Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=O.[CH2:25]([N:27]([CH2:30][CH2:31][CH2:32][CH2:33][C:34](=O)[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:28][CH3:29])[CH3:26]>>[CH2:25]([N:27]([CH2:30][CH2:31][CH2:32][CH2:33][C:34]1[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=2)[C:4]2[C:3](=[CH:20][C:19]([O:21][CH3:22])=[C:18]([O:23][CH3:24])[CH:17]=2)[N:2]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: CCOC(=O)CC(=O)CCCCN(CC)CC
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Agent: Cl
Product: CCOC(=O)c1c(CCCCN(CC)CC)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
According to the same manner as that described in Example 49, 2-amino-4,5,3',4'-tetramethoxybenzophenone hydrochloride was reacted with ethyl 7-(N,N-diethylamino)-3-oxoheptanoate to give ethyl 2-[4-(N,N-diethylamino)butyl]-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline-3-carboxylate. This compound was recrystallized from ethyl acetate - hexane. Colorless prisms, mp. 171°-172° C.
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.[CH2:6]([O:13][CH2:14][CH2:15][CH2:16]CO)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:6]([O:13][CH2:14][CH2:15][CH2:16][CH2:2][Br:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCCOCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCCOCc1ccccc1
Temperature: -15 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
239 g of tetrabromomethane are added in portions to the solution of 105 g of 4-benzyloxybutan-1-ol and 191 g of triphenylphosphine in 1 l of methylene chloride cooled to −15° C. and the mixture is stirred at 0° C. for 1 h after addition is complete. After the reaction mixture has been concentrated in vacuo, purification is carried out by chromatography on silica gel using a hexane-ethyl acetate gradient. 133 g of 4-benzyloxy-1-bromobutane are obtained as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[N:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([NH:27][CH2:28][C@@H:29]3[C@H:34]([CH3:35])[CH2:33][CH2:32][CH2:31][NH:30]3)=[N:24][C:23]=2[CH:36]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([NH:27][CH2:28][C@@H:29]3[C@H:34]([CH3:35])[CH2:33][CH2:32][CH2:31][N:30]3[C:7]([C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:11]3[N:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=3)=[O:9])=[N:24][C:23]=2[CH:36]=1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Reactant: Cc1ccc(-c2nccc(C)n2)c(C(=O)O)c1
Product: Cc1ccc(-c2nccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(4-methylpyrimidin-2-yl)benzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 490 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([S:16]([F:19])(=[O:18])=[O:17])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].[I:22]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>FC(F)(F)S(O)(=O)=O>[F:21][C:2]([F:1])([F:20])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[C:12]([I:22])=[CH:13][C:14]([S:16]([F:19])(=[O:17])=[O:18])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(N1CCc2ccc(S(=O)(=O)F)cc2CC1)C(F)(F)F
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: O=S([O-])[O-]
Product: O=C(N1CCc2cc(S(=O)(=O)F)cc(I)c2CC1)C(F)(F)F
Reaction time: 1 h
Yield: 67.8 %

