Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:12]([NH:22][C@H:23]([C:28]([OH:30])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[NH2:22][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:2][CH:3]=[CH:4][CH:5]=2)[N:10]=1.[C:12]([NH:22][C@H:23]([C:28]([OH:30])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: Nc1cccc2cccnc12
Agent: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: Nc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 8-aminoquinoline (1 g, 6.9 mmol) and N-CBZ-L-leucine (2.2 g, 8.3 mmol) in dry methylene chloride (35 mL) was mixed with 1-hydroxybenzotriazole (1.1 g, 8.3 mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.6 g, 8.3 mmol) . The reaction mixture was stirred overnight at room temperature and then worked up with saturated sodium chloride, saturated sodium bicarbonate, and water. The organic layer was dried with magnesium sulfate. Following solvent removal, product was purified by column chromatography on silica gel eluted with hexane-ethyl acetate (4:1) to give pure CBZ-L-leucine aminoquinoline. It was deprotected by treating it with hydrogen gas and 10% palladium on carbon in ethyl acetate to give pure 8-(L)-leucylaminoquinoline (60% yield).
Reaction SMILES: N1C=CC=CC=1.B.[N+:8]([C:11]1[CH:33]=[CH:32][C:14]([CH2:15][CH:16]2[C:27](=O)[NH:26][CH2:25][C:24](=O)[NH:23][CH2:22][C:21](=O)[NH:20][CH2:19][C:18](=O)[NH:17]2)=[CH:13][CH:12]=1)([O-:10])=[O:9]>N1C=CC=CC=1>[N+:8]([C:11]1[CH:33]=[CH:32][C:14]([CH2:15][C@H:16]2[CH2:27][NH:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18][NH:17]2)=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=C1CNC(=O)CNC(=O)C(Cc2ccc([N+](=O)[O-])cc2)NC(=O)CN1
Agent: B
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(C[C@H]2CNCCNCCNCCN2)cc1
Temperature: 120 °C

Procedure:
Borane-pyridine (available from Aldrich) is added to a suspension of 2-(4-nitrobenzyl)-3,6,9,12-tetraoxo-1,4,7,10-tetraazacyclododecane in pyridine. The mixture is heated under reflux at 120° C. for 14 hours. The solvent is removed under reduced pressure. The residue is taken up in methanol and heated under reflux for 2 hours. The solvent is removed under reduced pressure. The residue is dissolved in methanol and re-evaporated. The solid residue is purified by chromatography on reverse phase Baker G18 silica gel available from J. T. Baker, Inc., Phillipsburg, N.J. Conversion of this product to nitro-benzyl-DOTA is accomplished via the procedure discussed in Renn et al., Bioconj. Chem., 3:563-569, 1992 or as set forth is subpart A above.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[O:32]1[C:36]2[C:37]([S:41](Cl)(=[O:43])=[O:42])=[CH:38][CH:39]=[CH:40][C:35]=2[CH:34]=[CH:33]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:41]([C:37]1[C:36]2[O:32][CH:33]=[CH:34][C:35]=2[CH:40]=[CH:39][CH:38]=1)(=[O:42])=[O:43]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)c1cccc2ccoc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1cccc2ccoc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. benzofuran-7-sulfonyl chloride (15 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([NH:10][C@H:11]([C:29]([N:31]1[CH2:70][CH2:69][CH2:68][C@H:32]1[C:33]([NH:35][C@H:36]([C:38]([NH:40][C@H:41]([C:58]([O:60]CC1C=CC=CC=1)=[O:59])[CH2:42][CH2:43][CH2:44][CH2:45][NH:46]C(OCC1C=CC=CC=1Cl)=O)=[O:39])[CH3:37])=[O:34])=[O:30])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:28])[NH:17]S(C1C=CC(C)=CC=1)(=O)=O)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].C1(OC)C=CC=CC=1>>[NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:29]([N:31]1[CH2:70][CH2:69][CH2:68][C@H:32]1[C:33]([NH:35][C@H:36]([C:38]([NH:40][C@H:41]([C:58]([OH:60])=[O:59])[CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])=[O:39])[CH3:37])=[O:34])=[O:30])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:17])[NH2:28])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Solvent: COc1ccccc1
Product: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 111.4 %

