Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[O:14]2)(=O)=O)=CC=1.[C-:24]#[N:25].[K+].O>CS(C)=O>[C:24]([CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[O:14]1)#[N:25]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCc3ccccc3O2)cc1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCC1CCc2ccccc2O1
Reaction time: 2 h

Procedure:
A mixture of 15.8 g (47 mmol) of 2-p-toluenesulfonyloxyethyl-3,4-dihydro-2H-1-benzopyran and 3.4 g (52 mmol) of potassium cyanide in 320 ml of dimethyl sulfoxide is stirred for 2 hours. After addition of water, the product is extracted with chloroform containing a little methanol and then the organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. By chromatography of the residue on a silica column using cyclohexane containing 10% ethyl acetate, 7.8 g of compound are obtained in oil form.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([NH:16][C:17]([CH3:19])=[O:18])[C@H:12]([O:20][C@H:21]3[C@@H:26]([O:27][P:28]([O:31][CH2:32][C@H:33]([O:37][CH2:38]/[CH:39]=[C:40](/[CH2:42][CH2:43]/[CH:44]=[CH:45]/[C:46]([CH2:49][CH2:50][C:51]([CH2:53]/[CH:54]=[C:55](/[CH2:57][CH2:58][CH:59]=[C:60]([CH3:62])[CH3:61])\[CH3:56])=[CH2:52])([CH3:48])[CH3:47])\[CH3:41])[C:34]([OH:36])=[O:35])([OH:30])=[O:29])[O:25][C@H:24]([C:63]([NH2:65])=[O:64])[C@:23]([OH:67])(C)[C@@H:22]3[O:68][C:69]([NH2:71])=[O:70])[O:11][C@@H:10]2[CH2:72][O:73][C@@H:74]2[O:79][C@H:78]([CH2:80][OH:81])[C@@H:77]([OH:82])[C@H:76]([OH:83])[C@H:75]2[OH:84])[C@H:5]([NH:85][C:86]([CH3:88])=[O:87])[C@@H:4]([OH:89])[C@@H:3]1[O:90][C@@H:91]1[O:96][C@H:95]([C:97]([NH:99][C:100]2[C:104](=[O:105])[CH2:103][CH2:102][C:101]=2[OH:106])=[O:98])[C@H:94]([OH:107])[C@H:93]([OH:108])[C@H:92]1[OH:109].CCN(CCO)CC>>[CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([NH:16][C:17]([CH3:19])=[O:18])[C@H:12]([O:20][C@H:21]3[C@@H:26]([O:27][P:28]([O:31][CH2:32][C@@H:33]([O:37][CH2:38]/[CH:39]=[C:40](\[CH2:42][CH2:43]/[CH:44]=[CH:45]/[C:46]([CH2:49][CH2:50][C:51]([CH2:53]/[CH:54]=[C:55](/[CH2:57][CH2:58][CH:59]=[C:60]([CH3:61])[CH3:62])\[CH3:56])=[CH2:52])([CH3:47])[CH3:48])/[CH3:41])[C:34]([OH:36])=[O:35])([OH:30])=[O:29])[O:25][C@H:24]([C:63]([NH2:65])=[O:64])[C@@H:23]([OH:67])[C@@H:22]3[O:68][C:69]([NH2:71])=[O:70])[O:11][C@@H:10]2[CH2:72][O:73][C@@H:74]2[O:79][C@H:78]([CH2:80][OH:81])[C@@H:77]([OH:82])[C@H:76]([OH:83])[C@H:75]2[OH:84])[C@H:5]([NH:85][C:86]([CH3:88])=[O:87])[C@@H:4]([OH:89])[C@@H:3]1[O:90][C@@H:91]1[O:96][C@H:95]([C:97]([NH:99][C:100]2[C:101](=[O:106])[CH2:102][CH2:103][C:104]=2[OH:105])=[O:98])[C@H:94]([OH:107])[C@H:93]([OH:108])[C@H:92]1[OH:109]
Reactant: C=C(C/C=C(\C)CCC=C(C)C)CCC(C)(C)/C=C/CC/C(C)=C/CO[C@@H](COP(=O)(O)O[C@H]1O[C@H](C(N)=O)[C@@](C)(O)[C@H](OC(N)=O)[C@H]1O[C@@H]1O[C@H](CO[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O[C@@H]2O[C@H](C)[C@@H](O[C@@H]3O[C@H](C(=O)NC4=C(O)CCC4=O)[C@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2NC(C)=O)[C@H](O)[C@H]1NC(C)=O)C(=O)O
Agent: CCN(CC)CCO
Product: C=C(C/C=C(\C)CCC=C(C)C)CCC(C)(C)/C=C/CC/C(C)=C\CO[C@H](COP(=O)(O)O[C@H]1O[C@H](C(N)=O)[C@@H](O)[C@H](OC(N)=O)[C@H]1O[C@@H]1O[C@H](CO[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O[C@@H]2O[C@H](C)[C@@H](O[C@@H]3O[C@H](C(=O)NC4=C(O)CCC4=O)[C@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2NC(C)=O)[C@H](O)[C@H]1NC(C)=O)C(=O)O
Yield: 0.4 %

