Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:35]2C=C[CH:38]=[CH:37][CH:36]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11]([NH:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C:26]4=[N:27][C:28]([CH3:32])=[CH:29][C:30]([CH3:31])=[C:25]4[N:24]=[C:23]3[CH2:33][CH3:34])=[CH:18][CH:17]=2)=[O:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1C2C(=CC=CC=2)C=CC=1S(N)(=O)=O>>[CH2:33]([C:23]1[N:22]([C:19]2[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][NH:13][C:11]([NH:10][S:7]([C:4]3[CH:5]=[CH:6][C:1]4[C:2](=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:3]=3)(=[O:8])=[O:9])=[O:12])=[CH:21][CH:20]=2)[C:26]2=[N:27][C:28]([CH3:32])=[CH:29][C:30]([CH3:31])=[C:25]2[N:24]=1)[CH3:34]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(-c3ccccc3)cc2)cc1
Agent: NS(=O)(=O)c1ccc2ccccc2c1
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc3ccccc3c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1 of Example 18) and 2-naphtylsulfonamide.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH2:3][C:4](=[O:6])[OH:5].Cl.[CH3:22]O>>[CH3:22][O:19][C:18](=[O:20])[C@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][C:7](=[O:8])[C@H:2]([CH2:3][C:4](=[O:5])[OH:6])[NH2:1]
Reactant: CO
Reactant: N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O

Procedure:
A solution of 1.86 g. of α-L-aspartyl-L-phenylalanine, 2.9 ml. of 2.6 N hydrochloric acid in methanol and 7.2 ml. of methanol was stirred at 30°C. for 2 hours. The resulting yields, based on the initial charge of α-L-aspartyl-L-phenylalanine, are as follows (by TLC):
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[C:3]#[C:4][CH3:5].[Li]CCCC.CCCCCC.Br[CH2:20][C:21]#[C:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1>C1COCC1>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]#[C:21][CH2:20][CH2:5][C:4]#[C:3][Si:2]([CH3:7])([CH3:6])[CH3:1])=[CH:24][CH:25]=1
Reactant: Fc1ccc(C#CCBr)cc1
Reactant: CC#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCCC#Cc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a solution of trimethyl(prop-1-ynyl)silane (2.19 g, 19.50 mmol) in 22 mL of THF at −78° C., was added dropwise n-BuLi 2.5M in hexane (7.8 mL, 20 mmol). After stirring 2 hours at −78° C., 1-(3-bromoprop-1-ynyl)-4-fluorobenzene (1.40 g, 6.5 mmol) in 6 mL of THF was slowly added and the resulting mixture was stirred for 1 h at −78° C. and warmed to room temperature for an additional 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated to afford 1.57 g of (6-(4-fluorophenyl)hexa-1,5-diynyl)trimethylsilane (99%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH:11]=[C:10]([CH3:15])[CH:9]1C(OCC)=O.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH:11]=[C:10]([CH3:15])[CH2:9]1
Reactant: CCOC(=O)C1C(C)=CC(=O)CC1c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1=CC(=O)CC(c2ccccc2F)C1
Yield: 98.6 %

Procedure:
To 5-(2-fluorophenyl)-3-methyl-4-carbethoxy-2-cyclohexen-1-one (57.3 g, 0.21 mole) was added a solution of sodium hydroxide (11.5 g, 0.29 mole) in 35 ml of ethanol and 80 ml of water. The stirred reaction mixture was heated under reflux for 8 hours. The ethanol was removed by evaporation under reduced pressure, and the residue was extracted with diethyl ether. The ether extract was dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give 5-(2-fluorophenyl)-3-methyl-2-cyclohexen-1-one (42.3 g).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.CCO>[OH-].[OH-].[Pd+2]>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]2[N:18]=[C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[NH:15][CH:16]=2)=[CH:20][CH:21]=1
Reactant: Fc1ccc(-c2c[nH]c(C3CCN(Cc4ccccc4)CC3)n2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Fc1ccc(-c2c[nH]c(C3CCNCC3)n2)cc1

