Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)N[C@H]1C[C@H](NC2SC3C=CC=CC=3N=2)C1)(C)(C)C.Cl.Cl.[NH2:25][C@H:26]1[CH2:29][C@H:28]([N:30]2[C:34]3=[N:35][CH:36]=[CH:37][CH:38]=[C:33]3[N:32]([CH3:39])[C:31]2=[O:40])[CH2:27]1.C(N(C(C)C)CC)(C)C.Cl[C:51]1[O:52][C:53]2[CH:59]=[CH:58][CH:57]=[CH:56][C:54]=2[N:55]=1>CN(C)C1C=CN=CC=1.CS(C)=O>[O:52]1[C:53]2[CH:59]=[CH:58][CH:57]=[CH:56][C:54]=2[N:55]=[C:51]1[NH:25][C@H:26]1[CH2:29][C@H:28]([N:30]2[C:34]3=[N:35][CH:36]=[CH:37][CH:38]=[C:33]3[N:32]([CH3:39])[C:31]2=[O:40])[CH2:27]1
Reactant: Clc1nc2ccccc2o1
Reactant: Cn1c(=O)n([C@H]2C[C@H](N)C2)c2ncccc21
Agent: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cn1c(=O)n([C@H]2C[C@H](Nc3nc4ccccc4o3)C2)c2ncccc21

Procedure:
The title compound was synthesized following the procedure described for INTERMEDIATE 10, using 3-(trans-3-aminocyclobutyl)-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one dihydrochloride (0.146 g, 0.501 mmol), diisopropylethylamine (1 ml, 5.75 mmol), 4-dimethylaminopyridine (6.13 mg, 0.050 mmol), and 2-chlorobenzoxazole (0.057 ml, 0.501 mmol) in DMSO (0.5 mL) to afford 3-(trans-3-(benzo[d]oxazol-2-ylamino)cyclobutyl)-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.102 g, 0.304 mmol, 60.7% yield). m/z: 336.2 (M+1); 1H NMR (400 MHz, DMSO-dh) δ: ppm 8.44 (d, J=5.87 Hz, 1 H), 8.04 (d, J=4.69 Hz, 1 H), 7.50 (d, J=7.43 Hz, 1 H), 7.37 (d, J=7.82 Hz, 1 H), 7.28 (d, J=7.63 Hz, 1 H), 7.05-7.19 (m, 2 H), 6.92-7.03 (m, 1 H), 5.26 (t, J=8.22 Hz, 1 H), 4.53 (br. s., 1 H), 3.23-3.46 (m, 5 H), 2.38-2.61 (m, 2 H).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)=[O:28])=[CH:22][CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:37]#[N:38])C1C=CC=CC=1.C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O>[C:37]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[OH:8])[N:16]=[CH:15][CH:14]=[C:13]2[O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)=[O:28])=[CH:24][CH:25]=1)#[N:38]
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccnc2cc1O
Temperature: 60 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
After dissolving N-(4-(7-(benzyloxy)-6-cyano-4-quinolyl)oxyphenyl)-N′-(4-fluorophenyl)urea (6.20 g, 12.3 mmol) in trifluoroacetic acid (60 ml) and thioanisole (3.6 ml, 30.7 mmol) under a nitrogen atmosphere, the solution was stirred at 60° C. overnight. The reaction solution was concentrated under reduced pressure, and after adding water (100 ml) to the obtained residue, sodium bicarbonate was added to neutralization, diethylether (200 ml) was added, the mixture was stirred, and the precipitated crystals were filtered out, washed with water and diethyl ether and dried at 70° C. to obtain the title compound (4.816 g, 11.6 mmol, 94.8%) as yellow crystals.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[CH:9]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH3:10][CH:9]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[N:14]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1)[CH3:11]
Reactant: ClCCNCCCl
Reactant: CC(C)c1ccccc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CC(C)c1ccccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 30.1 %

Procedure:
