Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:49][C:50]1[CH:55]=[N:54][CH:53]=[CH:52][N:51]=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:49][C:50]2[CH:55]=[N:54][CH:53]=[CH:52][N:51]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Nc1cnccn1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Br
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnccn2)cc1Br
Temperature: 25 °C
Reaction time: 19 h
Yield: 15.9 %

Procedure:
A solution of 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 148A, 375 mg, 1.0 mmol) and triphenylphosphine (446 mg, 1.7 mmol) in methylene chloride (5 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (303 mg, 1.7 mmol) in small portions. The reaction mixture color changed from light yellow to a darker yellow then to brown. After the complete addition of the N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The brown reaction mixture was then treated with 2-aminopyrazine (238 mg, 2.5 mmol). The resulting reaction mixture was stirred at 25° C. for 19 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. Biotage chromatography (FLASH 40S, Silica, 2/3 hexanes/ethyl acetate) afforded 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-propionamide (72 mg, 16%) as pink foam: EI-HRMS m/e calcd for C19H22BrN3O3S (M+) 451.0565, found 451.0547.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([CH2:10][CH3:11])[CH:3]=1.II.FC(F)(F)C(O[I:19](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O>ClCCl.CO>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:10][CH3:11])[N:5]=[C:6]([CH2:8][CH3:9])[C:7]=1[I:19]
Reactant: CCc1cc(N)cc(CC)n1
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: II
Solvent: ClCCl
Solvent: CO
Product: CCc1cc(N)c(I)c(CC)n1
Reaction time: 16 h
Yield: 40.2 %

Procedure:
(EXAMPLE 7B): 4-Amino-2,6-diethylpyridine (1.8 g) was added to a solution of iodine (3.1 g) and [bis(trifluoroacetoxy)iodo]benzene (5.7 g) in a mixture of dichloromethane (70 ml) and methanol (20 ml) and the mixture was stirred for 16 hours. Solvent was removed by evaporation and the residue was partitioned between ethyl acetate and a mixture of saturated sodium metabisulphite solution (50 ml) and saturated sodium carbonate solution (150 ml). The organic phase was separated, washed with saturated sodium chloride solution and dried. Solvent was removed by evaporation and the residue was purified by flash chromatography eluting with dichloromethane/methanol (97:3 v/v) to give 4-amino-2,6-diethyl-3-iodopyridine (1.33 g) as a solid, m.p. 72°-74° C.; NMR (CDCl3): 1.25(m,6H), 2.65(q,2H), 2.96(q,2H), 4.59(broad s,2H), 6.30(s,1H); mass spectrum (chemical ionisation, ammonia): 277(M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH2:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([NH2:43])([CH3:42])[CH3:41])=[CH:36][CH:35]=1)[CH3:32]>>[CH2:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([NH:43][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:30])([CH3:42])[CH3:41])=[CH:36][CH:35]=1)[CH3:32]
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Reactant: CCOc1ccc(C(C)(C)N)cc1
Product: CCOc1ccc(C(C)(C)NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C#N)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Yield: 91 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 1-(4-ethoxyphenyl)-1-methylethylamine (prepared as described in Preparation 10g) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 91%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[C:32]4[N:31]=[N:30][N:29]([CH3:33])[C:28]=4[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=3)[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].C=O>FC(F)(F)C(O)=O.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[C:32]4[N:31]=[N:30][N:29]([CH3:33])[C:28]=4[CH:27]=[C:26]([C:34]([F:37])([F:35])[F:36])[CH:25]=3)[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cn1nnc2c(COCC3(c4ccc(F)cc4)CCN(C(=O)OC(C)(C)C)CC3)cc(C(F)(F)F)cc21
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(COCc2cc(C(F)(F)F)cc3c2nnn3C)(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-(4-fluorophenyl)-4-(((1-methyl-6-(trifluoromethyl)-1H-benzo[d][1,2,3]triazol-4-yl)methoxy)methyl)piperidine-1-carboxylate (14 mg, 0.027 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 1 mL) and stirred at room temperature for 30 min. The reaction was concentrated, loaded onto a strong cation exchange cartridge in methanol, and flushed with several volumes of methanol which were discarded. The crude secondary amine was eluted in 2M ammonia and concentrated. The resulting residue was dissolved in acetonitrile (1 mL), cooled to 0° C., and treated with sodium cyanoborohydride (3.4 mg, 0.054 mmol) and formalin (75 μl). After 5 min, the reaction was treated with 1 drop of acetic acid. The ice bath was removed and stirring continued for 1 h. The reaction was diluted with ether and washed with 1M sodium hydroxide. The ethereal was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which was discarded. The product was eluted with 2 M ammonia and concentrated to give 8 mg (68%) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 7.70 (s, 1H), 7.36 (s, 1H), 7.33 (m, 2H), 6.99 (m, 2H), 5.01 (s, 2H), 4.34 (s, 3H), 3.57 (s, 2H), 2.59 (m, 2H), 2.22 (m, 7H), 2.02 (m, 2H). Mass spec.: 437.16 (MH)+.
Reaction SMILES: [S:1]([C:4]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8]=2[C:7]([OH:13])=[CH:6][CH:5]=1)C#N.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>C(#N)C>[CH3:25][O:24][C:22](=[O:23])[CH2:21][O:13][C:7]1[CH:6]=[CH:5][C:4]([SH:1])=[C:12]2[C:8]=1[CH2:9][CH2:10][CH2:11]2
Reactant: N#CSc1ccc(O)c2c1CCC2
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)COc1ccc(S)c2c1CCC2

