Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:9][C:10]=2[C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:28]([C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]Br)#[N:29]>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:9][C:10]=2[C:11]2[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=2)[O:17][CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[C:28]#[N:29])[CH:5]=[CH:6][N:7]=1
Reactant: N#Cc1ccccc1CBr
Reactant: Nc1nccn2c(C3CCC3)nc(-c3cccc(O)c3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1COc1cccc(-c2nc(C3CCC3)n3ccnc(N)c23)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenol (500 mg, 1.78 mmol) in DMF (8.9 mL) was charged with Cs2CO3 (871 mg, 2.68 mmol) and stirred for 30 min. at rt. A solution of 2-cyanobenzyl bromide (500 mg, 1.78 mmol) in DMF was added to the reaction mixture. After 24 h at rt the reaction mixture was concentrated in vacuo and chromatographed on silica gel [Jones Flashmaster, 10 g cartridge, eluting with 50% EtOAc:hexanes to 100% EtOAc]. The product was then recrystalized with CH2Cl2 and hexanes yielding the title compound as a light red solid; 1H NMR (CDCl3, 400 MHz) δ 2.02-2.06 (m, 1H), 2.11-2.33 (m, 1H), 2.45-2.53 (m, 2H), 2.59-2.69 (m, 2H), 3.77-3.86 (m, 1H), 5.33 (s, 2H), 7.02-7.04 (m, 1H), 7.05 (dd, J=2.4 Hz, 1H), 7.10 (d, J=5.2 Hz, 1H), 7.29-7.30 (m, 1H), 7.33 (q, J=3.6, 11H), 7.40-7.64 (m, 2H), 7.61-7.66 (m, 1H), 7.70-7.72 (m, 2H); MS (ES+): m/z 395.99 (100) [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:34]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([Cl:32])[CH:34]=4)(=[O:41])=[O:40])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cccc(Cl)c4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3-chloro-benzenesulfonyl chloride. Purity (ELSD, based on MW=596.1)=90%.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O-:3])=[O:2].C[O:13][CH:14](OC)[CH2:15][CH2:16][CH2:17][CH:18]=O>CCOC(C)=O.CCCCCC>[N+:1](/[C:4](/[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH:18]/[CH2:17][CH2:16][CH2:15][CH:14]=[O:13])([O-:3])=[O:2]
Reactant: O=[N+]([O-])CCc1ccccc1
Reactant: COC(CCCC=O)OC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=CCCC/C=C(\Cc1ccccc1)[N+](=O)[O-]
Yield: 39.9 %

Procedure:
Prepared according to the general procedure B from 1-(2-nitroethyl)benzene 112e (24 mmol) and 5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound as yellow oil (1.49 g, 40% yield) after silica gel chromatography (EtOAc/Hexane).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C@@:17]2([CH3:23])[O:21][C:20](=[O:22])[NH:19][CH2:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1.C(Cl)(Cl)Cl>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C@@:17]2([CH3:23])[O:21][C:20](=[O:22])[NH:19][CH2:18]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc([C@]2(C)CNC(=O)O2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1ccc([C@]2(C)CNC(=O)O2)cc1O

Procedure:
1.1 g of (R)-(-)-5-(3-benzyloxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone is dissolved in 40 ml of ethyl acetate and mixed with 100 mg of palladium/10% carbon. It is hydrogenated until hydrogen absorption is completed. After filtration on silica gel and concentration by evaporation in a vacuum, 750 mg of (R)-(-)-5-(3-hydroxy-4-methoxyphenyl)-5-methyl-2-oxazolidinone, melting point 141.6° C., is obtained. [α]D =-28.2° (CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:27])[C:6]=1[C:7]1[CH:8]=[C:9]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH:10]=[CH:11][C:12]=1[OH:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]([NH2:38])=[O:37]>CC(C)=O>[C:36]([CH2:35][O:13][C:12]1[CH:11]=[CH:10][C:9]([NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)=[CH:8][C:7]=1[C:6]1[N:5]([CH3:27])[N:4]=[CH:3][C:2]=1[Cl:1])(=[O:37])[NH2:38]
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1O
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(N)=O
Temperature: 25 °C
Yield: 83.2 %