Procedure:
Hydrogenate 1-Benzyl-4-[4-(4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidine in 20% Pd(OH)2/C (Pearlman's catalyst) (0.15 gm) in 125 mL 2B EtOH, at 30° C. for 23 h at 60 PSI. Filter and concentrate to yield the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH2:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[C:22]([Cl:29])[N:21]=1>CO>[Cl:29][C:22]1[N:21]=[C:20]([NH:11][CH:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=3)[CH2:6][CH2:7]2)[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: NC1CCc2ccc(F)cc21
Solvent: CCN(CC)CC
Solvent: CO
Product: O=[N+]([O-])c1ccc(Cl)nc1NC1CCc2ccc(F)cc21
Yield: 52 %

Procedure:
Dissolve 6-fluoroindan-1-ylamine (8.50 g, 56.22 mmol) in methanol (200 mL) and triethylamine (8.62 mL, 61.84 mmol). Add 2,6-dichloro-3-nitropyridine (10.85 g, 56.22 mmol) and stir under nitrogen for 14 hours. Filter the reaction mixture and wash the solids with methanol and hexanes to give the title compound as a yellow solid (9.00 g, 52%). MS (ES) m/z=308 [M+1].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1)([O-])=O.[H][H].ClCCl>[Pd].C(OCC)(=O)C.C(O)(=O)C>[N:17]1([CH2:16][C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(CN2CCOCC2)cc(-c2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1cc(CN2CCOCC2)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Palladium on carbon (10 wt %, 47.8 mg, 0.045 mmol) was added to a solution of 4-[(5-nitrobiphenyl-3-yl)methyl]morpholine in ethyl acetate (4.1 mL) and acetic acid (0.408 mL). The reaction mixture was fitted with a hydrogen balloon and stirred at room temperature for 3 hours. Dichloromethane was added to the reaction mixture, and then filtered through CELITE and washed with dichloromethane. The organic fractions were washed with saturated aqueous NaHCO3, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 5-(morpholin-4-ylmethyl)biphenyl-3-amine which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.58 (t, J=5.9 Hz, 2H), 7.43 (dd, J=9.5, 5.6 Hz, 2H), 7.35 (t, J=7.3 Hz, 1H), 6.97 (s, 1H), 6.83 (s, 1H), 6.71 (s, 1H), 3.92-3.61 (m, 4H), 3.49 (s, 2H), 2.50 (s, 4H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8].[C:14]1([Mg]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.CCOC(C)=O>[C:14]1([CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([O:3][C:2]([F:12])([F:13])[F:1])[CH:5]=2)[OH:8])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cccc(OC(F)(F)F)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
To a solution of 3-(trifluoromethoxy)benzaldehyde (1.30 g, 6.84 mmol) in anhydrous THF (50 mL) was added phenylmagnesium bromide (1.0 M, 17 mL, 17 mmol) dropwise at 0° C. The resulting mixture was stirred at 80° C. for 3 h. The mixture was cooled to room temperature and diluted with EtOAc (100 mL). The organic layer was washed with saturated NH4Cl (50 mL) and brine (50×2 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase Combiflash (50%-55% MeCN in 0.5% NH4HCO3) to give target product (1.36 g, 74%) as a pale yellow oil. LCMS (ESI) m/z: 267.1 [M−H]. 1H-NMR (500 MHz, DMSO-d6): δ 7.44-7.40 (m, 5H), 7.33-7.30 (m, 2H), 7.23-7.18 (m, 2H), 6.13 (d, J=4.0 Hz, 1H), 5.79 (d, J=4.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][C@H:15]([CH3:18])[N:14]3[C:19]([O:21]C(C)(C)C)=O)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:27][O:28][C:29]([NH:31][C@@H:32]([CH:36]([CH3:38])[CH3:37])C(O)=O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O.CN(C=O)C.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][C@H:15]([CH3:18])[N:14]3[C:19](=[O:21])[C@@H:32]([NH:31][C:29](=[O:30])[O:28][CH3:27])[CH:36]([CH3:38])[CH3:37])=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: C[C@H]1CC[C@@H](c2ncc(-c3ccc(Br)cc3)[nH]2)N1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Reaction time: 4 h
Yield: 78.7 %

