Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[O:20][CH3:21])[C:4]=1[C:22]([OH:24])=O.C(N(CC)CC)C.S(Cl)(Cl)=O.[CH2:36]([N:38]([CH2:41][CH:42]([OH:45])[CH2:43][NH2:44])[CH2:39][CH3:40])[CH3:37]>C(Cl)Cl>[CH2:36]([N:38]([CH2:41][CH:42]([OH:45])[CH2:43][NH:44][C:22]([C:4]1[N:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[O:20][CH3:21])[C:6]2[C:11]([C:3]=1[O:2][CH3:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:24])[CH2:39][CH3:40])[CH3:37]
Reactant: COc1ccc(-n2c(C(=O)O)c(OC)c3ccccc32)c(OC)c1
Reactant: CCN(CC)CC(O)CN
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN(CC)CC(O)CNC(=O)c1c(OC)c2ccccc2n1-c1ccc(OC)cc1OC
Temperature: 0 °C

Procedure:
16.8 g of 3-methoxy-1-(2',4'-dimethoxyphenyl)-indole-2-carboxylic acid and 7 ml of triethylamine are dissolved in 50 ml of methylene chloride and the solution is added dropwise to 4 ml of thionyl chloride in 5 ml of methylene chloride. 8 g of 3-(N,N-diethylamino)-2-hydroxypropylamine dissolved in 10 ml of methylene chloride are added dropwise to this solution. The solution is poured into ice-water, the mixture is extracted with methylene chloride and the organic phase is washed with water, dried and evaporated. The 2-[3-(N,N-diethylamino)-2-hydroxypropylaminocarbonyl]-3-methoxy-1-(2',4'-dimethoxyphenyl)-indole which remains is dissolved in isopropanol, and gaseous hydrogen chloride is added to the solution, whereupon the hydrochloride of the title compound crystallises out. Yield: 13.4 g, melting point: 166°-168° C.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)([O-:4])=[O:3].[N+]([C:22]1C=CC(CCBr)=CC=1)([O-])=O.N1(C(OC(C)(C)C)=O)CCCNCC1>>[ClH:1].[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][N:13]2[CH2:22][CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Agent: CC(C)(C)OC(=O)N1CCCNCC1
Agent: Cl
Product: O=[N+]([O-])c1ccc(CCN2CCCNCC2)cc1

Procedure:
1-[2-(4-nitrophenyl)ethyl]-1,4-diazepane hydrochloride was prepared in an analogous fashion to that described above for 1-[2-(4-nitrophenyl)ethyl]piperazine hydrochloride starting with 4-nitrophenethyl bromide and tert-butyl 1,4-diazepane-1-carboxylate. LC-MS: M+1=250.2.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[NH:20][C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[CH:13]=2)=[CH:3]1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:8][CH:9]=2)[C:4]([C:12]2[NH:20][C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[CH:13]=2)=[CH:3]1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(-c2cc3cccnc3[nH]2)c2cc(N)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(-c2cc3cccnc3[nH]2)c2cc(NS(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indol-5-ylamine [52.4 mg, Example 18] in dichloromethane (5 mL) was treated with triethylamine (30 μl) followed by methane sulfonyl chloride (17 μl). After stirring at ambient temperature for 16 hours the reaction mixture was diluted with dichloromethane (10 mL), then washed with water (10 mL), then washed with brine (10 mL), then dried over magnesium sulfate and then evaporated. The residual solid was triturated with diethyl ether to give the title compound as a yellow solid, m.p. 223-224° C. MS: 341 (MH+).
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[CH:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1)([CH3:11])[CH3:10].[CH2:21](O)C>CCOCC>[CH:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH2:19][C:3]([O:6][CH2:7][CH3:21])=[O:8])=[O:20])=[CH:14][CH:13]=1)([CH3:11])[CH3:10]
Reactant: CC(=O)c1ccc(C(C)C)cc1
Reactant: COC(=O)OC
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)CC(=O)c1ccc(C(C)C)cc1
Temperature: 0 °C

