Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1.Cl[C:13]1[N:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[N:16]=[C:15]([NH:25][C:26]2[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:28][CH:27]=2)[N:14]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[Cl:11][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[OH:10])[CH2:3][NH:2][C:13]1[N:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:22])[F:23])[N:16]=[C:15]([NH:25][C:26]2[CH:38]=[CH:37][C:29]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])=[CH:28][CH:27]=2)[N:14]=1
Reactant: NCc1ccc(O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(O)c(Cl)c3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.3 %

Procedure:
To a 100 mL round-bottom flask equipped with a stir bar was added 4-(aminomethyl)-2-chlorophenol hydrobromide (1.34 g, 5.63 mmol), tert-butyl 4-((4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoate (3.00 g, 5.63 mmol) and THF (28 mL). To the solution was added N,N-diisopropylethylamine (2.95 ml, 16.9 mmol). The mixture was stirred at room temperature for 3 days. The mixture was concentrated in vacuo and the resulting residue was subjected to C18 chromatography (water:methanol 1:1 to methanol) to afford tert-butyl 4-((4-((3-chloro-4-hydroxybenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoate as a colorless solid (2.88 g, 90%). MS m/z=526.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O:28][C@@H:29]([C:35]1[C:50]([CH3:51])=[CH:49][C:38]2[N:39]=[C:40]([C:42]3[CH:47]=[CH:46][N:45]=[C:44](Cl)[CH:43]=3)[S:41][C:37]=2[C:36]=1[C:52]1[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][CH:53]=1)[C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH3:27])([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[N:10]=[CH:11][C:12]([C:44]2[CH:43]=[C:42]([C:40]3[S:41][C:37]4[C:36]([C:52]5[CH:53]=[CH:54][C:55]([Cl:58])=[CH:56][CH:57]=5)=[C:35]([C@H:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:50]([CH3:51])=[CH:49][C:38]=4[N:39]=3)[CH:47]=[CH:46][N:45]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Reactant: CC1(C)OB(c2ccc(OCc3ccccc3)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc(OCc5ccccc5)nc4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A mixture of 2-(benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (15 mg, 0.048 mmol), (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (17 mg, 032 mmol) and 2M potassium carbonate solution (48 μL, 0.096 mmol) in dioxane (0.5 mL) was sparged with nitrogen for 10 minutes, Pd(PPh3)4 (3.7 mg, 0.0032 mmol) was added and reaction mixture was heated at 100° C. for 4 h. Reaction mixture was diluted with ethyl acetate, washed with brine. The aqueous layer was back extracted with ethyl acetate and the combined organic layer was dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 20% EtOAc/Hex) to give product. LCMS-ESI+: calc'd for C39H37ClN3O4S: 678.2 (M+H+); Found: 678.3 (M+H+).
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[CH:30]=3)[C:25]([OH:27])=O)=[CH:17][CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:39][C:40]1[CH:45]=[N:44][CH:43]=[CH:42][N:41]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]4[CH2:36][CH2:35][N:34]([CH3:37])[C:33]4=[O:38])[CH:30]=3)[C:25]([NH:39][C:40]3[CH:45]=[N:44][CH:43]=[CH:42][N:41]=3)=[O:27])=[CH:17][CH:16]=2)=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: Nc1cnccn1
Reactant: CN1CC[C@H](Oc2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(C(=O)O)c2)C1=O
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN1CC[C@H](Oc2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(C(=O)Nc3cnccn3)c2)C1=O
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 22 %