Procedure:
The solution of 250 mg (0.225 mmol) of Boc-Gln-Arg(Tos)-Pro-Ala-Lys(ClZ)-OBzl (SEQ ID NO: 16), 1 ml of anisole and 2 ml of HF was stirred at 0° C. for 2 h. The reaction mixture was evaporated under reduced pressure to remove HF. To the residue 2 ml of HF were added and the solution was stirred at 0° C. for another 1 h. The reaction mixture was evaporated under reduced pressure to remove HF. The residue was triturated with ether and the resulted solid was purified on the Sephadex G-10 column. The collected fractions were lyophilized to provide 150 mg (98%) of the title compound. Mp. 180–182° C., FAB-MS (m/e) 600[M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[CH3:20])[NH2:16]>>[F:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:17]=[CH:18][C:19]=1[CH3:20]
Reactant: Cc1ccc(N)cc1F
Reactant: O=C(O)Cc1ccccc1Br
Product: Cc1ccc(Nc2ccccc2CC(=O)O)cc1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-fluoro-4-methylaniline to yield 2-[(3-fluoro-4-methylphenyl)amino]phenylacetic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)[CH:8]=2)[CH:6]=1.[BH4-].[Na+]>CO.C1COCC1.Cl[Ni]Cl>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[O:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH:8]=2)[CH:6]=1
Reactant: Cc1cnn(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4)c3s2)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cnn(-c2cc3nccc(Oc4ccc(N)cc4)c3s2)c1
Reaction time: 0.17 h
Yield: 87.3 %

Procedure:
To a solution of 256 (168.4 mg, 0.478 mmol) and NiCl2×6H2O (226 mg, 0.956 mmol) in MeOH/THF (10/10 mL) NaBH4 (72 mg, 1.92 mmol) was carefully added. The reaction mixture was stirred for 10 min, concentrated to dryness and the resultant solid was suspended in 10% HCl. The aqueous solution was basified (pH ˜11) with concentrated aqueous NH4OH and extracted with EtOAc. The organic extract was collected, dried over anhydrous Na2SO4 and concentrated under reduced pressure, to afford title compound 257 (134.6 mg, 87% yield) as a white solid. MS (m/z): 322.09 (M+1).
Reaction SMILES: [C:1]([N:4]1[C:13]2[CH:12]=[CH:11][C:10]([NH2:14])=[CH:9][C:8]=2[C:7]2[N:15]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[N:16]=[C:17]([C:18]([NH2:20])=[O:19])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[CH3:28][S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[C:1]([N:4]1[C:13]2[CH:12]=[CH:11][C:10]([NH:14][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:9][C:8]=2[C:7]2[N:15]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[N:16]=[C:17]([C:18]([NH2:20])=[O:19])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1Cc2c(C(N)=O)nn(-c3ccc(F)cc3)c2-c2cc(N)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)N1Cc2c(C(N)=O)nn(-c3ccc(F)cc3)c2-c2cc(NS(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
The material from step 3 of Example 24 (1 g, 0.0027 mol) was combined with methane sulfonyl chloride (345 mg, 0.003 mol) in 10 mL pyridine. The mixture was stirred at room temperature, under argon, for 3 hours. The reaction was then concentrated in vacuo. The resulting solid was washed with water and diethyl ether, and was then air dried to give the desired as a tan solid. 950 mg. (MW=443.46, 79% yield). LC/MS m/z=444 (m+1).
Reaction SMILES: Cl[SiH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH2:4][CH2:3]1.[Cl-].[CH2:27]([Zn+])[CH2:28][CH3:29].Cl[SiH]1CCC(CC[C@H]2CC[C@H](C3C=CC(F)=CC=3)CC2)CC1.[Cl-].C([Zn+])CCCC>>[F:23][C:22]([F:25])([F:24])[C:19]1[CH:20]=[CH:21][C:16]([C@H:13]2[CH2:14][CH2:15][C@H:10]([CH2:9][CH2:8][C@H:5]3[CH2:6][CH2:7][Si@H:2]([CH2:27][CH2:28][CH3:29])[CH2:3][CH2:4]3)[CH2:11][CH2:12]2)=[CH:17][CH:18]=1
Reactant: CCC[Zn+]
Reactant: FC(F)(F)c1ccc([C@H]2CC[C@H](CCC3CC[SiH](Cl)CC3)CC2)cc1
Agent: CCCCC[Zn+]
Agent: Fc1ccc([C@H]2CC[C@H](CCC3CC[SiH](Cl)CC3)CC2)cc1
Agent: [Cl-]
Product: CCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(C(F)(F)F)cc3)CC2)CC1