A mixture of bis(2-chloroethyl)amine hydrochloride (19.78 g, 0.111 mole) and 200 mL of n-butanol was treated dropwise with 2-isopropylaniline (15.0 g, 0.111 mole) and the resulting mixture was stirred for 48 hr at reflux under an argon atmosphere. After cooling to room temperature, anhydrous sodium carbonate (5.86 g, 0.555 mole) was added and the reaction mixture was stirred for another 24 hr at reflux. The reaction was cooled in ice and a white precipitate was filtered off. This material was mixed thoroughly in methylene chloride and 3N sodium hydroxide until the aqueous layer was basic. The methylene chloride layer was separated, dried over anhydrous potassium carbonate, filtered and evaporated affording 6.82 g of 1-[2-(methylethyl)phenyl]piperazine as an oil. The fumarate acid salt was prepared from isopropanol/methanol and recrystallized from methanol to give a white crystalline solid, mp 188-189° C. (Ho).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:9]=1[CH:10]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([OH:32])(=[O:31])[CH2:21]NC(C1C=CC=CC=1)=O.C([O-])(=O)C.[Na+].S(=O)(=O)(O)O>C(OC(=O)C)(=O)C.O>[F:17][C:16]([F:19])([F:18])[C:14]1[CH:13]=[CH:12][C:9]2[CH:10]=[C:21]([C:20]([OH:32])=[O:31])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[O:1][C:8]=2[CH:15]=1
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1Oc1ccccc1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)C1=Cc2ccc(C(F)(F)F)cc2Oc2ccccc21
Temperature: 85 °C
Yield: 65 %

Procedure:
A mixture of 10.0 g (37.59 mmol) of 2-phenoxy-4-trifluoromethyl-benzaldehyde, 10.09 g (56.40 mmol) of hippuric acid and 3.70 g (45.10 mmol) of sodium acetate in 38 ml of acetic anhydride is heated at 85° C. for 80 minutes, then cooled to 32° C. 19 ml of water are added and the mixture is heated at 65° C. for 30 minutes. After cooling the mixture to approximately 5° C., 19 ml of concentrated sulfuric acid are added dropwise and the mixture is then heated under reflux (bath: 140° C.) for 2 hours. The brown precipitate that forms on cooling is filtered and washed with 50% acetic acid, washed with water until neutral and dried to yield 7.42 g (24.23 mmol)=65% of 3-trifluoromethyl-dibenz[b,f]oxepine-10-carboxylic acid in the form of beige crystals; melting point: 180° C.; 1H-NMR (CDCl3, 200 MHz): 7.2-7.65 (m, 8H) 8.09 (s, 1H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][C:11]([N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[CH:12][CH:13]=3)[C:8]2=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:23]([O:25][C:26](Cl)=[O:27])[CH3:24]>>[CH:1]1([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][C:11]([N:16]4[CH2:17][CH2:18][N:19]([C:26]([O:25][CH2:23][CH3:24])=[O:27])[CH2:20][CH2:21]4)=[CH:12][CH:13]=3)[C:8]2=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1c2cc(N3CCNCC3)ccc2CN1C1CCCCC1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCN(c2ccc3c(c2)C(=O)N(C2CCCCC2)C3)CC1

Procedure:
In the same manner as in Example 28, the title compound was prepared from the compound obtained in step (e) of Example 1 and ethoxycarbonyl chloride.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1O[C@H]1CCl.[CH:26]1([C:32]2C=C[C:35]([OH:38])=[CH:34][CH:33]=2)CCCC[CH2:27]1.C(OC)(=O)C#CCCC>C(O)C>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:35](=[O:38])[CH:34]=[C:33]([CH2:32][CH2:26][CH3:27])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Reactant: Oc1ccc(C2CCCCC2)cc1
Agent: CCCC#CC(=O)OC
Agent: ClC[C@H]1CO1
Solvent: CCO
Product: CCCc1cc(=O)nc2n1C[C@@H](COc1ccc(C3CCCCC3)cc1)O2
Temperature: 25 °C
Yield: 27 %

Procedure:
