Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:11].Br[CH2:13][CH2:14][CH2:15][OH:16].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[OH:16][CH2:15][CH2:14][CH2:13][O:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C=O)cc(C)c1OCCCO
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-hydroxy-3,5-dimethyl benzaldehyde (5.0 g, 33.29 mmol) in DMF (30 mL) were added 3-bromo propan-1-ol (5.56 g, 39.95 mmol) and Cs2CO3 (16.24 g, 50.0 mmol). Then, the reaction mixture was stirred at room temperature for 48 hours. Then, water was added and the products were extracted with ethyl acetate (2×250 mL). The combined organic phase was washed with water (100 mL), then brine (100 mL), and dried over anhydrous Na2SO4. Removal of solvent gave 4-(3-hydroxypropoxy)-3,5-dimethyl benzaldehyde as a colorless liquid. Yield: 5.38 g (77%).
Reaction SMILES: C([O-])(O)=O.[Na+].[CH3:6][S:7][C:8]1[S:9][C:10]([CH:16]=O)=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14].[NH2:18]O.Cl.C(O)=O>O>[CH3:6][S:7][C:8]1[S:9][C:10]([C:16]#[N:18])=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14]
Reactant: CSc1sc(C=O)cc1[N+](=O)[O-]
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: CSc1sc(C#N)cc1[N+](=O)[O-]

Procedure:
A sodium methyl mercaptide solution was prepared by adding 5 ml of methylmercaptan to 1.75 g of Na in 60 ml of absolute ethanol. While stirring and cooling this solution to below 10° C. it was added to a solution of 17.6 g of 2-bromo-3-nitro-5-formylthiophene in 200 ml of ethanol. After stirring at room temperature for another 2 hours, 200 ml of water were added, after which the formed precipitate was sucked off, washed with water-ethanol mixture (1:1 v/v), and recrystallized from isopropanol. 6.5 g of 2-methylthio-3-nitro-5-formylthiophene of melting point 129°-131° C. were obtained. Then 2.35 g of NaHCO3, 3.1 g of 2-methylthio-3-nitro-5-formylthiophene, and 1.2 g of NH2OH.HCl were added successively to 50 ml of formic acid. The reaction mixture was refluxed for 1 hour, after which, water was added and the formed precipitate was sucked off. After recrystallization from isopropanol the desired 2-methylthio-3-nitro-5-cyanthiophene was obtained in a yield of 2.3 g; melting point 150° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[O:19]=[CH:20][C:21]1[CH:29]=[CH:28][C:26]([OH:27])=[C:23]([O:24][CH3:25])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:20]([C:21]1[CH:29]=[CH:28][C:26]([O:27][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])=[C:23]([O:24][CH3:25])[CH:22]=1)=[O:19]
Reactant: CCOC(=O)c1ccc(-c2nc(CCl)c(C)o2)s1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2nc(COc3ccc(C=O)cc3OC)c(C)o2)s1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 5-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)thiophene-2-carboxylate (5.0 g), vanillin (2.66 g), anhydrous potassium carbonate (2.42 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration, and washed with diethyl ether. The obtained crystals were recrystallized from acetone-hexane to give ethyl 5-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}thiophene-2-carboxylate as colorless prism crystals (5.75 g, yield 82%). melting point: 155-156° C.
Reaction SMILES: [OH-].[K+].NC1[S:5][C:6]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:7]=2[N:8]=1.Cl>C(O)(=O)C>[NH2:8][C:7]1[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:6]=1[SH:5]
Reactant: COc1ccc2nc(N)sc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc(N)c(S)c1