Procedure:
81 g of 95% pure moenomycin A dissolved in 7 L of aqueous buffer solution, pH 7.9, conductivity 10.5 mS/cm (resulting from DEAE purification and ultrafiltration), are loaded onto a column with a capacity of 2.7 L (W×H=10 cm×35 cm) and packed with MCI GEL® CHP20P. Elution is carried out with a linear gradient from buffer A (m/15 phosphate buffer, pH 7.8) to buffer B (m/15 phosphate buffer, pH 7.8 with 33% 2-propanol). The column flow is fractionated and analyzed. The fractions with at least 98.8% pure moenomycin A are collected and, after removal of the salts as described in Example 4, dried, resulting in 71 g of 99.3% pure moenomycin A with 0.4% moenomycin A12 as concomitant substance.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)=[O:6].[H-].[Na+].C(OC(=O)C)C>CN(C=O)C.C1COCC1>[C:10]1([CH3:14])[CH:11]=[CH:12][CH:13]=[C:8]([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])[CH:9]=1
Reactant: Cc1cccc(NC(=O)NCCCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc(N2CCNC2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
1-(2-Chloro-ethyl)-3-m-tolyl-urea (I-131a: 4 g, 18.86 mmol) in dry DMF (70 mL) was added to a stirred mixture of sodium hydride (1.358 g, 28.30 mmol) in THF (70 mL) at 0° C. The reaction was stirred at room temperature for 1 hour. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was quenched with MeOH at 0° C., concentrated under reduced pressure and partitioned between ice water and chloroform. The organic layer was washed with brine solution, dried over Na2SO4, and concentrated under reduced pressure to afford 2.7 g (81.34% yield) of 1-m-tolyl-imidazolidin-2-one.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][C@@H:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][OH:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[CH2:7]([O:14][C@@H:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH:17]=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCC[C@@H](CCO)OCc1ccccc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC[C@@H](CC=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Chromium trioxide (6.0 g., 0.06 mole) is added to a mechanically-stirred solution of dry pyridine (9.49 g., 0.12 mole) in methylene chloride (150 ml.) maintained at 0°-5° C. under a nitrogen atmosphere. The resulting reaction mixture is warmed to 25° C., stirred at 25° C. for 1/3 hour, and treated with a solution of 3(S)-benzyloxy-1-octanol (2.37 g., 0.01 mole) in methylene chloride (2 ml.) which initiates precipitation of a black, intractable precipitate. After stirring at 25° C. for 1/4 hour, the solution is decanted, and the insoluble precipitate washed with ether (200 ml.). The combined decantates are washed successively with 5% sodium hydroxide (3 × 100 ml.), 5% hydrochloric acid (100 ml.), and 5% aqueous sodium bicarbonate (100 ml.); dried over magnesium sulfate; and filtered. In vacuo evaporation of the filtrate affords the title compound as a pale yellow oil.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:11])[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13]1.[Br:18][CH2:19][CH:20](O)[CH2:21][OH:22].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([NH:8][C:9](=[O:10])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18][CH2:19][CH:20]1[CH2:21][O:22][C:14]2([CH2:15][CH2:16][NH:12][CH2:13]2)[O:17]1
Reactant: O=C1CCNC1
Reactant: OCC(O)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)NCc1ccccc1
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Product: BrCC1COC2(CCNC2)O1
Temperature: 110 °C