Procedure:
To a solution of 3-trifluoroacetyl-1,2,4,5-tetrahydro-3-benzazepine-7-sulfonyl fluoride (D1) (5.3 g, 17 mmol) in trifluoromethanesulfonic acid (30 ml) at 0° C. was added portionwise N-iodosuccinimide (5.9 g, 25 mmol). The resulting solution was stirred for 1 h without cooling then poured into saturated aqueous sodium hydrogencarbonate (200 ml) containing sodium sulfite (1 g), extracted with ethyl acetate (100 ml), and the resulting organic layer washed with brine (100 ml), dried (MgSO4), and evaporated. Chromatography on silica, eluting with 3:1 hexane:ethyl acetate gave the subtitle compound as a white solid (5.2 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:14]2[C:19]([C:20]3[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=3)C#N)=C(C3C=CC=CC=3)[NH:17][C:16](=[O:34])[NH:15]2)[CH:7]=[C:8]([N+]([O-])=O)[C:9]=1[OH:10])C.[CH2:35]([O:37][C:38]1[CH:39]=[C:40]([CH:43]=[C:44]([N+:47]([O-:49])=[O:48])[C:45]=1[OH:46])[CH:41]=O)[CH3:36].NC(N)=O.Cl>C(O)C>[O:10]1[C:9]2[CH:8]=[CH:7][C:6]([C:14]3[NH:15][C:16](=[O:34])[NH:17][CH:41]([C:40]4[CH:43]=[C:44]([N+:47]([O-:49])=[O:48])[C:45]([OH:46])=[C:38]([O:37][CH2:35][CH3:36])[CH:39]=4)[C:19]=3[C:20]3[CH:27]=[CH:26][CH:25]=[CH:22][CH:21]=3)=[CH:5][C:4]=2[O:3][CH2:1]1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2cccc(C#N)c2)cc([N+](=O)[O-])c1O
Agent: Cl
Agent: NC(N)=O
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccc4c(c3)OCO4)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 130 °C
Reaction time: 8 h
Yield: 11.4 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)-2-phenylethanone (Intermediate 29) (400 mg, 1.7 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (352 mg, 1.7 mmol), and urea (230 mg, 5.0 mmol) in 10 mL of ethanol was added 0.2 mL of concentrated HCl solution, the mixture was stirred at 130° C. overnight. After the solvent was removed under reduced pressure, the residue was purified by preparative HPLC (35-65% acetonitrile+0.1% trifluoroacetic acid in water, over 15 min.) to give Compound 61 (92.5 mg, yield 11.7%). 1H NMR (CD3OD 400 MHz): δ 7.60 (s, 1H), 7.18 (s, 1H), 7.12-7.09 (m, 3H), 6.92 (d, J=7.2 Hz, 2H), 6.78 (d, J=8.0 Hz, 1H), 6.71 (m, 2H), 5.92 (s, 2H), 5.32 (s, 1H), 4.11-4.03 (m, 2H), 1.41 (t, J=7.2 Hz, 3H); MS (ESI): m/z 476.3 [M+1]+.
Reaction SMILES: [Br-].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[C:12]1(C)C=CC=CC=1.[CH3:19][C:20]1[CH:21]=[C:22]([C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=1)[CH:23]=O.Cl>C1COCC1>[CH3:19][C:20]1[CH:21]=[C:22]([C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=1)[CH:23]=[CH2:12]
Reactant: Cc1ccccc1
Reactant: Cc1ccc([N+](=O)[O-])c(C=O)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cc(C)ccc1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
To a suspension of methyltriphenylphosphnium bromide (18.86 g, 52.8 mmol) in THF (120 mL) was added 0.5M potassium hexamethyldisilazide in toluene (106 mL, 53.0 mmol) at -10° C. The mixture was stirred for 40 min at the same temperature and 3-methyl-6-nitrobenzaldehyde (8.0 g, 48 mmol) in THF (60 mL) was added. The mixture was stirred for 1 h at -10° C. and 0.2N hydrochloric acid (400 mL) was added. The mixture was extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with 15:1 hexane/ethyl acetate to give 5.10 g of the title compound (65%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[C:27]([NH:31][C:32]([CH2:34][CH2:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][C:32]([CH2:34][CH2:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][NH:41][C:3]2[C:4]3[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6][C:5]=3[CH:17]=[CH:18][C:2]=2[Cl:1])=[CH:38][CH:37]=1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(C)(C)NC(=O)CCc1ccc(CN)cc1
