Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[C:3]([C:5]1[C:13]2[NH:12][C:11](=[O:14])[CH:10]=[N:9][C:8]=2[N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:6]=1)=[O:4].[CH:25]1(O)[CH2:29][CH2:28][CH2:27][CH2:26]1.C(P(CCCC)CCCC)CCC.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH:25]1([O:14][C:11]2[N:12]=[C:13]3[C:5]([C:3](=[O:4])[C:2]([CH3:24])([CH3:23])[CH3:1])=[CH:6][N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:22])[CH3:21])[C:8]3=[N:9][CH:10]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: OC1CCCC1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(=O)[nH]c12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(OC3CCCC3)nc12
Temperature: 65 °C
Reaction time: 2.5 h
Yield: 49.6 %

Procedure:
A solution of 7-(2,2-dimethyl-propionyl)-5-(2-trimethylsilanyl-ethoxymethyl)-1,5-dihydro-pyrrolo[2,3-b]pyrazin-2-one (0.029 g, 0.082 mmol), 1 mL of tetrahydrofuran, cyclopentanol (0.010 mL, 0.11 mmol), tributylphosphine (0.025 mL, 0.1 mmol), and diisopropyl azodicarboxylate (0.020 mL, 0.10 mmol) under nitrogen was stirred at 65° C. for 17.5 h then allowed to cool. Additional cyclopentanol (0.020 mL, 0.22 mmol), tributylphosphine (0.050 mL, 0.20 mmol), and diisopropyl azodicarboxylate (0.040 mL, 0.21 mmol) were added, and the solution stirred at 65° C. for 2.5 h. The yellow solution was partitioned between 5 mL of water and 5 mL of ethyl acetate. The organic layer was washed with 5 mL of a sat. aq. NaCl solution, dried over MgSO4, filtered and concentrated to a yellow oil. Silica gel chromatography (10% EtOAc/hexanes) afforded 0.017 g (51%) of 1-[2-cyclopentyloxy-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:12](=O)[CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH:6]=[CH:7][CH:8]=1.O=P(Cl)(Cl)[Cl:28]>C(Cl)(Cl)Cl>[ClH:28].[CH3:17][N:16]([CH3:18])[C:14]([CH:13]([C:12]1[C:6]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:9][CH2:10][N:11]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc(CCNC(=O)C(C(=O)N(C)C)c2ccccc2)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)CCN=C2C(C(=O)N(C)C)c1ccccc1
Product: Cl
Reaction time: 8 h

Procedure:
An amount of 3.9 gm (11.5 mmol) of phenylmalonic acid dimethylamide-[2-(3-methoxyphenyl)-ethylamide] was dissolved in 60 ml of chloroform, and the resulting solution was then mixed with 13.7 gm (90 mmol) of POCl3 and refluxed for 6 hours. The solvent was removed in a rotary vaporizer, the residue was dissolved in CH2Cl2, and that solution was added dropwise to a cold saturated K2CO3 solution. After extraction three times with CH2Cl2, the combined organic extracts were extracted three times with 2 N HCl. The combined HCl phases were made alkaline with K2CO3 and again extracted with CH2Cl2. The organic phase was dried and then concentrated under reduced pressure, and the residue was treated with ethereal HCl. The hydrochloride precipitated was dissolved in isopropanol, the solution was treated with active charcoal, and diethyl ether was added to the solution until the solution began to become turbid. After being left overnight in a refrigerator, the desired compound crystallized out as the hydrochloride.
Reaction SMILES: [CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]3[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=3)[N:8]=2)[CH2:3][CH2:2]1.[NH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.COC(OC)OC.[BH4-].[Na+]>CO.C1COCC1>[CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]3[CH:16]=[CH:15][C:12]([CH2:13][NH:17][CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=4)=[CH:11][CH:10]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(-c2coc(C3CC3)n2)cc1
Reactant: NCCc1ccc(O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: COC(OC)OC
Product: Oc1ccc(CCNCc2ccc(-c3coc(C4CC4)n3)cc2)cc1
Reaction time: 12 h
Yield: 86.3 %

