Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:23][C:24]1[S:25][C:26]([CH2:29]Cl)=[CH:27][CH:28]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]([CH2:29][C:26]3[S:25][C:24]([Cl:23])=[CH:28][CH:27]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: ClCc1ccc(Cl)s1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccc(OC)cc23)CC1
Product: CCOC(=O)N1CCC(c2cn(Cc3ccc(Cl)s3)c3ccc(OC)cc23)CC1
Reaction time: 15 h
Yield: 42 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) at room temperature for 15 hours, starting with 0.1 g (0.33 mmol) of 4-(5-methoxy-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 0.052 mL (0.43 mmol) of 2-chloro-5-chloromethyl-thiophene. After standard work-up, 0.06 g (44% of yield) of 4-[1-(5-chloro-thiophen-2-ylmethyl)-5-methoxy-1H-indol-3-yl]-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13]2[N:14]([CH3:21])[N:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)=[CH:10][CH:9]=[C:8]([CH3:22])[N:7]=1)=[O:5])C.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:4]([C:6]2[C:11]([NH:12][C:13]3[N:14]([CH3:21])[N:15]=[C:16]([CH:18]4[CH2:19][CH2:20]4)[CH:17]=3)=[CH:10][CH:9]=[C:8]([CH3:22])[N:7]=2)=[O:5])=[N:25][CH:26]=1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cc(C2CC2)nn1C
Reactant: Nc1ccc(F)cn1
Product: Cc1ccc(Nc2cc(C3CC3)nn2C)c(C(=O)Nc2ccc(F)cn2)n1

Procedure:
The tide compound, was prepared from 3-(5-Cyclopropyl-2-methyl-2H-pyrazol-3-ylamino)-6-methyl-pyridine-2-carboxylic acid ethyl ester and 2-Amino-5-fluoropyridine in accordance with the general method of Example 78, step 2 to yield the final compound as a yellow cristalline solid, MS (ISP): m/e=367.3 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:26])[NH:5][C:6](=[O:25])[N:7]([CH:24]=1)[C@@H:8]1[O:23][C@H:12]([CH2:13][N:14](C)[CH2:15]C2C=CC=CC=2)[C@@H:10]([OH:11])[CH2:9]1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([C:3]1[C:4](=[O:26])[NH:5][C:6](=[O:25])[N:7]([CH:24]=1)[C@@H:8]1[O:23][C@H:12]([CH2:13][NH:14][CH3:15])[C@@H:10]([OH:11])[CH2:9]1)[CH3:2]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CN(C)Cc3ccccc3)O2)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: CCO
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC)O2)c(=O)[nH]c1=O
Yield: 101.9 %

Procedure:
1.1 g of 2',5'-dideoxy-5-ethyl-5'-(N-methyl-N-benzylamino)uridine were taken up in 75 ml of ethanol and 1 g of 5% palladium-on-carbon catalyst in 25 ml of ethanol was added under a nitrogen atmosphere. The mixture was hydrogenated at room temperature and under atmospheric pressure. The catalyst was removed by filtration and the filtrate was evaporated to give 0.84 g of 2',5'-dideoxy-5-ethyl-5'-methylaminouridine of melting point 145°-147° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13](Br)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O>CN1C(=O)CCC1>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N:23]2[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]2)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1NCc1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(NCc3ccccc3)c2)CC1
Temperature: 25 °C
Yield: 68.8 %

Procedure:
A solution of N-benzyl-5-bromo-2-nitrobenzenamine (100 mg, 0.32 mmol) and 1-methylpiperazine (65 mg, 0.65 mmol) in NMP (1 mL) was heated to 110° C. for 16 h. The solution was cooled to room temperature to which was slowly added H2O (5 mL). The resulting yellow precipitate was filtered, washed with 2 mL of water, dried (high vacuum, 14 h) to furnish N-benzyl-5-(4-methylpiperazin-1-yl)-2-nitrobenzenamine (73 mg, 0.22 mmol), 69% yield. 1H NMR (500 MHz, DMSO-D6) d (ppm) 8.81 (m, 1H), 7.90 (d, J=9.5 Hz, 1H), 7.44-7.34 (m, 4H), 7.30-7.25 (m, 1H), 6.41 (dd, J=2.5 Hz, 10 Hz, 1H), 5.97 (d, J=2.5 Hz, 1H), 4.58 (d, J=6 Hz, 2H) 3.4-3.2 (m, 4H), 2.34 (m, 4H), 2.19 (s, 3H).+ESI HRMS (calcd for C18H23N4O2, M+1) 327.1821, found 327.1816
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].N[C:11]1[C:12](C)=CC=C[CH:16]=1>>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:11]([CH3:12])[CH3:16])[C:4]=1[NH2:5])[CH3:2]
Reactant: CCc1ccccc1N
Reactant: Cc1ccccc1N
Product: CCc1cccc(C(C)C)c1N