Procedure:
7-Thiocyanato-indan-4-ol (Example 7B) (1.47 g, 7.7 mmol), cesium carbonate (3.77 g, 11.6 mmol) and methyl bromoacetate (1.24 g, 8.08 mmol) were stirred in 20 ml acetonitrile at ambient temperature for 4 h. The reaction was filtered and concentrated. The crude product was treated under the conditions of Example 2D to afford the title product. MS m/z 239 (M+1).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.C(N(CC)CC)C.[C:13]([C:15]1[CH:16]=[C:17]([CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=1)[C:18]([O:20][CH3:21])=[O:19])#[N:14].Cl>CN(C=O)C>[CH2:26]([O:25][C:23]1[CH:22]=[C:17]([CH:16]=[C:15]([C:13]2[NH:14][N:3]=[N:2][N:1]=2)[CH:24]=1)[C:18]([O:20][CH3:21])=[O:19])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)c1cc(C#N)cc(OCc2ccccc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(OCc2ccccc2)cc(-c2nnn[nH]2)c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
Sodium azide (1.5 g) and triethylamine hydrochloride (3.2 g) were added to a DMF (70 mL) solution of methyl 3-cyano-5-benzyloxybenzoate (2.07 g), and stirred at 100° C. for 6 hours and then overnight at room temperature. With cooling with ice, diluted hydrochloric acid was added to it, the precipitate was taken out through filtration, washed with water, and dried to obtain the title compound as a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.O>CN(C=O)C>[Cl:1][C:2]1[N:3]([CH2:10][C:11]([CH3:14])([OH:12])[CH2:13][N:15]2[CH2:20][CH2:19][CH:18]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:26][CH:27]=3)[CH2:17][CH2:16]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: FC(F)(F)Oc1ccc(NC2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)(CN1CCC(Nc2ccc(OC(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 56.1 %