Procedure:
To a solution of 4-(2-cyclopropyl-1,3-oxazol-4-yl)benzaldehyde (0.318 g, 1.49 mmol) in MeOH (5 ml) was added tyramine (0.215 g, 1.57 mmol) and trimethylorthoformate (1.2 mL, 10.97 mmol). The resulting solid was redissolved in THF (3 ml) and allowed to stir for 12 h. Sodium borohydride (0.15 g, 3.94 mmol) was added and the mixture was stirred an additional 2 h. The reaction mixture was concentrated and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with MgSO4, and concentrated in vacuo. The crude material was purified by flash chromatography (MeOH/CH2Cl2, 5:95 to 10:90) to yield 4-(2-{[4-(2-cyclopropyl-1,3-oxazol-4-yl)benzyl]amino}ethyl)phenol as a white solid (0.43 g, 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][N:31]=1)[C:16]([NH:18][C@@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1)=[O:17].[CH3:32][C:33]([CH3:62])([O:35][C:36](=[O:61])[CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][CH2:51][C:52]1[CH:53]=[C:54]([CH:58]=[CH:59][CH:60]=1)[C:55](O)=[O:56])[CH3:34].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:9]1([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:55]([C:54]3[CH:53]=[C:52]([CH2:51][CH2:50][CH2:49][O:48][CH2:47][CH2:46][O:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][C:36]([O:35][C:33]([CH3:62])([CH3:34])[CH3:32])=[O:61])[CH:60]=[CH:59][CH:58]=3)=[O:56])=[C:3]([C:13]3[CH:14]=[C:15]([C:16](=[O:17])[NH:18][C@@H:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:22][CH2:21][CH2:20]4)[CH:29]=[CH:30][N:31]=3)[CH:4]=2)[CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCOCCCc1cccc(C(=O)O)c1
Reactant: Nc1ccc(OC2CCC2)cc1-c1cc(C(=O)N[C@H]2CCCc3ccccc32)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCOCCOCCOCCOCCCc1cccc(C(=O)Nc2ccc(OC3CCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 34.4 %

Procedure:
To a mixture of (S)-2-(2-amino-5-cyclobutoxyphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)isonicotinamide 132b (0.048 mmol, 20 mg), 3-(2,2-dimethyl-4-oxo-3,7,10,13,16-pentaoxanonadecan-19-yl)benzoic acid (0.053 mmol, 24 mg) and DIEA (0.29 mmol, 38 mg) in DMF (0.16 mL) was added HATU (0.053 mmol, 20 mg). The mixture was stirred at 60° C. for 1 h and purified by prep. TLC to give a yellow syrup (13.8 mg, 34%). MS (ES, m/z): 836.07 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]3[S:23][C:24]4[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:25]=4[N:26]=3)[CH2:18][CH2:17]2)[CH:13]([CH3:15])[CH3:14])[CH:6]=1.[OH-].[Na+].O1CCCC1.Cl>CO>[Cl:31][C:29]1[CH:28]=[CH:27][C:25]2[N:26]=[C:22]([N:19]3[CH2:20][CH2:21][CH:16]([N:12]([CH2:11][C:7]4[CH:6]=[C:5]([CH2:4][C:3]([OH:32])=[O:2])[CH:10]=[CH:9][CH:8]=4)[CH:13]([CH3:14])[CH3:15])[CH2:17][CH2:18]3)[S:23][C:24]=2[CH:30]=1
Reactant: COC(=O)Cc1cccc(CN(C(C)C)C2CCN(c3nc4ccc(Cl)cc4s3)CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)N(Cc1cccc(CC(=O)O)c1)C1CCN(c2nc3ccc(Cl)cc3s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
A mixture of [3-[[[1-(6-chlorobenzothiazole-2-yl)piperidine-4-yl]isopropylamino]methyl]phenyl]acetic acid methyl ester (90 mg), 2N sodium hydroxide (0.5 mL), tetrahydrofuran (2 mL) and methanol (1 mL) was stirred at room temperature for 1 hour. After neutralizing with 2N hydrochloric acid, the reaction solution was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (28 mg).
Reaction SMILES: I[C:2]1[C:7]2=[N:8][S:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:22])[C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[N:10]1[S:9][N:8]=[C:7]2[C:2]([C:16]3[CH:17]=[CH:18][C:13]([N:12]([CH3:22])[CH3:11])=[CH:14][CH:15]=3)=[CH:3][CH:4]=[CH:5][C:6]=12
Reactant: Ic1cccc2nsnc12
Reactant: CN(C)c1ccc(B(O)O)cc1
Product: CN(C)c1ccc(-c2cccc3nsnc23)cc1

