Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH2:25][CH:26]2[CH2:29][CH2:28][CH2:27]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][CH2:40][CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:34]=[CH:35][C:36]=1[F:37].Cl>>[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][CH2:40][CH:41]2[CH2:46][CH2:45][N:44]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:6][N:5]([C@H:14]([CH2:25][CH:26]4[CH2:27][CH2:28][CH2:29]4)[C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:16])[CH2:4]3)[CH2:43][CH2:42]2)[CH:34]=[CH:35][C:36]=1[F:37]
Reactant: Fc1ccc(CCCC2CCNCC2)cc1F
Reactant: O=C[C@H]1CN([C@H](CC2CCC2)C(=O)OCc2ccccc2)C[C@@H]1c1ccccc1
Agent: Cl
Product: O=C(OCc1ccccc1)[C@@H](CC1CCC1)N1C[C@H](CN2CCC(CCCc3ccc(F)c(F)c3)CC2)[C@@H](c2ccccc2)C1
Yield: 50.4 %

Procedure:
The title compound was prepared from 26 mg (0.06 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-3-(cyclobutyl)propanoic acid, benzyl ester (from EXAMPLE 25, Step B) and 17.5 mg (0.06 mmol) of 4-(3-(3,4-difluorophenyl)propyl)piperidine.HCl (from EXAMPLE 119, Step C) using a procedure analogous to that described in EXAMPLE 1, Step J to provide 18.6 mg (47%) of the title compound: RF: 0.33 (1:1 v/v hexanes/EtOAc); 1H NMR (500 MHz) δ 1.15-3.29 (m, 33H), 5.17 (ABq, 2H), 6.8-7.4 (m, 13H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[H-].[Na+].[C:12](OC)(=[O:20])[CH2:13][CH2:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17]>>[C:4]1([C:1](=[O:3])[CH2:2][C:12]([CH2:13][CH2:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:20])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: COC(=O)CCCC(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)CCCC(=O)CC(=O)c1ccccc1

Procedure:
Other hindered beta-diketones may be prepared by the method of Example A of U.S. Pat. No. 4,065,502. Alternatively, a preferred method of preparation is the condensation of acetophenone with an appropriate methyl ester in an aromatic hydrocarbon solvent using excess sodium hydride as base. Thus, methyl neooctanoate is condensed with acetophenone to give 1-phenyl-3-neoheptyl-1,3-propanedione, and methyl 2,2-dimethyl octanoate is condensed with acetophenone to give 1-phenyl-4,4-dimethyl-1,3-decanedione, in which the product is a mixture of branched chain isomers.
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[C:6]([F:16])[CH:5]=1.O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C>[Br:1][C:11]1[S:10][C:9]([CH2:8][C:7]2[CH:14]=[CH:15][C:4]([Br:3])=[CH:5][C:6]=2[F:16])=[CH:13][CH:12]=1
Reactant: Fc1cc(Br)ccc1Cc1cccs1
Reactant: BrBr
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Fc1cc(Br)ccc1Cc1ccc(Br)s1
Reaction time: 2 h
Yield: 72 %

Procedure:
A solution of bromine (0.44 ml) in acetic acid (5 ml) was added during 10 minutes to a stirred solution of (4-bromo-2-fluorobenzyl)thiophene (2.33 g) in acetic acid (10 ml). The solution was stirred for 2 hours, then poured into a mixture of water (50 ml) and a 20% w/v solution of sodium metabisulphite (20 ml). The mixture was extracted with ether (2×50 ml), the combined extracts washed with water and saturated brine, and then dried (MgSO4). The solvent was removed by evaporation to give 2-bromo-5-(4-bromo-2-fluorobenzyl)thiophene as an oil; in 72% yield; NMR: 4.04(s,2H), 6.55(d,1H), 6.85(d,1H), 7.07(t,1H), 7.14-7.30(m,2H); m/e, (chemical ionisation) 348(M+); which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[CH:5]=[C:4]([CH3:12])[N:3]=1.[I:13]N1C(=O)CCC1=O.S([O-])(O)=O.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([I:13])=[C:4]([CH3:12])[N:3]=1