Procedure:
To a solution of potassium hydroxide 8N (1.3 l) was added 2-amino-6-methoxybenzothiazole (750 g) and the mixture was refluxed for 18 hours. The resulting solution was neutralized by the addition of concentrated HCl, to pH 8.0, then acetic acid to pH 6.0. The precipitate which formed was filtered and washed with water to afford the title compound which was used immediately in Step 3.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[C:18]([CH2:33][CH2:34][O:35][CH3:36])=[N:19][C:20]([C:23]4[CH:24]=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=4)=[N:21][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[CH3:36][O:35][CH2:34][CH2:33][C:18]1[C:17]([CH2:16][O:15][C:12]2[CH:13]=[C:14]3[C:9]([CH:8]=[CH:7][N:6]3[CH2:5][C:4]([OH:37])=[O:3])=[CH:10][CH:11]=2)=[CH:22][N:21]=[C:20]([C:23]2[CH:24]=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=2)[N:19]=1
Reactant: CCOC(=O)Cn1ccc2ccc(OCc3cnc(-c4ccc(C(F)(F)F)nc4)nc3CCOC)cc21
Agent: [Li+]
Agent: [OH-]
Product: COCCc1nc(-c2ccc(C(F)(F)F)nc2)ncc1COc1ccc2ccn(CC(=O)O)c2c1

Procedure:
In analogy to the procedure described in example 5 g], {6-[4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-5-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain the title compound as yellow solid.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][NH:4][C@H:3]([C:7]([O:9]C)=O)[CH2:2]1.Cl.[O:19]([C:21]#[N:22])[K]>O1CCOCC1.O>[O:9]=[C:7]1[C@@H:3]2[CH2:2][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][N:4]2[C:21](=[O:19])[NH:22]1
Reactant: N#CO[K]
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN2C(=O)NC(=O)[C@@H]2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-tert-butyl 3-methyl (3S)-piperazine-1,3-dicarboxylate (AA3) (1.0 eq.) and 6 N aq. HCl sol. (1.0 eq.) in 1,4-dioxane (1 M) was added a sol. of KOCN (2.0 eq.) in H2O (2 M). The reaction mixture was stirred at RT for 2 h, then the organic solvent was removed under reduced pressure. The desired product precipitated from H2O: it was filtered off, washed with cold water and dried at the high vacuum pump. Mother liquors were extracted with EtOAc, the organic phase was washed with brine, dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 10-100% EtOAc/petroleum ether to afford the desired product (H1) as a white powder which was combined with the previously isolated precipitate. 1H-NMR (300 MHz, DMSO-d6, 300K) δ 10.95 (1H, bs), 4.15-4.00 (2H, m), 3.97-3.75 (2H, m), 2.97-2.67 (3H, m), 1.42 (9H, s). MS (ES) C11H17N3O4 requires: 255, found: 256 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23](O)=[O:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[NH2:27][CH2:28][C:29](=[O:31])[CH3:30].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([NH:27][CH2:28][C:29](=[O:31])[CH3:30])=[O:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(=O)CN
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(=O)O)(c2ccccc2)OC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)CNC(=O)C[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a solution of 2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetic acid (200 mg, 0.5 mmol) in anhydrous CH2Cl2 (10 mL) was added 1-aminopropan-2-one (119 mg, 0.7 mmol), HOBt (195 mg, 1.44 mmol), EDCl (283 mg, 1.44 mmol) and DIEA (620 mg, 4.8 mol) at 0° C. The formed mixture was stirred overnight at ambient temperature under nitrogen. Then the reaction mixture was washed with 1N aq HCl and water. The organic phase was dried over Na2SO4, filtered and concentrated to afford the residue, which was purified by prep TLC to give 2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-N-(2-oxopropyl)acetamide (118 mg, 50%). 1H NMR (400 MHz, CDCl3): δ=1.43 (d, 3H), 2.06 (s, 3H), 2.20 (m, 1H), 2.43 (m, 2H), 2.68 (m, 1H), 2.86 (m, 2H), 3.90 (m, 1H), 4.12 (m, 1H), 5.51 (m, 1H), 6.53 (m, 1H), 6.78 (m, 2H), 7.14 (m, 2H), 7.30 (m, 5H).
Reaction SMILES: [CH2:1]([NH:9][C:10]([C@@H:12]1[CH2:14][C@H:13]1[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>[Fe].C(O)(=O)C>[CH2:1]([NH:9][C:10]([C@@H:12]1[CH2:14][C@H:13]1[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNC(=O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: CC(=O)O
Product: CCCCCCCCNC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 6.2 g. of trans-N-octyl-2-(4-nitrophenyl)cyclopropanecarboxamide in 70 ml. of glacial acetic acid, at 85° C., was added 5.3 g. of iron powder, portionwise, during 10 minutes. The temperature was kept between 85° and 90° C. during the addition. At the end of the addition, stirring was continued at 85°-90° C. for 10 minutes, and then the hot reaction mixture was filtered. The filtrate was evaporated in vacuo, and the residue thus obtained was partitioned between 350 ml. of ethyl acetate and 150 ml. of saturated sodium chloride solution. The ethyl acetate layer was removed, dried using sodium sulfate, and evaporated in vacuo. This gave 5.4 g. of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:5]([CH:6]=[O:7])[C:4]=1[OH:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:12]([O:11][C:4]1[C:3]([O:2][CH3:1])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(C=O)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cccc(C=O)c1OCc1ccccc1
Yield: 98.8 %