Procedure:
A 1.00 g (4.56 mmol) sample of 3-pyrrolidinone benzyl carbamate, from Step 2 Example 1, was dissolved in 20 mL of toluene with 1.00 g (11.4 mmol) of 3-bromo-1,2-propanediol and 0.043 g (0.23 mmol) of p-toluenesulfonic acid and heated at 110° C. for 24 hours. The reaction solution was poured into 20% sodium bicarbonate solution and the mixture extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent removed under vacuum to afford 1.22 g of the title compound as a dark liquid: MS M/Z 356 (M). NMR: d 2.06 (m, 2H), 3.32 (m, 1H), 3.44 (m, 2H), 3.55 (m, 3H), 3.91 (m, 1H), 4.11 (m, 1H), 4.37 (m, 1H), 5.13 (s, 2H), 7.35 (m, 5H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][CH2:16][CH2:17][CH3:18])[CH:3]([OH:14])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[N:19]1([C:25]([NH:27][C:28]2([C:34](O)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[OH:14][CH:3]([C@@H:2]([NH:1][C:34]([C:28]1([NH:27][C:25]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:26])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)=[O:35])[CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5]
Reactant: O=C(NC1(C(=O)O)CCCCC1)N1CCOCC1
Reactant: CCCC[C@H](N)C(O)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)C1(NC(=O)N2CCOCC2)CCCCC1)C(O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.7 %

Procedure:
Subsequently, under ice-cooled condition, to 9.3 g (37 mmol) of phenylmethyl (2RS,3S)-3-amino-2-hydroxyheptanoate, 9.5 g (37 mmol) of 1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarboxylic acid synthesized in Reference Example 5 and 6.0 g (45 mmol) of 1-hydroxybenzotriazole in 100 ml of dichloromethane, 8.5 g (45 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added and then was stirred at the room temperature for 18 hours. The reaction solution was concentrated under reduced pressure. The residue was washed successively with water, aqueous solution of 10% of potassium hydrogensulfate, aqueous solution of saturated sodium hydrogen-carbonate and saturated brine in addition of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled away from the reaction mixture under reduced pressure. The residue was purified by the silicagel column chromatography, whereby 16.8 g of phenylmethyl (2RS,3S)-2-hydroxy-3-[N-[1-[N-(morpholine-4-carbonyl)amino]cyclohexanecarbonyl]amino]heptanoate was obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][N:7]=1)=O)C.[BH4-].[Na+]>C(O)(C)(C)C>[CH3:13][O:12][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([CH2:4][OH:3])[N:11]=1
Reactant: CCOC(=O)c1nccc(OC)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: COc1ccnc(CO)n1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of 3.7 g (20.3 mMol) 4-methoxy-pyrimidine-2-carboxylic acid ethyl ester in 37 ml of tert-butanol, 2.3 g (61 mMol) of NaBH4 are added. The mixture is stirred at 60° C. for 5 h and cooled to rt. 15 min after quenching with 5 ml of acetone, the mixture is poured into 20 ml of a sat. NaHCO3 solution and 0.4 l EtOAc and stirred for 20 min. The inorganic phase is separated off and extracted twice with EtOAc. The organic layers are washed with 20 ml of a 1:1 mixture of brine and water, dried (Na2SO4) and concentrated, yielding (4-methoxy-pyrimidin-2-yl)-methanol (MS: [M+1]+=141).
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[CH:8][C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:14][CH2:15][O:16][CH3:17].COC(=O)N=C(SC)C(C1C=C(OC)C=C(O)C=1F)=NC1C=CC(C2N=C(C)ON=2)=CC=1.FCCI>>[F:1][C:2]1[C:9]([O:10][CH2:14][CH2:15][O:16][CH3:17])=[CH:8][C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COCCBr
Reactant: COc1cc(O)c(F)c(C=O)c1
Agent: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(O)c1F
Agent: FCCI
Product: COCCOc1cc(OC)cc(C=O)c1F