Reactant: CCCNc1cc(C)nc(Cl)n1
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCNc1nc(Cl)nc(C)c1I
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
To a suspension of 2-chloro-6-methyl-N-propylpyrimidin-4-amine (T1, 200 mg) in acetic acid (4 mL), N-iodosuccinimide (485 mg) was added at room temperature, and the mixture was stirred at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature, and then saturated aqueous sodium hydrogensulfite, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 90-75% hexane in ethyl acetate) to obtain 2-chloro-5-iodo-6-methyl-N-propylpyrimidin-4-amine (T2, 252 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[CH2:18][CH3:19].C[N:21]([CH:23]=O)C.Br[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[CH:31][CH:30]=1)=O>O.CCOC(C)=O>[CH2:17]([C:23]1[N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][C:5]3[CH:16]=[CH:17][C:2]([Cl:1])=[C:3]([CH2:18][CH3:19])[CH:4]=3)=[CH:8][CH:9]=2)[CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[CH:31][CH:30]=2)[N:21]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCN(CC)CCCOc1ccc(C(=O)CBr)cc1
Reactant: CN(C)C=O
Reactant: CCc1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCc1nc(-c2ccc(OCCCN(CC)CC)cc2)cn1-c1ccc(Oc2ccc(Cl)c(CC)c2)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-(4-chloro-3-ethylphenoxy)-1-nitrobenzene (1.2 eq., 2.5 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 7.5 mmol) was added, followed by slow addition of the 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (2.4 mmol), according to General Procedure R2. The reaction mixture was stirred under nitrogen at rt until completion, as indicated by TLC or HPLC. The reaction mixture was then diluted with cold H2O and the product was isolated in EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. Evaporation of solvent in vacuuo afforded the desired product. The crude alkylated aniline was used for further transformation.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[C:16]2[C:19]([CH3:22])=[CH:20][S:21][C:15]=2[N:14]([CH3:23])[C:13]1=[O:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C(=O)N([Br:32])C(=O)C1>C(Cl)Cl>[Br:32][C:20]1[S:21][C:15]2[N:14]([CH3:23])[C:13](=[O:24])[N:12]([CH2:11][CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2])[C:17](=[O:18])[C:16]=2[C:19]=1[CH3:22]
Reactant: Cc1csc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Cc1c(Br)sc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
To a solution of 3-(3-(tert-butyldimethylsilyloxy)propyl)-1,5-dimethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (3.0 g, 8.14 mmol) in DCM (30 mL) at 0° C. was added NBS (1.6 g, 8.95 mmol). The reaction was stirred at 0° C. for 2 h then diluted with DCM (100 mL) and washed with water (2×50 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography PE/EA (1:1) to give 6-bromo-3-(3-(tert-butyldimethylsilyloxy) propyl)-1,5-dimethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (3.4 g, 93.4% yield) as a white solid. LCMS: MH+ 448 and TR=2.917 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28](O)=[O:29].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:28]([C:27]2[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:25]([O:24][CH3:23])[CH:26]=2)=[O:29])=[CH:20][CH:21]=1
