Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:4]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[CH2:10][CH2:11][N:12]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:13][CH2:14]2)[CH:4]=1
Reactant: Clc1ccnc(N2CCNCC2)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N1CCN(c2cc(Cl)ccn2)CC1

Procedure:
Stir 1-(4-chloro-pyridin-2-yl)-piperazine hydrochloride (2.2 mmol, 0.4 g), triethylamine (7.6 mmol, 1.1 mL) in 13 mL of CH2Cl2 and pivaloyl chloride (2.2 mmol, 0.3 mL) overnight at room temperature. Add CH2Cl2 and wash with saturated aq. sodium chloride and water. Dry over sodium sulfate, filter, and concentrate under reduced pressure to give 1-[4-(4-chloro-pyridin-2-yl)-piperazin-1-yl]-2,2-dimethyl-propan-1-one. MS(ES): m/z=282 [M+H].
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19]2.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([C:10]([NH:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:19]4)=[O:12])=[CH:13][CH:14]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(OCC2CC2)cc1
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(NC(=O)c3ccc(OCC4CC4)cc3)ccc2[nH]1
Yield: 72.3 %

Procedure:
A solution of 4-(cyclopropylmethoxy)benzoic acid (576 mg), ethyl 5-amino-1H-indole-2-carboxylate (612 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (690 mg), 1-hydroxybenzotriazole (551 mg) and N,N-dimethylaminopyridine (367 mg) in DMF (20 mL) was stirred at room temperature for 2 hr. The reaction solution was extracted with ethyl acetate, washed with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue (brown solid) was washed with a small amount of ethyl acetate to give the title compound (820 mg, yield 72%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:23])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)[N:13]=2)[CH:8]=1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>C1COCC1>[Cl:23][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:8][C:7]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)[N:13]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(F)c(Cl)c3)c(=O)[nH]2)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(F)c(Cl)c3)c(=O)[nH]2)c1
Yield: 13.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chlorophenyl)-2-(3-chloro-4-fluorophenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-92, 0.300 g, 0.852 mmol), pivaloyl chloride (0.108 g, 0.852 mmol), DIPEA (2.0 mL), dry THF (10 mL) to afford 0.050 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.13 (s, 9H), 4.29 (d, J=5.4 Hz, 2H), 7.40 (d, J=7.8 Hz, H-0, 7.52-7.59 (m, 3H), 7.91-8.18 (m, 3H), 12.65 (s, 11-0; MS (m/z): 437.23 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][C:4]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=1)=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[N:13]2)=[CH:8][CH:7]=1.[OH-].[Na+]>CO.O1CCCC1>[CH3:1][CH:2]([CH3:31])[CH2:3][C:4]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=1)=[CH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH:16]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:14]=[N:13]2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(C(=Cc2ccc(-n3cc(C(F)(F)F)cn3)cc2)CC(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CC(=Cc1ccc(-n2cc(C(F)(F)F)cn2)cc1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 96 %

