water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by column chromatography to yield 37 mg of product. 1H NMR (CDCl3, Freebase) d (ppm): 8.45 (d, 2H), 7.1-7.0 (m, 3H), 6.9 (d, 2H), 4.28 (s, 2H), 3.63 (s, 2H), 2.7 (t, 2H), 2.5-2.6 (m, 5H), 2.42 (s, 3H), 1.0-0.85 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[CH2:8][C@H:7]1[C:12](=[O:17])[NH:13][CH2:14][C:15]#[N:16])=[O:5])[CH3:2].CN(C=O)C.[BH4-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([OH:11])[CH2:8][C@H:7]1[C:12](=[O:17])[NH:13][CH2:14][C:15]#[N:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(=O)C[C@H]1C(=O)NCC#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)NCC#N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of (1R,2R)-2-(cyanomethyl-carbamoyl)-4-oxo-cyclopentanecarboxylic acid ethyl ester (2.7 mmol) in THF (12 ml) was added DMF (1 ml), the solution was cooled to 0° C., sodium borohydride (3.3 mmol) was added and stirring was continued for 2 h. The mixture was partitioned between 1N aqueous HCl and ethyl acetate, the organic layer was dried, evaporated and the residue chromatographed on silica using dichloromethane/MeOH (97:3) to give in the first fraction (1R,2R,4R)-2-(cyanomethyl-carbamoyl)-4-hydroxy-cyclopentanecarboxylic acid ethyl ester as a white solid. MS: 241.4 (M+H)+. The second fraction contained the desired isomer,
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:15]=1[C:16]([OH:18])=O.[NH2:24][CH:25]1[CH2:32][CH2:31][CH2:30][NH:29][C:27](=[O:28])[CH2:26]1>C1COCC1>[F:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:14]([F:13])[C:15]=1[C:16]([NH:24][CH:25]1[CH2:32][CH2:31][CH2:30][NH:29][C:27](=[O:28])[CH2:26]1)=[O:18]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: NC1CCCNC(=O)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1CC(NC(=O)c2c(F)cccc2F)CCCN1
Reaction time: 0.25 h
Yield: 66.3 %

Procedure:
1,1'-Carbonyldiimidazole (14.8 g), was added to a solution of 2,6-difluorobenzoic acid (12 g) in THF (200 ml) and followed by stirring for 15 mins. at room temperature. Then to the mixture was added 9.73 g of 3-amino-ε-caprolactam, and the whole was stirred for 5 hrs. at room temperature and the solvent was distilled off under reduced pressure. The residue was washed with methylenechloride to give 3-(2,6-difluorobenzoyl)amino-ε-caprolactam (13.5 g) as crude crystals. The crude crystals and phosphorus pentasulfide (8.96 g) were added to 200 ml of pyridine, and the whole was refluxed under stirring for 24 hrs. After cooling, the mixture was distilled to remove the solvent. To the residue was added a saturated sodium hydrogen carbonate solution and extracted with chloroform. The extract was washed with water, dried and concentrated under reduced pressure. The residue was purified by a column chromatography on silica gel and then recrystallized from a mixture of methylenechloride and isopropyl ether to give the title compound (3.19 g, 23.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:9][CH2:10][N:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:4][CH:3]=1.[C:25]([NH:27][C:28](=[N:36][CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[CH:42]=1)OC1C=CC=CC=1)#[N:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:28]([NH:27][C:25]#[N:26])=[N:36][CH2:37][CH2:38][CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)[CH:42]=2)[CH3:18])=[CH:4][CH:3]=1
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Reactant: CN(CCCCCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Product: CN(CCCCCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 1.09 g (3.15 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,5-pentanediamine and 1.23 g (3.1 mmol) of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil; IR (KBr): 2163 cm-1 (C≡N).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.FC(F)(F)S(O[C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[CH:27][CH:26]=[CH:25]2)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2].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>[N:28]1[C:29]2[C:24](=[CH:23][CH:22]=[CH:21][C:20]=2[N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(Oc1cccc2cccnc12)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3cccnc23)CC1
Temperature: 25 °C
Yield: 74.9 %