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 8 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (56 mg) and commercially available 3,4-dimethoxybenzoic acid (60 mg) were dissolved in N,N-dimethylformamide (2 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (81 mg) was added, and the admixture was stirred at room temperature for 22 hours. The reaction mixture was partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with brine and then dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting chloroform/acetone (10/1) to obtain 7 mg of the title compound (yield: 8%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1.[Cl:13]C(Cl)(Cl)[C:15]([C:17]1[NH:18][CH:19]=[CH:20][CH:21]=1)=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[ClH:13].[NH2:12][C:9]1[NH:10][CH:11]=[C:7]([CH2:6][CH2:5][CH2:4][NH:3][C:15]([C:17]2[NH:18][CH:19]=[CH:20][CH:21]=2)=[O:16])[N:8]=1
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: NCCCc1c[nH]c(N)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(CCCNC(=O)c2ccc[nH]2)c[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(3-amino-propyl)-1H-imidazol-2-ylamine dihydrochloride 16 (0.100 g, 0.458 mmol), 2-trichloroacetyl pyrrole 6 (0.103 g, 0.488 mmol), and anhydrous sodium carbonate (0.172 g, 1.63 mmol), were dissolved in anhydrous N,N-dimethylformamide (5 mL). The reaction was stirred at ambient temperature for 16 h. Evaporation of the reaction under reduced pressure and purification of the residue by column chromatography (CH2Cl2/MeOH sat. NH3 85:15) afforded the desired compound in its free base form. Addition of a single drop of concentrated hydrochloric acid to a methanol solution (8 mL) and evaporation under reduced pressure yielded 0.078 g (63%) of the title compound 17 as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 12.07 (s, 1H), 11.59 (s, 1H), 11.45 (s, 1H), 8.14 (t, 1H, J=5.1 Hz), 7.30 (s, 2H), 6.81 (m, 2H), 6.74 (s, 1H), 6.59 (s, 1H), 6.04 (s, 1H), 3.19 (dt, 2H, J=6.6, 12.6 Hz), 2.42 (t, 2H, J=6.9 Hz), (tt, 2H, J=6.6, 13.8 Hz); 13C NMR (100 MHz, DMSO-d6) δ 160.74, 146.76, 126.43, 126.40, 121.13, 110.28, 108.65, 108.50, 37.59, 28.14, 21.60; HRMS (ESI) calcd for C11H16N5O (MH+) 234.1349. found 234.1354.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][N:7]=1>CO.[Pd]>[ClH:4].[ClH:4].[CH3:1][N:2]([CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][NH:7]1)[CH3:3]
Reactant: CNC
Reactant: ClCC1=NCC(c2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CN(C)CC1NCC(c2ccccc2)c2ccccc21
Product: Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of dimethylamine (250 ml) in methanol (1 liter) maintained under nitrogen and cooled in an ice bath was added portionwise 1-chloromethyl-3,4-dihydro-4-phenylisoquinoline (25.0 g, 0.084 m) and the mixture stirred for 4 hours while being allowed to warm to ambient temperature. The solution was poured into a pressure bottle and hydrogenated on a Parr apparatus over 5% Pd/C catalyst (5.0 g) at 40 psi. for 16 hours. The catalyst was removed by filtration and the solvent evaporated to a gummy residue. The residue was dissolved in methanol (300 ml) and isopropanol (100 ml) and acidified with HCl gas. Upon cooling and standing, a solid crystallized which was collected by filtration. Recrystallization from methanol/isopropanol/water gave 12.2 g of the major isomer of 1,2,3,4-tetrahydro-1-dimethylaminomethyl-4-phenylisoquinoline dihydrochloride as a monohydrate, m.p. 278°-279°.