Procedure:
A solution of 2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 6 (0.3 g, 1.38 mmol) and N-(piperidin-4-yl)-4-trifluoromethoxyaniline (0.43 g, 1.66 mmol) in DMF (8 ml) was stirred at 80° C. for 2 hours. To the reaction mixture, water was added, and the solution was extracted with ethyl acetate, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1) to afford 1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-[4-(4-trifluoromethoxyphenylamino)piperidin-1-yl]propan-2-ol (0.37 g, yield 56%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[N:6][C:7]=1[CH2:8][CH3:9].C(Cl)Cl.CO>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[O:11])[CH:5]=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1ncc(CO)cc1Cl
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CO
Product: CCc1ncc(C=O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
MnO2 (620 mg, 7.13 mmol) was added to a solution of (5-chloro-6-ethyl-3-pyridinyl)methanol (103 mg, 0.600 mmol) in DCM (4 ml) and the mixture was stirred at room temperature overnight. TLC (10% DCM/MeOH) showed starting material remaining. An excess of MnO2 (261 mg, 3.00 mmol) was added. After stirring for 3 h, the reaction went to completion. The resulting suspension was filtered and washed with DCM. The filtrate was concentrated under reduced pressure to give 52 mg of the title compound as colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH:11]=O)=[CH:4][CH:3]=1.C(O)(=O)C(C(C(O)=O)O)O.[CH3:23][C@@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1.C([BH3-])#N.[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][N:25]2[CH2:26][CH2:27][CH2:28][C@H:24]2[CH3:23])=[CH:4][CH:3]=1
Reactant: C[C@@H]1CCCN1
Reactant: O=C[C@@H]1C[C@H]1c1ccc(Br)cc1
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: C[C@@H]1CCCN1C[C@@H]1C[C@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (1R,2R)-2-(4-bromophenyl)cyclopropanecarbaldehyde (the product of Example 3B, 600 mg, 2.67 mmol) and (R)-2-methylpyrrolidine tartaric acid salt (0.82 g, 3.47 mmol) in ethanol (30 mL) was treated with sodium cyanoborohydride (252 mg 4 mmol). The mixture was stirred at room temperature for two hours. The mixture was quenched with HCl (1N) and then basified to pH=10-12 with NaOH (10%) and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified on silica gel with 1% to 2% methanol (containing 10% concentrated NH4OH) in dichloromethane to provide the title compound. 1H NMR (300 MHz, CD3OD): δ 0.89 (m, 1H), 0.98 (m, 1H), 1.14 (d, J=6 Hz, 2H), 1.19 (m, 1H), 1.43 (m, 1H), 1.75 (m, 3H), 1.95 (m, 2H), 2.30 (q, J=9 Hz, 1H), 2.37 (m, 1H), 3.14 (dd, J=12 Hz, J=6 Hz, 1H), 3.22 (m, 1H), 7.00 (d, J=9 Hz, 2H), 7.36 (d, J=9 Hz, 2H). MS (DCl—NH3) m/z 294 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)[C:5]([Cl:24])=[CH:4][N:3]=1.Cl.[CH3:26][N:27]1[CH:31]=[C:30]([NH2:32])[CH:29]=[N:28]1.C(N(C(C)C)C(C)C)C>CCCCO>[Cl:24][C:5]1[C:6]([NH:8][CH:9]2[CH2:23][CH:12]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]3[CH2:10]2)=[N:7][C:2]([NH:32][C:30]2[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Cl)ncc3Cl)CC2C1
Reactant: Cn1cc(N)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Nc2ncc(Cl)c(NC3CC4CN(C(=O)OC(C)(C)C)CC4C3)n2)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 115.7 %

Procedure:
To a suspension of tert-butyl 5-((2,5-dichloropyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (579.6 mg, 1.55 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (213.0 mg, 1.34 mmol) in n-BuOH (5 mL) was added N-ethyldiisopropylamine (668.2 mg, 5.17 mmol). The reaction mixture was stirred at 150° C. in a sealed tube overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/80) to give the title compound as a beige solid (672.6 mg, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:21]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=1[C:23]#[N:24].[F-].[K+]>C1COCC1.O.C(Cl)Cl.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:21]2[C:22]([C:23]#[N:24])=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(F)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: N#Cc1cc(F)ccc1Br
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1ccc(F)c(-c2ccc(F)cc2C#N)c1
Temperature: 70 °C
Yield: 58.2 %

Procedure:
To a degassed solution of 1-[4-fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]ethanone (12 g, 45.43 mmol), 2-bromo-5-fluorobenzonitrile (9.09 g, 5.28 ml, 45.44 mmol), potassium fluoride (7.92 g, 136.31 mmol) and tris(dibenzylideneacetone)palladium(0) (0.834 g, 0.908 mmol) in THF (200 ml) and water (10 ml) was added tri-tert butylphosphine (10% weight solution) (0.368 g, 3.63 ml, 1.817 mmol). The reaction was heated at 70° C. for 14 h then allowed to cool to ambient temperature. The reaction was partitioned between water (200 ml) and ether (300 ml). The aqueous phase was extracted with ether (150 ml) and the combined organics washed with brine (200 ml), dried (MgSO4), filtered and evaporated to give a brown solid. The solid was dissolved in DCM and adsorbed onto silica. The crude product was chromatographed on silica (5-20% EtOAc in isohexane) to give the title product as a white solid (6.8 g): δH (400 MHz, CDCl3) 2.63 (3H, s), 7.31 (1H, t, J 9.0 Hz), 7.40-7.44 (1H, m), 7.50-7.53 (2H, m), 8.02-8.10 (2H, m).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19][CH2:18]2)=[CH:13][C:12]([C:31]2[CH:32]=[N:33][NH:34][CH:35]=2)=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[NH2:23][C@H:20]1[CH2:21][CH2:22][C@H:17]([NH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:31]4[CH:32]=[N:33][NH:34][CH:35]=4)[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:5])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cn[nH]c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cn[nH]c4)cc23)CC1