Procedure:
1-Chloro-N,N,2-trimethyl-prop-1-en-1-amine (0.08 0 mL, 0.60 mmol) was added to a solution of 3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoic acid (Intermediate 30) (202 mg, 0.49 mmol) in DCM (5 mL) and stirred at ambient temperature for 50 minutes. 2-Amino-pyrazine (CAS no. 5049-61-6) (94 mg, 0.98 mmol) and pyridine (0.80 mL, 0.98 mmol) were added and the reaction stirred for 16 hours. The solvent was removed under reduced pressure and the residue taken up in ethyl acetate (40 mL), washed with saturated sodium bicarbonate (20 mL), water (10 mL), and brine (10 mL), dried (MgSO4) and evaporated under reduced pressure to give the crude product. The residue was purified by chromatography on silica, eluting with a gradient of 0-4% methanol in DCM to give product (53 mg, 22%). 1H NMR δ300 MHz, CDCl3) 2.13-2.27 (m, 1H), 2.35 (quintet, 2H), 2.52-2.67 (m, 1H), 2.93 (s, 3H), 3.34-3.59 (m, 2H), 4.24 (t, 2H), 4.70 (t, 2H), 4.94 (t, 1H), 6.98 (s, 1H), 7.23 (s, 1H), 7.39 (d, 1H), 7.48 (s, 1H), 8.12 (d, 1H), 8.27 (q, 1H), 8.33 (d, 1H), 8.39 (d, 1H), 8.66 (s, 1H), 9.66 (s, 1H); m/z 489 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH:7]([OH:29])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[O:28])[CH2:17][CH2:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH:21]=[CH:22][NH:23]2)([CH3:4])[CH3:3].[Cl:30]N1C(=O)CCC1=O.C(O)(=O)C.[OH-].[Na+]>O>[Cl:30][C:21]1[C:20]2[C:24](=[CH:25][CH:26]=[CH:27][C:19]=2[CH2:18][CH2:17][C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH:7]([OH:29])[CH2:6][NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:28])[NH:23][CH:22]=1
Reactant: CC(C)(C)NCC(O)COc1ccccc1C(=O)CCc1cccc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)NCC(O)COc1ccccc1C(=O)CCc1cccc2[nH]cc(Cl)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
A mixture of 8.6 g of 1-[2-[3-(1,1-dimethylethylamino)-2-hydroxypropoxy]-phenyl]-3-(1H-indol-4-yl)-1-propanone, 3 g of N-chlorosuccinimide and 170 ml of acetic acid was stirred at room temperature for 2 hours and was then diluted with water. The mixture was made alkaline by addition of sodium hydroxide and was extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica and eluted with a 6-3-1 chloroform-acetone-triethylamine mixture to obtain 6.37 g of 3-(3-chloro-1H-indol-4-yl)-1-[2-[3-(1,1-dimethylethylamino)-2-hydroxypropoxy]-phenyl]-1-propanone.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([I:18])[C:12]=1[O:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:5][N:6]([OH:9])[CH:7]=[O:8].[C:19](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH2:14]([O:13][C:12]1[C:2]([NH:1][CH3:19])=[CH:3][C:4]([CH2:5][N:6]([OH:9])[CH:7]=[O:8])=[CH:10][C:11]=1[I:18])[CH2:15][CH2:16][CH3:17]
Reactant: CCCCOc1c(N)cc(CN(O)C=O)cc1I
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCCOc1c(I)cc(CN(O)C=O)cc1NC
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.2 %

Procedure:
A mixture of N-(3-amino-4-butoxy-5-iodo-benzyl)-N-hydroxy-formamide (36 mg, 0.1 mmol), potassium carbonate (11 mg, 0.11 mmol) and iodomethane (9.2 ul, 0.15 mmol) in DMF (1 ml) was stirred 18 h at room temperature. The mixture was partitioned between ethyl acetate and water, the organic extract was washed with brine then dried with sodium sulfate and all voltiles removed. Purification by preparative HPLC afforded the title compound (8 mg, 22%) 1H NMR (400 MHz, CD3OD) δ 8.36* 7.16 (s, 1H), 7.00 (s, 1H), 6.59 (s, 1H), 4.58* 4.54 (s, 2H) 3.84 (t, j=6.2 Hz, 2H), 2.83* 2.81 (s, 3H) 1.83-1.87 (m, 2H), 1.54-1.59 (m, 2H), 1.03 (t, j=7.1 Hz, 3H). M+1=379.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH3:19][C@@H:20]1[O:25][C@H:24]([CH3:26])[CH2:23][NH:22][CH2:21]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:22]3[CH2:21][C@@H:20]([CH3:19])[O:25][C@@H:24]([CH3:26])[CH2:23]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Reactant: C[C@@H]1CNC[C@H](C)O1
Product: COc1cc(N2CCC(N3C[C@@H](C)O[C@@H](C)C3)CC2)ccc1[N+](=O)[O-]