Reaction SMILES: C(O[C:6](=[O:21])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)(C)(C)C.[CH2:22]([O:24][C:25](=[O:37])[CH:26](C(OCC)=O)[C:27](OCC)=[O:28])[CH3:23]>>[CH2:22]([O:24][C:25]([C:26]1[C:6](=[O:21])[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[N:8]2[CH:9]=[CH:10][CH:11]=[C:12]2[C:27]=1[OH:28])=[O:37])[CH3:23]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1Cl)n1cccc1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1c(O)c2cccn2n(Cc2ccccc2Cl)c1=O

Procedure:
Prepared according to the thermal cyclization condition used in Example 1 step c) from (2-chloro-benzyl)-pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.) and 2-ethoxycarbonyl-malonic acid diethyl ester (3.0 eq.). ESI (m/z): 347 (M+H)+.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C(Cl)Cl.[CH3:8][NH:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:23]=[C:22]2[C:17]([CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[NH:20][C:21]2=[O:24])=[CH:16][CH:15]=1.C(N(CC)CC)C>O>[CH3:8][N:9]1[CH2:10][CH2:11][CH2:12][N:13]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:33])([F:34])[F:32])[NH:20][C:21]3=[O:24])=[CH:16][CH:15]=2)[C:1]1=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CNCCCNc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CN1CCCN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C1=O
Reaction time: 0.17 h
Yield: 13.7 %

Procedure:
Phosgene (294 μl, 0.559 mmol) was added at 0° C. to an anhydrous methylene chloride solution (2 ml) that contained the 7-(3-methylaminopropylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (70 mg, 0.186 mmol) obtained in step B. The obtained mixture was stirred for 10 minutes. Thereafter, triethylamine (156 μl, 0.112 mmol) was added to the reaction solution, and the obtained mixture was then stirred for 30 minutes. Thereafter, water was added to the reaction solution. An organic layer was separated, and a water layer was then extracted with methylene chloride. The organic layer was mixed with the extract. The obtained mixture was washed with water and a saturated saline solution, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (methylene chloride:methanol=40:1), so as to obtain 7-(3-methyl-2-oxotetrahydropyrimidin-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (10.2 mg, 14%).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[C:12]([S-:14])#[N:13].[K+]>>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][S:14][C:12]#[N:13])=[CH:6][CH:7]=1
Reactant: O=C(CCl)c1ccc(Cl)cc1
Reactant: N#C[S-]
Agent: [K+]
Product: N#CSCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of 945 mg (5 mmol) 2,4′-dichloroacetophenone and 583 mg (6 mmol) potassium rhodanide was heated to reflux for 30 minutes. After a few minutes a precipitation was formed. The solvent was evaporated under reduced pressure and the residue was suspended in tetrahydrofurane, stirred for 1 hour at room temperature, filtered and the filtrate was concentrated in vacuo. The residue was stirred with heptane and little ethanol for 15 minutes. The product was filtered off and dried to yield 953 mg (90%) 1-(4-chloro-phenyl)-2-thiocyanato-ethanone as a light yellow solid. 1H NMR (CDCl3, 250 MHz): δ (ppm)=7.89 (d, 2H), 7.51 (d, 2H), 4.692 (s, 2H).