Procedure:
50 g (0.3 mole) of 3-methoxysalicylaldehyde are heated to reflux for 3 hours with 51.3 g (0.3 mole) of benzyl bromide and 48.4 g of potassium carbonate in 300 ml of acetone. After filtration, the filtrate is concentrated. 71.8 g of the title compound are obtained as a yellow oil.
Reaction SMILES: [OH-].[Na+].[NH:3]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:4]([C:8]([N:10]1[CH2:40][CH2:39][CH2:38][C@H:11]1[C:12]([NH:14][CH2:15][C:16]([NH:18][C@H:19]([C:30]([NH:32][CH2:33][C:34]([O:36]C)=[O:35])=[O:31])[CH2:20][CH:21]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:22](=[O:24])[OH:23])=[O:17])=[O:13])=[O:9])[CH:5]([CH3:7])[CH3:6]>CO>[NH:3]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])[C@H:4]([C:8]([N:10]1[CH2:40][CH2:39][CH2:38][C@H:11]1[C:12]([NH:14][CH2:15][C:16]([NH:18][C@H:19]([C:30]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:31])[CH2:20][CH:21]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:22](=[O:23])[OH:24])=[O:17])=[O:13])=[O:9])[CH:5]([CH3:7])[CH3:6]
Reactant: COC(=O)CNC(=O)[C@H](CC(OC(C)(C)C)C(=O)O)NC(=O)CNC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CC(OC(C)(C)C)C(=O)O)C(=O)NCC(=O)O
Reaction time: 2 h

Procedure:
1 N sodium hydroxide (3.92 mol) was added to a solution of XVIII (1.64 g, 2.61 mmol) in methanol (15 ml) and the mixture was allowed to stand for 2 h at room temperature. The reaction mixture was treated in the same manner as described for the preparation of IX. The resulting oil showed a single spot on TLC; yield 1.32 g (82%), Rf1 0.14.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>CCCCO.CCOC(C)=O>[OH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)[CH:7]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(O)ccn2)CC1
Temperature: 140 °C
Yield: 43.7 %