(S)-5-(4-Cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.37 g, 1.35 mmol), prepared in accordance with the procedures in Steps 1 and 2 of Example 1 and starting from R-epichlorohydrin and 4-cyclohexylphenol, was dissolved in ethanol (6 mL). Methyl 2-hexynoate (0.34 g, 2.70 mmol) was then added and the reaction mixture was heated at reflux for 24 hrs and then cooled to room temperature. The resulting crystalline solid was isolated by filtration, washed with heptane 3 times, and dried under vacuum to afford 135 mg (27% yield) of (S)-2-(4-cyclohexyl-phenoxymethyl)-5-propyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[C:4]2[CH:15]=[C:14]([S:16][CH3:17])[CH:13]=[CH:12][C:5]=2[S:6][C:7]=1[C:8](OC)=[O:9].[NH2-:19].[Li+]>>[CH3:1][N:2]([CH3:18])[C:3]1[C:4]2[CH:15]=[C:14]([S:16][CH3:17])[CH:13]=[CH:12][C:5]=2[S:6][C:7]=1[C:8]([NH2:19])=[O:9]
Reactant: COC(=O)c1sc2ccc(SC)cc2c1N(C)C
Reactant: [NH2-]
Agent: [Li+]
Product: CSc1ccc2sc(C(N)=O)c(N(C)C)c2c1
Yield: 64 %

Procedure:
Prepared from methyl 3-dimethylamino-5-(methylthio)benzo[b]thiophene-2-carboxylate by reaction with lithium amide as described in Example 19. Purification of the crude product by flash chromatography (silica gel, elution with 30% ethyl acetate in hexane) gives 64% of product; mp=140°-142° C.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].CCN(C(C)C)C(C)C.[C:15]([SiH2:19][O:20][C:21]([CH3:32])([CH3:31])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:25][NH2:26])([CH3:18])([CH3:17])[CH3:16]>C(Cl)Cl>[C:15]([SiH2:19][O:20][C:21]([CH3:32])([CH3:31])[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:25][NH:26][C:1](=[O:4])[CH2:2][CH3:3])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CN)ccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)NCc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
Propionyl chloride (2.02 mL, 23.1 mmol) and DIPEA (14.4 mL, 84.0 mL) were added to a sol. of 3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzylamine (6.00 g, 20.9 mmol) in CH2Cl2 (195 mL). The mixture was stirred for 15 min at rt, and more CH2Cl2 was added. The mixture was washed with aq. sat. NH4Cl (2×), with aq. 1M NaOH (1×) and with brine (1×). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:9→3:2) yielded the title compound (5.08 g, 71%). LC-MS: tR=1.09 min; ES+: 383.41.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21](O)=O)[C:9]=2[CH3:24])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:32][C:33]([CH3:38])([CH3:37])[C:34]([NH2:36])=[O:35].C(N(CC)CC)C.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1.C1COCC1.ClCCl.O.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[NH:36][C:34](=[O:35])[C:33]([CH3:38])([CH3:37])[N:32]=3)[C:9]=2[CH3:24])=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: CC(C)(N)C(N)=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1c(C2=NC(C)(C)C(=O)N2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
To a solution of 4a (1.01 g, 2.62 mmol) in toluene (30 mL) at 0° C. were sequentially added DMF (0.2 mL) and oxalyl chloride (1.48 g, 11.66 mmol) dropwise. The mixture was allowed to warm to room temperature and stirred for 2 h, then transferred slowly to a mixture of 5i (0.56 g, 4.07 mmol) and triethylamine (0.42 g, 4.20 mmol) in THF (120 mL) at 0° C. After the mixture was warmed and stirred at room temperature for 15 h, water was added and the resulting mixture was extracted with ethyl acetate (2×30 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude amide (1.02 g) thus obtained was treated with a solution of POCl3 (1.25 g, 8.15 mmol) in dichloromethane (25 mL) at 80° C. for 4 h. The mixture was concentrated and poured into ice water. The resulting mixture was extracted with ethyl acetate (2×50 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with ethyl acetate/hexanes (7:3) afforded 23 (0.62 g, 53%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.43 (br s, 1H), 7.32˜7.27 (m, 4H), 7.05 (d, 2H), 7.00 (br s, 1H), 2.38 (s, 3H), 1.81 (s, 6H); ESMS m/z: 447.0 (M+1).