Reaction SMILES: [C:1]12([C:11](Cl)=O)CC3CC(CC(C3)[CH2:2]1)C2.FC(F)(F)S(OC)(=O)=O.C1(NC(=S)NN)C=CC=CC=1.C(N(CC)CC)C.[C:41]12([C:51]([NH:53][NH:54][C:55]([NH:57][C:58]3[CH:63]=CC=C[CH:59]=3)=S)=O)[CH2:50][CH:45]3[CH2:46][CH:47]([CH2:49][CH:43]([CH2:44]3)[CH2:42]1)[CH2:48]2>C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:41]12([C:51]3[N:57]([CH:58]4[CH2:59][CH2:63]4)[C:55]([CH:11]4[CH2:1][CH2:2]4)=[N:54][N:53]=3)[CH2:48][CH:47]3[CH2:49][CH:43]([CH2:44][CH:45]([CH2:46]3)[CH2:50]1)[CH2:42]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: O=C(NNC(=S)Nc1ccccc1)C12CC3CC(CC(C3)C1)C2
Agent: COS(=O)(=O)C(F)(F)F
Agent: NNC(=S)Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C1C2CC3CC1CC(c1nnc(C4CC4)n1C1CC1)(C2)C3
Reaction time: 0.33 h
Yield: 92.8 %

Procedure:
A mixture of N-(cyclopropyl)cyclopropanecarboxamide (A) (2.08 g, 16.6 mmol) and methyl trifluoromethanesulfonate (1.88 mL, 16.6 mmol) was warmed at 65° in a nitrogen atmosphere. After a few minutes a clear melt was obtained. After 20 min, the melt was cooled and formation of the imino ether triflate salt (B) confirmed by an NMR spectrum. Toluene (26 mL), triethylamine (3.86 mL, 27.7 mmol) and adamantane-1-carbohydrazide (C) (2.15 g, 11.1 mmol) were added, and the two-phase mixture was stirred at 65° for 5 h. The mixture was heated at 110° for 3 h. The cooled reaction was diluted with ethyl acetate (75 mL), washed with water (75 mL) and saturated brine (30 mL), and dried (MgSO4). The ethyl acetate was evaporated in vacuo to give 2.92 g of a yellow syrup. Flash chromatography on silica gel with ethyl acetate eluted the oxadiazole D. Elution with 7% methanol in chloroform and evaporation in vacuo gave crude 4-77. Recrystallization from isopropyl ether afforded pure 3-(1-adamantyl)-4,5-dicyclopropyl-4H-1,2,4-triazole) (4-77). MS: 284 (M+1).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[C:10]([F:19])=[C:11]([C:15]([F:18])=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.[CH2:28]([Sn](CCCC)(CCCC)CCCC)[CH:29]=[CH2:30].O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:30]([C:2]1[S:6][C:5]([CH2:7][O:8][C:9]2[C:10]([F:19])=[C:11]([C:15]([F:18])=[CH:16][CH:17]=2)[C:12]([NH2:14])=[O:13])=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:29]=[CH2:28]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)sc2Br)cc1
Agent: [Pd]
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: C=CCc1sc(COc2ccc(F)c(C(N)=O)c2F)nc1-c1ccc(OC)cc1
Temperature: 120 °C
Yield: 144.1 %

Procedure:
To a solution of 3-[5-bromo-4-(4-methoxy-phenyl)-thiazol-2-ylmethoxy]-2,6-difluoro-benzamide (0.1 g, 0.0002 mol) in 5 ml of anhydrous DMF was added Allyl tributyltin (0.072 g, 0.0002 mol) and degassed the reaction mixture for the 10 minutes. Then added tetraphenylphosphine Palladium (0) (0.025 g, 0.00002 mol). The reaction mixture was heated at 120° C. for 12 h under the nitrogen atmosphere. Then reaction mixture was cooled to rt. 100 ml of water was added into it and extracted the compound with ethyl acetate, The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was purified by column chromatography on silica (230-400μ) using methanol/DCM (2:98) as the eluent to provide the title compound as brown solid (0.120 g, 60%). 1H NMR (DMSO-d6, 400 MHz): δ 3.79 (s, 3H), 5.11-5.14 (m, 1H), 5.16 (s, 1H), 5.48 (s, 2H), 5.57 (s, 1H), 5.99-6.06 (m, 1H), 7.03 (d, 2H, J=8.4 Hz (o-coupling), 7.11 (dt, 1H, J=9.2 Hz (o-coupling), 7.36-7.42 (m, 1H), 7.56 (d, 2H, J=8.8 Hz (o-coupling), 7.88 (broad s, 1H), 8.16 (broad s, 1H). MS ES+ (417.06), HPLC (method 5) Rt=16.96 min.