Procedure:
The preparation was conducted in the same manner as in Example 6, except that 8.2 g (21 mmol) of 1-chloro-4-(2-(trans-4-(p-trifluoromethylphenyl)cyclohexyl)ethyl)-1-silacyclohexane and n-propylzinc chloride were used instead of 7.0 g (21 mmol) of 1-chloro-4-(2-(trans-4-(p-fluorophenyl)cyclohexyl)ethyl)-1-silacyclohexane and n-pentylzinc chloride.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[CH3:29][S:30](O)(=[O:32])=[O:31].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[C:3]([CH2:2][NH:1][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Reactant: CS(=O)(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CNS(C)(=O)=O)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
A round bottom flask was charged with (5)-3-(aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3; 0.025 g, 0.065 mmol), methanesulfonic acid loaded TFP resin (0.9 mmol/g loading, 0.065 mmol), DIEA (0.017 g, 0.13 mmol), DMAP (0.09 g, 0.072 mmol), and THF (5 ml). The resulting solution was shaken vigorously at 60° C. for 8 hrs. The reaction was filtered and the resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.016 g, 53%). 1H NMR (400 MHz, CD3OD) δ 7.42-7.39 (m, 2H), 7.14 (d, J=10.7 Hz, 1H), 7.01-6.97 (m, 2H), 5.16-5.09 (m, 1H), 4.15-4.06 (m, 2H), 2.99 (s, 3H), 1.88-1.83 (m, 1H), 1.52 (d, J=6.8 Hz, 3H), 0.95-0.93 (m, 2H), 0.66-0.64 (m, 2H). MS: Calcd.: 462. Found: [M+H]+ 463.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][CH:19]([C:21]2C3C(=CC=CC=3)N=C[CH:22]=2)C)=[CH:5][CH:4]=1.[C:31]1([C@H](N)CC)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.COC1C(C2C=CC(OC)=CC=2)=CC(C=O)=CC=1.C([BH3-])#N.[Na+]>>[C:31]1([C@H:19]([NH:18][CH2:17][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[CH:7]=2)[CH2:21][CH3:22])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC[C@@H](N)c1ccccc1
Reactant: COc1ccc(-c2cc(CNC(C)c3ccnc4ccccc34)ccc2OC)cc1
Agent: COc1ccc(-c2cc(C=O)ccc2OC)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC[C@@H](NCc1ccc(OC)c(-c2ccc(OC)cc2)c1)c1ccccc1
Yield: 52 %

Procedure:
The title compound was prepared by the same procedure for (6,4′-dimethoxybiphenyl-3-ylmethyl)-(1-quinolin-4-yl-ethyl)-amine from (R)-(+)-1-phenyl-propylamine (405 mg, 3.0 mmol, Lancaster Synthesis Ltd.), 6,4′-Dimethoxybiphenyl-3-carbaldehyde (242 mg, 1.0 mmol) and sodium cyanoborohydride (1.0 g, 16 mmol, Aldrich). The title compound was purified by column chromatography (silica gel, hexane/ethyl acetate 2/3) in form as white solid in 52% yield (187 mg, 0.52 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[NH:9]1[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:8][C:4]1[N:3]=[C:2]([N:9]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=1
Reactant: OCCCCNC1CCCNCC1
Reactant: Brc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: OCCCCNC1CCCN(c2cccc(Br)n2)CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
545 mg (2.3 mmol) of 2,6-dibromopyridine, the product from step c (428 mg, 2.3 mmol) and 954 mg of potassium carbonate (6.9 mmol) are suspended in 20 ml of DMSO and stirred at 120° C. overnight. Water is then added to the mixture, which is then extracted with EA. The organic phase is washed with a saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The residue formed is purified by means of RP flash chromatography on C18 silica gel.
Reaction SMILES: COC([C@@H]1C[C@H](O)CN1C(OC(C)(C)C)=O)=O.[CH3:18][O:19][C:20]([C@@H:22]1[CH2:26][C@H:25]([NH2:27])[CH2:24][N:23]1[CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:21]>>[CH3:18][O:19][C:20]([C@@H:22]1[CH2:26][C@@H:25]([NH2:27])[CH2:24][N:23]1[CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:21]
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1CC1CCCCC1
Agent: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Product: COC(=O)[C@@H]1C[C@@H](N)CN1CC1CCCCC1