Procedure:
Starting materials: 1-(3-methoxy-4-nitrophenyl)piperidin-4-one (INTERMEDIATE 18) and (2S,6R)-2,6-dimethylmorpholine. m/z 350.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[C:3]#[CH:4].[Li]CCCC.[I:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]=[C:19]=[O:20]>C1COCC1.[Cl-].[Na+].O>[I:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:20])[C:4]#[C:3][CH:2]([CH3:5])[CH3:1]
Reactant: O=C=Nc1ccccc1I
Reactant: C#CC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C#CC(=O)Nc1ccccc1I
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
3-Methyl-but-1-yne (11 g, 0.16 mol) in THF (100 ml) was added n-BuLi (2.5M in hexane) (59 ml, 0.15 mol) at 0° C. The resulting mixture was stirred for 30 minutes. Then a solution of 1-iodo-2-isocyanato-benzene (33 g, 0.14 mol) in THF (100 ml) was dropped into the mixture. After stirring for 2 hours at 0° C., the mixture was treated with brine (100 ml) and extracted with ether (200 ml). The organic layer was dried over sodium sulfate and concentrated to give the crude product 4-methyl-pent-2-ynoic acid (2-iodo-phenyl)-amide (38 g, 90%) as a yellow oil which was used in next step without purification. MS calcd. for C12H12INO 313.1, obsd. (ESI+) [(M+H)+] 314.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:16])[C:14]=1[F:15])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[CH3:17][C:18]1[N:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21].CCN=C=NCCCN(C)C.C1C(NN)=NN=C(N(CCO)CCO)C=1.Cl.Cl>N1C=CC=CC=1.C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:16][C:20](=[O:21])[C:19]3[CH:23]=[CH:24][CH:25]=[N:26][C:18]=3[CH3:17])[C:14]=1[F:15])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: Cc1ncccc1C(=O)O
Reactant: Nc1c(F)c(Cl)cc2c1[nH]c1cnccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NNc1ccc(N(CCO)CCO)nn1
Solvent: c1ccncc1
Solvent: O=CO
Product: Cc1ncccc1C(=O)Nc1c(F)c(Cl)cc2c1[nH]c1cnccc12
Temperature: 100 °C

Procedure:
A solution of 6-chloro-7-fluoro-9H-β-carbolin-8-ylamine (100 mg, 0.424 mmol) in pyridine (2.5 ml) was stirred at RT. 2-methyl nicotinic acid (70 mg, 0.509 mmol) was added, followed by EDCI (130 mg, 0.678 mmol). The suspension was stirred at 100° C. for a day. The pyridine was removed under reduced pressure and the resulting dark oil was triturated with saturated aqueous NaHCO3. The precipitate which formed was filtered and washed with MeOH. The material was treated with 2M HCl in Et2O to yield a gray solid, the di-HCl salt N-(6-chloro-7-fluoro-9H-β-carbolin-8-yl)-2-methyl-nicotinamide (110 mg). 1H-NMR (300 MHz, DMSO-d6): δ 13.15 (s, 1); 11.03 (s, 1); 9.33 (s, 1); 8.99-8.97 (m, 1); 8.92-8.89 (m, 1); 8.79-8.73 (m, 2); 8.50 (m, 1); 7.70 (m, 1); 2.80 (s, 3). HCOOH standard conditions. DAD Rf=0.91 min. MS (M+H+): 355.
Reaction SMILES: [F:1][C:2](=[C:6]([F:8])[F:7])[CH2:3][CH2:4][OH:5].CC(C)=[O:11].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[F:1][C:2](=[C:6]([F:8])[F:7])[CH2:3][C:4]([OH:11])=[O:5]
Reactant: OCCC(F)=C(F)F
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)CC(F)=C(F)F

Procedure:
The first method involves hydrolysis of 4-bromo-1,1,2-trifluoro-1-butene (II) with water in the presence of N-methyl pyrrolidinone to give 3,4,4-trifiuoro-3-buten-1-ol (III), followed by Jones oxidation under conditions not previously known. These conditions are at a temperature of about 51°-54° C. In addition, the 3,4,4-trifluoro-3-buten-1-ol in acetone solvent and the Jones reagent are added to the reaction vessel simultaneously to afford 3,4,4-trifluoro-3-butenoic (IV) acid in 52% overall yield. ##STR4##
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:23][CH3:24])=[CH:12][CH:11]=2)=[O:9])[CH:2]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH+:7]([O-:33])[C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:23][CH3:24])=[CH:12][CH:11]=2)=[O:9])[CH:2]=1
Reactant: COc1ccc(C(=O)Nc2cccnc2)c2c1oc1ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)[NH+]([O-])c2cccnc2)c2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.9 %