Reaction SMILES: CN(C)CCCN=C=NCC.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([OH:19])=O.[NH2:20][C@@H:21]([CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[C:22]([NH:24][C@H:25]1[CH2:31][CH2:30][C@@H:29]([CH3:32])[N:28]([CH2:33][CH2:34][CH3:35])[CH2:27][C@@H:26]1[OH:36])=[O:23].CN1CCOCC1.OC1C2N=NNC=2C=CC=1>CN(C=O)C.CCOC(C)=O>[CH:38]1([CH2:37][C@H:21]([NH:20][C:17]([C:13]2[O:12][CH:16]=[CH:15][CH:14]=2)=[O:19])[C:22](=[O:23])[NH:24][C@H:25]2[CH2:31][CH2:30][C@@H:29]([CH3:32])[N:28]([CH2:33][CH2:34][CH3:35])[CH2:27][C@@H:26]2[OH:36])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CCCN1C[C@H](O)[C@@H](NC(=O)[C@@H](N)CC2CCCCC2)CC[C@H]1C
Reactant: O=C(O)c1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCN1C[C@H](O)[C@@H](NC(=O)[C@H](CC2CCCCC2)NC(=O)c2ccco2)CC[C@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.10 g, 0.53 mmol) was added to a solution of furan-2-carboxylic acid (0.059 g, 0.53 mmol), (S)-2-Amino-3-cyclohexyl-N-((3S,4S,7R)-3-hydroxy-7-methyl-1-propyl-azepan-4-yl)-propionamide (0.15 g, 0.36 mmol), 4-methylmorpholine (0.14 g, 0.16 ml, 1.44 mmol), hydroxybenztriazole (0.071 g, 0.53 mmol) in DMF (2.0 ml) and was stirred at RT overnight. The reaction mixture was then warmed to RT and was stirred overnight. The reaction mixture was diluted with EtOAc (30 ml), washed with H2O, brine, dried with magnesium sulfate, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 2.5% MeOH/CH2Cl2) to yield the title compound (0.12 g, 76%): Electrospray mass spec: M+H+=434.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]1[S:14][C:13]([C:15]2[S:16][CH:17]=[CH:18][C:19]=2[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:12][CH:11]=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH3:24][O:23][C:21](=[O:22])[CH2:20][C:19]1[CH:18]=[C:17]([C:31]([C:27]2[S:26][CH:30]=[CH:29][CH:28]=2)=[O:32])[S:16][C:15]=1[C:13]1[S:14][C:10]([C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH2:4][C:3]([O:2][CH3:1])=[O:25])=[CH:11][CH:12]=1
Reactant: COC(=O)Cc1ccsc1-c1ccc(-c2sccc2CC(=O)OC)s1
Reactant: O=C(Cl)c1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)Cc1ccsc1-c1ccc(-c2sc(C(=O)c3cccs3)cc2CC(=O)OC)s1
Reaction time: 26 h
Yield: 33.7 %

Procedure:
Intermediate C (146 mg, 0.372 mmol) was dissolved in dry CH2Cl2 (3 ml), 2-thiophenecarbonyl chloride (92 μL, 0.856 mmol) and AlCl3 (114 mg, 0.856 mmol) were added and the mixture was sealed under Ar-atmosphere. After 26 hrs, the reaction was diluted with CH2Cl2 (10 ml), washed with water (20 ml) and the aqueous layer was subsequently washed with CH2Cl2 (10 ml×2). The organic layers were combined and evaporated to dryness to obtain the crude product. The residue was purified by flash chromatography using toluene/EtOAc (19:1→9:1→6:1) as eluent to first obtain the monoacylated product methyl 2-(2-{5-[3-(2-methoxy-2-oxoethyl)-5-(thiophene-2-carbonyl)thiophen-2-yl]thiophen-2-yl}thiophen-3-yl)acetate Yield: 63 mg (34%). 1H NMR (400 MHz, CDCl3): δ 3.75 (s, 3H), 3.77 (s, 3H), 3.81 (s, 2H), 3.87 (s, 2H), 7.08 (d, J 4.0 Hz, 1H), 7.20-7.23 (m, 2H), 7.29-7.31 (m, 2H), 7.72 (dd, J 2.0, 4.0 Hz, 1H), 7.87 (s, 1H), 7.94 (dd, J 2.0, 4.0 Hz, 1H). Second eluted compound; the diacylated product methyl 2-(2-{5-[3-(2-methoxy-2-oxoethyl)-5-(thiophene-2-carbonyl)thiophen-2-yl]thiophen-2-yl}-5-(thiophene-2-carbonyl)thiophen-3-yl)acetate. Yield: 90 mg (39%) 1H NMR (400 MHz, CDCl3): δ 3.79 (s, 6H), 3.87 (s, 4H), 7.23 (dd, J 4.0, 4.0 Hz, 2H), 7.36 (s, 2H), 7.73 (dd, J 2.0, 4.0 Hz, 2H), 7.88 (s, 2H), 7.94 (dd, J 2.0, 4.0, 2H).