Procedure:
Methyl 4-(4-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pent-1-en-2-yl)benzoate (19.8 mg, 0.0460 mmol) was dissolved in methanol (0.5 mL) and tetrahydrofuran (0.5 mL). 1 N Sodium hydroxide (0.092 mL) was added and the reaction was stirred at room temperature for 60 hours. The reaction was concentrated. The crude residue was taken up in water and acidified to pH=2 with 1N HCl. This solution was extracted four times with ethyl acetate, dried over magnesium sulfate, filtered, and concentrated to provide 4-(4-methyl-1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)pent-1-en-2-yl)benzoic acid (18.3 mg, 96%) as an approximate 1:1 mixture of E/Z isomers. 1H NMR (400 MHz, CD3OD, δ): 8.76 (s, 1H), 8.62 (s, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.98 (s, 1H), 7.97-7.93 (m, 2H), 7.90 (s, 1H), 7.85-7.79 (m, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.54-7.47 (m, 4H), 7.30-7.24 (m, 2H), 7.06-7.00 (m, 2H), 6.84 (s, 1H), 6.56 (s, 1H), 2.70 (d, J=7.2 Hz, 2H), 2.46 (dd, J=7.2, 1.0 Hz, 2H), 1.63 (dt, J=13.5, 6.7 Hz, 1H), 1.57-1.46 (m, 1H), 0.92 (d, J=6.6 Hz, 6H), 0.80 (d, J=6.6 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=Cc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-fluorophenol (4.52 g, 40.29 mmol), 4-fluorobenzaldehyde (5.00 g, 40.29 mmol) and potassium carbonate (6.70 g, 48.35 mmol) in DMAC (40 mL) was refluxed for 12 h and cooled to room temperature. Water was added and the reaction mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated to afford an oil which was chromatographed on silica gel (15% ethyl acetate/hexane) to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[CH:2].[C:10]1([CH3:19])[CH:15]=[CH:14][CH:13]=[C:12]([N:16]=[C:17]=[O:18])[CH:11]=1>C1COCC1>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:17]([NH:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH3:19])[CH:11]=2)=[O:18])=[CH:5][CH:4]=1)#[CH:2]
Reactant: Cc1cccc(N=C=O)c1
Reactant: C#Cc1ccc(N)cc1
Solvent: C1CCOC1
Product: C#Cc1ccc(NC(=O)Nc2cccc(C)c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-ethynylaniline (1.308 g, 11.18 mmol, 1 eq) in anhydrous THF (20 mL) under nitrogen atmosphere at room temperature was added dropwise m-tolyl isocyanate (1.684 mL, 1.2 eq). The yellow reaction solution was stirred at room temperature for 3 hours. The reaction was then partitioned between EtOAc and aq NH4Cl. The organic layer was isolated, washed with saturated aq NaHCO3, brine, and dried with anhydrous sodium sulfate. The upper solvent layer was decanted and concentrated. The resulting solid residue was chromatographed initially with EtOAc-Hex from 1:100 to 1:4 and then continued with an eluent from dichloromethane to MeOH-DCM 1:10. The product fractions were collected, concentrated, and the white solid was triturated with EtOAc-Hex (2:1) at room temperature for 18 h. Upon filtration, 1-(4-ethynylphenyl)-3-(3-methylphenyl)urea was obtained as white solid in amount of 2.134 g.
Reaction SMILES: [C:1]1([C:7]2([CH2:17][CH:18]([CH3:20])[CH3:19])[C:11]3[CH2:12][NH:13][CH2:14][CH2:15][C:10]=3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]([CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[C:22]=[S:23]>ClCCl>[CH2:17]([C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]2[CH2:12][N:13]([C:22](=[S:23])[NH:21][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:14][CH2:15][C:10]=2[C:9](=[O:16])[O:8]1)[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CNCC2
Reactant: S=C=NCCN1CCCCC1
Solvent: ClCCl
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=S)NCCN1CCCCC1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
A mixture of 3-phenyl-3-isobutyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (50 mg, 0.18 mmol) and 1-(isothiocyanatoethyl)piperidine (45.7 mg, 0.28 mmol) in dichloromethane (5 mL) was stirred at room temperature for 1 h. The solvent was removed and the resulting residue was purified on silica to give the desired product (52 mg, 64.0%). 1H NMR (300 Hz, CDCl3) δ 0.87 (t, J=6.0, 3H), 0.96 (t, d=6.0, 3H), 1.40-1.63 (m, 6H), 1.63-1.75 (m, 1H), 1.78-1.90 (m, 1H), 2.30-2.60 (m, 10H), 2.58-2.70 (m, 3H), 3.83-3.95 (m, 1H), 4.26 (d, J=18.0, 1H), 5.17 (d, J=18.0, 1H), 7.02 (br s, 1H), 7.26-7.40 (m, 5H).
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:16]([C:18]1([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:19]1=[O:25])[CH3:17].[F-].[K+].C1OCCOCCOCCOCCOCCOC1>CC#N>[CH2:16]([C:18]1([C:26]2[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=2)[O:32][C:2]2[CH:9]=[C:8]([CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)[CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:19]1=[O:25])[CH3:17]
Reactant: CCC1(c2cccc(O)c2)CCCCNC1=O
Reactant: N#Cc1ccc(Cn2ccnc2)cc1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: CCC1(c2cccc(Oc3cc(Cn4ccnc4)ccc3C#N)c2)CCCCNC1=O