Procedure:
(2S,5S)-tert-butyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate (562 mg, 1.38 mmol) was dissolved in DCM (8 mL), MeOH (2 mL) and HCl (4 M in dioxane, 2 mL) was added. The reaction mixture was stirred for 4 h and then concentrated under reduced pressure. The crude residue was treated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (241 mg, 1.38 mmol), HATU (525 mg, 1.38 mmol) and DMF (14 mL), then DIPEA (1.2 mL, 6.9 mmol) was added dropwise. After 30 min, the mixture was diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 10% MeOH/EtOAc) to afford methyl (S)-1-((2S,5S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (503 mg, 79%).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>CN(C=O)C>[O:9]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
To a solution of NaH (765 mg, 31.89 mmol) in DMF (10 mL) was added phenol (1 g, 10.63 mmol) at 25° C. The mixture was heated at reflux temperature for 15 min, and then ethyl 2-bromopropanoate (2.3 g, 12.75 mmol) was added. The resulting mixture was stirred at 25° C. for another 16 h before quenching with water (50 mL). The mixture was extracted with ethyll acetate (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound (1.8 g, 85.7%) as colorless oil which was used in next step without further purification.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([C:17]#[C:18][Si](C)(C)C)=[CH:12][CH:13]=2)[CH:8]=1)(C)C.[OH-].[Na+]>C1COCC1>[C:6]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([C:17]#[CH:18])=[CH:12][CH:13]=2)[CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc2ccc(C#C[Si](C)(C)C)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C#Cc1ccc2ccc(C#C)cc2c1
Yield: 98 %

Procedure:
2,7-bis((Trimethylsilyl)ethynyl)naphthalene 2 (0.45 g, 1.39 mmol) was dissolved in THF (80 ml) and aqueous 1M NaOH solution (80 ml) and the mixture stirred for two hours at room temperature. The reaction was extracted with DCM (3×250 ml), dried (MgSO4) and taken to dryness in vacuo. The pale yellow crude solid obtained was purified by flash column chromatography (hexane), to give 2,7-diethynylnaphthalene 3 (0.24 g, quantitative) as an off white solid; Rf 0.56 [5% EtOAc in hexane]; mp: 124-126° C.; δH (CDCl3, 400 MHz) 7.97 (2H, s, 2×ArH), 7.76 (2H, d, J=8.8 Hz, 2×ArH), 7.54 (2H, dd, J1=8.4 Hz, J2=1.6 Hz, 2×ArH), 3.17 (2×HC≡C); δC (CDCl3, 100 MHz) 132.57 (Ar—C), 132.30 (Ar—C), 132.00 (2×Ar—CH), 129.58 (2×Ar—CH), 127.90 (2×Ar—CH), 120.33 (2×Ar—C), 83.57 (2×C≡C), 77.99 (2×HC≡C); HRMS m/z calc. C14H8 [M]+176.0620. found [M+H]+176.0625; anal. CHN calcd. C14H8 C, 95.4%; H, 4.6%. found C, 95.3%; H, 4.3%.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:42])[CH2:7][CH2:8][CH2:9][N:10]([C:16](=[O:41])[C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([O:24][CH2:25][CH2:26][N:27]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[CH:18]=1)[CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)C.Cl>O1CCOCC1>[C:37]([O:36][C:34]([N:27]([C:28]1[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=1)[CH2:26][CH2:25][O:24][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([Cl:23])[CH:20]=1)[C:16]([N:10]([CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]1)[CH2:9][CH2:8][CH2:7][C:6]([OH:42])=[O:5])=[O:41])=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: CCOC(=O)CCCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCC(=O)O)C2CCCC2)c1)c1ccncc1
Yield: 76.8 %