Procedure:
Starting from 4-iodo-benzo[1,2,5]thiadiazole and 4-(dimethylamino)phenylboronic acid. Orange powder. MS(ES+): 256 (M+1).
Reaction SMILES: [C@@H:1]1([C:10]2[Se:11][CH:12]=[C:13]([C:15]([O:17]C)=O)[N:14]=2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[NH3:19].ClCCl.CO>CO>[C@@H:1]1([C:10]2[Se:11][CH:12]=[C:13]([C:15]([NH2:19])=[O:17])[N:14]=2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: N
Reactant: COC(=O)c1c[se]c([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1c[se]c([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reaction time: 8 h

Procedure:
A solution of 168 g (521 mmol) of the methyl ester, VI, in 2.0 l of methanol was cooled to approximately 10° and treated with anhydrous ammonia gas for eight hours. The solution was allowed to stand at room temperature overnight. The TLC (SiO2, dichloromethane-methanol, 5:1) indicated complete conversion to the desired product. A very small amount of a red solid was removed by filtration. The filtrate was evaporated under reduced pressure and the residue was recrystallized from 2-propanol and dried at 40° under 0.5 atmospheres to give 136 g (84.9%) of the product, mp 128-130 (lit. (see below) mp 131°-133°).
Reaction SMILES: [OH:1][CH:2]([CH2:42][OH:43])[CH2:3][CH2:4][CH2:5][C:6]1([CH2:35][CH2:36][CH2:37][CH:38]([OH:41])[CH2:39][OH:40])[CH2:11][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][C:15]([O:20][CH2:21][CH2:22][CH2:23][O:24][C:25]3[C:34]4[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=4[CH:28]=[CH:27][CH:26]=3)=[C:16]([CH2:17][CH2:18][CH3:19])[C:8]=2[O:7]1.C(O[C:48](=[O:50])[CH3:49])(=O)C>N1C=CC=CC=1.C(OCC)(=O)C>[C:2]([O:41][CH:38]([CH2:39][O:40][C:48](=[O:50])[CH3:49])[CH2:37][CH2:36][CH2:35][C:6]1([CH2:5][CH2:4][CH2:3][CH:2]([O:1][C:10](=[O:12])[CH3:9])[CH2:42][O:43][C:6](=[O:7])[CH3:5])[CH2:11][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][C:15]([O:20][CH2:21][CH2:22][CH2:23][O:24][C:25]3[C:34]4[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=4[CH:28]=[CH:27][CH:26]=3)=[C:16]([CH2:17][CH2:18][CH3:19])[C:8]=2[O:7]1)(=[O:1])[CH3:3]
Reactant: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCCC(O)CO)(CCCC(O)CO)CC2=O
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCCC(COC(C)=O)OC(C)=O)(CCCC(COC(C)=O)OC(C)=O)CC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.7 %