Product: CC(C)(C)NC(=O)CCc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 73.5 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (85 mg, 0.2 mmol) and 4-[2-(tert-butylcarbamoyl)-ethyl]-benzylamine (80 mg, 0.34 mmol). Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (95:5 to 1:1 gradient) to obtain 6-{4-[2-(tert-butylcarbamoyl)-ethyl]benzylamino}-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (75 mg, 74%). MS (ES+) m/z: 510 (M+H)+.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[CH3:47][O:48][C:49](=[O:64])[C:50]1[CH:55]=[CH:54][C:53](Cl)=[N:52][C:51]=1[C:57]1[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=1.C([NH:72][C:73]1[C:78]([F:79])=[CH:77][CH:76]=[CH:75][C:74]=1[F:80])(OC(C)(C)C)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl.CCOCC>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O>[CH3:47][O:48][C:49](=[O:64])[C:50]1[CH:55]=[CH:54][C:53]([NH:72][C:73]2[C:78]([F:79])=[CH:77][CH:76]=[CH:75][C:74]=2[F:80])=[N:52][C:51]=1[C:57]1[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=1
Reactant: CC(C)(C)OC(=O)Nc1c(F)cccc1F
Reactant: COC(=O)c1ccc(Cl)nc1-c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Nc2c(F)cccc2F)nc1-c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a nitrogen purged flask was charged palladium acetate (13.2 g, 59 mmoles, 0.04 eq), racemic BINAP (36.6 g, 59 mmoles, 0.04 eq), followed by 1.9 L toluene. The heterogeneous slurry was heated to 50° C. under nitrogen for 2 hours, cooled to 30° C., then the pyridyl chloride 41 (386.4 g, 1.45 moles, 1.0 eq) and Boc-2,6-difluoroaniline 42 (386.4 g, 1.69 moles, 1.2 eq), and K3PO4 (872 g, 4.1 moles, 2.8 eq) were added all at once followed by a 1.9 L toluene rinse. The heterogeneous reaction mixture was heated to 100° C. overnight and monitored by HPLC. When the reaction showed complete conversion to 43 by HPLC [Tret 41=17 min, Tret 43=20.5 min, Tret 44=17.6 min, monitored at 229 nm] (usually between 18–20 hours) the reaction was cooled to room temperature and the contents diluted with 1.94 L EtOAc. To this was added 1×1.94 L of 6N HCl, and both layers were filtered through celite. The celite wet cake was rinsed with 2×1.9 L EtOAc. The layers were separated and the organic layer washed with 1×1.9 L of brine, dried (MgSO4), filtered and concentrated to a brown, viscous oil. To remove the Boc-protecting group, the oil was dissolved in 1.94 L of methylene chloride and 388 mL TFA was added. The reaction was stirred overnight to facilitate Boc removal. The volatiles were removed in vacuo, EtOAc (1.9 L) and sufficient quantity of 1 or 6N NaOH was added until the pH was 2–7. Then a sufficient quantity of 5% NaHCO3 was added to bring the pH to 8–9. The organic layer was separated and washed with 1×5% NaHCO3, dried (MgSO4), filtered an concentrated to a brown oil/liquid. The crude oil/liquid was azeodried twice with a sufficient quantity of toluene. At times the free base precipitated out resulting in a slurry. The residue was dissolved in 500 mL toluene and 1.6 L 1N HCl/ether solution was added, which resulted in the solids crashing out. Heat was applied until the homogenized/solids broke up. If necessary, 200 mL of EtOAc can be added to facilitate the break up. After cooling, the solid 44 was isolated by vacuum filtration.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][NH:5][CH:6]=1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Cl)Cl.O>CCOCC>[CH3:1][C:2]1[C:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][NH:5][C:6]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1c[nH]cc1C
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c[nH]c(C(=O)c2ccccc2)c1C