Reaction SMILES: II.[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)(=[O:5])[CH3:4].C(COC)OC.CC([C@H]1N=C(C2C=CC=C(C3OC[C@@H](C(C)C)N=3)N=2)OC1)C.CC([C@@H]1N=C(C2C=CC=C(C3OC[C@H](C(C)C)N=3)N=2)OC1)C.I[CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][O:76][CH:77]1[CH2:82][CH2:81][CH2:80][CH2:79][O:78]1>CN1C(=O)N(C)CC1.C1COCC1.[Zn].Cl[Ni]Cl>[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][O:76][CH:77]1[CH2:82][CH2:81][CH2:80][CH2:79][O:78]1)(=[O:5])[CH3:4]
Reactant: ICCCCCCOC1CCCCO1
Reactant: CC(=O)OCCCCCCCCCCCBr
Agent: Cl[Ni]Cl
Agent: CC(C)[C@@H]1COC(c2cccc(C3=N[C@H](C(C)C)CO3)n2)=N1
Agent: CC(C)[C@H]1COC(c2cccc(C3=N[C@@H](C(C)C)CO3)n2)=N1
Solvent: C1CCOC1
Solvent: COCCOC
Solvent: CN1CCN(C)C1=O
Product: CC(=O)OCCCCCCCCCCCCCCCCCOC1CCCCO1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
In a 10-ml Schlenk tube, zinc powder (98 mg, 1.5 mmol) was dried at 70° C. under high vacuum for 30 min. After back-filling with nitrogen, DMI (1 ml) and iodine (13 mg, 0.05 mmol) were added. The mixture was stirred until disappearance of the iodine color, after which neat 11-bromoundecyl acetate (293 mg, 1 mmol) was added. The tube was sealed, and the mixture was stirred at 70° C. for 12 h, cooled to the room temperature and zinc excess was allowed to settle. In a 5-ml flask, NiCl2.glyme (17 mg, 0.08 mmol) and (R)-(i-Pr)-Pybox (or (S)-(i-Pr)-Pybox) (30 mg, 0.1 mmol) were dissolved in DMI (1 ml) and THF (0.3 ml), then neat I(CH2)6OTHP 38 (240 mg, 0.77 mmol) was added followed by addition of the organozinc solution 33 via cannula. Reaction mixture was stirred at room temperature for 14 h, quenched with NH4Cl and extracted with EtOAc. Extract was dried over Na2SO4 and concentrated by solvent evaporation. Chromatography in hexane-ethyl ether (15:1, 10:1) gave the product, 212 mg (69%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[C:4]([N:14]2[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]2)[CH:3]=1.[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[C:23]([NH2:28])[N:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[Cl:20][C:21]1[CH:26]=[C:25]([O:13][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[N:14]2[CH:18]=[CH:17][C:16]([CH3:19])=[N:15]2)[C:9]([F:12])([F:11])[F:10])[N:24]=[C:23]([NH2:28])[N:22]=1
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](O)C(F)(F)F)n1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(Cl)nc(N)n2)C(F)(F)F)n1
Temperature: 80 °C

Procedure:
To a solution of (1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethanol (40 g, 138 mmol) in dioxane (400 mL) was added 4,6-dichloropyrimidin-2-amine (113 g, 690 mmol) and Cs2CO3 (132 g, 405 mmol). The mixture was heated for 24 h at 80° C. The reaction was then cooled to RT and filtered. The solvent was removed in vacuo, then CH2Cl2 and heptane was added. The solvent volume was reduced until a solid precipitated out. The solid was filtered and the procedure repeated several times to provide 4-chloro-6-[(1R)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethoxy]pyrimidin-2-amine as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]([NH2:30])[CH:27]([CH3:29])[CH3:28].C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:30][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CC(C)CN
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)CNC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), isobutylamine (0.240 g, 3.28 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-isobutyl-3,4,5,6-tetrahydrophthalamide as white crystals (0.936 g, 77.8% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][C:25]4[CH2:26][NH:27][CH:28]([CH3:32])[CH2:29][C:30]=4[N:31]=3)=[O:22])[CH:17]([C:33](O)=[O:34])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[O:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[O:42][NH2:43].O.ON1C2C=CC=CC=2N=N1.Cl.CN(CCCN=C=NCC)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][C:25]4[CH2:26][NH:27][CH:28]([CH3:32])[CH2:29][C:30]=4[N:31]=3)=[O:22])[CH:17]([C:33](=[O:34])[NH:43][O:42][CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][O:36]3)[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: NOC1CCCCO1
Reactant: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3C(=O)O)sc2CN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3C(=O)NOC3CCCCO3)sc2CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In N,N-dimethylformamide (20 ml), 4-[(6-chloronaphthalen-2-yl)sulfonyl]-1-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine-2-carboxylic acid (141 mg), 2-tetrahydropyranyloxyamine (180 mg), 1-hydroxybenzotriazole monohydrate (11 mg), 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (145 mg) and potassium carbonate (129 mg) were dissolved, followed by stirring overnight at room temperature. The reaction mixture was concentrated under reduced pressure. Dichloromethane was added to the residue, followed by washing with water. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (Φ0.7×25.0 cm, dichloromethane:methanol=100:3), whereby the title compound (308 mg) was obtained as a colorless foam.