Procedure:
To a solution of 404 mg (0.708 mmol) of the title product of Example 71 in 4.4 ml of pyridine was added 0.70 ml (7.4 mmol) of acetic anhydride. After stirring overnight at room temperature, the mixture was taken up in ethyl acetate, and washed sequentially with two portions of aqueous sodium bicarbonate, water, and brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure. Chromatography of the residue over silica gel, using 40% ethyl acetate/hexane as the eluent, gave the title compound (314 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)[CH:18]=2)=[CH:4][CH:3]=1.CN(C(O[N:36]1N=N[C:38]2C=CC=[CH:42][C:37]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14]2[N:15]=[CH:16][N:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH:36][CH:37]([CH3:42])[CH3:38])=[O:25])=[CH:21][CH:20]=3)[CH:18]=2)=[CH:6][CH:7]=1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(C)N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)nnn3C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a solution of 4-{4-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-imidazol-1-yl}-benzoic acid (75 mg, 0.21 mmol) and TBTU (73 mg, 0.23 mmol) in DMF (0.8 mL) was added DIPEA (177 μL, 1.03 mmol). Then isopropylamine (19 μL, 0.23 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 0 to 100% ethyl acetate in heptane, then 0 to 10% methanol in dichloromethane) afforded the title compound (57 mg, 68%) as a white solid. MS: m/e=405.4 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.S(=O)(=O)(O)O.[N+:19]([O-:22])([OH:21])=[O:20]>CC(C)=O>[CH3:1][O:2][C:3]1[C:4]([N+:19]([O-:21])=[O:20])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:19]([O-:22])=[O:20])[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: COc1cc2c(cc1[N+](=O)[O-])C(=O)CCC2
Product: COc1ccc2c(c1[N+](=O)[O-])CCCC2=O
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To an ice-cold, stirred sloution of 6-methoxy-1-tetralone (17.6 g, 0.10 mol) in acetone (30 mL) was added dropwise a mixture of sulfuric acid (18 mL, 96.0%) and nitric acid (15 mL, 68.0-70.0%). After the addition was complete, the reaction was stirred at 0° C. for 6 hours, and TLC was employed to monitor the reaction progress. The reaction mixture was poured into ice-water, and the mixture was partitioned between CH2Cl2 (3*200 mL) and water (200 mL). The organic layer was washed by saturated NaHCO3 solution and water (200 mL each), dried over anhydrous sodium sulfate, and, after filtration, the organic layer was concentrated in vacuo to provide a yellow oil. 6-Methoxy-5-nitro-1-tetralone (7.74 g, 0.035 mol) and 6-methoxy-7-nitro-1-tetralone (6.63 g, 0.030 mol) was obtained after purification by column chromatography.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:11]([NH:13][C@@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:15](O)=[O:16])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.OC(C(F)(F)F)=O.[NH2:66][C@@H:67]([CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[C:68]([C@@:70]1([CH3:73])[CH2:72][O:71]1)=[O:69].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][CH2:9][C@H:10]([NH:27][C:28](=[O:29])[O:30][C:31]([CH3:33])([CH3:34])[CH3:32])[C:11]([NH:13][C@@H:14]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)[C:15]([NH:66][C@@H:67]([CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[C:68]([C@@:70]1([CH3:73])[CH2:72][O:71]1)=[O:69])=[O:16])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C[C@H](NC(=O)[C@H](COCc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: C[C@]1(C(=O)[C@@H](N)Cc2ccccc2)CO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C[C@H](NC(=O)[C@H](COCc2ccccc2)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Reaction time: 0.08 h