Procedure:
Sodium hydride (2.4 grams) and 4.5 grams of dimethyl carbonate are suspended in 150 ml of ether. 8.1 grams of p-isopropylacetophenone is gradually dropped thereinto under heating to reflux, then a small amount of ethanol is added thereto, heated to reflux for one hour, cooled, and the reaction is stopped by the addition of 20 ml of ethanol. The mixture is poured into ice water and extracted with ether. The ether extracts are combined, washed with water, dried with anhydrous magnesium sulfate and ether is evaporated therefrom. The resulting oil is purified by distillting in vacuo to give 6.5 grams of colorless oily product, b.p. 80° C./5 mmHg.
Reaction SMILES: BrC(C=O)C=O.Br[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([CH:17]=[O:18])=[CH:15][N:16]=2)[CH:13]=1.Br[C:20]1[CH:21]=[CH:22][C:23](N)=[N:24][CH:25]=1.C(#N)C>>[N:24]1[CH:25]=[CH:20][CH:21]=[C:22]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH:17]=[O:18])=[CH:15][N:16]=3)[CH:13]=2)[CH:23]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=Cc1cnc2ccc(Br)cn12
Agent: O=CC(Br)C=O
Solvent: CC#N
Product: O=Cc1cnc2ccc(-c3cccnc3)cn12
Yield: 53 %

Procedure:
6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde Bromomalonaldehyde (5230 mg, 34.68 mmol) was added to a solution of 5-bromopyridin-2-amine in acetonitrile (5000 mg, 28.90 mmol). The reaction mixture was refluxed for 2 hours. After completion of the reaction, the reaction mixture was quenched with sodium bicarbonate solution and extracted with EtOAc. The organic layer was washed with brine and dried over sodium sulfate. The organic layer was concentrated in vacuo and the product was purified by column chromatography using EtOAc-petroleum ether gradient to obtain the title compound. Yield: 53%; 1H NMR (DMSO-d6; 300 MHz): δ 9.94 (s, 1H), 9.50 (s, 1H), 8.54 (s, 1H), 7.86-7.85 (m, 2H); MS (m/z): 226 (M+1)+.
Reaction SMILES: B(Br)(Br)[Br:2].CO.C([N:9]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]2[CH:22]=[C:23]([O:31]C)[C:24]([O:29]C)=[C:25]([CH2:26][CH2:27][CH3:28])[C:12]=2[CH2:11][CH2:10]1)=O>C(Cl)Cl.O>[BrH:2].[OH:29][C:24]1[C:23]([OH:31])=[CH:22][C:13]2[CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:15][NH:9][CH2:10][CH2:11][C:12]=2[C:25]=1[CH2:26][CH2:27][CH3:28]
Reactant: CCCc1c2c(cc(OC)c1OC)C(c1ccccc1)CN(C=O)CC2
Reactant: BrB(Br)Br
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: Br
Product: CCCc1c(O)c(O)cc2c1CCNCC2c1ccccc1

