Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[C:18]3[CH2:17][N:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[C:15](=[O:28])[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[C:37](=[O:45])[C:38]([C:42](O)=[O:43])=[CH:39][NH:40][CH:41]=2)=[CH:32][CH:31]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:16]2[CH2:17][C:18]3[C:9]([O:8][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:42]([C:38]5[C:37](=[O:45])[C:36]([C:33]6[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=6)=[CH:41][NH:40][CH:39]=5)=[O:43])=[N:7][CH:6]=4)=[CH:10][CH:11]=[N:12][C:13]=3[NH:14][C:15]2=[O:28])=[CH:21][CH:22]=1
Reactant: COc1ccc(CN2Cc3c(Oc4ccc(N)nc4)ccnc3NC2=O)cc1
Reactant: O=C(O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3c(Oc4ccc(NC(=O)c5c[nH]cc(-c6ccc(F)cc6)c5=O)nc4)ccnc3NC2=O)cc1
Yield: 31.8 %

Procedure:
A solution of 5-[(6-aminopyridin-3-yl)oxy]-3-(4-methoxybenzyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one (100.00 mg; 0.26 mmol; 1.00 eq.), 5-(4-fluoro-phenyl)-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (67.97 mg; 0.29 mmol; 1.10 eq.), pybop (179.26 mg; 0.34 mmol; 1.30 eq.), DMF (4.00 ml), and N,N-diisopropylethylamine (131.72 μl; 0.79 mmol; 3.00 eq.) was stirred at room temperature for 4 days. The reaction was concentrated, redissolved in DMSO, and purified via prep HPLC to afford 49 mg (26%) of 284 as a tan solid. LC-MS (M+H=593, obsd.=593).
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[C:6]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[CH3:14][O:15][C:16](=[O:37])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][CH3:36])=[CH:29][CH:28]=2)[CH:19]=1.C(N(CC)C(C)C)(C)C>ClCCCl.CCOC(C)=O>[CH3:14][O:15][C:16](=[O:37])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]([S:10]([C:6]2[C:3]3=[N:4][O:5][N:1]=[C:2]3[CH:9]=[CH:8][CH:7]=2)(=[O:12])=[O:11])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][CH3:36])=[CH:29][CH:28]=2)[CH:19]=1
Reactant: CCCCc1ccc(CNCc2cccc(CC(=O)OC)c2)cc1
Reactant: O=S(=O)(Cl)c1cccc2nonc12
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1ccc(CN(Cc2cccc(CC(=O)OC)c2)S(=O)(=O)c2cccc3nonc23)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Benzofurazan-4-sulfonyl chloride (109 mg, 0.50 mmol) was added to a solution of {3-[(4-butyl-benzylamino)-methyl]-phenyl}-acetic Acid methyl ester (163 mg, 0.50 mmol) and N,N-diisopropylethylamine (65 mg, 0.50 mmol) in 1,2-dichloroethane. The reaction mixture was stirred at room temperature for 20 h. The reaction was diluted with EtOAc and the organic solution was washed with water followed by brine. The organic solution was dried over MgSO4, filtered, and concentrated to afford (3-{[(benzo[1,2,5]oxadiazole-4-sulfonyl)-(4-butyl-benzyl)-amino]- methyl}-phenyl)-acetic Acid methyl ester. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, 1H), 7.88 (d, 1H), 7.37-7.41 (m, 1H), 7.06-7.10 (m, 2H), 6.90-6.97 (m, 6H), 4.56 (s, 2H), 4.51 (s, 2H), 3.66 (s, 3H), 3.45 (s, 2H), 2.48 (t, 2H), 1.45-1.53 (m, 2H), 1.23-1.32 (m, 2H), 0.89 (t, 3H); MS 508 (M+18).