Procedure:
To (S)-2-((S)-3-(benzyloxy)-2-((tert-butoxycarbonyl)amino)propanamido)-3-(4-methoxyphenyl)propanoic acid (3.39 mmol assumed) and HATU (1.45 g, 3.82 mmol) in DMF (10 mL) at 0° C. was added (S)-2-amino-1-((R)-2-methyloxiran-2-yl)-3-phenylpropan-1-one TFA salt (1.05 g, 3.47 mmol). The mixture was stirred for 5 min to dissolved the solids and DIEA (2.41 mL, 13.88 mmol) was added. The reaction mixture was stirred at this temperature for 15 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated to provide crude tert-butyl ((S)-3-(benzyloxy)-1-(((S)-3-(4-methoxyphenyl)-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)carbamate (quant.) as a yellow oil that was carried forward without further purification. MS (EI) for C37H45N3O8, found 660.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][CH2:12][CH3:13])=[C:7]([C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][C:25]#[N:26])=[CH:18][CH:17]=3)=[O:15])[C:6]=2[CH:27]=1.N1C=CC=CC=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH2:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:27][C:6]=2[C:7]=1[C:14](=[O:15])[C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][C:25]#[N:26])=[CH:20][CH:21]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1oc2ccc(N)cc2c1C(=O)c1ccc(OCCC#N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)c1ccc(OCCC#N)cc1
Temperature: 32.5 °C
Reaction time: 3 h

Procedure:
4.0 g of (5-amino-2-butyl-benzofur-3-yl)-[4-(2-cyanoethoxy)phenyl]methanon (VI) is dissolved in 40 ml of dichloromethane. The mixture is warmed to 30-35° C. and 1.05 g of pyridine is added at this tempereature in 5 minutes. At this temperature 1.5 g of methane sulfonyl chloride is added in 5 minutes and the mixture is stirred at 30-35° C. for 3 hours: The mixture is cooled to 20° C. and washed with 2×15 ml of water, 2×15 ml of NaHCO3 of 5% and 1×15 ml of water. The phases are separated and the dichloromethane is evaporated.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](C#C)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:13]C1C=C(C=CC=1)C(O)=O.C[Al](C)C>CCCCCC>[C:1]([C:5]1[CH:6]=[C:7]([Br:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cccc(C(C)(C)C)c1
Reactant: O=C(O)c1cccc(Br)c1
Agent: C[Al](C)C
Solvent: CCCCCC
Product: CC(C)(C)c1cccc(Br)c1

Procedure:
Reaction Scheme 4 discloses a specific synthetic route to 3-tert-butylphenyl ethyne (Compound 22) starting with meta bromobenzoic acid (Compound 23), which is treated with trimethylaluminum in hexane to yield 3-tert-butyl bromobenzene (Compound 24). 3-Tert-butyl bromobenzene 24 is thereafter converted into the ethyne derivative 22 through the trimethylsilyl ethyne intermediate 25 in steps similar to the steps described in connection with Reaction Scheme 3.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.[OH-].[Na+].[ClH:15]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][C:7]=1[Cl:15]
Reactant: COC(=O)c1cc(Cl)c(Br)cn1
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(Br)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 5-bromo-4-chloropicolinate (1.08 g) in THF (25 mL) and methanol (12.5 mL) was added 1N aqueous sodium hydroxide solution (25 mL), and the mixture was stirred at room temperature for 30 min. 1N Hydrochloric acid was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound (944 mg) as a pale-yellow solid. This compound was used for the next step without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=O.[CH2:18]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[C:23]2=O)[CH3:19].C([OH:33])C.O>O1CCCC1>[NH2:2][C:3]1[C:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][CH:7]=2)=[N:25][C:26]2[C:22]([C:23]=1[C:24]([OH:29])=[O:33])=[CH:21][C:20]([CH2:18][CH3:19])=[CH:28][CH:27]=2
Reactant: CCO
Reactant: NCC(=O)c1ccc(-c2ccccc2)cc1
Reactant: CCc1ccc2c(c1)C(=O)C(=O)N2
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc2nc(-c3ccc(-c4ccccc4)cc3)c(N)c(C(=O)O)c2c1