Procedure:
To a mixture of N-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-3-(trifluoromethyl)benzamide (51 mg, 0.13 mmol) and potassium carbonate (27 mg, 0.20 mmol) in acetone (1 mL) was added 2-bromoacetamide (27 mg, 0.20 mmol). The resultant mixture was heated to 65° C. for 1 hour. Cooled to room temperature and partitioned between EtOAc and water. Layers were separated. The organic layer was washed with water (2×) and brine, dried (MgSO4) and reduced to give the title compound as a white solid (49 mg, 83%). LCMS m/z (%)=453 (M+H 35Cl, 100), 455 (M+H 37Cl, 30). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.73 (s, 3H), 4.46-4.61 (m, 2H), 7.09 (d, J=9.09 Hz, 1H), 7.24 (s, 1H), 7.38 (s, 1H), 7.65 (s, 1H), 7.72 (d, J=2.78 Hz, 1H), 7.73-7.84 (m, 1H), 7.87 (dd, J=8.97, 2.65 Hz, 1H), 7.97 (d, J=6.57 Hz, 1H), 8.21-8.36 (m, 2H), 10.53 (s, 1H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.[Na+]>CS(C)=O.C(OCC)(=O)C.[Cu]I>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=Cc1cccc(I)c1
Reactant: O=S([O-])c1ccc(Br)cc1
Agent: [Cu]I
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=Cc1cccc(S(=O)(=O)c2ccc(Br)cc2)c1
Temperature: 110 °C
Yield: 35.8 %

Procedure:
3-Iodobenzaldehyde (1.0 g, 4.3 mmol), copper(I) iodide (2.45 g, 12.9 mmol) and sodium 4-bromophenylsulfinate (1.55 g, 5.59 mmol) were combined in dimethylsulfoxide (8.6 mL) and heated to 110° C. for 4 hours. The cooled reaction mixture was diluted with ethyl acetate and filtered through Hyflo®. The filtrate was washed with water (×2) and brine and dried over MgSO4. The solvent was removed in vacuo and the residue purified by flash column chromatography on silica, eluting with 25% ethyl acetate/isohexane, to give 3-[(4-bromophenyl)sulfonyl]benzaldehyde (0.5 g, 35%). δH (400 MHz, d6 DMSO): 10.09 (1H, s), 8.47-8.44 (1H, m), 8.29-8.25 (1H, m), 8.21 (1H, d, J=7.6 Hz), 7.96-7.94 (2H, m), 7.88-7.84 (3H, m).
Reaction SMILES: N[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([I:9])=[C:4]([CH3:10])[N:3]=1.N([O-])=[O:12].[Na+]>OS(O)(=O)=O.O>[CH3:8][C:7]1[C:2](=[O:12])[NH:3][C:4]([CH3:10])=[C:5]([I:9])[CH:6]=1
Reactant: Cc1cc(I)c(C)nc1N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1[nH]c(=O)c(C)cc1I
Temperature: 0 °C
Yield: 96.9 %

Procedure:
2-Amino-3,6-dimethyl-5-iodopyridine (4.01 g, 16.2 mmol) was dissolved in 0.5 M H2SO4 (70 mL) and the resulting solution cooled to 0° C. with stirring. A solution of sodium nitrite (3.3 g, 48.0 mmol) in H2O (5 mL) was added dropwise over 10 min. at 0° C. with vigorous stirring. After 1.5 h the cooling bath was removed and the mixture warmed to r.t. over 1 h. The solid was vacuum filtered, washed with H2O (50 mL), the solids air dried and then dried under vacuum for 18 h, yielding 3.9 g (15.7 mmol, 97%) of white solid.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.N1C=CC=CC=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>O>[CH3:24][S:25]([O:4][C@@H:3]1[C@@H:5]([CH2:6][O:7][S:25]([CH3:24])(=[O:27])=[O:26])[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: O
Solvent: c1ccncc1
Product: Cc1cn([C@H]2C[C@H](OS(C)(=O)=O)[C@@H](COS(C)(=O)=O)O2)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
A 3 liter, 3 necked round-bottomed flask was equipped with an overhead stirrer and paddle, a 500 mL dropping funnel and a Claisen adapter containing a drying tube and a thermometer. Thymidine (200 g, 0.82M) and pyridine (750 mL) were added to the flask. The mixture was stirred and warmed with a water bath (20 mins) to give a clear solution. The solution was then cooled in an ice bath to 0°-3° C. and the dropping funnel was charged with methanesulfonyl chloride (206.5 g, 1.08M). The methanesulfonyl chloride was then added dropwise over 40 minutes with no noticeable exotherm. The solution was stirred at 0° C. for 1 hr and then stored at 5° C. for 18 hr. The light brown mixture was then poured onto rapidly stirred water (3 L) containing ice (approx. 500 g). The desired product crystallised immediately. After stirring for 0.5 hr, the product was collected by filtration and washed several times with water (3×100mL). The white solid was then dried under vacuum overnight (crude weight, 322 g, 98% yield). The product was recrystallised from hot acetone to give 267 g of a white solid (81% yield), mp 169°-171° C. (lit. 170°-171° C.) 1H NMR (360 MHz, d6 -DMSO) 11.40 (s, 1H, NH), 7.50 (s, 1H, H-6), 6.21 (t, 1H, H-1'), 5.29 (m, 1H, H-3'), 4.45 (m, 2H, H-5'), 4.35 (m, 1H, H-4'), 3.31 (s, 6H, SO2CH3), 2.50 (m, 2H, H-2'), 1.78 (s, 3H, CH3). Analysis (C12H18N2O9S2) C, H, N.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]([CH2:8][Cl:9])=[O:7])[CH3:2]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][C@@H:6]([OH:7])[CH2:8][Cl:9])[CH3:2]
Reactant: CCOC(=O)CC(=O)CCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C[C@@H](O)CCl