Procedure:
The same procedure was carried out as in Example (3e), except that 2-25 fluoro-3-hydroxy-5-methoxybenzaldehyde [CAS No. 883576-31-6] and 2-bromoethylmethyl ether were used instead of respectively [2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester and 1-fluoro-2-iodoethane, to give the title compound was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[S:23](=[O:24])[CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[NH2:25][CH2:26][C:27]1[CH:28]=[C:29]([OH:33])[N:30]([CH3:32])[N:31]=1.C(N(C(C)C)CC)(C)C.O>O1CCOCC1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]3[N:7]=[C:2]([NH:25][CH2:26][C:27]4[CH:28]=[C:29]([OH:33])[N:30]([CH3:32])[N:31]=4)[C:3]4[S:23](=[O:24])[CH2:22][CH2:21][C:4]=4[N:5]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(Cl)c21
Reactant: Cn1nc(CN)cc1O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1nc(CNc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc3c2S(=O)CC3)cc1O
Temperature: 130 °C
Yield: 52.6 %

Procedure:
200 mg 4-chloro-2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidine 5-oxide (cf Example 124), 313.3 mg 5-aminomethyl-2-methyl-2H-pyrazol-3-ol and 359.25 μl diisopropylethylamine are placed in 4 ml dioxane, heated to 130° C. in the microwave for 0.3 hours and for a further 0.3 hours to 130° C. Then the reaction mixture is mixed with water. The precipitated substance is suction filtered and washed with water. The product is purified by semipreparative HPLC (method A). 130 mg of the product are obtained as a powder. Analytical HPLC-MS (method B): RT=1.61 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][CH:17]=[CH2:18])[CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].OS([O-])(=O)=O.[K+]>CO>[C:1]([O:5][C:6]([N:8]([CH2:16][CH:17]=[CH2:18])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCN(CCC(=O)OCC)C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: CO
Product: C=CCN(CCC(=O)O)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a solution of ethyl N-(tert-butoxycarbonyl)-3-(2-propenylamino)propionate (1.0 g, 3.89 mmol) in methanol (10 mL) was added 1N aqueous LiOH solution (5.0 mL). After stirring overnight, the mixture was acidified to pH 2.5 with 20% aqueous KHSO4 solution, and extracted with ethyl acetate. The extract was dried over Na2SO4, and evaporated in vacuo to give N-(tert-butoxycarbonyl)-3-(2-propenylamino)propionic acid (0.8 g, 3.49 mmol, 89.7%) as a colourless oil.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:20])[CH2:11][N:10]=2)=[CH:5][CH:4]=1.[N+](C1C=CC2NC(=O)CN=C(C3C=CC=CC=3)C=2C=1)([O-])=O.C(N1C2C=CC=C(C)C=2C=NCC1=O)(C)C.[N+](C1C=CC2N(C)C(=O)CN=C(C3C=CC=CC=3)C=2C=1)([O-])=O.C1(C2C3C=CC=CC=3NC(=O)CN=2)CCCCC1.S1C=CC=C1C1C2C=CC=CC=2NC(=O)CN=1.OC1C=CC(C2N=C(C3C=CC=CC=3)C3C=CC=CC=3NC2=O)=CC=1.[Cl:140]C1C=CC2NC(=O)C(C3C=CC(O)=CC=3)N=C(C3C=CC=CC=3)C=2C=1.COC1C=CC(C2C3C=CC=CC=3NC(=O)C(C3C=CC(O)=CC=3)N=2)=CC=1>>[Cl:140][C:17]1[CH:18]=[CH:19][C:14]2[NH:13][C:12](=[O:20])[CH2:11][N:10]=[C:9]([C:6]3[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=3)[C:15]=2[CH:16]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1c1ccc(O)cc1
Reactant: COc1ccc(C2=NCC(=O)Nc3ccccc32)cc1
Agent: CN1C(=O)CN=C(c2ccccc2)c2cc([N+](=O)[O-])ccc21
Agent: COc1ccc(C2=NC(c3ccc(O)cc3)C(=O)Nc3ccccc32)cc1
Agent: Cc1cccc2c1C=NCC(=O)N2C(C)C
Product: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1