Procedure:
Ethyl 4-methylpyrrole-3-carboxylate (920 mg., 6 mmoles) was combined with benzoyl chloride (0.7 ml., 6 mmoles), stannic chloride (1.2 ml., 12 mmoles) in 25 ml. of methylene chloride and stirred under nitrogen for 2 hours at room temperature. Water (15 ml.) was added slowly, dissolving the precipitate which had formed. Ether (50 ml.) was then added, and the organic phase separated, back-washed with 20 ml. of water, and evaporated to an oil. The oil was triturated with hexane to yield crystalline product (1.12 g.). Recrystallization from acetone/hexane afforded purified ethyl 4-methyl-5-benzoylpyrrole-3-carboxylate (900 mg., m.p. 127°-129° C.).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C=O)C>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:17][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1
Reactant: COC(CN)OC
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc([N+](=O)[O-])c(NCC(OC)OC)n1
Temperature: 40 °C

Procedure:
A mixture of 2-chloro-6-(methyloxy)-3-nitropyridine (10 g, 53 mmol), aminoacetaldehyde dimethylacetal (5.6 g, 6.2 ml, 53 mmol) and potassium carbonate (7.4 g, 53 mmol) in acetonitrile (100 mL) and DMF (10 mL) was heated at 40° C. for 30 minutes. The mixture was filtered and extracted with DCM and brine. The organic extract was added to a silica column which was then eluted with 0-100% ethyl acetate in hexane affording a yellow solid (12.4 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22][CH2:23][C:24](OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.C(OC(=O)CN)(C)(C)C.[NH2:47][C:48]1C=NC=[CH:52][CH:53]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][C@@H:19]([C:20]([NH:22][C:23]2[CH:24]=[N:47][CH:48]=[CH:53][CH:52]=2)=[O:21])[CH2:31][CH3:32])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1
Reactant: Nc1cccnc1
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1cccnc1

Procedure:
Instead of the starting material compound of Example 220, that is, glycine tert-butyl ester hydrochloride, 3-aminopyridine was used for the similar procedure as in Example 220 to obtain the title compound.
Reaction SMILES: [NH2:1]N.C[N:4](/[CH:6]=[C:7]1/[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][C:11]/1=O)C>C(O)C>[NH:1]1[C:11]2[CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][C:7]=2[CH:6]=[N:4]1
Reactant: CN(C)/C=C1/CN(C(=O)OC(C)(C)C)CC1=O
Reactant: NN
Solvent: CCO
Product: CC(C)(C)OC(=O)N1Cc2cn[nH]c2C1

Procedure:
A solution of hydrazine (3 mL) and tert-butyl (3Z)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1-carboxylate (19.22 g) in ethanol (40 mL) was heated at 85° C. in a sealed tube for 4 h. Solvent was removed under reduced pressure, and the residue was triturated with dichloromethane (160 mL) and ethyl acetate (15 mL). The resulting solid was filtered. The filtrate was concentrated and the resulting solid was triturated again. The combined solids were used in the next step.
Reaction SMILES: C(OC([NH:8][CH:9]([CH:13]([CH3:16])[CH:14]=[CH2:15])[C:10]([OH:12])=[O:11])=O)(C)(C)C.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)(O)[O-].[Na+]>C(O)=O>[NH2:8][CH:9]([CH:13]([CH3:16])[CH:14]=[CH2:15])[C:10]([O:12][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:11]
Reactant: C=CC(C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: C=CC(C)C(N)C(=O)OCc1ccccc1

Procedure:
The substrate tripeptide A used in the process, δ-(L-α-aminoadipoyl)-L-cysteinyl-D-γ,δ-didehydroisoleucine, is prepared in the following manner. First, 2-(t-butyloxycarbonylamino)-3-methylpent-4-eneoic acid (prepared according to the method of P. A. Bartlett and J. F. Barstow, J. Org. Chem., 1982, 47, 3933) is esterified with benzyl bromide and sodium bicarbonate. The benzyl ester is treated with formic acid to remove the t-BOC amino-protecting group to provide the amino ester, benzyl 2-amino-3-methylpent-4-eneoate, as the formate salt as shown below. ##STR3##
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[CH3:19][S:20]([C:23]1[S:27][C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:25][CH:24]=1)(=[O:22])=[O:21]>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:31]1[CH2:32][CH2:33][N:28]([C:26]2[S:27][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:24][N:25]=2)[CH2:29][CH2:30]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)c1cnc(N2CCNCC2)s1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(C)(=O)=O)s2)CC1
Yield: 43 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(5-methanesulfonyl-thiazol-2-yl)-piperazine hydrochloride. The crude material was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a white crystalline solid (yield 43%). MS (m/e): 488.1 (M+H+, 100%), 505.0 (M+NH4+, 75%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[O:24]1[C:28]2[CH:29]=[CH:30][C:31](B(O)O)=[CH:32][C:27]=2[O:26][CH2:25]1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[O:24]1[C:28]2[CH:29]=[CH:30][C:31]([C:2]3[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=3[O:22][CH3:23])[C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:32][C:27]=2[O:26][CH2:25]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: COc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1ccc2c(c1)OCO2