Procedure:
This material (1.9 g, 0.0054 mole) in 50 ml of ethanol and 10 ml of 40% sodium hydroxide was heated at reflux for 2 hours. After stripping, the residue was taken up in methylene chloride-water. The combined organic layers were dried and evaporated to give the 7,8-dimethoxy compound which (1 g) was reacted with 1 ml of boron tribromide in dry methylene chloride for 3 hours. After stripping and cooling the residue was treated with methanol. The methanol was taken off and the residue dissolved in hot water (20 ml). Evaporation and cooling gave the dopaminergic agent 7,8-dihydroxy-6-n-propyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, m.p. 226°-229° (dec.).
Reaction SMILES: [F:1][CH2:2][CH:3]([OH:5])[CH3:4].N1C=CC=CC=1.[C:12](Cl)(Cl)=[O:13].[NH2:16][CH:17]([CH2:36][C:37]1([F:42])[CH2:41][CH2:40][CH2:39][CH2:38]1)[C:18]([NH:20][C:21]1([CH:25]([OH:35])[C:26](=[O:34])[NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH3:33])[N:29]=2)[CH2:24][CH2:23][CH2:22]1)=[O:19].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][CH2:2][CH:3]([O:5][C:12](=[O:13])[NH:16][CH:17]([C:18](=[O:19])[NH:20][C:21]1([CH:25]([OH:35])[C:26](=[O:34])[NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH3:33])[N:29]=2)[CH2:22][CH2:23][CH2:24]1)[CH2:36][C:37]1([F:42])[CH2:38][CH2:39][CH2:40][CH2:41]1)[CH3:4]
Reactant: Cn1ccc(NC(=O)C(O)C2(NC(=O)C(N)CC3(F)CCCC3)CCC2)n1
Reactant: O=C(Cl)Cl
Reactant: CC(O)CF
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(CF)OC(=O)NC(CC1(F)CCCC1)C(=O)NC1(C(O)C(=O)Nc2ccn(C)n2)CCC1
Temperature: 0 °C

Procedure:
1-fluoropropane-2-ol (38 mg, 0.48 mmol) and pyridine (39 μL, 0.48 mmol) were dissolved in DCM (1.5 mL), and the mixture was stirred and cooled to 0° C. Phosgene (1.9 M solution in toluene, 232 μL, 0.44 mmol) was added in one portion and the reaction was allowed to warm to rt and was stirred for 3 h during which a white precipitate formed. In a separate flask, the amine 56-b (36 mg, 0.080 mmol) and DIPEA (45 μL, 0.26 mmol) were dissolved in DCM (1 mL) and the mixture was stirred and cooled to 0° C. 250 μL of the mixture in the first flask were added to the second, and the reaction was monitored by HPLC. Another 250 μL aliquot was added after 15 min and the reaction was stirred for 15 more minutes after which it was quenched by the addition of sat aq NaHCO3 (10 mL) and Et2O (10 mL). The layers were separated and the aqueous phase was extracted with 2×5 mL EtOAc. The combined organic phases were washed with sat aq NaHCO3 (5 mL) and the solvent was removed by rotary evaporation. The product was purified by gradient column chromatography (DCM-10% MeOH in DCM). This gave the title compound as a mixture of diastereomers (22 mg, 57%). ES+ 486.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[NH:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:48]2[CH2:47][CH2:46][CH:45]([NH:44][C:36]3[NH:35][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]=3)[CH2:50][CH2:49]2)([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:9]1)=[O:7]
Reactant: c1ccc2[nH]c(NC3CCNCC3)nc2c1
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccc(F)cc3)C2)cc(OC)c1OC
Agent: I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccc(F)cc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 4.1 using 1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (2.65 g, 5.5 mmol) (prepared from (+)-1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine) and (1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydriodic acid salt (3.9 g, 8.25 mmol) to give, after chromatography on silica gel eluting with methanol/ethyl acetate 1/1, the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[N+:10]([C:13]1[S:17][C:16]([CH:18]=O)=[CH:15][CH:14]=1)([O-:12])=[O:11]>CN1C(=O)CCC1.[N+](C1C=CC=CC=1)([O-])=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:18]([C:16]3[S:17][C:13]([N+:10]([O-:12])=[O:11])=[CH:14][CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Cl)cnc1N
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Solvent: CN1CCCC1=O
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(-c2nc3cc(Cl)cnc3[nH]2)s1
Temperature: 170 °C
Reaction time: 3 h
Yield: 25.4 %