Procedure:
The procedure of Example 6 was repeated, except that 2-ethylaniline was substituted for ortho-toluidine. Table 5 sets forth the reaction conditions and product selectivity.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[CH2:13][C:14]1[CH:27]=[CH:26][C:25]2[C:24](=[O:28])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:29])[C:16]=2[CH:15]=1>C(O)C.C1COCC1>[CH3:13][C:14]1[CH:27]=[CH:26][C:25]2[C:24](=[O:28])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:29])[C:16]=2[C:15]=1[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=C1c2ccccc2C(=O)c2cc(CBr)ccc21
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1c(C)ccc2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C

Procedure:
Na metal (425 mg, 21.3 mmole) was dissolved in 50 mL of ethanol. To 5 mL of this solution, diethyl malonate (32 mg, 199 μmole) in 5 mL of THF was added, and the mixture was refluxed for 1 hour. 2-bromomethylanthraquinone (Compound 4.1) (50 mg, 166 μmole) in 5 mL of THF was then added to the refluxing reaction mixture. The reaction was refluxed for 8 hours, cooled to room temperature, and then quenched with 5 mL of saturated NH4Cl solution. The mixture was concentrated under vacuum, and redissolved in 20 mL of ethyl acetate for H2O extraction. The organic layer was dried over MgSO4 and filtered, and the solvent was removed under reduced pressure. The residue was purified by flash silica column chromatography to yield 41 mg (54 %). 1H NMR (300 MHz, CDCl3) δ 8.11 (2H, m), 7.96 (1H, s), 7.88 (1H, d), 7.64 (1H, d), 7.37 (2H, m), 4.61 (2H, d), 4.20 (5H, m), 1.21 (6H, t).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH2:11][CH3:12])=O.[NH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([C:23](=[S:25])[NH2:24])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[CH2:11]([C:10]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:3]1[N:24]=[C:23]([C:20]2[CH:19]=[CH:18][C:17]([S:14]([NH2:13])(=[O:15])=[O:16])=[CH:22][CH:21]=2)[S:25][CH:2]=1)[CH3:12]
Reactant: NC(=S)c1ccc(S(N)(=O)=O)cc1
Reactant: CCc1ccncc1C(=O)CBr
Product: CCc1ccncc1-c1csc(-c2ccc(S(N)(=O)=O)cc2)n1
Yield: 51.7 %

Procedure:
By the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(4-ethylpyridin-3-yl)ethanone hydrobromate (161 mg) and 4-(aminosulfonyl)benzenecarbothioamide (109 mg), the title compound (90 mg) was obtained as colorless powder crystals.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]([CH3:22])=[N:20][N:21]=2)=[CH:13][C:12]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:31])=O)=[CH:25][CH:24]=1.[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36][NH2:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:32][N:33]([CH2:34][CH2:35][CH2:36][NH:37][C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:12]2[CH:13]=[C:14]([C:17]3[O:18][C:19]([CH3:22])=[N:20][N:21]=3)[CH:15]=[CH:16][C:11]=2[CH3:10])=[CH:28][CH:27]=1)=[O:31])[CH3:38]
Reactant: CN(C)CCCN
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCCCN(C)C)cc3)c2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
DIPEA (76 μl, 0.6 mmol) was added to a solution of 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid (59 mg, 0.2 mmol), 3-dimethylaminopropylamine (20 mg, 0.2 mmol), HBTU (91 mg, 0.24 mmol) and HOBT (27 mg, 0.2 mmol) in DMF (0.5 ml). The reaction was stirred at room temperature for 16 h. The DMF was evaporated under vacuum and the residue partitioned between DCM (5 ml) and water (5 ml). The organic phase was absorbed onto a silica flash column and eluted with DCM/ethanol/ammonia (80:8:1). The product fractions were concentrated under vacuum to give N-[(dimethylamino)propyl]-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide (37 mg, 49%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:27]([Cl:28])[C:21]=2[N:20]=1>>[Cl:28][C:27]1[C:21]2[N:20]=[C:19]([N:15]3[CH2:16][CH2:17][N:12]([C:3]4[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:5][N:4]=4)[CH2:13][CH2:14]3)[NH:23][C:22]=2[CH:24]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:26]=1
Reactant: FC(F)(F)c1cc(Cl)c2nc(Cl)[nH]c2c1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(Cl)c1
Product: FC(F)(F)c1cnc(N2CCN(c3nc4c(Cl)cc(C(F)(F)F)cc4[nH]3)CC2)c(Cl)c1