Procedure:
The procedure of example 375 was repeated using ethyl-4-chloroacetoacetate as the substrate to afford ethyl-4-chloro-3(R)-hydroxybutyrate, [α]D23 +22.7° (c, 4.7, CHCl3).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[C:18]([C:20]3[N:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=4)[CH:23]=[C:22]([C:34]([F:37])([F:36])[F:35])[N:21]=3)[CH:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:33][C:28]1[CH:27]=[C:26]([C:24]2[CH:23]=[C:22]([C:34]([F:35])([F:36])[F:37])[N:21]=[C:20]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=4)[CH:19]=3)[N:25]=2)[CH:31]=[CH:30][C:29]=1[F:32]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)ccn2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)ccn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 30.7 %

Procedure:
To a cooled and stirred solution of 5-{4-[4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.29 g) in dichloromethane (4 ml) was added TFA (4 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N NaHCO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.08 g, 24%). MS (ISP) 499.1 [(M+H)+]; mp 281° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][C:9]=1[CH3:10])=[O:4].[O:17]1[CH2:21][CH2:20][O:19][CH:18]1[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[O:17]1[CH2:21][CH2:20][O:19][CH:18]1[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:2][C:3]([C:5]2[N:6]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][C:9]=2[CH3:10])=[O:4])=[CH:26][CH:25]=1
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)CBr
Reactant: Oc1ccc(CCC2OCCO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1C(=O)COc1ccc(CCC2OCCO2)cc1
Reaction time: 20 h
Yield: 57 %