Procedure:
2M Aqueous sodium hydroxide (0.33 ml) was added to a stirred solution of 4-({3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoyl}-cyclopentyl-amino)-butyric acid ethyl ester (0.189 g) in 1,4-dioxan (2 ml). 2M aqueous hydrochloric acid (0.33 ml) was added after 1 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was removed and the organic phase was dried with brine and over sodium sulphate and then concentrated under reduced pressure to give the title compound (0.138 g) as a white foam.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[CH3:26][O:27][C:28]([CH:30]1[CH2:33][NH:32][CH2:31]1)=[O:29].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:32]3[CH2:33][CH:30]([C:28]([O:27][CH3:26])=[O:29])[CH2:31]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: COC(=O)C1CNC1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(C(=O)/C=C\n2cnc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C1
Temperature: -60 °C
Reaction time: 0.75 h
Yield: 23.5 %

Procedure:
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.5 g, 1.0 eq.) was dissolved in DCM (20 mL). The reaction mixture was cooled to −60° C. where methylazetidine-3-carboxylate hydrochloride (0.25 g, 1.2 eq.), T3P (50% in EtOAc) (1.0 mL, 1.2 eq.) followed by DIPEA (0.48 mL, 2 eq.) were added. The clear reaction mixture was stirred at −60° C. for 45 min. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product, which was purified by chromatography (2-3% Methanol in DCM) to give (Z)-methyl 1-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)azetidine-3-carboxylate (0.15 g, 24% yield).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[CH:3]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.O.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>[CH3:20][O:19][C:4]1[CH:3]=[C:2]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=1
Reactant: COc1ccc(-c2nc3cc(OC)cc(Br)c3o2)cc1
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2nc3cc(OC)cc(-c4ccccc4)c3o2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
7-Bromo-5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole (200 mg, 0.60 mmol) and tetrakis(triphenylphosphine)palladium(0) (63 mg, 0.03 mmol) were dissolved in toluene (5 mL) and stirred for 10 min at room temperature under a nitrogen atmosphere. Benzene boronic acid (110 mg, 0.90 mmol) was added, followed by aqueous sodium carbonate (2 M, 1.5 mL) and ethanol (2 mL). The mixture was refluxed for 12 h, diluted with water and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (20%–40% EtOAc/petroleum ether) gave the title compound as a light pink solid, mp 92° C.; MS m/e 332 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11](=[S:31])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].Br.Br[CH2:34][C:35]1[NH:36][CH:37]=[CH:38][N:39]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11]([S:31][CH2:34][C:35]3[NH:36][CH:37]=[CH:38][N:39]=3)=[N:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1
Reactant: BrCc1ncc[nH]1
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(SCc2ncc[nH]2)=NC1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-(4-cyanophenyl)-6-methyl-2-thioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (Example 3; 100 mg, 0.22 mmol), 2-(bromomethyl)-1H-imidazole hydrobromide (64.5 mg, 0.25 mmol), N,N,N-tributyl-1-butanaminium iodide (7 mg, 0.03 mmol) and potassium carbonate (65.2 mg, 0.47 mmol) are dissolved in 3 ml acetone and stirred at room temperature overnight. The solvent is removed by distillation in vacuo and the product is purified via preparative HPLC (RP18-column; eluent: acetonitrile-water, gradient 10:90 to 90:10).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[CH:32][C:33]([O:38][CH3:39])=[C:34]([CH:37]=1)[CH:35]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[C:30]([F:29])[CH:31]=[CH:32][C:33]=3[O:38][CH3:39])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: COc1ccc(F)cc1C=O
Product: COc1ccc(F)cc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 5-fluoro-2-methoxy-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 517.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[NH:29]N.Cl>>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1[N:29]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: Cc1ccc(C)c(NN)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Agent: Cl
Product: Cc1ccc(C)c(-n2nccc2-c2nn(-c3ccccc3)ccc2=O)c1
Yield: 74 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 2,5-dimethyl-phenylhydrazine×HCl according to the method described for Example 1 in 74% yield. MS: M=343.2 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]2[O:18][C:17](=[O:19])[CH2:16][C@@H:15]([CH:20]=[CH2:21])[CH2:14]2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>CO.C1COCC1.O.C1COCC1.CCOC(C)=O.CCCCCC>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]2[O:18][C:17](=[O:19])[CH2:16][C@@H:15]([CH:20]=[CH2:21])[CH2:14]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: C=C[C@@H]1CC(=O)O[C@@H](CCCCc2ccc(C#N)cc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: C=C[C@@H]1CC(=O)O[C@H](CCCCc2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.7 %