Procedure:
1,3-dihydro-5-(4-methoxyphenyl)-2H-1,4-benzodiazepin-2-one; 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one; 1,3-dihydro-1-isopropyl-6-methyl-2H-1,4-benzodiazepin-2-one; 7-nitro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one; 5-cyclohexyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one; 1,3-dihydro-5-(2-thienyl)-2H-1,4-benzodiazepin-2-one; 1,3-dihydro-3-(4-hydroxyphenyl)-5-phenyl-2H-1,4-benzodiazepin-2-one; 7-chloro-1,3-dihydro-3-(4-hydroxyphenyl)-5-phenyl-2H-1,4-benzodiazepin-2-one; 1,3-dihydro-5-(4-methoxyphenyl)-3-(4-hydroxyphenyl)-2H-1,4-benzodiazepin-2-one;
Reaction SMILES: [Br:1][C:2](C)([CH3:6])[C:3](Br)=[O:4].Cl.[CH2:9]([O:16][NH2:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCOC(C)=O>[Br:1][CH:2]([CH3:6])[C:3]([NH:17][O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: NOCc1ccccc1
Reactant: CC(C)(Br)C(=O)Br
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(Br)C(=O)NOCc1ccccc1
Yield: 53 %

Procedure:
Prepared in 53% yield (631 mg, 2.44 mmol) from the reaction of 2-bromo-2-methylpropanoyl bromide (1.0 g, 4.6 mmol) with O-benzylhydroxylamine hydrochloride (742 mg, 4.6 mmol) via general procedure A. Rf=0.28 (3:1, hexanes:EtOAc); mp=75.3-77.4° C.; 1H-NMR (500 MHz, CDCl3): δ 9.61 (br s, 1H), 7.44-7.26 (m, 5H), 4.90 (s, 2H), 4.31 (q, J=7.7 Hz, 1H), and 1.77 (d, J=6.4 Hz, 3H); 13C-NMR (126 MHz, CDCl3): δ 167.5, 134.8, 129.45, 128.9, 128.7, 78.3, 40.5, and 22.2; FT-IR (neat) 3110 (br), 2924, 2852, 1675 (s), 1508, 1495, 1453, 1364, 1188, 1038, 1023 cm-1;
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:22]2[CH:21]=[CH:20][N:19]=[C:18]([O:17][CH3:16])[CH:23]=2)[C:11]=1[CH3:12]
Reactant: COc1cc(B(O)O)ccn1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1cc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)ccn1

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 2-methoxypyridin-4-ylboronic acid (0.308 g, 2.0 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 19.7 h to give 4-chloro-5,7-difluoro-2-(2-methoxypyridin-4-yl)-3-methylquinoline as an off white solid. Mass Spectrum (ESI) m/e=321.0 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[C:15]([C:21]([F:24])([F:23])[F:22])[C:14]=1[F:25].C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CC(O)C>[CH3:27][N:2]([CH3:1])[C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[C:15]([C:21]([F:22])([F:23])[F:24])[C:14]=1[F:25]
Reactant: C=Cc1ccc(Nc2ccc(C)cc2CC(=O)N(C)C)c(F)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)O
Product: CCc1ccc(Nc2ccc(C)cc2CC(=O)N(C)C)c(F)c1C(F)(F)F
Temperature: 80 °C

Procedure:
The above styrene is reduced under conditions outlined in. The styrene is dissolved in i-PrOH and toluene and degassed for 10 minutes. Then Cs2CO3 (22 mg, 0.07 mmol), [Ir(cod)Cl]2 (44 mg, 0.07 mmol), and dppp (27 mg, 0.07 mmol) are added and the reaction is heated to 80° C. over night. The cooled solution is concentrated in vacuo and the residue purified by flash chromatography eluting with 10, then 20, then 30% EtOAc/hexanes to give the title 5-methyl-2-(2′-fluoro-4′-ethyl-3′-trifluoromethylanilino)phenylacetic acid N,N-dimethyl amide.
Reaction SMILES: Cl.CO[C:4]([C:6]1[S:7][CH:8]=[C:9]([CH3:12])[C:10]=1[NH2:11])=[O:5].COC(C1SC=C(C)C=1N=C=S)=O.COC(=O)C[N:30]1[C:35](=[O:36])[C:34]2SC=C(C)C=2[NH:32][C:31]1=S>>[CH3:12][C:9]1[C:10]2[N:11]=[C:31]3[NH:30][C:35](=[O:36])[CH2:34][N:32]3[C:4](=[O:5])[C:6]=2[S:7][CH:8]=1
Reactant: COC(=O)c1scc(C)c1N
Reactant: COC(=O)Cn1c(=S)[nH]c2c(C)csc2c1=O
Agent: COC(=O)c1scc(C)c1N=C=S
Agent: Cl
Product: Cc1csc2c(=O)n3c(nc12)NC(=O)C3