Procedure:
Following general procedure A-2, tert-butyl trans-4-[3-(cyclopropanecarbonyl)-6-(1H-pyrazol-4-yl)quinolin-4-ylamino]cyclohexylcarbamate (17 mg, 0.036 mmol) was reacted with TFA (2 mL) to afford the desired product (6.1 mg, 45%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.30 (br s, 1H), 8.54 (br s, 1H), 8.29 (dd, J=8.7, 1.7 Hz, 1H), 8.19 (s, 2H), 7.94 (d, J=8.8 Hz, 1H), 2.84 (s, 1H), 2.44 (s, 2H), 2.24 (d, J=11.1 Hz, 2H), 1.89-1.76 (m, 2H), 1.67 (br s, 2H), 1.35-1.19 (m, 6H); ESI MS m/z 376 [C22H25N5O+H]+; HPLC 97.6% (AUC), tR=9.39 min.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].Cl[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1>CN(C=O)C>[F:18][C:2]([F:1])([F:17])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([O:16][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=3)[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(N1CCc2ccc(O)cc2CC1)C(F)(F)F
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)C(F)(F)F)CC3)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
Add 2,2,2-trifluoro-1-(7-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)ethanone (0.750 g, 2.89 mmol), 6-chloronicotinamide (0.377 g, 2.41 mmol) and K2CO3 (0.833 g, 6.03 mmol) to a round bottom equipped with a Dean-Stark trap. Add toluene (6 mL) and DMF (18 mL). Heat at reflux for two hours. Cool the reaction mixture to 100° C. and stir overnight. Remove the toluene and DMF as an azeotrope with xylenes. Suspend the solid in 5% methanol/ethyl acetate (100 mL) and filter. Wash the filter cake with ethyl acetate. Concentrate the filtrate, then purify by flash chromatography, eluting with 40% ethyl acetate in dichloromethane to give the title compound (0.312 g, 34.0%): MS ES+ 380 (M+H)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=8.5 min, 89% purity.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]=[C:18]=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][NH:21][CH3:22].O.Cl>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([N:21]([CH3:22])[CH3:20])=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C=NC1CCN(C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.2 %

Procedure:
To 0.83 g (3.2 mmol) of (1-benzyloxycarbonylpiperidin-4-yl)isocyanate from Procedure 1, Step A in 10 mL was added 16 mL (32 mmol) of 2 M dimethylamine in THF. The reaction was stirred under nitrogen at rt for 24 h and then poured into water containing 20 mL of 2N hydrochloric acid and was extracted twice with ethyl acetate. The organic layers were each washed with a portion of brine, dried over sodium sulfate, combined and concentrated to give 0.95 g of the crude title compound which can be used directly in subsequent reactions.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]([C:7]2[S:15][C:14]3[C:13]([NH:16][NH2:17])=[N:12][CH:11]=[N:10][C:9]=3[CH:8]=2)=[CH:3]1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=O)[CH:19]=1>C(O)C>[S:2]1[CH:6]=[CH:5][C:4]([C:7]2[S:15][C:14]3[C:13]([NH:16][N:17]=[CH:24][C:20]4[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=4)=[N:12][CH:11]=[N:10][C:9]=3[CH:8]=2)=[CH:3]1
Reactant: O=Cc1cccnc1
Reactant: NNc1ncnc2cc(-c3ccsc3)sc12
Agent: Cl
Solvent: CCO
Product: C(=NNc1ncnc2cc(-c3ccsc3)sc12)c1cccnc1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
A suspension of (6-(3-thienyl)thieno[3,2-d]pyrimidin-4-yl)hydrazine hydrochloride (222, 39 mg, 0.14 mmol) and 3-pyridinecarboxaldehyde(20 mg, 0.19 mmol) in ethanol (2 mL) was heated at reflux for 4 hours. After cooling to room temperature, the solid product was collected by vacuum filtration to yield 3-pyridinecarboxaldehyde(6-(3-thienyl)thieno[3,2-d]pyrimidin-4-yl)hydrazone (40 mg, 87% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][C:23](=[O:25])[NH:22][C:21]([CH3:26])=[C:20]2[C:27](O)=[O:28])=[CH:15][C:14]=1[O:30][CH3:31].C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:27]([C:20]3[CH:19]([C:16]4[CH:17]=[CH:18][C:13]([Cl:12])=[C:14]([O:30][CH3:31])[CH:15]=4)[CH2:24][C:23](=[O:25])[NH:22][C:21]=3[CH3:26])=[O:28])[CH:9]=2)[NH:4][N:3]=1
Reactant: COc1cc(C2CC(=O)NC(C)=C2C(=O)O)ccc1Cl
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc(C2CC(=O)NC(C)=C2C(=O)Nc2ccc3[nH]nc(Cl)c3c2)ccc1Cl
Temperature: 30 °C
Reaction time: 18 h
Yield: 47.6 %