Reaction SMILES: [H-].[Na+].C(=S)=S.CI.C(SC)(=S)O[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([NH2:25])[CH:19]=2)=[CH:13][N:12]=1.C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C>C1COCC1.C1(C)C=CC=CC=1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:14]2[CH:13]=[N:12][C:11]([CH3:10])=[CH:16][CH:15]=2)=[CH:19][C:20]=1[NH2:25]
Reactant: CSC(=S)OCc1ccc(Oc2ccc(F)c(N)c2)cn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Agent: [H-]
Solvent: CI
Solvent: S=C=S
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc(F)c(N)c2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
NaH (100 mg, 3.3 mmol) was slowly added to a solution of Example A12 (0.50 g, 2.1 mmol) in dry THF (50 mL) at 0° C. After 30 min, CS2 (0.49 g, 6.4 mmol) was added and the reaction mixture was stirred at 0° C. for 1 hour. Methyl iodide (2.4 g, 17 mmol) was added at 0° C. and the reaction mixture was allowed to warm to RT overnight. The solvent was removed under reduced pressure to obtain the crude product. The crude, O-(5-(3-amino-4-fluorophenoxy)pyridin-2-yl)methyl S-methyl carbonodithioate (0.69 g, 2.1 mmol) was dissolved in toluene (5 mL) and tributyltin hydride (1 mL) and AIBN (50 mg) were added. The reaction mixture was heated under reflux for 3 hours. The solvent was removed under reduced pressure and the residue was filtered and washed with CH2Cl2. The filtrate was evaporated and the residue was purified by silica gel column chromatography to obtain 2-fluoro-5-(6-methylpyridin-3-yloxy)benzenamine (0.26 g, 56% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J=2.8 Hz, 1H), 7.30 (dd, J=2.8, and 8.4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 6.97 (dd, J=8.8, 11.6 Hz, 1H), 6.38 (dd, J=3.2, 7.6 Hz, 1H), 6.13 (dt, J=3.2, 8.8 Hz, 1H), 5.31 (s, 1H), 2.44 (s, 3H); MS (ESI) m/z: 219.0 (M+H+).
Reaction SMILES: [CH:1]([N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13])=[CH2:2].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:44]1[CH:45]=[CH:46][C:47]2[C:48]3[N:56]([CH2:57][C:58]([CH3:61])([OH:60])[CH3:59])[C:55]([CH2:62][CH3:63])=[N:54][C:49]=3[CH:50]=[N:51][C:52]=2[CH:53]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:62]([C:55]1[N:56]([CH2:57][C:58]([OH:60])([CH3:61])[CH3:59])[C:48]2[C:47]3[CH:46]=[CH:45][C:44]([CH:2]=[CH:1][N:3]4[C:7](=[O:8])[C:6]5[C:5](=[CH:12][CH:11]=[CH:10][CH:9]=5)[C:4]4=[O:13])=[CH:53][C:52]=3[N:51]=[CH:50][C:49]=2[N:54]=1)[CH3:63]
Reactant: C=CN1C(=O)c2ccccc2C1=O
Reactant: CCc1nc2cnc3cc(Br)ccc3c2n1CC(C)(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1nc2cnc3cc(C=CN4C(=O)c5ccccc5C4=O)ccc3c2n1CC(C)(C)O
Temperature: 120 °C
Yield: 77.1 %

Procedure:
A thick walled glass tube, equipped with a stir bar, was charged with palladium (II) acetate (64 mg, 0.29 mmol), acetonitrile (50 mL), N-vinylphthalimide (1.19 g, 6.89 mmol), triethylamine (2.4 mL, 17 mmol), tri-o-tolylphosphine (260 mg, 0.86 mmol) and 1-(7-bromo-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol (2.00 g, 5.74 mmol). The reaction mixture was purged with nitrogen and the tube was sealed and heated at 120° C. in an oil bath for 16 hours. The reaction was cooled to ambient temperature and silica gel (20 g) was added followed by concentration under reduced pressure. The sample absorbed on silica was purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a 0-7% gradient of methanol in dichloromethane). The recovered solid was washed with 1% aqueous sodium carbonate to provide 1.95 g of 2-{2[2-ethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]ethenyl}-1H-isoindole-1,3(2H)-dione as a bright yellow solid. MS (APCI) m/z 441 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([F:12])=[CH:5][C:3]=1[NH2:4].[CH3:13][C:14]([CH3:18])([CH3:17])[C:15]#[CH:16].CCN(CC)CC>C1(C)C=CC=CC=1.O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][C:14]([CH3:18])([CH3:17])[C:15]#[C:16][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([F:12])=[CH:5][C:3]=1[NH2:4]
Reactant: C#CC(C)(C)C
Reactant: Nc1cc(F)c([N+](=O)[O-])cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)C#Cc1cc([N+](=O)[O-])c(F)cc1N
Temperature: 70 °C
Yield: 46.3 %

Procedure:
A mixture of 2-bromo-5-fluoro-4-nitroaniline (9.0 g, 38.4 mmol), 3,3-dimethylbut-1-yne (9.95 g, 121 mmol), CuI (0.5 g 2.6 mmol), Pd(PPh3)2Cl2 (3.4 g, 4.86 mmol) and Et3N (14 mL, 6.9 mmol) in toluene (100 mL) and water (50 mL) was heated at 70° C. for 4 h. The aqueous layer was separated and the organic layer washed with water (80 mL×2) and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to dryness. The residue was recrystallized with ether to afford 2-(3,3-dimethylbut-1-ynyl)-5-fluoro-4-nitroaniline (4.2 g, 46%). 1H-NMR (400 MHz, DMSO-d6) δ 7.84 (d, J=8.4 Hz, 1H), 6.84 (brs, 2H), 6.54 (d, J=14.4 Hz, 1H), 1.29 (s, 9H).