Procedure:
3-Bromo-4-methoxy-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 30.1, 60 mg, 0.154 mmol), benzo[d][1,3]dioxol-5-ylboronic acid (33.2 mg, 0.200 mmol), (Ph3P)4Pd (9 mg, 6.94 μmol), 2 M Na2CO3 (0.115 mL, 0.231 mmol), DME (2.4 mL) and water (0.8 mL) were subjected to MW irradiation at 150° C. for 10 min. The RM was filtered through a PL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL), the cartridge was washed with MeOH (10 mL) and the combined filtrates were evaporated under reduced pressure to give the crude product was purified by preparative HPLC to afford the title compound. UPLC-MS (Condition 6) tR=2.37 min, m/z=432.3 [M+H]+.
Reaction SMILES: [C:1]([NH:4][CH:5]([S:16][CH3:17])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2].[C:18](NC(OCC)C(NCC1C=CC=CC=1)=O)(=O)C.CCS>>[C:1]([NH:4][CH:5]([S:16][CH2:17][CH3:18])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CSC(NC(C)=O)C(=O)NCc1ccccc1
Reactant: CCOC(NC(C)=O)C(=O)NCc1ccccc1
Solvent: CCS
Product: CCSC(NC(C)=O)C(=O)NCc1ccccc1
Yield: 38 %

Procedure:
Using the procedure described for the synthesis of 2-acetamido-N-benzyl-2-(methylmercapto)acetamide, 2-acetamido-N-benzyl-2-ethoxyacetamide (2.00 g, 8.0 mmol) and EtSH (0.65 g, 10.4 mmol) were converted to 0.80 g (38%) of the desired product. The compound was further purified by recrystallization from chloroform/hexane to give a beige solid. Rf 0.60 (4% MeOH/CHCl3). mp 146°-148° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:10]1([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CN1CCCC1=O.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([N:16]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: c1ccc(NC2CCCCC2)cc1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Clc1ncc(Br)c(N(c2ccccc2)C2CCCCC2)n1
Temperature: 120 °C
Yield: 20.4 %

Procedure:
5-Bromo-2,4-dichloropyrimidine (2.17 ml, 17.14 mmol) and cyclohexyl-phenyl-amine (2.0 g, 11.43 mmol) were dissolved in N-methylpyrrolidone (NMP) (25 ml), and this reaction was heated to 120° C. for 24 hours. The reaction was cooled to room temperature and diluted with ethyl acetate, washed with water and brine. The organic phase was dried using sodium sulfate and concentrated. Purification by flash chromatography (ethyl acetate/hexane) gave compound 37 as a yellow solid (855 mg, 24%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.27 (1 H, s), 7.41 (3 H, m), 7.21 (2 H, m), 4.62 (1 H, m), 1.93 (2 H, d, J=10 Hz), 1.75 (2 H, d, J=10 Hz), 1.58 (1 H, d, J=10 Hz), 1.34 (2 H, m), 1.15 (2 H, m), 0.91 (1 H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[CH2:25](Br)[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>COCCOC>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:25][CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:22])[CH3:10]
Reactant: CCOC(=O)C(Cc1cccc2ccccc12)C(=O)OCC
Reactant: BrCC=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(CC=Cc1ccccc1)(Cc1cccc2ccccc12)C(=O)OCC
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To a solution of 1.50 g of 2-(1-naphthylmethyl)malonic acid diethyl ester in 20 ml of 1,2-dimethoxyethane was added 0.3 g of a 50% sodium hydride (suspension in oil) under cooling, and then the mixture was stirred for 1 hour. To the mixture was added 1.18 g of cinnamyl bromide, and the mixture was heated under reflux for 5 hours. After cooling, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The ethereal layer was washed with a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The ethereal layer was concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (eluent: benzene/hexane=1/1 by volume) to obtain 1.6 g of 2-cinnamyl-2-(1-naphthylmethyl)malonic acid diethyl ester as a colorless oil.