Procedure:
(2S,4R)-4-Amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester was prepared from (2S,4S)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in a similar reaction sequence used in the preparation of (2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester. MS calcd. for C13H25N2O2 [(M+H)+] 241, obsd. 241.
Reaction SMILES: [CH3:1][CH:2]([C:5]1[S:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:8][N:9]=1)[CH2:3][CH3:4].[CH2:17]([C@H:22]1[CH2:27][CH2:26][C@H:25]([C:28](O)=[O:29])[CH2:24][CH2:23]1)[CH2:18][CH2:19][CH2:20][CH3:21].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CN=2)CCCC1>C(Cl)Cl>[CH3:1][CH:2]([C:5]1[S:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:28]([C@H:25]3[CH2:26][CH2:27][C@H:22]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:23][CH2:24]3)=[O:29])=[CH:14][CH:15]=2)=[N:8][N:9]=1)[CH2:3][CH3:4]
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCC(C)c1nnc(-c2ccc(O)cc2)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ncn1
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](C(=O)Oc2ccc(-c3nnc(C(C)CC)s3)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Into a mixture of 0.3 g (1.28×10-3 mol) of 1-methylpropyl-5-[4-hydroxyphenyl]-1,3,4-thiadiazole, 0.26 g (1.31×10-3 mol) of trans-4-n-pentylcyclohexanecarboxylic acid, 0.27 g (1.31×10-3 mol) of dicyclohexylcarbodiimide and 0.03 g of 4-(1-pyrrolidinyl)pyrimidine, 15 ml of methylene chloride was added, followed by 20 hours of stirring at room temperature. After the reaction, the reaction was filtered and the solid was washed with methylene chloride. The filtrate and the washing liquid were dehydrated, and the solvent was distilled off therefrom to obtain a crude product, which was then recrystallized twice to obtain 0.24 g of 2-(1-methylpropyl)-5-[4-(trans-4-n-pentylcyclohexylcarbonyloxy)-phenyl]-1,3,4-thiadiazole. (Yield: 45.2%).
Reaction SMILES: O[CH2:2][C:3]([N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])([CH3:5])[CH3:4].[CH3:17][C:18]1[CH:25]=[C:24]([C:26]2[CH:30]=[CH:29][NH:28][N:27]=2)[CH:23]=[CH:22][C:19]=1[C:20]#[N:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:16]=[C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14](=[O:15])[N:6]1[C:3]([CH3:5])([CH3:4])[CH2:2][N:28]1[CH:29]=[CH:30][C:26]([C:24]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([CH3:17])[CH:25]=2)=[N:27]1
Reactant: Cc1cc(-c2cc[nH]n2)ccc1C#N
Reactant: CC(C)(CO)N1C(=O)c2ccccc2C1=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(-c2ccn(CC(C)(C)N3C(=O)c4ccccc4C3=O)n2)ccc1C#N
Temperature: 25 °C
Yield: 16.3 %