Reaction SMILES: [CH2:1](Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:24]([NH2:28])(=[O:27])[CH:25]=[CH2:26].[Cl-].[Al+3].[Cl-].[Cl-].Cl.C(NC(=O)C=C)CCCCCCCCCCCCCCC>CC(C)=O>[CH2:1]([NH:28][C:24](=[O:27])[CH:25]=[CH2:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: C=CC(N)=O
Reactant: CCCCCCCCCCCCCCCCCCCCCCCl
Agent: C=CC(=O)NCCCCCCCCCCCCCCCC
Agent: Cl
Agent: [Al+3]
Solvent: CC(C)=O
Product: C=CC(=O)NCCCCCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a 250 ml capacity conical flask 8.63 g behenyl chloride (0.025 M), 1.75 g acrylamide (0.025 M) and 50 ml acetone were placed to obtain a clear solution. The solution was stirred with a magnetic needle at room temperature. 3.25 g anhydrous aluminium chloride (0.025 M) was added and the reaction mixture was stirred at room temperature. After 5 to 10 minutes of stirring vigorous evolution of hydrogen chloride took place which ceased after about 5 minutes. The product was isolated following the procedure described for synthesis of N-cetylacrylamide.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=[CH:4]1)=O.[F:13][C:14]([F:30])([F:29])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[C:21]1[O:25][N:24]=[C:23]([C:26]([OH:28])=O)[N:22]=1.CNC>O1CCCC1>[CH3:1][N:3]([CH3:4])[C:26]([C:23]1[N:22]=[C:21]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[C:14]([F:13])([F:30])[F:29])[O:25][N:24]=1)=[O:28]
Reactant: O=C(O)c1noc(-c2cnccc2C(F)(F)F)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)c1noc(-c2cnccc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5.8 g of carbonyldiimidazole are initially charged in 90 ml of tetrahydrofuran and, a little at a time, admixed with 9 g of 5-(4-trifluoromethyl-3-pyridyl)-1,2,4-oxadiazole-3-carboxylic acid. The mixture is stirred at room temperature for 15 min and then heated at 50° C. for 2 h. After cooling to room temperature, 2.3 g of dimethylamine are introduced in a very gentle gas stream over a period of 2 h. After a reaction time of 12 h, the mixture is concentrated and taken up in 200 ml of diethyl ether. The mixture is washed with ice-cold half conc. hydrochloric acid solution, washed neutral with sat. sodium bicarbonate sol., dried over magnesium sulfate and concentrated under reduced pressure. This gives a slightly yellow oil which solidifies after a number of days to a solid of mp. 52-54° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[N:9])[C:3]=1[CH2:10][C:11]([OH:13])=O.O=S(Cl)[Cl:16]>ClCCl>[Cl:16][C:8]1[C:4]2[C:3](=[C:2]([Cl:1])[CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:11]([OH:13])[N:9]=1
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cccc(Cl)c1CC(=O)O
Solvent: ClCCl
Product: Oc1cc2c(Cl)cccc2c(Cl)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
2-(2-chloro-6-cyanophenyl)acetic acid (10.5 g, 53.7 mmol) and SOCl2 (20 mL, 274 mmol) were stirred in dichloromethane (25 mL) at RT. The suspension became a solution over 4 h. The reaction was stirred overnight. The volitile organics were removed under vacuum and the residue was taken up in DCM and filtered. The filtrate was concentrated and then dissolved in 4 N HCl dioxane (30 mL) and transfered to a sealed vessel and heated to 60° C. for 3 h. The reaction was cooled and the solid was collected, washed with dioxane, and dried under vacuum to give the product 1,5-dichloroisoquinolin-3-ol (8 g, 69.6% yield) as a solid 1H NMR (400 MHz, DMSO-d6) δ 11.66 (s, 1H), 8.11 (dt, J=8.6, 1.0 Hz, 1H), 7.90 (dd, J=7.6, 1.0 Hz, 1H), 7.46 (dd, J=8.6, 7.6 Hz, 1H), 7.11 (d, J=1.0 Hz, 1H). MS: MS m/z 214.08(M++1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:15][CH2:14][CH2:13][C:12]3[CH:11]=[C:10]([C:16]([OH:18])=O)[S:9][C:8]=3[C:7]=2[CH:19]=1)#[N:2].S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[Cl:30][C:31]1[CH:32]=[C:33]([CH:38]=[CH:39][C:40]=1[NH:41][CH3:42])[C:34]([NH:36][CH3:37])=[O:35]>C1(C)C=CC=CC=1.C(#N)C.O>[Cl:30][C:31]1[CH:32]=[C:33]([C:34](=[O:35])[NH:36][CH3:37])[CH:38]=[CH:39][C:40]=1[N:41]([CH3:42])[C:16]([C:10]1[S:9][C:8]2[C:7]3[CH:19]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[O:15][CH2:14][CH2:13][C:12]=2[CH:11]=1)=[O:18]
Reactant: CNC(=O)c1ccc(NC)c(Cl)c1
Reactant: N#Cc1ccc2c(c1)-c1sc(C(=O)O)cc1CCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CNC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2cc(C#N)ccc2OCC3)c(Cl)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 9-cyano-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-2-carboxylic acid (300 mg) in toluene (10 mL) was added thionyl chloride (2 mL) and the reaction heated at 80° C. for 2 h. After cooling to room temperature, the solvent was reduced in vacuo and the residue redissolved in acetonitrile (10 mL). Potassium carbonate (306 mg) and 3-chloro-N-methyl-4-methylamino-benzamide from Example 21 (263 mg) were added and the reaction stirred at room temperature for 16 h. Water (20 mL) was added and the product extracted into ethyl acetate (2×20 mL). The organics were dried (MgSO4), reduced in vacuo and purified on silica to give 298. NMR: (CDCl3): 2.95-2.98 (5H, m), 3.31 (3H, s, Me), 4.19-4.21 (2H, m), 6.10 (1H, s, NH), 0.76 (1H, s, Ar), 6.96 (1H, d, J 8.4, Ar), 7.31-7.36 (2H, m, Ar), 7.64-7.67 (2H, m, Ar) and 7.87 (1H, d, J 1.8, Ar). MS: (ESI+) MH+ 451.25
Reaction SMILES: Br[C:2]1[CH:33]=[CH:32][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:15](=[O:31])[C@@H:16]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:17][C:18]4[S:19][CH:20]=[CH:21][CH:22]=4)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.[Cl-].[Na+].O>[O:31]=[C:15]([N:12]1[CH2:11][CH2:10][N:9]([C:7]2[S:8][C:4]3[CH:3]=[C:2]([C:39]4[CH:40]=[CH:41][C:36]([C:35]([F:46])([F:45])[F:34])=[CH:37][CH:38]=4)[CH:33]=[CH:32][C:5]=3[N:6]=2)[CH2:14][CH2:13]1)[C@@H:16]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:27])[CH3:28])[CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCN(c2nc3ccc(Br)cc3s2)CC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCN(c2nc3ccc(-c4ccc(C(F)(F)F)cc4)cc3s2)CC1
Temperature: 95 °C
Yield: 107.3 %

Procedure:
(S)-tert-Butyl 1-(4-(6-bromobenzo[d]thiazol-2-yl)piperazin-1-yl)-1-oxo-3-(thiophen-2-yl)propan-2-ylcarbamate (80 mg), 4-(trifluoromethyl)phenylboronic acid (33 mg), palladium tetrakistriphenylphosphine (8 mg), and potassium carbonate (54 mg) were combined in 1,4-dioxane (5 mL) and water (1 mL). The resulting mixture was heated to 95° C. overnight, then diluted with brine, extracted with DCM, concentrated, and chromatographed (100% DCM) to yield (S)-tert-butyl 1-oxo-3-(thiophen-2-yl)-1-(4-(6-(4-(trifluoromethyl)phenyl)benzo[d]thiazol-2-yl)piperazin-1-yl)propan-2-ylcarbamate as a colorless oil (96 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH2:11]([Li])[CH2:12][CH2:13][CH3:14].ICCCCI.O>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:14][CH2:13][CH2:12][CH2:11]2)[C:2]1=[O:10]
Reactant: [Li]CCCC
Reactant: O=C1Cc2ccccc2N1
Agent: ICCCCI
Solvent: O