Procedure:
A mixture of 4-bromoacetyl-5-methyl-2-phenyloxazole (2.60 g), 4-[2-(1,3-dioxolan-2-yl)ethyl]phenol (1.82 g), potassium carbonate (1.28 g) and 2-butanone (60 ml) was stirred for 20 hours at temperatures ranging from 70 to 80° C. The reaction mixture was poured into water. Resulting crystalline precipitate was collected by filtration, which was purified by means of a silica gel column chromatography. From the fractions eluted with chloroform-methanol (100:1, v/v), 4-[4-[2-(1,3-dioxolan-2-yl)ethyl]phenoxyacetyl]-5-methyl-2-phenyloxazole (2.08g, 57%) was obtained. Recrystallization from dichloromethane-isopropyl ether gave colorless prisms, m.p.119-120° C.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][CH2:8][CH2:9][CH2:10][S:11]([NH:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][N:31]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:32][C@H:33]([OH:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:25][CH:24]=2)=[CH:19][C:18]=1[O:48][CH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1)=[O:16])(=[O:13])=[O:12])(=O)C>CO>[CH:49]1([O:48][C:18]2[CH:19]=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][N:31]([CH2:32][C@H:33]([OH:40])[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:41](=[O:42])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:27][CH:28]=3)[CH:21]=[CH:22][C:17]=2[C:15]([NH:14][S:11]([CH2:10][CH2:9][CH2:8][CH2:7][OH:6])(=[O:12])=[O:13])=[O:16])[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: CC(=O)OCCCCS(=O)(=O)NC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)cc1OC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C(=O)NS(=O)(=O)CCCCO)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
1N Sodium hydroxide (575 μl) was added to a solution of 4-[[[[4′-[2-[(tert-butoxycarbonyl)[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-(cyclohexyloxy)-4-biphenylyl]-carbonyl]amino]sulfonyl]butyl acetate (212 mg) in methanol (4.24 ml). The mixture was stirred at room temperature overnight. The mixture was evaporated in vacuo. The residue was purified by silica gel column chromatography to give tert-butyl [2-[3′-(cyclohexyloxy)-4′-[[[(4-hydroxybutyl)sulfonyl]amino]carbonyl]-4-biphenylyl]ethyl]-[(2R)-2-hydroxy-2-phenylethyl]carbamate (111 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[C:13]([CH2:15][C:16]([OH:18])=O)[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].CCN=C=NCCCN(C)C.[CH:30]1[CH:31]=[CH:32][C:33]2N(O)N=[N:36][C:34]=2[CH:35]=1.NC1C=CC=CC=1>CN(C=O)C>[NH:36]([C:16](=[O:18])[CH2:15][C:13]1[CH:12]=[CH:11][C:9]2[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:7][C:8]=2[CH:14]=1)[C:34]1[CH:35]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: On1nnc2ccccc21
Reactant: CCOC(=O)c1cc2ccc(CC(=O)O)cc2s1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Product: CCOC(=O)c1cc2ccc(CC(=O)Nc3ccccc3)cc2s1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.2 %

Procedure:
[2-(ethoxycarbonyl)-1-benzothien-6-yl]acetic acid (0.2 g, 0.757 mmol), EDCI (0.22 g, 1.15 mmol) and HOBt (0.16 g, 1.18 mmol) were stirred in DMF (6 mL) for 10 minutes before adding aniline (85 mg, 0.913 mmol). The solution was stirred at room temperature for 3 days. The solvent was removed in vacuo and the residue partitioned between H2O-EtOAc. The aqueous phase was extracted with further portions of EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Et2O was added and the resulting beige solid collected by filtration to give 0.17 g of product (66%). 1H NMR (DMSO-d6) δ 10.21 (s, 1H), 8.15 (s, 1H), 7.96 (s, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.57 (d, J=7.8 Hz, 2H), 7.42 (dd, J=8.4, 1.2 Hz, 1H), 7.27 (t, J=7.2 Hz, 2H), 7.01 (t, J=7.2 Hz, 1H), 4.32 (q, J=7.2 Hz, 2H), 3.78 (s, 2H), 1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].C1CCN2C(=NCCC2)CC1>CC#N>[N:1]1([CH2:12][CH2:11][C:10]([O:14][CH3:15])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C=CC(=O)OC
Reactant: c1ccc2[nH]ccc2c1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CCn1ccc2ccccc21
Temperature: 50 °C
Yield: 43.3 %

Procedure:
To the solution of indole (1.20 g, 10.24 mmol) and methyl acrylate (1.384 mL, 15.37 mmol) in MeCN (20 mL) was added DBU (0.772 mL, 5.12 mmol). The mixture was heated at 50° C. overnight. Purification via flash chromatography then afforded the title compound (1.0 g, 4.43 mmol, 90% purity, 43.2% yield). LCMS: rt=3.04 min, [M+H+]=204
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C:10]([NH:12][N:13]1[CH2:17][CH2:16][C@H:15]([N:18]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:19](=[O:27])[C@H:20]([CH3:26])[CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH2:14]1)=[O:11].[NH:42]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][C:44](O)=[O:45]>>[C:47]([NH:42][CH2:43][C:44]([NH:8][C@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)[C:10]([NH:12][N:13]1[CH2:17][CH2:16][C@H:15]([N:18]([CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)[C:19](=[O:27])[C@H:20]([CH3:26])[CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH2:14]1)=[O:11])=[O:45])([O:49][C:50]([CH3:51])([CH3:52])[CH3:53])=[O:48]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(=O)OC[C@@H](C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@H](N)Cc2ccc(Cl)cc2)C1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC[C@@H](C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)CNC(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared following the procedure described in Step A of Example 1 using (2R)-2-amino-N-{(3S)-3-[cyclohexyl((2R)-2-methyl-3-acetyloxypropionyl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step B of Example 187 and N-BOC-Gly.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11](=[S:35])[CH2:12][C@H:13]1[C@H:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[O:18][CH2:17][CH2:16][N:15]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:14]1.C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)([O-])O.[Na+]>CCO>[Cl:27][C:22]1[CH:21]=[C:20]([C@@H:19]2[O:18][CH2:17][CH2:16][N:15]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:14][C@H:13]2[CH2:12][C:11]2[S:35][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:10]=2)[CH:25]=[CH:24][C:23]=1[Cl:26]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CC(N)=S)C1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO[C@H]2c2ccc(Cl)c(Cl)c2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 101.7 %