Procedure:
5-Chloropyridine-2,3-diamine (4.0 g, 28 mmol) was dissolved in NMP (3 ml) and heated to 170° C. 5-Nitrothiophene-2-carbaldehyde (4.4 g, 28 mmol) dissolved in nitrobenzene (3 ml) and NMP (2 ml) was added slowly over 30 min. After 3 h, the reaction mixture was diluted with EtOAc and purified by dry flash chromatography (0%, 10%, 50%, 70% EtOAc in toluene), giving the title product (2 g, 25%).
Reaction SMILES: C([O:8][NH:9][C:10]([CH2:12][CH2:13][C:14]1[CH:44]=[CH:43][C:17]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([NH:32][S:33]([C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1)=[O:11])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][NH:9][C:10]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH:26]([NH:32][S:33]([C:36]3[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=3)(=[O:35])=[O:34])[C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[CH:23][CH:24]=2)=[CH:43][CH:44]=1)=[O:11]
Reactant: Cc1ccc(S(=O)(=O)NC(Cc2ccc(Oc3ccc(CCC(=O)NOCc4ccccc4)cc3)cc2)C(=O)N(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(Cc2ccc(Oc3ccc(CCC(=O)NO)cc3)cc2)C(=O)N(C)C)cc1
Yield: 58.6 %

Procedure:
Palladium on BaSO4 (5%, 0.5 g) was added to a degassed solution of the benzyl hydroxamate 26 (0.8 g) in MeOH (50 mL) and the suspension was treated with hydrogen at atmospheric pressure for 4 h. The suspension was filtered over a Celite® bed and concentrated to yield the desired hydroxamate 27 (0.4 g, 59%). 1H NMR (400 MHz, DMSO-d6): 10.36 (s, 1H), 8.70 (br, 1H), 8.05 (d, J=9.2 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.29 (d, J=7.6 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H), 7.10 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 6.82 (d, J=8.8 Hz, 2H), 4.29 (m, 1H), 2.73-2.80 (m, 3H), 2.67 (s, 3H), 2.59 (dd, J=13.2 and 7.6 Hz, 1H), 2.99 (s, 3H), 2.24 (t, J=8.0 Hz, 2H). LCMS (m/e): Obsd. 511, Calcd. 510.6
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1)[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C=O)cc(OCc2ccccc2)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1cc(OC)cc(OCc2ccccc2)c1
Yield: 84.7 %

Procedure:
To a solution of 3-(benzyloxy)-5-methoxybenzaldehyde (5.50 g) in toluene (50 mL) was added ethyl (triphenylphosphoranylidene)acetate (7.90 g), and the mixture was heated under reflux for 4 hr. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.00 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(Br)c1
Reaction time: 3.5 h