Procedure:
The reaction of 1-(3-chloro-5-trifluoromethylpyridin-2-yl)piperazine (186 mg, 0.7 mmol, ABCR) and 2,4-dichloro-6-trifluoromethyl-1H-benzoimidazole (127 mg, 0.5 mmol, Example 5b) under the conditions of Example 3c afforded the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 484 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)=[O:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=[O:32])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2ccccc2C(F)(F)F)CC1
Reactant: CN1CCN(C(=O)CCl)CC1
Product: CN1CCN(C(=O)Cn2cc(C(=O)N3CCC(c4ccccc4C(F)(F)F)CC3)c3ccc(Cl)cc32)CC1

Procedure:
Analogous to general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-trifluoromethyl-phenyl)-piperidin-1-yl]-methanone (prepared herein) with (commercially available) 2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][NH:27][CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:30][CH2:31][C:32](Cl)=[O:33]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][N:27]([C:32](=[O:33])[CH2:31][Cl:30])[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCC2
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(C(=O)CCl)CC2
Reaction time: 1 h
Yield: 100.1 %

Procedure:
4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (75 mg, 0.16 mmol) was dissolved in a mixture of CH2Cl2 (1 mL) and sat. NaHCO3 solution (1 mL) and chloroacetyl chloride (28 mg, 0.25 mmol) was added. The reaction mixture was vigorously stirred for 1 h then the phases were separated. The aqueous phase was extracted with CH2Cl2 and the combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness providing the title compound (74 mg, 97%) as a beige solid which was a mixture of rotamers: ESI MS m/z 462 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]1([C:26]([OH:28])=O)[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([OH:25])=O)[CH:18]=1>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:23](=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:26]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:28])[CH:18]=1)=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1cccc(C(=O)O)c1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)c1cccc(C(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)c1
Yield: 72.1 %

Procedure:
Using General Procedure A with 5.8 g (24.0 mmol) D-Proline benzyl ester hydrochloride and 2.0 g (12.0 mmol) benzene-1,3-dioic acid afforded, after flash chromatography (EtOAc), 4.68 g (72%) of the title compound as a yellow oil. MS m/e (%): 558 (M+NH4+, 100), 541 (M+H+, 90).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[S:7]([Cl:10])(=[O:9])=[O:8].[S][Cl:13].O>S(Cl)(Cl)(=O)=O.[Cl-].[Cl-].[Cl-].[Al+3]>[Cl:1][C:2]1[S:3][C:4]([Cl:11])=[C:5]([Cl:13])[C:6]=1[S:7]([Cl:10])(=[O:8])=[O:9]
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Reactant: [S]Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(=O)(Cl)Cl
Solvent: O
Product: O=S(=O)(Cl)c1c(Cl)sc(Cl)c1Cl
Temperature: 60 °C
Yield: 991.6 %