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2C12CCCC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 50 %

Procedure:
To a −25° C. solution of oxindole (2.0 g, 15.0 mmol) in 40 (cm3) of anhydrous THF under N2 was added n-butyllithium (1.6 M in hexanes, 19.7 cm3, 31.5 mmol) drop-wise. To the resulting milky solution was added N,N,N,N′N′-tetramethylethylenediamine (4.75 cm3, 31.5 mmol). After 30 min. a solution of 1,4-diiodobutane (21.9 g, 70.6 mmol) in THF (3 cm3) was added and the reaction mixture was allowed to warm to RT and stirred for 14 h. The reaction mixture was poured into water, extracted with EtOAc (×2), the combined organic layers were washed with dilute HCl (pH 1) and water (×2), dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, EtOAc: hexane 1:4) to afford the subtitled compound (1.4 g, 7.5 mmol, 50%) as a tan solid: 1H NMR (CDCl3) δ1.8-2.2 (m, 8H), 6.94 (dd, J=7.5, 1.0 Hz, 1H), 7.01 (dd, J7.5, 1.0Hz, 1H), 7.14-7.25 (m, 2H), 9.30 (br s, 1H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH3:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl.C(OCC)(=O)C>[CH3:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH:38][C:28]([C:23]1[CH:24]=[N:25][C:26]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]1[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:31])([F:32])[F:1])=[CH:8][CH:7]=3)=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[CH:27]=2)=[O:29]
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: COc1ccccc1CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccccc1CNC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (50 mg, 0.11 mmol) was combined with 2-methoxybenzylamine (16 mg, 0.11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.14 mmol), 1-hydroxybenzotriazole (17 mg, 0.13 mmol), and triethylamine (0.064 ml, 0.46 mmol) in 1 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 30 ml of ethyl acetate, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 46 mg of the title compound as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:21]2[S:25][C:24]3[CH:26]=[CH:27][C:28]([NH2:30])=[CH:29][C:23]=3[CH:22]=2)O1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[N:12]1[NH:11][N:10]=[N:9][C:8]=1[C:6]1[CH:7]=[C:2]([C:21]2[S:25][C:24]3[CH:26]=[CH:27][C:28]([NH2:30])=[CH:29][C:23]=3[CH:22]=2)[CH:3]=[N:4][CH:5]=1.[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[CH:7]=1
Reactant: CC1(C)OB(c2cc3cc(N)ccc3s2)OC1(C)C
Agent: [Pd+2]
Agent: Brc1cncc(-c2nn[nH]n2)c1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: Nc1ccc2sc(-c3cncc(-c4nn[nH]n4)c3)cc2c1
Temperature: 100 °C

Procedure:
The reaction mixture of 3-bromo-5-(2H-tetrazol-5-yl)pyridine (226 mg, 1.0 mmol, 1 eq), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophen-5-amine (316 mg, 1.15 eq), triphenylphosphine (53 mg, 0.2 eq), and palladium diacetate (22 mg, 0.1 eq) in dioxane (3 mL) and aqueous sodium carbonate (2 M, 2 mL, 4 eq) under nitrogen atmosphere was vigorously stirred and heated at 100° C. for three hours. It was then cooled to room temperature, filtered through a Buchner funnel, and rinsed with small amount of water and ethyl acetate. The filtrate was isolated and concentrated down with silica gel. Upon a gradient column chromatography (EtOAc to MeOH-EtOAc 1:4), 2-(5-(2H-tetrazol-5-yl)pyridin-3-yl)benzo[b]thiophen-5-amine was obtained as an orange colored solid in the amount of 92 mg while the starting material, 3-bromo-5-(2H-tetrazol-5-yl)pyridine was recovered in the amount of 90 mg.