Procedure:
t-Butyl piperazine-1-carboxylate (8.6 g, 46 mmol) and quinolin-8-yl trifluoromethanesulfonate (11 g, 39.6 mmol) were added to a solution of Cs2CO3 (18 g, 55 mmol), BINAP (1.07 g) and Pd(OAc)2 (367 mg) in THF (100 ml). The reaction mixture was refluxed for 1 day and then cooled down to room temperature. The resulting solution was diluted with Et2O (100 ml) and then filtered with Celite. The organic solution was evaporated under reduced pressure, and the residue was purified with normal preparative column to give rise to desired compound (9.3 g, 74% yield) as light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Cl:21])[C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[C:22]([C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1)#[N:23].C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:16])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30](=[O:31])[C:27]3[CH:26]=[CH:25][C:24]([C:22]#[N:23])=[CH:29][N:28]=3)[CH:3]=[C:4]([Cl:21])[C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: C[C@@]1(c2cc(N)cc(Cl)c2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: N#Cc1ccc(C(=O)O)nc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(C#N)cn3)cc(Cl)c2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reaction time: 1.5 h
Yield: 68.5 %

Procedure:
To a cooled (ice bath) solution of (4S,6S)-4-(5-amino-3-chloro-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.090 g, 0.276 mmol) and 5-cyano-2-pyridinecarboxylic acid (0.060 g, 0.405 mmol) in n,n-Dimethylformamide (1.5 mL) was added dropwise 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.352 mL, 0.553 mmol). After stirred for 1.5 h, reaction went to completion. The reaction mixture was quenched with saturated NaHCO3 and diluted with water. The resulted suspension was stirred for 30 min, and filtered. The filter caked was washed with water and purified by Shimadzu HPLC to afford the title compound (0.086 g, 0.189 mmol, 68.3% yield) as off-white solid. MS m/z=456.0 [M+H]+. Calculated for C19H14ClF4N5O2: 455.79
Reaction SMILES: COC1C=CC(C[N:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3=[N:18][N:19]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:27][CH:26]=4)[C:20]([NH:21]C(=O)C)=[C:10]3[C:9]2=[O:39])=CC=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1.FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>>[NH2:21][C:20]1[N:19]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:27][CH:26]=2)[N:18]=[C:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[NH:8][C:9](=[O:39])[C:10]=12
Reactant: COc1ccc(Cn2c(=O)c3c(NC(C)=O)n(-c4ccc(CCN5CCCCC5)cc4)nc3c3ccccc32)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1c2c(=O)[nH]c3ccccc3c2nn1-c1ccc(CCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 26 h
Yield: 43.6 %

Procedure:
A mixture of N-{5-(4-methoxybenzyl)-4-oxo-2-[4-(2-piperidin-1-ylethyl)phenyl]-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-3-yl}acetamide (0.13 g), trifluoroacetic acid (2.5 ml), anisole (1 ml) and trifluoromethanesulfonic acid (0.5 ml) was stirred at room temperature for 26 hours. Ice and 2N aqueous sodium hydroxide solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with propylaminated silica gel column chromatography, and the obtained crystals were recrystallized from ethyl acetate to obtain the target compound (0.04 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:5]=[CH:4][CH:3]=1.[F:17][C:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[C:21]([CH3:33])=[CH:20][N:19]=1.C(Cl)Cl>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=3)[N:7]=2)[C:21]([CH3:33])=[CH:20][N:19]=1
Reactant: Fc1cccc(CNc2cccc(Br)n2)c1
Reactant: Cc1cnc(F)cc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1cnc(F)cc1-c1cccc(NCc2cccc(F)c2)n1
Temperature: 110 °C
Yield: 45.7 %

Procedure:
To a solution of 6-bromo-N-(3-fluorobenzyl)pyridin-2-amine (85 mg, 0.302 mmol) and 2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (102 mg, 0.430 mmol) in DME (2 mL) and 2M Na2CO3 aq (1 mL) was added PdCl2(dppf).CH2Cl2 adduct (21 mg, 0.026 mmol). This was then heated at 110° C. for 16 h. The reaction mixture was allowed to cool and then the DME was evaporated under reduced pressure. The resulting residue was partitioned between EtOAc and water. The organics were combined, then washed with H2O (×3), saturated aq. brine (×3), then dried (Na2SO4), filtered and evaporated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel; 15% to 25% EtOAc/hexane) to give 2′-fluoro-N-(3-fluorobenzyl)-5′-methyl-2,4′-bipyridin-6-amine (43 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:29])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.O=[Pt]=O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:29])[C:17]1[CH:18]=[CH:19][C:20]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)=[CH:21][CH:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2cccnc2)cc1
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CCCNC2)cc1
Temperature: 80 °C
Yield: 94.2 %