Procedure:
0.5 g of 3-bromophenol and 0.33 ml of ethyl bromoacetate were dissolved in 4 ml of dimethylformamide, and 0.4 g of potassium carbonate was added. The mixture was stirred at 65°-70° C. for 3.5 hours. The solvent was evaporated, and the residue was worked up in a customary manner to give 0.6 g of ethyl 3-bromophenoxyacetate as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]([CH3:33])([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[O:19][CH2:20][C:21]1[CH:22]=[N:23][C:24]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:25][CH:26]=1)=[O:8])[CH3:5].[OH-].[Na+].O.Cl>C1COCC1.CO>[CH3:33][C:4]([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[O:19][CH2:20][C:21]1[CH:22]=[N:23][C:24]([O:27][CH2:28][C:29]([F:31])([F:32])[F:30])=[CH:25][CH:26]=1)=[O:8])([CH3:5])[C:3]([OH:34])=[O:2]
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCc1ccc(OCC(F)(F)F)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(NC(=O)c1ccc2ccccc2c1OCc1ccc(OCC(F)(F)F)nc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
To 124 mg 2-methyl-2-({1-[6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethoxy]-naphthalene-2-carbonyl}-amino)-propionic acid methyl ester in 4 mL THF and 1 mL methanol was added 1.3 mL of 1 M aqueous sodium hydroxide solution. After stirring at room temperature for 1 h the mixture was poured into cold water, acidified to pH 2 with 2 M HCl and extracted with ethyl acetate three times. The combined organic layers were dried over magnesium sulphate, filtrated and concentrated to provide a yellow oil, which could be crystallized from diisopropylether to yield 43 mg of 2-methyl-2-({1-[6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethoxy]-naphthalene-2-carbonyl}-amino)-propionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]#[N:14])[CH:7]=[CH:6]2.[I:15]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(C(F)(F)F)=O>[I:15][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([C:13]#[N:14])=[CH:9]2
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc2cc(C#N)ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1ccc2cc(C#N)ccc2c1I
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 6-methoxynaphthalene-2-carbonitrile (1.0 g, 5.5 mmol), N-iodosuccinimide (1.4 g, 6.0 mmol) in ACN (10 ml) and TFA (125 μl) is stirred at RT for 4 h. A saturated aqueous solution of sodium hydrogencarbonate is added and the mixture extracted with DCM. The combined organic layers are extracted with an aqueous solution of sodium thiosulfate, dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 1.68 g (99%). HPLC-MS: tR=1.32 min (METHOD—1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:5](=[C:23]([CH3:26])[O:24][N:25]=3)[C:6](=[O:22])[N:7]([C:12]3[N:17]=[C:16]([CH2:18][C:19](O)=[O:20])[CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1.CCN=C=NCCCN(C)C.[CH3:38][O:39][C:40]1[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=1)[NH2:43].CC(C)=O.ClCCl>CN(C1C=CN=CC=1)C.ClCCl>[Cl:1][C:2]1[C:3]2[C:4]3[C:5](=[C:23]([CH3:26])[O:24][N:25]=3)[C:6](=[O:22])[N:7]([C:12]3[N:17]=[C:16]([CH2:18][C:19]([NH:43][C:42]4[CH:44]=[CH:45][CH:46]=[C:40]([O:39][CH3:38])[CH:41]=4)=[O:20])[CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc(N)c1
Reactant: Cc1onc2c1c(=O)n(-c1cccc(CC(=O)O)n1)c1cccc(Cl)c21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1cccc(NC(=O)Cc2cccc(-n3c(=O)c4c(C)onc4c4c(Cl)cccc43)n2)c1
Yield: 52.6 %

Procedure:
[6-(9-Chloro-3-methyl4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-pyridin-2-yl]-acetic acid (0.075 g, 0.2 mmol), EDCI (0.055 g, 0.3 mmol), 3-methoxyaniline (0.03 ml, 0.26 mmol), DMAP (0.005 g, 0.04 mmol) in dichloromethane (4.5 ml) and DMP (0.75 ml) react for 5.5 h in a fashion similar to that of Example 3. Column chromatography (silica gel, acetone/dichloromethane gradient) gives the title compound (0.05 g, 53%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Br:23]N1C(=O)CCC1=O>C(#N)C>[F:22][C:2]([F:1])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:23])[C:17]([O:19][CH3:20])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2C(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1cc2c(cc1Br)C(C(C)C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 8 h
Yield: 49 %

Procedure:
A solution of N-trifluoroacetyl-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.091 g, 0.29 mmol) in acetonitrile (3 mL) was treated with N-bromosuccinimide (0.057 g, 0.32 mmol), and stirred overnight at 20 C. After removing the solvent, flash chromatography (10% EtOAc in hexanes, silica) resulted in 0.056 g of a clear oil. MS calculated for C16H19BrF3NO2+H: 394, observed: 394.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)[C:10]([OH:12])=O)=[O:7])(C)(C)C.CN1CCOCC1.C(OC(Cl)=O)(C)C.[F:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[CH:44]([NH:50][C@H:51](C(O)=O)[CH2:52][CH:53]([CH3:55])[CH3:54])[C:45]([N:47]([CH3:49])[CH3:48])=[O:46]>O1CCCC1.C1(C)C=CC=CC=1>[F:36][C:37]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=1[C@@H:44]([N:50]1[C@H:51]([CH2:52][CH:53]([CH3:55])[CH3:54])[C:6](=[O:7])[NH:8][C@H:9]([CH:13]2[CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:21]2)[C:10]1=[O:12])[C:45]([N:47]([CH3:48])[CH3:49])=[O:46]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1Cc2ccccc2C1
Reactant: CC(C)C[C@H](NC(C(=O)N(C)C)c1ccc(F)cc1F)C(=O)O
Agent: CC(C)OC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)N(C)C)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.3 %