Reaction SMILES: [BH4-].[Na+].O.[CH2:4]([O:6][C:7]([C@@H:9]1[CH2:11][C@H:10]1[CH:12]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])S(C1C=CC(C)=CC=1)(=O)=O)=[O:8])[CH3:5]>O1CCCC1>[CH2:4]([O:6][C:7]([C@@H:9]1[CH2:11][C@H:10]1[CH2:12][NH:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])=[O:8])[CH3:5]
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1C[C@H]1CNC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
Sodium Borohydride (2.3 g, 58.55 mol) was suspended in tetrahydrofuran (150 mL) and 4 mL of water was added. (13.3 g, 33.46 mmol) of trans-2-[tert-Butoxycarbonylamino-(toluene-4-sulfonyl)-methyl]-cyclopropanecarboxylic acid ethyl ester was added portionwise (0.8 g portions) and the temperature was kept to 18-30° C. After 1.5 h water (4 mL) and 0.4 g (10.15 mmol) of sodium borohydride were added again. The resulting mixture was quenched with ammonium chloride 2M (300 mL) and 100 mL of 1M K2CO3 and stirring was continued for 0.5 h. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (300 mL) and the combined organic layers were dried over MgSO4 and concentrated to dryness under vacuum and purified with column chromatography on silica with heptane/AcOEt (9/1) to obtain 7.5 g (92.1% yield) of the title compound. as a white solid. MS (m/e): 244.1 (M+H+)
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1B(O)O>>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][C:19]=1[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: COc1ccc(C(F)(F)F)cc1B(O)O
Product: COc1ccc(C(F)(F)F)cc1-c1cccc2nc(N)nn12

Procedure:
5-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2yl-amine was prepared from 5-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-yl-amine (0.5 g, 2.3 mmol), and 2-methoxy-5-trifluoromethylbenzeneboronic acid (0.76 g, 3.4 mmol) in a manner analogous to Example 2c. Product was isolated as a foam (0.63 g, 87%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.79-7.73 (m, 2H), 7.49-7.44 (m, 2H), 7.15 (d, J=8.9 Hz, 1H), 6.85 (t, J=4.2 Hz, 1H), 4.45 (brs, 2H), 3.85 (s, 3H). MS=309 (MH)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8]>C1COCC1>[Br:1][CH2:2][CH2:3][C:4]([N:9]([CH2:10][CH3:11])[CH2:7][CH3:8])=[O:5]
Reactant: CCNCC
Reactant: O=C(Cl)CCBr
Solvent: C1CCOC1
Product: CCN(CC)C(=O)CCBr
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-bromopropanoyl chloride (1.0 g, 5.8 mmol) and diethylamine (1.9 g, 26 mmol) in THF (20 ml) was stirred at 0° C. for 30 min, the resulting white solid was filtered and the filtrate was concentrated to give a crude oil which was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].Cl.CCN(C(C)C)C(C)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][C:31]2[S:35][C:34]([S:36](Cl)(=[O:38])=[O:37])=[CH:33][CH:32]=2)=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl.CN(C=O)C>[C:6]([O:5][C:3](=[O:4])[CH2:2][NH:1][S:36]([C:34]1[S:35][C:31]([CH2:30][NH:29][C:27]([C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=2)=[O:28])=[CH:32][CH:33]=1)(=[O:38])=[O:37])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(NCc1ccc(S(=O)(=O)Cl)s1)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc(CNC(=O)c2ccc(Cl)cc2)s1
Reaction time: 8 h
Yield: 62.9 %

Procedure:
H-Gly-OtBu.HCl (263 mg, 1.57 mmol) is dissolved in 20 ml CH2Cl2. pH is adjusted to 9 using i-Pr2NEt as a base (537 μl, 3.14 mmol). To this solution is added dropwise 1b (500 mg, 1.43 mmol) in 10 ml DMF. The reaction is stirred overnight. 30 ml of CH2Cl2 are added and the organic phase washed with HCl (0.1N) and sat. NaCl sol. Drying over MgSO4 and evaporating the solvent to dryness affords 1c (400 mg, 63%) as a white solid. mp °C., 1H NMR (d6-DMSO) δ 9.34 (t, J=6.40 Hz, 1H), 8.25 (t, J=6.40 Hz, 1H), 7.89 (d, J=8.67 Hz, 2H), 7.56 (d, J=8.67 Hz, 2H), 7.41 (d, J=3.77 Hz, 1H), 7.05 (d, J=3.7 Hz, 1H), 4.62 (d, J=6.40 Hz, 2H), 3.59 (d, J=6.40 Hz, 2H), 1.3 (s, 9H).