Procedure:
A suspension of N-(pyrid-3-yl)-4-methoxy dibenzo[b,d]furan-1-carboxamide (50 mg, 0.15 mmol) (example 8) and m-chloroperbenzoic acid (50-55%) (135 mg, 0.78 mmol) in chloroform (10 ml) was stirred at room temperature for 16 h. Chloroform was evaporated and the resulting solid was washed with saturated sodium bicarbonate solution, water, dried and then purified by column chromatography using 20% acetone-chloroform as the eluent to give 15 mg of N-(pyrid-3-yl)-4-methoxy dibenzo[b,d]furan-1-carboxamide-N1-oxide as white solid; mp: 239-241° C.
Reaction SMILES: [N:1]1([C:10](OC(C)(C)C)=O)CCC[CH:3]2[CH2:7][NH:8][CH2:9][CH:2]12.CC1C=CC(S(O[C:28]2[C:29]3[CH2:38][CH2:37][CH2:36][C:35]4[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=4[C:30]=3[N:31]=[CH:32][N:33]=2)(=O)=O)=CC=1.CC1C=CC(S(OC2C3CCCC4C=CC=CC=4C=3N=C(N)N=2)(=O)=O)=CC=1>>[CH3:10][NH:1][C@@H:2]1[CH2:3][CH2:7][N:8]([C:28]2[C:29]3[CH2:38][CH2:37][CH2:36][C:35]4[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=4[C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:9]1
Reactant: Cc1ccc(S(=O)(=O)Oc2ncnc3c2CCCc2ccccc2-3)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC2CNCC21
Agent: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCc2ccccc2-3)cc1
Product: CN[C@@H]1CCN(c2ncnc3c2CCCc2ccccc2-3)C1

Procedure:
The title compound was prepared using the procedure outlined in Example 59D substituting Example 1E for t-butyl octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate, and substituting the product from Example 118C for the product from Example 59C, followed by the procedure outlined in Example 59E. 1H NMR (CD3OD) δ 1.84-1.98 (m, 1H), 2.17-2.27 (m, 1H), 2.28-2.36 (m, 2H), 2.41-2.50 (m, 5H), 2.66 (t, 2H), 3.33-3.40 (m, 1H), 3.52-3.61 (m, 1H), 3.72-3.80 (m, 1H), 3.83-3.93 (m, 2H), 7.27-7.33 (m, 1H), 7.37-7.43 (m, 2H), 7.65-7.71 (m, 1H), 8.40-8.44 (m, 1H). MS (M+H)+ m/z 295.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].I[C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1>C(N(CC)CC)C.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.[Cu]I>[CH3:2][CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]#[C:11][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[CH:8][CH:9]=1)[CH3:3]
Reactant: CC(C)c1ccc(I)cc1
Reactant: C#Cc1ccc(C(C)C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(C#Cc2ccc(C(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87 %