Procedure:
To a solution of 2-chloro-4-hydroxypyridine (12.9 g, 100 mmol) in n-BuOH (50 mL) was added t-butyl piperazine-1-carboxylate (46.5 g, 250 mmol). The mixture was heated at 140° C. for 3 days and then diluted with EtOAc (2 L) at ambient temperature. The organic phase was washed with saturated NH4Cl solution and then brine. The organic layer was separated, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (5%-20% MeOH/CH2Cl2) to give 12.2 g (44%) of t-butyl 4-(4-hydroxypyridin-2-yl)piperazine-1-carboxylate as a white solid. MS m/z 280.2 [M+H]+; 1H NMR (500 MHz, CDCl3) δ (ppm) 7.72 (1H, d, J=6.62 Hz), 6.20 (1H, dd, J=6.31, 2.21 Hz), 6.02 (1H, d, J=1.89 Hz), 3.56 (4H, m), 3.42 (4H, m), 1.50 (9H, s).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15]([C:19]([N:21]4[CH2:26][CH2:25][CH:24]([C:27]([F:30])([F:29])[F:28])[CH2:23][CH2:22]4)=[O:20])[CH2:14][C:13]=3[CH:31]=2)O1.Br[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:41](C(OCC(C)C)=O)[CH:42]=[CH:43][N:44]=2)=[CH:36][CH:35]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1.O>[NH:41]1[CH:42]=[CH:43][N:44]=[C:40]1[C:37]1[CH:38]=[CH:39][C:34]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15]([C:19]([N:21]4[CH2:22][CH2:23][CH:24]([C:27]([F:28])([F:30])[F:29])[CH2:25][CH2:26]4)=[O:20])[CH2:14][C:13]=3[CH:31]=2)=[CH:35][CH:36]=1
Reactant: CC(C)COC(=O)n1ccnc1-c1ccc(Br)cc1
Reactant: CC1(C)OB(c2ccc3c(c2)CN(C(=O)N2CCC(C(F)(F)F)CC2)CCO3)OC1(C)C
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCC(C(F)(F)F)CC1)N1CCOc2ccc(-c3ccc(-c4ncc[nH]4)cc3)cc2C1
Temperature: 120 °C
Yield: 14 %

Procedure:
To a solution of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-{[4-(trifluoromethyl)piperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepine (0.4 g, 0.88 mmol) and isobutyl 2-(4-bromophenyl)-1H-imidazole-1-carboxylate (0.6 g, 1.86 mmol) in dioxane (4 mL) and water (0.5 ml) was added diisopropylethylamine (0.34 g, 2.64 mmol). The solution was sparged with N2(g) for ten minutes before the addition of dichloro[1,1-bis-(diphenylphosphino]ferrocenepalladium (II) dichloromethane adduct (0.072 g, 10 mol %). The resulting suspension was heated at 120° C. for 2 hours in a sealed tube on a CEM Explorer microwave synthesizer. On cooling to room temperature the mixture was diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate (70 mL), brine (50 mL) then dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel chromatography (97:3 dichloromethane/methanol) then preparative reverse phase HPLC of the combined product containing fractions (0.1% aqueous ammonium acetate-acetonitrile) to afford 7-[4-(1H-imidazol-2-yl)phenyl]-4-{[4-(trifluoromethyl)piperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepine (0.058 g, 12% yield) as a white solid. 1H NMR (400 MHz, methanol-d4): 7.92 (d, 2H), 7.70 (d, 2H), 7.58-7.50 (m, 2H), 7.15 (s, 2H), 7.05 (d, 1H), 4.52 (s, 2H), 4.22 (t, 2H), 3.77 (d, 2H), 3.71 (t, 2H), 2.87 (t, 2H), 2.39 (m, 1H), 1.86 (d, 2H), 1.59 (m, 2H); MS (EI) for C25H25F3N4O2: 471 (MH+).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])=[O:4].[CH2:23]([CH2:25][NH2:26])O.O>CS(C)=O>[Cl:20][C:17]1[CH:18]=[CH:19][C:6]2[NH:5][C:3](=[O:4])[N:26]3[CH2:25][CH2:23][O:9][C:8]3([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=2[CH:16]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NC(=O)C(Cl)(Cl)Cl
Reactant: NCCO
Solvent: O
Solvent: CS(C)=O
Product: O=C1Nc2ccc(Cl)cc2C2(c3ccccc3)OCCN12
Yield: 66.3 %