Procedure:
A mixture of 2,5-dichlorothiophene-3-sulfonyl chloride (1.2 g, 5 mmol) and sulfur monochloride (10 mg) in sulfuryl chloride (500 mg) was heated at 60° C. for 30 min, at which time was added dropwise a mixture of aluminum trichloride (10 mg) in sulfuryl chloride (500 mg). The reaction was heated at 60° C. for an additional 3 hours, at which time it was allowed to cool to ambient temperature. Cold water (20 mL) was added and the reaction extracted with dichloromethane (2×20 mL). The combined organic layers were washed with saturated sodium bicarbonate solution, dried (Mg2SO4) and concentrated to furnish a tan solid (420 mg, 33%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](O)=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:21]([O-:23])=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[CH:34]1([O:39][C:40](=[O:47])[C@H:41]([CH2:43][CH:44]([CH3:46])[CH3:45])[NH2:42])[CH2:38][CH2:37][CH2:36][CH2:35]1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl.Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:19])[NH:42][C@H:41]([C:40]([O:39][CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38]2)=[O:47])[CH2:43][CH:44]([CH3:46])[CH3:45])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N+:21]([O-:23])=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Reactant: CC(C)(C)OC(=O)N1Cc2cc([N+](=O)[O-])ccc2C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@@H]1Cc2ccc([N+](=O)[O-])cc2CN1C(=O)OC(C)(C)C)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.4 %

Procedure:
(S)-7-Nitro-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid-2-tert-butyl ester (2.5 g, 7.76 mmol) was dissolved in DCM (100 ml). HOBt (1.16 g, 8.53 mmol) was added, L-leucine cyclopentyl ester (3.19 g, 8.53 mmol) was added followed by triethylamine (2.38 ml, 17.1 mmol). EDCl.HCl (1.46 g, 8.5 mmol) was added and the reaction stirred at room temperature for 16 h. To the reaction was added DCM (100 ml) and the organic layer washed with water (3×300 ml), dried with Na2SO4 and the solvent removed in vacuo. The crude product was purified by chromatography (EtOAc:heptane 1:2→EtOAc) to give the required product 3.14 g (82% yield), LCMS purity 100%, m/z 504 [M++H]+
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)([F:4])[F:3].[Na].Br[CH:15]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:18])=[O:17]>>[F:1][C:2]([F:4])([F:3])[S:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C@H:15]([C:16]([OH:18])=[O:17])[CH:19]([CH3:21])[CH3:20])=[CH:8][CH:7]=1
Reactant: Nc1ccc(SC(F)(F)F)cc1
Reactant: CC(C)C(Br)C(=O)O
Agent: [Na]
Product: CC(C)[C@H](Nc1ccc(SC(F)(F)F)cc1)C(=O)O

Procedure:
Alternatively, using the procedure of Example 38, p-aminophenyl trifluoromethyl sulfide is reacted with the sodium salt of α-bromoisovaleric acid to yield N-(4-trifluoromethylthiophenyl)valine, which is esterified to yield the m-phenoxybenzyl ester of N-(4-trifluoromethylthiophenyl)valine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:9])([O:11][CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])[CH3:10])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(O)c1ccc(Br)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(OCOCC[Si](C)(C)C)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine from Step 1 (14 mmol) in methylene chloride (50 mL) at 0° C. was added N,N-diisopropylethylamine (37.3 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (15.3 mmol). The resulting mixture was stirred at room temperature for 18 hours, then refluxed for 24 hours. After cooling to room temperature the mixture was quenched with saturated aqueous ammonium chloride solution and partitioned between methylene chloride and water. The crude product from the organic phase was chromatographed on silica gel eluting with 6% ethyl acetate in hexane to afford the 5-bromo-2-(1-methyl-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)pyridine compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-])=O)[CH:30]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1>CCOC(C)=O.CCO.[Pt]=O>[NH2:35][C:31]1[CH:30]=[C:29]([CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:14]2[CH2:13][C@@H:12]([C:10]3[CH:9]=[CH:8][C:6]4[O:7][C:2]([CH3:1])([CH3:38])[O:3][CH2:4][C:5]=4[CH:11]=3)[O:16][C:15]2=[O:17])[CH:34]=[CH:33][CH:32]=1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc([N+](=O)[O-])c4)C(=O)O3)ccc2O1
Agent: O=[Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(N)c4)C(=O)O3)ccc2O1
Yield: 107.1 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-{6-[2-{(3-nitro-phenyl)methoxy}ethoxy]hexyl}-1,3-oxazolidin-2-one (9.50 g) in EtOAc (120 ml) and EtOH (120 ml) was hydrogentated over platinum oxide (0.20 g) for 1.75 h. The mixture was filtered through celite and washed with EtOH. Solvent evaporation in vacuo gave the title compound (9.60 g). LCMS RT=3.25 min, ES+ve 499 (MH)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[N:5][N:4]=[N:3]1.C([Li])CCC.[CH3:13][C:14]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:15]=1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[CH3:25])=[O:17]>O1CCCC1>[CH3:25][C:19]1[CH:20]=[C:21]([CH3:24])[CH:22]=[CH:23][C:18]=1[C:16]([C:15]1[CH:26]=[CH:27][C:28]([CH3:30])=[CH:29][C:14]=1[CH3:13])([OH:17])[CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[N:4][N:5]=1
Reactant: Cc1ccc(C(=O)c2ccc(C)cc2C)c(C)c1
Reactant: Cc1nnnn1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C(O)(Cc2nnnn2C)c2ccc(C)cc2C)c(C)c1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
A solution of 1,5-dimethyltetrazole (8.9 g, 91.0 mmoles) in 100 mL of dry tetrahydrofuran at -60° C. was treated with n-butyl lithium (48 mL of 1.89M solution, 91.0 mmoles). After stirring for 20 minutes, 2,2',4,4'tetramethylbenzophenone (18 g, 76 mmoles) [prepared by the procedure described in J. Am. Chem. Soc., 81, 4858 (1959)] in 50 mL dry tetrahydrofuran was added and the solution was stirred for 1 hour during which time it was allowed to warm to -20° C. The reaction was quenched with 1N HCl, then extracted with chloroform. The combined organic extracts Were dried (MgSO4) and evaporated to give 22 g of the title compound; m.p.=175°-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(C)(CN)c1nc(-c2ccc(Cl)cc2)cs1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1nc(-c2ccc(Cl)cc2)cs1
Yield: 35 %