Procedure:
To a solution of N-(2-t-butoxycarbonylaminophenyl)-4-pyridin-3-ylbenzamide (2.0 g, 5.1 mmol) (Method 3) in ethanol (20 ml) was added PtO2 (200 mg) and the resulting mixture was heated at 80° C. under an atmosphere of hydrogen at 80 Bar for 16 hours. The mixture was allowed to cool and was filtered and evaporated to afford (RS)—N-(2-t-butoxycarbonylaminophenyl)-4-piperidin-3-ylbenzamide (1.9 g, 94%).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27]C(=O)OC(C)(C)C)[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12]([C:14]3([C:17]([F:20])([F:19])[F:18])[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[ClH:35]>C(O)(C(F)(F)F)=O.CO.CCOCC>[ClH:35].[NH2:27][C@@H:23]1[CH2:24][CH2:25][CH2:26][N:21]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12]([C:14]4([C:17]([F:18])([F:19])[F:20])[CH2:16][CH2:15]4)=[O:13])[C:4]=23)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4(C(F)(F)F)CC4)c23)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CCOCC
Product: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4(C(F)(F)F)CC4)c23)C1
Yield: 94 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-(1-(trifluoromethyl)cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (65 mg, 0.12 mmol) in TFA (5 mL) was stirred at room temperature for 1.5 hours and concentrated in vacuo. The residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 12M column, 3-65% CH3CN/water gradient; 14 CV). The residue obtained was dissolved in minimal methanol, and 2N HCl in ether was added. The precipitate formed was filtered and dried under high vacuum to yield (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(trifluoromethyl)cyclopropanecarboxamide hydrochloride (58 mg, 94% yield). 1H NMR (400 MHz, (CD3)2SO) δ 11.97 (br s, 1H), 9.32 (s, 1H), 8.39 (s, 2H), 8.27 (s, 1H), 7.63 (s, 1H), 3.50-3.22 (m, 4H), 3.15-3.04 (m, 1H), 2.20-2.10 (m, 1H), 1.90-1.78 (m, 1H), 1.76-1.46 (m, 4H), 1.36-1.44 (m, 2H); LCMS (APCI+) m/z 429.2, 446.1, 448.0 (M+H)+, Retention time=2.07 minutes (Method 3).
Reaction SMILES: [CH3:1][NH:2][C:3](SC)=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:14][CH2:15][CH:16]1[O:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:17]1>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:18]2[CH2:19][CH2:20][O:21][CH:16]([CH2:15][NH:14][C:3]([NH:2][CH3:1])=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:17]2)=[CH:24][CH:25]=1
Reactant: NCC1CN(Cc2ccc(F)cc2)CCO1
Reactant: CCOC(=O)C(C#N)=C(NC)SC
Product: CCOC(=O)C(C#N)=C(NC)NCC1CN(Cc2ccc(F)cc2)CCO1
Yield: 53 %

Procedure:
This compound was synthesized as a yellow oily substance from ethyl 3-methylamino-3-methylthio-2-cyanoacrylate and 2-aminomethyl-4-(p-fluorobenzyl)morpholine according to the same procedure as in Example 8. Yield=53%.
Reaction SMILES: [C:1](/[N:3]=[C:4](\OC1C=CC=CC=1)/[NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[N:11][C:10]=2[CH:20]=1)#[N:2].[NH:28]([C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][N:31]=1)[NH2:29]>CN1CCCC1=O>[C:30]1([N:28]2[C:1]([NH2:2])=[N:3][C:4]([NH:5][C:6]3[CH:7]=[CH:8][C:9]4[O:13][C:12]([CH2:14][N:15]5[CH2:16][CH2:17][CH2:18][CH2:19]5)=[N:11][C:10]=4[CH:20]=3)=[N:29]2)[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][N:31]=1
Reactant: N#C/N=C(/Nc1ccc2oc(CN3CCCC3)nc2c1)Oc1ccccc1
Reactant: NNc1nccc2ccccc12
Solvent: CN1CCCC1=O
Product: Nc1nc(Nc2ccc3oc(CN4CCCC4)nc3c2)nn1-c1nccc2ccccc12
Temperature: 25 °C