Procedure:
2-Fluoro-4-imidazol-1-ylmethyl-benzonitrile (as described in Example 1, Step E) (0.065 g, 0.325 mmol), 3-ethyl-3-(3-hydroxy-phenyl)-azepan-2-one (as described in Step B above) (0.076 g, 0.325 mmol), KF.Al2O3 (0.091 g) and 18-Crown-6 (0.008 g, 0.030 mmol) were refluxed in CH3CN (8 mL) under Ar for 72 h. The solution was filtered, concentrated in vacuo, and purified using SiO2 chromatography (0.5-3.0% MeOH/CH2Cl2). The compound was treated with 1N HCl ethereal solution to give the title compound.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:3]=1.[CH2:16]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17]#[CH:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.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)I>[O:19]([CH2:16][C:17]#[C:18][C:2]1[S:6][CH:5]=[C:4]([C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[CH:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C#CCOc1ccccc1
Reactant: O=C(Oc1ccccc1)c1csc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Oc1ccccc1)c1csc(C#CCOc2ccccc2)c1
Temperature: 120 °C
Reaction time: 0.42 h

Procedure:
A mixture of phenyl 5-bromothiophene-3-carboxylate, Example 113 (100 mg, 0.35 mmol), (prop-2-ynyloxy)benzene (93 mg, 0.71 mmol), triphenylphosphine (19 mg, 0.071 mmol), dichlorobis(triphenylphosphine)palladium(II) (12 mg, 0.018 mmol), copper iodide (1 mg, 0.006 mmol) and triethylamine (0.74 mL, 5.30 mmol) in N,N-dimethylformamide (1 mL) was stirred under nitrogen in a heavy walled process vial in a microwave synthesizer at about 120° C. for about 25 minutes. The reaction mixture was concentrated under vacuum and the residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate (2:1) as the mobile phase to provide the desired product. MS (DCI-NH3): m/z 352 (M+NH4)+.
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH:19]=[O:20])[CH2:14][CH2:13][CH2:12][CH2:11]1.OS(O)(=O)=O>C(OCC)C>[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([CH:19]([OH:20])[CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: BrCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: COc1ccc(C(O)Cc2ccccc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a magnetically-stirred solution of freshly crushed magnesium turnings (36.54 mmol, 0.888 g) in anhydrous ethyl ether (20 mL) at room temperature is added a solution of benzyl bromide (36.54 mmol, 4.35 mL) in anhydrous ethyl ether (15 mL) dropwise via addition funnel. The addition is slow at first; only 2 to 3 mL of reagent is added and the reaction mixture is heated until gas evolution is observed. Dropwise addition of benzyl bromide is begun at this point, and the reaction mixture is diluted with ethyl ether (20 mL) to prevent dimerization of the Grignard reagent. Once the addition of benzyl bromide is complete, the reaction is allowed to stir at room temperature for 1 hour and then a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (30.00 mmol, 6.61 g) in anhydrous ethyl ether (30 mL) is added dropwise at room temperature. The reaction mixture is allowed to stir at room temperature for 30 minutes and then poured into a solution of ice water (500 mL) containing concentrated H2SO4 (7 mL). The aqueous mixture is extracted with ethyl acetate (2×300 mL) and the combined organic layers are washed with saturated NaHCO3 (300 mL). The organic layer is dried (Na2SO4) and concentrated in vacuo to afford the title compound as a white solid (25.97 mmol, 8.06 g; 86%) of sufficient purity to be used directly in subsequent transformation.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)=[N:7][CH2:8][C:9](=S)[NH:10][C:4]=2[CH:3]=1.[CH3:23][O:24][CH2:25][C:26]([NH:28][NH2:29])=O>C(O)CCC>[CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)=[N:7][CH2:8][C:9]3[N:10]([C:26]([CH2:25][O:24][CH3:23])=[N:28][N:29]=3)[C:4]=2[CH:3]=1
Reactant: COCC(=O)NN
Reactant: Cc1ccc2c(c1)NC(=S)CN=C2c1ccc(C(C)C)cc1
Solvent: CCCCO
Product: COCc1nnc2n1-c1cc(C)ccc1C(c1ccc(C(C)C)cc1)=NC2

Procedure:
In the manner given in Example 1, a solution of 1,3-dihydro-8-methyl-5-(p-isopropylphenyl)-2H-1,4-benzodiazepine-2-thione in n-butyl alcohol was heated to reflux with methoxyacetic acid hydrazide to give 9-methyl-1-(methoxymethyl)-6-(p-isopropylphenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].Cl[C:13]1[C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=[CH:15][N:14]=1>>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:13]1[C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: Clc1ncccc1OCc1ccccc1
Product: Cc1[nH]cnc1CSCCNc1ncccc1OCc1ccccc1
Yield: 9.8 %