Procedure:
The starting material can be prepared in an analogous manner to Example 1 starting from 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester hydrochloride via 4-methyl-3-isothiocyanato-2-thiophenecarboxylic acid methyl ester (70 g, melting point 227°-228°) and 1,4-dihydro-7-methyl-4-oxo-2-thioxothieno[3,2-d]pyrimidine-3(2H)-acetic acid methyl ester (69 g, melting point 227°-228°); yield 68.9 g, melting point 131°-132°.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=1.[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:22][CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1ccc(Cl)cc1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
0.38 ml of 4-tert-butylbenzaldehyde (2.25 mmol) and 0.200 ml 2-(4-chloro-phenyl)-ethylamine (1.5 mmol) were dissolved in 4.5 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2.5 h. After cooling down to rt, 85 mg (2.25 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 2 h. After cooling down to rt, the reaction mixture was treated with 4 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2) to give 437 mg light yellow oil (96%). MS (ISP) 302.3 (M+H)+.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][C:5]1[C:10](=[O:11])[N:9]2[CH:12]=[CH:13][CH:14]=[C:15]([OH:16])[C:8]2=[N:7][C:6]=1[CH3:17].Br>CO.[Pd]>[Br:2][CH2:3][CH2:4][C:5]1[C:10](=[O:11])[N:9]2[CH2:12][CH2:13][CH2:14][CH:15]([OH:16])[C:8]2=[N:7][C:6]=1[CH3:17]
Reactant: Cc1nc2c(O)cccn2c(=O)c1CCBr
Agent: [Pd]
Agent: Br
Solvent: CO
Product: Cc1nc2n(c(=O)c1CCBr)CCCC2O
Yield: 39.2 %

Procedure:
A mixture of intermediate 15 (55 g) and hydrobromic acid (48%) (55 g) in methanol (700 ml) was hydrogenated with palladium on activated carbon (10%) (5 g) as a catalyst. After completion, the precipitate was filtered off and the filtrate evaporated. Ammonium hydroxide was added to the residue which was subsequently extracted with CHCl3. The separated organic layer was dried and evaporated. The residue was purified by column chromatography over silica gel (eluent: CHCl3 /CH3OH 90/10). The pure fractions were collected, the solvent was evaporated and the residue was recrystallized from 4-methyl-2-pentanone, yielding 17 g (44%) of (±)-6,7,8,9-tetrahydro-3-(2-bromoethyl)-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (intermediate 16).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:15]([O:17][C:18](=[O:24])[C@H:19]([C@@H:21]([CH3:23])[OH:22])[NH2:20])C>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:20][C@H:19]([C:18]([O:17][CH3:15])=[O:24])[C@@H:21]([CH3:23])[OH:22])=[O:13])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)[C@@H](N)[C@@H](C)O
Agent: Cl
Product: COC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)[C@@H](C)O

Procedure:
The preparation was performed in a similar manner as Example 1.001 (d) Method B from N-(tert-butoxycarbonyl)-L-alanine (5.62 g, 29.7 mmol) and L-threonine ethyl ester hydrochloride (4.58 g, 27.0 mmol) to give methyl N-(tert-butoxycarbonyl)-L-alanyl-L-threoninate. MS (APCI): m/z 305 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C.CO>C1COCC1.C(Cl)Cl>[CH2:9]([NH:16][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: C1CCOC1
Product: Clc1nccc(NCc2ccccc2)n1
Yield: 54.8 %

Procedure:
To a solution of 2,4-dichloropyrimidine (0.15 g, 1.0 mmol), benzylamine (0.109 ml, 1.0 mmol) in THF was added DIPEA (0.526 ml, 3.0 mmol) and the reaction was heated at reflux for 2 hours resulting in formation of a 4:1 mixture of regioisomers (desired versus undesired) by TLC (5% Methanol:methylene chloride). The reaction was stripped down in vacuo and purified by silica column (eluent:2% methanol:methylene chloride) giving 0.12 g (0.548 mmol) of desired product 10 in 54% yield. LC/MS (M+1)=220