Procedure:
To a solution of 1.89 g of 2-trichloroacetamido-5-chlorobenzophenone in 40 ml of dimethylsulfoxide was added 3.05 g of monoethanolamine, and the resultant mixture was heated at about 90°C for 3 hours. After cooling, the reaction mixture was poured into 300 ml of water and extracted with chloroform. The extract was washed twice with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel using chloroform as an eluent to give 1.0 g of 9-chloro-2,3,6,10b-tetrahydro-10b-phenyl-5H-oxazolo[3,2-C]quinazolin-5-one. Recrystallization from ethanol gave pale yellow prisms, having a melting point of 219° - 220°C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([CH:13]1[CH:39]=[C:38]([CH3:40])[CH:37]([F:41])[CH:36]([CH3:42])[CH2:35][CH:34]([O:43][CH3:44])[CH:33]2[O:45][C:29]([OH:49])([CH:30]([CH3:48])[CH2:31][CH:32]2[O:46][CH3:47])[C:28](=[O:50])[C:27](=[O:51])[N:26]2[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25]2)[C:20](=[O:52])[O:19][CH:18]([C:53]([CH3:64])=[CH:54][CH:55]2[CH2:60][CH2:59][CH:58]([OH:61])[CH:57]([O:62][CH3:63])[CH2:56]2)[CH:17]([CH3:65])[CH:16]([O:66][Si:67]([CH:74]([CH3:76])[CH3:75])([CH:71]([CH3:73])[CH3:72])[CH:68]([CH3:70])[CH3:69])[CH2:15][C:14]1=[O:77])[CH3:12].C(N(CC)CC)C>C(Cl)Cl.O>[CH2:11]([CH:13]1[CH:39]=[C:38]([CH3:40])[CH:37]([F:41])[CH:36]([CH3:42])[CH2:35][CH:34]([O:43][CH3:44])[CH:33]2[O:45][C:29]([OH:49])([CH:30]([CH3:48])[CH2:31][CH:32]2[O:46][CH3:47])[C:28](=[O:50])[C:27](=[O:51])[N:26]2[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25]2)[C:20](=[O:52])[O:19][CH:18]([C:53]([CH3:64])=[CH:54][CH:55]2[CH2:60][CH2:59][C:58](=[O:61])[CH:57]([O:62][CH3:63])[CH2:56]2)[CH:17]([CH3:65])[CH:16]([O:66][Si:67]([CH:74]([CH3:76])[CH3:75])([CH:71]([CH3:73])[CH3:72])[CH:68]([CH3:70])[CH3:69])[CH2:15][C:14]1=[O:77])[CH3:12]
Reactant: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=O)C(OC)C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution (-78° C.) of oxalyl chloride (1.5 ml of 2M solution in CH2Cl2) is added dimethyl sulfoxide (361 mg) dropwise, followed by a solution of 17-ethyl-20-fluoro-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-14-triisopropylsilyloxy-23,25-dimethoxy-13,19,21, 27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ] octacos-18-ene-2,3,10,16-tetraone (947 mg) in dry methylene chloride (3 ml). The reaction mixture is stirred for 30 min. at -78° C. and then triethylamine (1 ml) is added. The reaction temperature is raised to room temperature, reaction is poured into water (20 ml), and extracted with ethyl acetate (three times). Combined organic layers are washed (water, sat'd NaHCO3), dried (anhydrous Na2SO4), and filtered. Removal of solvent followed by purification (silica gel column chromatography), gives the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([NH:15][C@H:16]([C:25](O)=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>C(OCC)(=O)C>[C:11]([O:10][C:8](=[O:9])[NH:15][C@@H:16]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[C:25]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:26])([CH3:14])([CH3:12])[CH3:13]
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N1CCC(O)CC1