Reaction SMILES: [CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH:4]=[CH2:5].C(Cl)(=O)C(Cl)=O.[CH3:21][C:22]([CH3:25])([O-])[CH3:23].[Li+]>C1C=CC=CC=1.O1CCCC1>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][C:22]([CH3:25])([CH3:23])[CH3:21])=[O:11])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCCc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: C=CCCCc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(4-pentenyl)benzoic acid (42 g, 0.22 mol) in benzene (250 ml) was added dropwise to a solution of oxalyl chloride (60 ml) in benzene (200 ml) over 1 hour. The solution was stirred for 1 hour at room temperature and then heated under reflux for 2 hours. The solvent and excess oxalyl chloride was evaporated off under reduced pressure to give an oily residue which was dissolved in dry tetrahydrofuran (250 ml) and added dropwise over 1 hour to a stirred solution of lithium t-butoxide [prepared from t-butanol (21 g, 0.283 mol) in dry tetrahydrofuran (200 ml) at -20° C. and n-butyl lithium (114 ml of 2.5M solution in hexane, 0.285 mol)]. The resulting mixture was allowed to warm up to room temperture and stirred for an additional 12 hours. The solvent was evaporated off under reduced pressure and the residue was treated with water (500 ml) and extracted with chloroform (3×500 ml). The combined extracts were dried over sodium sulfate and the solvent was evaporated off under reduced pressure to yield crude 1,1-dimethylethyl 4-(4-pentenyl)benzoate as an oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH:13]=O.[Li+].[OH-:16]>C1COCC1.CCOCC>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH:13]=[CH:7][C:5]([O:6][CH2:2][CH3:1])=[O:16]
Reactant: Cc1oc(-c2ccccc2)nc1C=O
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C=Cc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
5-Methyl-2-phenyloxazole-4-carbaldehyde [Hulin, et al., J. Med. Chem. (1992) 35(10), 1853-64] (5.62 g, 30 mmol), triethylphosphonoacetate (6.55 mL, 33 mmol), and LiOH (1.38 g, 33 mmol) were dissolved in anhydrous THF (150 mL) and stirred for 18 h at ambient temperature under an atmosphere of nitrogen. The reaction mixture was then diluted with ether (100 mL) and washed with saturated NH4Cl solution (100 mL), then water (100 mL). The aqueous layers were back-extracted with ether (100 mL) and the combined organic layers were again washed with water (100 mL). The ether layer was dried over MgSO4 and concentrated. The resultant residual solids were purified by column chromatography (250 mg silica, 100% hexanes to 10% EtOAc/hexanes) to provide a white crystalline solid (3.46 g, 45%): Rf=0.55 (50% hexanes/EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.97-8.05 (m, 2H), 7.50 (d, 1H), 7.40-7.44 (m, 3H), 6.63 (d, 2H) 4.26 (q, 2H), 2.43 (s, 3H), 1.33 (t, 3H); MS(EI): 258 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([OH:10])[CH:9]=1)=[O:4].[C:11](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[C:8]([OH:10])[CH:9]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)n[nH]1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(O)nn1C
Reaction time: 2.5 h
Yield: 17.4 %

Procedure:
To a solution of 5-hydroxy-2H-pyrazole-3-carboxylic acid methyl ester (2.3 g, 16 mmol) in DMF (10 mL) at room temperature was added cesium carbonate (5.27 g, 16 mmol) and methyl iodide (2.3 g, 1.0 mL, 16 mmol) and the resulting mixture stirred for 2.5 h. The mixture was then filtered off to afford the title compound (434 mg, 17%) as a white solid after trituration with ethyl acetate. MS: m/e=157.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.CN(C=O)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:31]=[C:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[CH3:33]>>[CH3:41][O:40][C:37]1[CH:38]=[CH:39][C:34](/[C:32](/[CH3:33])=[CH:31]/[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:16])=[CH:11][C:12]=3[C:13]3[CH2:14][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][C:5]2=3)=[CH:35][CH:36]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: COc1ccc(C(C)=CBr)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(/C(C)=C/n2c3c(c4cc(C)ccc42)CCN(C)CC3)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (78 mg, 0.36 mmol) was dissolved in DMF (5 mL) Copper (I) iodide (7 mg, 0.036 mmol) L-proline (8 mg, 0.073 mmol) and K3PO4 (156 mg, 0.734 mmol) were added and the reaction mixture was stirred for 10 min at RT. 1-(1-Bromoprop-1-en-2-yl)-4-methoxybenzene (100 mg, 0.44 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 80° C. for overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). 1HNMR (DMSO-d6 , Oxalate salt) δ (ppm): 7.62 (d, 2H), 7.30 (s, 1H), 7.0 (m, 4H), 6.95 (d, 1H), 3.80 (s, 3H), 3.40 (m, 4H), 3.10 (m, 4H), 2.80 (s, 3H), 2.40 (s, 3H), 1.82 (s, 3H).