Procedure:
A solution of (Z)-phenyl N′-cyano-N-(2-(pyrrolidin-1-ylmethyl)benzo[d]oxazol-5-yl)carbamimidate (36 mg, 0.1 mmol) and 1-hydrazinoisoquinoline in N-methyl-2-pyrrolidone (0.5 mL) was shaken at 100° C. for 3 hours. After cooling to ambient temperature, the volatiles were evaporated under reduced pressure. The residue was purified by HPLC eluting with acetonitrile-water to provide 1-(isoquinolin-1-yl)-N3-(2-(pyrrolidin-1-ylmethyl)benzo[d]oxazol-5-yl)-1H-1,2,4-triazole-3,5-diamine, compound #1; 1H NMR (CD3OD, 300 MHz) 8.98 (d, J=8.4 Hz, 1H), 8.36 (d, J=5.7 Hz, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.84-7.58 (m, 4H), 7.26 (dd, J=2.4, 8.7 Hz, 1H), 6.99 (d, J=9.0 Hz, 1H), 5.05 (s, 2H), 3.76 (m, 2H), 3.65 (m, 2H), 3.30 (m, 3H), 2.11 (m, 4H) ppm; MS (ES) 427.16 (M+H).
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([Cl:11])[N:9]=[CH:10][C:5]=2[S:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH2:30])[CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>CC(O)CC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:11][C:8]1[N:9]=[CH:10][C:5]2[S:4][CH:3]=[C:2]([NH:30][C:22]3[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:20]([O:19][CH3:18])[CH:21]=3)[C:6]=2[N:7]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Clc1ncc2scc(Br)c2n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)O
Product: COc1cc(Nc2csc3cnc(Cl)nc23)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 42.1 %

Procedure:
7-Bromo-2-chlorothieno[3,2-d]pyrimidine (200 mg, 0.81 mmol) was dissolved in 2-butanol (4 mL) and then potassium carbonate (223 mg, 1.61 mmol) and 3,4,5-trimethoxybenzenamine (110 mg, 0.81 mmol) were added. After blowing nitrogen to the reaction mixture for 10 minutes, Pd2(dba)3 (50 mg, 0.048 mmol) and Xphos (35 mg, 0.073 mmol) were added. The reaction mixture was stirred at 80° C. for 2.5 hours and then filtered with celite. The filtrate was diluted with ethyl acetate and washed with brine. The organic layer was dried with magnesium sulfate, filtered with celite, and then concentrated. Purification by chromatography (15% ethyl acetate/hexane) yielded the target compound (120 mg, 43% yield).
Reaction SMILES: C(O[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1/[CH:19]=[CH:20]/[C:21]([O:23]C)=[O:22])CCCCCC.S(=O)(=O)(O)O>[OH-].[K+]>[CH2:21]([O:22][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[CH:9]=[C:10](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])[CH:11]=[CH:12]2)[CH2:20][CH2:19][CH2:10][CH2:9][CH2:18][CH3:17]
Reactant: CCCCCCCOc1c(/C=C/C(=O)OC)ccc2ccccc12
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCOc1ccc2cc(/C=C/C(=O)O)ccc2c1
Reaction time: 16 h