Procedure:
Ethyl bromopyruvate (0.070 mL, 0.50 mmol) was added to a solution of tert-butyl (6R,7R)-6-(2-amino-2-thioxoethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (140 mg, 0.33 mmol) in EtOH (5 mL). The reaction mixture was stirred at 80° C. for 2 hr, triethylamine (0.140 mL, 1.00 mmol) and di-tert-butyl dicarbonate (0.115 mL, 0.50 mmol) were added at room temperature, and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (173 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH2:54]O)[CH:49]=1>C1COCC1>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:16][C:13]=3[N:14]([CH2:54][C:50]3[CH:49]=[N:48][CH:53]=[CH:52][CH:51]=3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: OCc1cccnc1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)cc1)c1cn(Cc2cccnc2)c2sc(CN3CCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 12 %

Procedure:
1,4-Diethylazodicarboxylate (205 μL) is added to a solution of N-(4-chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41, triphenylphospine (341 mg), and 3-pyridylmethanol (243 μL) in THF (10 mL). The reaction mixture is stirred at room temperature for 20 h and then the resulting suspension is filtered. The crude product is purified by recrystallization from ethanol to afford 63 mg (12%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([OH:3])C.C[N:5]([CH3:8])[CH:6]=[O:7]>>[CH3:1][O:3][N:5]([CH3:8])[C:6]([C:6]([N:5]([O:3][CH3:1])[CH3:8])=[O:7])=[O:7]
Reactant: CN(C)C=O
Reactant: CCO
Product: CON(C)C(=O)C(=O)N(C)OC
Yield: 77.5 %

Procedure:
The reaction was carried out in the same manner as in Example 3 except for changing ethanol to dimethylformamide in Example 3. As a result, 1.16 g (Reaction yield: 77.5%) of N,N′-dimethoxy-N,N′-dimethyl oxamide was found to be formed.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[C:12]#[N:13])=[CH:7][CH:6]=1>[Ni].CO.[H][H]>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][NH2:13])=[CH:9][CH:10]=1
Reactant: COCOc1ccc(C(C#N)Cc2cccnc2)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: COCOc1ccc(C(CN)Cc2cccnc2)cc1
Yield: 84.6 %

Procedure:
An appropriate amount of Raney nickel was suspended in 30 ml of saturated ammonical methanol solution, followed by addition of 3.81 g of 2-(4-methoxymethyloxyphenyl)-3-(3-pyridyl)propionitrile, and stirred for 72 hours in hydrogen atmosphere of 15 atm. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue obtained was subjected to chromatography on a silica gel column, which was then eluted with aqueous ammonia-methanol-chloroform (1:10:100 v/v), and from the eluted fraction was obtained 3.27 g of 2-(4-methoxymethyloxyphenyl)-3-(3-pyridyl)propylamine.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[C:4]([CH3:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.C([Li:15])CCC>CCCCCC>[CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][Li:15]
Reactant: [Li]CCCC
Reactant: Cc1ccccc1N(C)C
Solvent: CCCCCC
Product: [Li]Cc1ccccc1N(C)C
Reaction time: 48 h
Yield: 100 %

Procedure:
A mixture of 96.0 g of N,N-dimethyl-o-toluidine and 444 ml of a 1.6 M solution of butyllithium in hexane was stirred for two days. Stirring was stopped and the orange solution was cooled in ice until it became cloudy, whereupon stirring was resumed with continuing cooling. A yellow solid separated. Volatile materials were removed, about 50 ml of ethyl ether was added, and the solution was stirred for another 24 hours. During this time a large amount of solid separated. It was washed from the flask with pentane to give 2-dimethylaminobenzyllithium in 100% yield (mp above 200° C with decomposition). The infrared absorption spectrum of the product was in agreement with its assigned structure.