Procedure:
2-(5-Methyl-4-imidazolylmethylthio)ethylamine (18.13 g; 0.105 moles) and 2-chloro-3-benzyloxypyridine (11.63 g; 0.053 moles) were mixed and heated to 120° for 9 days. The resulting reaction mixture was purified by chromatography using silica-gel, and chloroform as eluant. The red oil obtained, corresponding to 2-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amino-3-benzyloxypyridine (1.85 g), was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:32]#[C:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:23][C@@H:22]([O:24]CC2C=CC=CC=2)[CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:32]#[C:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:23][C@@H:22]([OH:24])[CH2:21]1)[C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1C[C@@H](OCc2ccccc2)C1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1C[C@@H](O)C1
Reaction time: 0.25 h

Procedure:
3-[(cis-3-benzyloxy-cyclobutyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (290 mg, 0.55 mmol) in DCM (2 mL) at 0 deg C. was treated with boron tribromide (0.85 mL, 1.0 M solution in DCM). The mixture was stirred at 0 deg C. for 15 minutes and quenched with the addition of silica gel. Volatiles were evaporated under reduced pressure and the reaction mixture was purified by silica gel chromatography (0-100% ethyl acetate:hexanes). This resulted in 210 mg (88% yield) of 5-(3,3-Dimethyl-but-1-ynyl)-3-[(cis-3-hydroxy-cyclobutyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][CH:5]=[C:4]([C:13]#[C:14][CH:15]2[CH2:17][CH2:16]2)[N:3]=1.[OH-].[Li+]>CO.O>[Cl:1][C:2]1[N:3]=[C:4]([C:13]#[C:14][CH:15]2[CH2:17][CH2:16]2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1ccc(C#CC2CC2)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(C#CC2CC2)nc1Cl
Yield: 64.5 %

Procedure:
The ester was hydrolyzed as follows: Ethyl 2-chloro-6-(2-cyclopropylethynyl)pyridine-3-carboxylate (0.7 g, 2.8 mmol) and lithium hydroxide (0.4 g, 16.86 mmol) were refluxed in a mixture of 30 mL MeOH and 10 mL water. The mixture was cooled and the methanol was removed in vacuo. The remaining solution was acidified to pH 2 with 1M HCl at 0° C. The precipitate was filtered and dried to give 0.4 g (57%) of the title compound. m/z=222.4 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:7][C:6]([C:8]2[NH:25][C:11]3=[N:12][CH:13]=[CH:14][C:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[O:23][CH3:24])=[C:10]3[CH:9]=2)=[CH:5][CH2:4][NH:3]1.Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(N(CC)CC)C>CN(C)C=O>[F:22][C:20]1[CH:19]=[CH:18][C:17]([O:23][CH3:24])=[C:16]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]3[NH:25][C:8]([C:6]4[CH2:7][C:2]([CH3:26])([CH3:1])[N:3]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:4][CH:5]=4)=[CH:9][C:10]=23)[CH:21]=1
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCNC(C)(C)C3)cc12
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCN(CC(=O)OC(C)(C)C)C(C)(C)C3)cc12

Procedure:
A mixture of Example 272B (0.388 g, 0.915 mmol), tert-butyl bromoacetate (0.264 g, 1.35 mmol) and triethylamine (0.7 mL, 5.02 mmol) in N,N-dimethylformamide (2 mL) was heated at 70° C. for 8 hours and was concentrated. The residue was partitioned between ethyl acetate and water and the organic layer was dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel eluting with 50% ethyl acetate in hexanes gave the title compound. MS (ESI) m/e 466.4 (M+1)1.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH2:11][CH2:12][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]3)O1.Br[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=1[N:38]1[C:42]([CH3:43])=[CH:41][N:40]=[CH:39]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O>[CH3:43][C:42]1[N:38]([C:29]2[CH:30]=[C:31]([C:34]([F:37])([F:35])[F:36])[CH:32]=[CH:33][C:28]=2[C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH2:11][CH2:12][N:13]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:14]3)[CH:39]=[N:40][CH:41]=1
Reactant: Cc1cncn1-c1cc(C(F)(F)F)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CCc2c(cccc2B2OC(C)(C)C(C)(C)O2)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cncn1-c1cc(C(F)(F)F)ccc1-c1cccc2c1CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C