Procedure:
A 12.63 g portion of 2-amino-4'-phenylacetophenone, hydrochloride was dissolved in a mixture of 168 ml of absolute ethanol:water (1:1) and 40 ml of tetrahydrofuran. This solution was kept warm and with stirring, added dropwise to the 5-ethylisatin solution over 2 hours. The mixture was refluxed for 2 hours, then the solvent was distilled off at 85° C. and the reaction cooled for 1 hour. The red solids were collected, stirred with 2 liters of water for 1.5 hours and then filtered. The filtrate was acidified to pH 5 with glacial acetic acid. The resulting yellow solids were collected and dried, giving 4.47 g of the desired product, mp 240°-241° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][C:17]1[C:18]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][C:29]([O:35][CH3:36])=[CH:30][CH:31]=3)[CH:26]2[CH3:37])=[N:19][C:20]([Cl:24])=[N:21][C:22]=1[CH3:23]>CN(C)C=O>[ClH:24].[CH3:16][C:17]1[C:18]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][C:29]([O:35][CH3:36])=[CH:30][CH:31]=3)[CH:26]2[CH3:37])=[N:19][C:20]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[N:21][C:22]=1[CH3:23]
Reactant: COc1ccc2c(c1)C(C)N(c1nc(Cl)nc(C)c1C)CC2
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(C)N(c1nc(Nc3ccc(F)cc3)nc(C)c1C)CC2
Product: Cl
Yield: 58.3 %

Procedure:
After 4-fluoroaniline(0.32 ml, 3.3 mmol) and triethylamine(0.46 ml, 3.3 mmol) were added to a solution of 5,6-dimethyl-2-chloro-4-(7-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(0.7 g, 2.2 mmol) in dimethylformamide(5 ml), 0.55 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 25.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.[CH2:7]([Li])[CH2:8][CH2:9][CH3:10]>CCOCC>[CH:1]1([C:4]([CH2:7][CH2:8][CH2:9][CH3:10])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CC1
Reactant: [Li]CCCC
Solvent: CCOCC
Product: CCCCC(=O)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a vigorously-stirred solution of 31.0 g of cyclopropanecarboxylic acid in 330 ml of ether is added a solution of n-butyllithium (748 mmoles) in ca. 750 ml. of 2:1 ether-hexane during 1 hour at 5°-10° C. The resulting suspension is diluted with 300 ml of ether and stirred at room temperature for 2 hours and at reflux for 2 hours. The mixture is cooled and poured into several portions of 1:1 ice-4 N hydrochloric acid. The ethereal phases are combined and washed with brine, sodium carbonate solution, and brine. The extract is dried over magnesium sulfate and concentrated. The residue is distilled to provide a liquid, b.p. 102°-104° C. (80 mm), pmr spectrum (CDCl3): δ2.55 (triplet, --CH2CO--).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([C:12]1[CH:26]=[CH:25][C:15]([CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH:14][CH:13]=1)=O)#[N:2].[CH3:27][NH2:28]>C1COCC1>[CH3:27][NH:28][C:1]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:9]=[C:10]([C:12]2[CH:26]=[CH:25][C:15]([CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)[N:2]=1
Reactant: CN
Reactant: CCOP(=O)(Cc1ccc(C(=O)Nc2ccccc2C#N)cc1)OCC
Solvent: C1CCOC1
Product: CCOP(=O)(Cc1ccc(-c2nc(NC)c3ccccc3n2)cc1)OCC
Temperature: 70 °C

Procedure:
A 3.7 g portion of diethyl 4-[N-(2-cyanophenyl)carbamoyl]benzylphosphonate and 10 ml of a 40% aqueous methylamine solution were dissolved in 50 ml of THF and refluxed with heating at 70° C. for 30 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: chloroform: methanol=100:1) and the crude crystals obtained were recrystallized from chloroform-n-hexane to provide 1.0 g of the objective compound as colorless crystals. Table 1 also shows the structure and physical property (melting point) of the compound thus obtained.