Procedure:
4-Hydroxypiperidine (3.9 mmol) and Boc-L-tyrosine (3.7 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, 60 hour reaction time) with the following workup: the reaction mixture was diluted with ethyl acetate and washed once with base, the base layer was acidified with 2 N HCl and extracted three times with chloroform, and the chloroform extracts concentrated. The resulting foam was purified by chromatography on silica gel eluted with 1-8% ethanol in dichloromethane containing 0.5% NH4OH. Yield 550 mg, 41%; HPLC (40/60) 5.02 minutes (87%).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:23]=[CH:22][C:12]([C:13]([C:15]2[N:19]=[C:18]([CH2:20]Cl)[O:17][N:16]=2)=[O:14])=[CH:11][CH:10]=1.[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCOCC.CC(C)=O>[Cl:8][C:9]1[CH:23]=[CH:22][C:12]([C:13]([C:15]2[N:19]=[C:18]([CH2:20][S:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:17][N:16]=2)=[O:14])=[CH:11][CH:10]=1
Reactant: O=C(c1ccc(Cl)cc1)c1noc(CCl)n1
Reactant: Sc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(c1ccc(Cl)cc1)c1noc(CSc2ccccc2)n1
Reaction time: 1 h

Procedure:
A solution of 8.1 ml of triethylamine in 30 ml Et2O was added to a solution of 7.5 g of 3-(4-chlorobenzoyl)-5-chloromethyl-1,2,4-oxadiazole and 3.0 ml of thiophenol in 20 ml of acetone and 80 ml of Et2O at room temperature. This mixture was stirred for one hour. The reaction mixture was diluted with Et2O, washed with 5% HCl (2×) and brine, and dried over MgSO4. Concentration gave 9.0 g of an oil. Purification by high pressure liquid chromatography with 70% CH2CL2 /hexane as an eluent yielded 6.0 g (62%) of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[CH2:16][CH:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[C:4]([F:19])[CH:3]=1.BrBr>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[C:4]([F:19])[CH:3]=1
Reactant: O=C1CC2CCCCC2=NN1c1ccc(Cl)cc1F
Agent: BrBr
Solvent: CC(=O)O
Product: O=c1cc2c(nn1-c1ccc(Cl)cc1F)CCCC2

Procedure:
12.9 Parts of 2-(4-chloro-2-fluorophenyl)-4,4a,5,6,7,8-hexahydro-3(2H)-cinnolinone was dissolved in 30 parts of glacial acetic acid. To the reaction solution was added a solution of 7.4 parts of bromine in 5 parts glacial acetic acid. After addition was complete, the reaction solution was refluxed for 1.5 hours, then cooled, and the solvent removed under a reduced pressure of 300 mm Hg. The resulting residual brown oil was dissolved in 150 parts of methylene chloride; the organic solution was washed with saturated aqueous sodium bicarbonate solution, dried with anhydrous magnesium sulfate, and the solvent removed under a reduced pressure of 300 mm Hg. The residual brown, oily, solid was chromatographed on alumina, eluting with a mixture of ether (67% by volume) and hexane (33% by volume) to afford 2-(4-chloro-2-fluorophenyl)-5,6,7,8-tetrahydro-3(2H)-cinnolinone as a brown oil that solidified on scratching. Purification was achieved by recrystallization from benzene-hexane to yield 2.5 parts of tan crystalline solid, mp 104°-108°.
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:9]([OH:11])=[O:10].[CH3:17]O>>[CH3:17][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:6]([OH:5])[CH:7]=1
Reactant: CO
Reactant: COc1ccc(C(=O)O)cc1O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(OC)c(O)c1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
10 ml of thionyl chloride was added to 250 ml of MeOH at 0° C. The solution was stirred for 10 min. and 25 g of 3-hydroxy-4-methoxybenzoic acid was added. The reaction was stirred for 16 h at RT then heated to 50° C. for 3 h. The solvents were removed under reduced pressure. The residue was directly used in the next reaction.
Reaction SMILES: Br[C:2]1[C:3]([NH:22][CH2:23][CH2:24][OH:25])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1>>[OH:25][CH2:24][CH2:23][NH:22][C:3]1[C:2]([C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(NCCO)c(Br)c1
Reactant: OB(O)c1cccnc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(NCCO)c(-c2cccnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 152 using 5-bromo-6-((2-hydroxyethyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 159.1) and pyridin-3-ylboronic acid. LC-MS (Condition 6) tR=0.88 min, m/z=419.0 [M+H]+.