Procedure:
2-(1-hydroxy-2-methylpropan-2-yl)isoindoline-1,3-dione (1.10 g; 5 mmol) and 2-methyl-4-(1H-pyrazol-3-yl)benzonitrile (0.366 g; 2.0 mmol) were dissolved in 5 ml of THF under nitrogen atmosphere. Triphenylphosphine (1.05 g; 4.0 mmol) and DIAD (0.79 ml; 4.0 mmol) were added and the reaction stirred at RT over the weekend. Additional triphenylphosphine (0.525 g; 2.0 mmol) and DIAD (0.39 ml; 2.0 mmol) were added and the mixture was stirred at RT for 2 days and then refluxed for 2 hours. Solvent was evaporated, 50 ml of water was added and the mixture was washed with 3×50 ml of DCM, dried over Na2SO4, filtered and evaporated to dryness. The crude mixture was purified twice by CombiFlash (column: silica, eluent 0-100% EtOAc in heptane) to obtain 125 mg (16%) of the title product. 1H-NMR (400 MHz; CDCl3): δ 1.56 (s, 6H), 2.60 (s, 3H), 4.2-4.38 (m, 2H), 6.50 (d, 1H), 7.33-7.87 (m, 8H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:13]([Mg]Cl)=[CH2:14].[Cl-].[NH4+]>C(OCC)C.[Cu]I>[CH2:1]([O:8][CH2:9][C@H:10]([OH:11])[CH2:12][CH:13]=[CH2:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COC[C@H]2CO2)cc1
Reactant: C=C[Mg]Cl
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CC[C@@H](O)COCc1ccccc1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
A mixture of (2R)-2-[(benzyloxy)methyl]oxirane (9.8 g, 60 mmol) and copper(I) iodide (648 mg, 3.40 mmol) in diethyl ether (150 mL) was cooled to −78° C. Vinylmagnesium chloride (1.6 M solution in tetrahydrofuran; 41.0 mL, 65.6 mmol) was added drop-wise, and the reaction mixture was allowed to warm slowly to room temperature and stir for 18 hours. Ice and saturated aqueous ammonium chloride solution were added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with aqueous ammonium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. This material was used in the following step without further purification. 1H NMR (400 MHz, CDCl3), product peaks only: δ 2.25-2.31 (m, 2H), 3.39 (dd, J=9.4, 7.4 Hz, 1H), 3.53 (dd, J=9.5, 3.4 Hz, 1H), 3.87-3.93 (m, 1H), 4.57 (s, 2H), 5.09-5.16 (m, 2H), 5.78-5.89 (m, 1H), 7.3-7.4 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH2:18][C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:36]=[CH:35][C:31]5[O:32][CH2:33][O:34][C:30]=5[CH:29]=4)[CH2:23][CH2:22]2)=[O:20])[CH2:13][CH2:12]3)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:44][C:45]1[CH:46]=[C:47]([CH:51]=[CH:52][C:53]=1[Cl:54])[C:48](Cl)=[O:49]>C1COCC1.[Cl-].[Na+].O>[O:32]1[C:31]2[CH:35]=[CH:36][C:28]([CH2:27][N:24]3[CH2:23][CH2:22][N:21]([C:19](=[O:20])[CH2:18][N:14]4[C:15]5[C:11](=[CH:10][C:9]([O:8][C:5]6[N:6]=[CH:7][C:2]([NH:1][C:48](=[O:49])[C:47]7[CH:51]=[CH:52][C:53]([Cl:54])=[C:45]([Cl:44])[CH:46]=7)=[CH:3][CH:4]=6)=[CH:17][CH:16]=5)[CH2:12][CH2:13]4)[CH2:26][CH2:25]3)=[CH:29][C:30]=2[O:34][CH2:33]1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(Oc2ccc3c(c2)CCN3CC(=O)N2CCN(Cc3ccc4c(c3)OCO4)CC2)nc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Oc2ccc3c(c2)CCN3CC(=O)N2CCN(Cc3ccc4c(c3)OCO4)CC2)nc1)c1ccc(Cl)c(Cl)c1
Yield: 44 %

Procedure:
2-[5-(5-Aminopyridin-2-yloxy)-2,3-dihydroindol-1-yl]-1-(4-benzo[1,3]dioxol-5-ylmethylpiperazin-1-yl)ethanone (0.240 g, 0.492 mmol) was dissolved in THF (10 mL). To the solution were added triethylamine (0.0686 mL, 0.492 mmol), then 3,4-dichlorobenzoyl chloride (0.103 g, 0.492 mmol), and the resulting solution was stirred for 30 minutes at room temperature. Brine (50 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL). After the organic layer was washed with brine, then dried over anhydrous sodium sulfate, the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (CH2Cl2:MeOH=40:1), to yield 0.143 g of the title compound as a grayish white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:7]=1.[CH:19](OC)(OC)OC>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][CH2:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:19]=[N:18][C:4]=2[CH:3]=1
Reactant: Nc1cc(Br)ccc1NCCCc1ccccc1
Reactant: COC(OC)OC
Product: Brc1ccc2c(c1)ncn2CCCc1ccccc1

Procedure:
A solution of Example 170A (560 mg, 1.83 mmol) in trimethyl orthoformate (10 mL) at 95° C. was stirred for 16 hours and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50-100% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)#[CH:20].[I-]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:20]#[C:19][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: C#Cc1ccccn1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCC1)c1ccc(C#Cc2ccccn2)cc1
Temperature: 70 °C
Yield: 96.7 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (1.0 g, 2.79 mmol) and triethylamine (4 mL, 0.02 mmol) in N,N-dimethylformamide (4 mL) was treated with 2-ethynylpyridine (345 mg, 3.34 mmol). The resulting reaction mixture was degassed with argon for 10 min and then treated with cooper iodide (168 mg, 0.88 mmol) and bis(triphenylphosphine)palladium (II) chloride (305 mg, 0.44 mmol). The reaction was then heated at 70° C. for 1.5 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-pyridin-2-ylethynyl-phenyl)-propionic acid methyl ester (900 mg, 97%) as a yellow oil: EI-HRMS m/e calcd for C22H23NO2 (M+) 333.1728, found 333.1724.