Procedure:
To a solution of the product of step B (1.52 g, 5.47 mmol) in 15 mL of MeOH:THF (2:1) was added 1H NaOH (5.9 mL, 5.9 mmol) and the reaction stirred at room temperature for 1.5 hours. The reaction was diluted with water and washed with Et2O. The aqueous phase was acidified with 1H NaHSO4, extracted with EtOAc, dried (MgSO4), filtered and evaporated under reduced pressure. The residue and Ph3P (1.86 g, 7.11 mmol) was immediately dissolved in dry THF (20 mL) and cooled to -40° C. Neat diethyl azodicarboxylate (1.27 g, 7.42 mmol) was added dropwise via syringe and the solution stirred at -40° C. for 3 hours. Concentration of the solvent under reduced pressure and silica gel chromatography (EtOAc:hexane 4:6) of the residue afforded 1.05 g (69%) of the title product as a colorless oil. NMR spectrum analysis indicated the product was contaminated with ~10% of the trans isomer. 1H-NMR (300 MHz, CDCl3) δ1.25-1.80 (m, 7H), 1.90-2.00 (m, 1H), 2.24 (dd, J=11 Hz, J=17 Hz, 1H), 2.55-2.79 (m, 4H), 4.30 (m, 1H) 5.02-5.14 (m, 2H), 5.66-5.80 (m, 1H), 7.27 (d, J=8 Hz, 2H), 7.57 (d, J=8 Hz, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.O>CO>[CH:12]1([NH:15][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:14][CH2:13]1
Reactant: ClCCCOc1cccnc1
Reactant: NC1CC1
Solvent: O
Solvent: CO
Product: c1cncc(OCCCNC2CC2)c1
Temperature: 120 °C
Yield: 29.3 %

Procedure:
An Ace Glass pressure tube (185 mL) was charged with 3-chloro-1-(3-pyridyloxy)propane (0.762 g, 4.437 mmol), cyclopropylamine (8.24 g, 194.3 mmol), water (20 mL) and methanol (20 mL). The resulting light-brown solution was heated at 120° C. (oil bath temperature) for 2.5 h and allowed to cool to ambient temperature over 16 h. The solution was concentrated by rotary evaporation to an oily residue that was diluted with saturated NaCl solution (25 mL). The mixture was acidified to pH 1.0 with 10% HCl solution and extracted with CHCl3 (2×35 mL) to remove impurities. The aqueous phase was basified to pH 6 with 10% NaOH solution and extracted (4×25 mL) to remove other impurities. The aqueous phase was basified to pH 10 with 10% NaOH solution and extracted with CHCl3 (4×50 mL). The combined CHCl3 extracts were dried (Na2SO4), filtered, concentrated (rotary evaporator) and briefly dried under high vacuum to give 0.250 g of a brown oil. The oil was purified by column chromatography on silica gel (20 g) eluting with CHCl3—CH3OH (100:2) to remove impurities, followed by CHCl3—CH3OH-Et3N (50:50:2) to remove the product. Selected fractions were combined to give 220 mg (25.8%) of a brown semi-solid.