Procedure:
A mixture of 0.8 g of methyl (E)-3-(heptyloxynaphth-2-yl)acrylate and 10 ml of 10 percent methanolic potassium hydroxide solution is allowed to stand for 16 hours at room temperature. Thereafter, acidification is effected with aqueous 1 N sulfuric acid with continuous stirring and with cooling, extraction is effected with methylene chloride and the organic phase is washed several times with water, dried over magnesium sulfate and evaporated down. Crystallization from hexane/ethyl acetate gives (E)-3-(6-heptyloxynaphth-2-yl)acrylic acid.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:22]([O:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30]Br)([CH3:25])([CH3:24])[CH3:23].[I-].[K+].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:22]([O:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30][N:18]1[CH2:19][CH2:20][O:21][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:14]=2)[CH2:17]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)CCCBr
Reactant: CCCCCCCCOc1ccc(C2CNCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCOc1ccc(C2CN(CCCC(=O)OC(C)(C)C)CCO2)cc1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
2-(4-Octyloxy-phenyl)-morpholine (1.50 g; 5.2 mmol), 4-bromo-butyric acid tert-butyl ester (1.38 g; 6.2 mmol) (prepared according to C. Morin, M. Vidal Tetrahedron, 1992, 48(42), 9277), potassium iodide (1.03 g; 6.2 mmol), K2CO3 (1.42 g; 10.29 mmol), and CH3CN (15 mL) were mixed and heated under reflux for 2 hours. After cooling to RT the reaction mixture was concentrated in vacuo, dissolved in EtOAc, washed with 5% aqueous NaHCO3 solution, dried (Na2SO4) concentrated in vacuo and purified by column chromatography (SiO2, Et2O:hexanes 1:1) to afford 4-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-butyric acid tert-butyl ester (1.90 g), TLC (SiO2Rf. 0.20 EtOAc:hexanes 1:1)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2C=C[CH:17]=[C:16](F)[CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[CH:33]2)[CH:27]=1)=O)(C)(C)C.[C:39](O)([C:41]([F:44])(F)F)=O>C(Cl)Cl>[F:44][C:41]1[CH:39]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([N:32]5[CH:36]=[CH:35][N:34]=[CH:33]5)[CH:27]=4)[CH2:23][C:22](=[O:37])[NH:21][C:9]=3[CH:10]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccc(F)c2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-n3ccnc3)c2)=Nc2ccc(-c3cccc(F)c3)cc2N1

Procedure:
Prepared from {3′-fluoro-3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K66) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (69 mg).
Reaction SMILES: C([O:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]3=[O:34])=[CH:20][C:19]=2[F:35])[CH2:14][CH2:13]1)=[O:11])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[OH:8][CH2:9][C:10]([N:12]1[CH2:13][CH2:14][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:28][C@H:27]([CH2:29][NH:30][C:31](=[O:33])[CH3:32])[O:26][C:25]3=[O:34])=[CH:20][C:19]=2[F:35])[CH2:16][CH2:17]1)=[O:11]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C(=O)COCc4ccccc4)CC3)c(F)c2)C(=O)O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1
Reaction time: 4 h

Procedure:
A mixture of (S)-(-)-N-[[3-[4-[1-[(benzyloxy)acetyl]-4-piperidinyl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (EXAMPLE 21, 5.00 g) and 20% palladium hydroxide on carbon (2.80 g) in methanol (500 mL) is stirred under a hydrogen atmosphere (balloon) for four hours, the catalyst is removed by filtration through Celite and the filtrate is concentrated under reduced pressure, triturated with methylene chloride/diethyl ether and filtered to give the title compound, mp 182-183° C.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=O.[CH3:17][S:18]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[N:25]([C:24]3[CH:23]=[CH:22][C:21]([S:18]([CH3:17])(=[O:20])=[O:19])=[CH:27][CH:26]=3)[CH:2]=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: O=C(CCC1OCCO1)c1ccc(F)cc1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-n2cccc2-c2ccc(F)cc2)cc1
Yield: 49.1 %

Procedure:
A mixture of the ketone (Step 2) (448 mg, 2 mmol), 4-(methylsulfonyl)aniline (380 mg, 2.2 mmol) and p-toluenesulfonic acid (30 mg) in toluene (40 ml) was heated to reflux for 18 hours. The reaction was cooled, filtered and concentrated. The crude solid (750 mg) was purified by chromatography (silica gel, hexane/ethyl acetate, 1/1) to give 2-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-pyrrole (310 mg, 55%) as a white solid: mp (DSC) 201° C. Anal Calc'd. for C17H14NSFO2 ·0.2 H2O: C, 64.01; H, 4.55; N, 4.39; S, 10.05. Found: C, 64.18; H, 4.33; N, 4.32; S, 10.36.