Procedure:
A solution of Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 0.165 g, 0.233 mmol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (ASW Medchem, Brunswick, N.J., 1.254 g, 3.49 mmol), 1-(2-bromo-5-(trifluoromethyl)phenyl)-5-methyl-1H-imidazole (derived above, 0.710 g, 2.327 mmol), and potassium phosphate (1.976 g, 9.31 mmol) in 10 mL dioxane 5 mL water was heated to 120° C. for 2 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc and the organics were concentrated. The resulting residue was purified by silica gel column chromatography (0 to 100% EtOAc/heptane) yielding tert-butyl 5-(2-(5-methyl-1H-imidazol-1-yl)-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.450 g, 0.984 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([F:22])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12]COC)[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:7]2[OH:21].O>O1CCOCC1.Cl>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([F:22])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([SH:12])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:7]2[OH:21]
Reactant: CCOC(=O)c1c(SCOC)nc2c(Cl)c(F)c(F)cc2c1O
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1c(S)nc2c(Cl)c(F)c(F)cc2c1O
Yield: 81.2 %

Procedure:
To a solution of 15.7 g of ethyl 8-chloro-6,7-difluoro-4-hydroxy-2-(methoxymethylthio)quinoline-3-carboxylate in 125 ml of 1,4-dioxane, 95 ml of 35% hydrochloric acid was added dropwise at 40° C. with stirring. The mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into 500 ml of water. The precipitate was collected by filtration and recrystallized from acetonitrile to give 11.2 g of the desired compound as pale yellow needles, m.p. 125°-130° C. (decomp.).
Reaction SMILES: Cl.[CH:2]([NH:5][NH2:6])([CH3:4])[CH3:3].[CH2:7]([O:14][C:15](=[O:21])[NH:16][CH2:17][CH2:18][CH:19]=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCN(CC)CC>C(O)(C)C>[CH2:7]([O:14][C:15](=[O:21])[NH:16][CH2:17][CH2:18][CH:19]=[N:6][NH:5][CH:2]([CH3:4])[CH3:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=CCCNC(=O)OCc1ccccc1
Reactant: CC(C)NN
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)NN=CCCNC(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a stirred solution of isopropylhydrazine hydrochloride (92.4 g, 0.84 mol) and (3-oxo-propyl)-carbamic acid benzyl ester (173 g, 0.84 mol) in isopropyl alcohol (1.7 L) was added Et3N (140 mL, 1.0 mol) over 20 min. The resulting slurry was heated at reflux for 3 h, and then was cooled to rt and concentrated. The residue was partitioned between EtOAc (700 mL) and water (700 mL). The organic layer was washed with water (3×500 mL), satd. aq. NaCl (300 mL), dried (MgSO4), and concentrated to afford the title compound. The crude product was used in next reaction without purification. MS (ESI): exact mass calcd. for C14H21N3O2, 263.16; m/z found, 264.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.36-7.25 (m, 5H), 7.02 (t, J=4.5, 1H), 5.10 (br s, 1H), 5.09 (s, 2H), 3.45-3.34 (m, 3H), 2.40-2.34 (m, 2H), 1.11 (d, J=6.4, 6H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]([CH2:14]Br)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:16]1([C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19])[OH:17]>CC(C)=O>[O:17]1[C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[O:19][CH2:14][CH:8]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: Oc1ccccc1O
Reactant: CCOC(=O)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1COc2ccccc2O1
Yield: 80 %

Procedure:
Under a nitrogen atmosphere, add 18.2 g (131 mmol) of dry potassium carbonate and 13 g (50 mmol) of ethyl 2,3-dibromopropionate in succession to a solution of 20 g (181 mmol) of catechol dissolved in 120 cm3 of anhydrous acetone. The operation is repeated four times in succession at intervals of 15 minutes. The reaction mixture is heated at reflux for 18 hours, and then cooled and filtered through Celite. The filtrate is concentrated to a residual volume of 60 cm3, then hydrolysed with 80 cm3 of water and extracted with diethyl ether. After drying over magnesium sulfate, the ethereal phase is concentrated under reduced pressure and the crude product is purified by distillation under reduced pressure (b.p.=155° C. under 15 mm Hg). Ethyl 2,3-dihydro-1,4-benzodioxin-2-carboxylate is thereby obtained in a yield of 80%. nD25 =1.5214 ##STR27##