Procedure:
To a solution of (2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoic acid (84 mg) in dry tetrahydrofuran (6 ml) at −20° C. under a nitrogen atmosphere was added N-methylmorpholine (32 l) and a solution of isopropylchloroformate in toluene (1.0M, 290 l). After 10 minutes, a solution of N-[1-(2,4-difluorophenyl)-2-(dimethylamino)-2-oxoethyl]-L-leucine (95 mg) in tetrahydrofuran (10 ml) was added and the reaction was allowed to warm to room temperature. After 20 hours, the solvent was removed in vacuo and the residue was dissolved in 4N hydrochloric acid in dioxan (4 ml). After 4 hours methanol (5 ml) was added and the reaction was left to stand for a further 18 hours. The solvent was then removed in vacuo and the residue was dissolved in dioxan (5 ml) and to this was added triethylamine (0.5 ml). After 1 hour, the solvent was removed and the residue was applied to an SPE (10 g, silica). The product was eluted using methanol. A second SPE was used to further purify the material (2 g, silica) using an ethyl acetate:methanol gradient (20:1 to 1:1) to afford (2R)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N,N-dimethylethanamide (38 mg).
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[O:16][CH3:17].COC(C)(C)C>CS(C)=O>[C:12]([C:10]1[CH:9]=[CH:8][C:7]([O:16][CH3:17])=[C:6]([CH2:5][C:1]#[N:2])[CH:11]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: [C-]#N
Reactant: COc1ccc(C(C)(C)C)cc1CBr
Agent: [K+]
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Product: COc1ccc(C(C)(C)C)cc1CC#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.9 %

Procedure:
Potassium cyanide (2.96 g) was added to a solution of 2-bromomethyl-4-tert-butyl-1-methoxybenzene (7.78 g) in dimethyl sulfoxide (50 mL), and the mixture was stirred at room temperature for 16 hours. Ice and tert-butyl methyl ether were added to the reaction solution, and the organic layer was separated. The aqueous layer was reextracted with tert-butyl methyl ether. The combined organic layers were sequentially washed with water (twice) and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane→ethyl acetate:heptane=1:49). The target fraction was concentrated. The resulting residue was triturated with hexane to obtain 1.90 g of the title compound. The trituration mother liquor was concentrated. Then, the resulting residue was triturated with hexane to obtain 0.47 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[C:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH3:12][S:13]([NH:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)(=[O:15])=[O:14]>>[CH3:8][N:6]1[C:5](=[O:9])[C:4]([CH3:10])=[C:3]([CH3:11])[C:2]([C:21]2[CH:22]=[C:17]([NH:16][S:13]([CH3:12])(=[O:14])=[O:15])[CH:18]=[CH:19][CH:20]=2)=[CH:7]1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: Cc1c(Br)cn(C)c(=O)c1C
Product: Cc1c(-c2cccc(NS(C)(=O)=O)c2)cn(C)c(=O)c1C

Procedure:
5-Bromo-1,3,4-trimethylpyridin-2-one was treated with [3-(methanesulfonamido)phenyl]boronic acid in a manner similar to Example 94 to give the title compound as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.42 (s, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.24 (s, 1H), 7.16 (s, 1H), 7.08 (s, 1H), 7.05 (d, J=7.6 Hz, 1H), 3.59 (s, 3H), 3.06 (s, 3H), 2.19 (s, 3H), 2.06 (s, 3H). LCMS (M+H)+ 307.