Procedure:
3-Chloro-1H-indazol-5-amine (99 mg, 0.59 mmol, 1.0 equiv) was combined with the product of Step 4 (175 mg, 0.592 mmol, 1.00 equiv), EDC (134 mg, 0.710 mmol, 1.20 equiv) and Et3N (99.0 μL, 0.710 mmol, 1.20 equiv) in DMF (1.75 mL) and stirred at 30° C. for 18 hours. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. Solid precipitated out of the organic phase and was filtered and triturated with ether to provide 125 mg (47%) of the title compound as a white solid. MS (ES+) m/e 446 [M+H]+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([CH2:12][CH2:13][C:14]([OH:16])=O)[O:9][N:8]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([NH2:28])[CH2:24][CH2:23]1.C(=O)([O-])O.[Na+]>ClCCl>[Cl:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:21][N:22]1[CH2:23][CH2:24][CH:25]([NH:28][C:14](=[O:16])[CH2:13][CH2:12][C:10]2[O:9][N:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[N:11]=2)[CH2:26][CH2:27]1
Reactant: O=C(O)CCc1nc(-c2ccccn2)no1
Reactant: NC1CCN(Cc2ccc(F)c(Cl)c2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CCc1nc(-c2ccccn2)no1)NC1CCN(Cc2ccc(F)c(Cl)c2)CC1
Reaction time: 24 h

Procedure:
3-[3-(2-Pyridinyl)-1,2,4-oxadiazol-5-yl]propanoic acid (0.218 g) and N,N′-carbonyldiimidazole (0.194 g) were stirred in dichloromethane (10 ml) under nitrogen for 1 hour. 1-(3-Chloro-4-fluorobenzyl)-4-piperidinamine (JP 59101483; 0.242 g) was then added and left to stir for 24 hours. Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure, triturated with ethyl acetate/ethanol and filtered to leave N-[1-(3-chloro-4-fluorobenzyl)-4-piperidinyl]-3-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanamide. m.p. 150° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]2[N:5]([CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[K+].[Br-]>>[N:11]1[CH:10]=[CH:9][N:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH:2]=[O:1])[C:4]=12
Reactant: OCc1cccn2ccnc12
Agent: [Br-]
Agent: [K+]
Product: O=Cc1cccn2ccnc12
Yield: 85 %

Procedure:
From 3a, reaction time 1.5 h (yield: 85%); mp 137-139° C. (in Yamanaka, M. and al. Chem. Pharm. Bull. 1991, 39, 1556-1567: 103-104° C.); IR (KBr) 1675, 1450, 1320, 1175 cm−1, 1H NMR (400 MHz, CDCl3) δ 7.01 (t, 1H, J=6.5 Hz), 7.75 (s, 1H), 7.82 (s, 1H), 7.86 (d, 1H, J=6.5 Hz), 8.42 (d, 1H, J=6.5 Hz), 10.8 (s, 1H); 13C NMR (CDCl3) δ 111.9, 113.3, 124.2, 126.9, 130.7, 134.9, 143.8, 188.9.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17](I)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)#[CH:22].C(NCC)C>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]#[C:21][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1ccccn1
Reactant: C#Cc1cccc(Nc2ncnc3ccc(I)cc23)c1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: C#Cc1cccc(Nc2ncnc3ccc(C#Cc4ccccn4)cc23)c1

Procedure:
The title compound was synthesized according to the method of Example 2 using (3-Ethynyl-phenyl)-(6-iodo-quinazolin-4-yl)-amine (125 mg, 0.506 mmol), 2-ethynyl-pyridine (66 mg, 0.505 mmol) and diethyl amine (72 mg, 0.99 mmol) in 2 mL, of DMF.