Procedure:
This compound was synthesized from 2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (80 mg, yield 35%): 1H NMR (400 MHz, CDCl3) δ 8.54 (m, 1H), 8.27 (d, J=7.8 Hz, 1H), 8.10-8.04 (m, 2H), 7.82-7.80 (d, J=8.5 Hz, 2H), −7.62-7.58 (t, J=7.8 Hz, 1H), 7.42 (s, 1H), 7.33 (d, J=8.5 Hz, 2H), 3.82 (d, J=5.8 Hz, 2H), 1.58 (s, 6H). MS (ESI) m/z: Calculated for C23H18ClF3N4O2S: 506.08. found: 507.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([O:18]C)=[O:17])[CH:15]=[C:10]3[C:9]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:8]2)=[CH:4][CH:3]=1.O.[OH-].[Li+].O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=[O:17])[CH:15]=[C:10]3[C:9]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:8]2)=[CH:26][CH:27]=1
Reactant: COCCOCc1cn(Cc2ccc(F)cc2)c2cnc(C(=O)OC)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCCOCc1cn(Cc2ccc(F)cc2)c2cnc(C(=O)O)cc12
Temperature: 40 °C

Procedure:
To a solution of methyl 1-(4-fluorobenzyl)-3-[(2-methoxyethoxy)methyl]-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (542 mg 1.4645 mmol) in THF (10 mL) was added lithium hydroxide monohydrate (123 mg 2.929 mmol, 2 eq.) and water (5 mL) and the clear solution was warmed to 40° C. for 3 hours. THF was removed under vacuum and 1 M HCl added (2.93 mL 2.93 mmol, 2 eq.) the crude product was extracted into EtOAc (3×30 mL) then DCM:MeOH 100:5 (3×30 mL). The organics were dried (Na2SO4) volatiles were removed in vacuo to give the title product as a cream colored powder 400 mg (76%). LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—5 minutes, ESI, +mode): RT—1.753 min, m/e=359.1 (M+H+, base). 1H-NMR (300 MHz, CD3OD): δ=3.68 (s, 3H), 3.60 (m, 2H), 3.73 (m, 2H), 4.86 (s, 2H), 5.64 (s, 2H), 7.12 (m, 2H), 7.36 (m, 2H), 8.06 (s, 1H), 8.3 (s, 1H), 8.86 (s, 1H).