Procedure:
The crude 4-isopropylphenylacetylene was dissolved in triethylamine (100 mL). 4-iodoisopropylbenzene (12.3 g, 50 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.70 g, 1 mmol), and copper(I) iodide (1.5 g) were added. The reaction was stirred at room temperature for 2 days, heated to reflux for 1 hour, cooled, diluted with hexanes, and filtered. The filtrate was evaporated under reduced pressure. The residue was filtered through a pad of silica gel with hexanes, and the solvent was evaporated to give 11.40 g (87%) of 1,2-bis(4-(2-propyl)phenyl)acetylene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:33][CH3:34])[CH:3]=1.[S:35]1[CH:39]=[CH:38][N:37]=[C:36]1[NH2:40].C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:40][C:36]4[S:35][CH:39]=[CH:38][N:37]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: Nc1nccs1
Reactant: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
A vial was charged with perfluorophenyl 1-(4-chloro-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE NNN) (82.4 mg, 0.160 mmol), thiazol-2-amine (17.60 mg, 0.176 mmol), and THF (799 μl) to give a clear, colorless solution. The vial was cooled in an ice-water bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (335 μl, 0.335 mmol) was added drop wise. After 30 min, the mixture was warmed to room temperature and loaded onto a 5-g silica gel loading column with the aid of DCM. The column was dried under vacuum for 5 min then eluted onto a pre-equilibrated 12-g column with 0 to 10% MeOH/DCM to give 1-(4-chloro-2-methoxyphenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (54 mg, 0.125 mmol, 78% yield) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=13.21-11.96 (m, 1H), 8.73-8.62 (m, 1H), 8.52 (d, J=1.8 Hz, 1H), 8.17-8.02 (m, 1H), 7.85 (dd, J=1.9, 8.9 Hz, 1H), 7.75-7.66 (m, 1H), 7.36-7.25 (m, 3H), 7.18 (dd, J=2.0, 8.0 Hz, 1H), 6.85 (d, J=4.6 Hz, 1H), 3.67 (s, 3H); m/z (ESI) 432.2 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:2].C([Sn]([N:24]=[N+:25]=[N-:26])(CCCC)CCCC)CCC.Cl>COCCOC.CO>[NH:24]1[C:1]([CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N:2][N:26]=[N:25]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCOC(=O)CCCC#N
Agent: Cl
Solvent: CO
Solvent: COCCOC
Product: CCOC(=O)CCCc1nnn[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 4-cyanobutyrate (approximately 15 g) was dissolved in DME. Tris(n-butyl)tin azide (5 ml) was added and the reaction solution was heated to 85° overnight then cooled to room temperature. The cooled solution was diluted with methanol (20 ml) then 1N hydrochloric acid (20 ml) was added. The solution was stirred for one hour then partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed by preparatory-scale HPLC (silcia column) eluted with a gradient of 30 to 70% ethyl acetate in hexane plus 1% acetic and to yield 3.39 g of the title product: n.m.r.(300 MHz, CDCl3) δ: 4.2 (q, 2H); 2.95 (t, 2H); 2.5 (t, 2H); 2.1 (t, 2H); 1.3 (t, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([S:37](Cl)(=[O:39])=[O:38])[CH3:36].C(OCC)(=O)C>N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCS(=O)(=O)N(Cc1ccc2ccc(C#N)cc2c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
7-[[4-[(1-t-Butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile obtained in Reference Example 2 (150 mg) was dissolved in 1 ml of pyridine, 211 mg of ethanesulfonyl chloride was added to the solution, and the mixture was stirred at 0° C. for 20 minutes and then at room temperature for 3 hours. Ethyl acetate was added to the reaction solution. The mixture was washed with 10% citric acid aqueous solution and brine in that order, dried over anhydrous sodium sulfate, and then evaporated. The resulting residue was purified by silica gel column chromatography using hexane:ethyl acetate (75:25) as the eluent to give 176 mg of N-[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]phenyl]-N-[(7-cyano-2-naphthyl)methyl]ethanesulfonamide.
Reaction SMILES: [CH:1]1([NH:7][NH:8]C(OC(C)(C)C)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[C:22]([C:23]([N:25]=[C:26]=[O:27])=O)=[C:21]([F:28])[C:20]([CH2:29][NH:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:19][CH:18]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:29][NH:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[C:21]([F:28])[C:22]=1[C:23]1[NH:25][C:26](=[O:27])[N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:8]=1
Reactant: CC(C)(C)OC(=O)NNC1CCCCC1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)N=C=O)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(C3CCCCC3)c(=O)[nH]2)c1F

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(cyclohexyl)hydrazinecarboxylate (Intermediate-64, 0.050 g, 0.23 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate (Intermediate-51, 0.225 g, 0.70 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.015 g of pure product. 1H NMR (400 MHz, DMSO d6): δ 1.13 (s, 9H), 1.22-1.23 (m, 2H), 1.30-1.37 (m, 2H), 1.62-1.64 (m, 2H), 1.78-1.81 (m, 4H), 3.90-3.92 (m, 1H), 4.27-4.28 (d, J=4.8 Hz, 2H), 7.37-7.41 (t, 1H), 7.46-7.48 (d, 1H), 8.17 (br s, 1H); MS (m/z): 409.36 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:24][OH:25])[CH2:4][C:5]1[CH:6]=[C:7]([CH:21]=[CH:22][CH:23]=1)[CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14].[C:26]([O:31][CH3:32])(=[O:30])[C:27]([CH3:29])=O.B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:29][C:27]1([C:26]([O:31][CH3:32])=[O:30])[O:1][CH2:2][CH:3]([CH2:4][C:5]2[CH:23]=[CH:22][CH:21]=[C:7]([CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])[CH:6]=2)[CH2:24][O:25]1
Reactant: COC(=O)C(C)=O
Reactant: Cc1oc(-c2ccccc2)nc1Cc1cccc(CC(CO)CO)c1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)C1(C)OCC(Cc2cccc(Cc3nc(-c4ccccc4)oc3C)c2)CO1
Temperature: 25 °C
Yield: 49.9 %

Procedure:
To 5 ml of acetonitrile, 297 mg of 4-{3-[2,2-bis-(hydroxymethyl)ethyl]benzyl}-5-methyl-2-phenyloxazole and 369 mg of methyl pyruvate were added. To the mixture was added 544 mg of boron trifluoride etherate (about 47%) with stirring at room temperature, and stirred for 14 hours at room temperature. The reaction solution was poured into an ice-cold water solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane: ethyl acetate=3:1) to provide 185 mg of a mixture (cis:trans=2.5:1, based on NMR integral value) as colorless oil.