Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=3)[O:9]2)[CH:5]=[CH:6][CH:7]=1.OC1C=CC(O)=CC=1C(=O)C.[F:31]C1C(F)=CC=CC=1C=O>>[F:31][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:19])[CH:14]=2)[O:9]1
Reactant: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Reactant: O=Cc1cccc(F)c1F
Agent: CC(=O)c1cc(O)ccc1O
Product: O=C1CC(c2cccc(F)c2F)Oc2ccc(O)cc21

Procedure:
2-(2,3-Difluorophenyl)-6-hydroxychroman-4-one was prepared as described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 3.0 g of 2′,5′-dihydroxyacetophenone and 2.6 ml of 2,3-difluorobenzaldehyde. 1H NMR (400 MHz, d6-DMSO) δ: 9.51 (s, 1H), 7.53-7.46 (m, 2H), 7.31 (m, 1H), 7.14 (d, 1H, J 3.0 Hz), 7.05 (dd, 1H, 3 8.8, 3.0 Hz), 6.96 (d, 1H, J 8.8 Hz), 5.82 (dd, 1H, J 13.4, 2.8 Hz), 3.26 (dd, 1H, J −16.9, 13.4 Hz), 2.79 (dd, 1H, J −16.9, 2.8 Hz).
Reaction SMILES: OC[C:3]1[S:4][S:5][C:6]([CH2:9][O:10][Si](C(C)(C)C)(C)C)=[CH:7][CH:8]=1.[CH3:18][N:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23](O)[CH:22]=1)[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:18][N:19]([C:21]1[CH:22]=[C:23]([O:10][CH2:9][C:6]2[S:5][S:4][CH:3]=[CH:8][CH:7]=2)[CH:24]=[CH:25][CH:26]=1)[CH3:20]
Reactant: CN(C)c1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)OCC1=CC=C(CO)SS1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)c1cccc(OCC2=CC=CSS2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
To a stirred solution of 200 mg (0.688 mmol) of 3-(hydroxymethyl)-6-[(tert-butyldimethylsilyloxy)methyl]-1,2-dithiin (U.S. Ser. No. 08/212,096) in 2 mL dry THF was added a solution of 3--N,N-dimethylaminophenol (190 mg, 1.376 mmol) in 2 mL THF, followed by addition of (220 mg, 0.839 mmol) triphenylphosphine. The resulting solution was cooled to 0° C., then 140 μL (155 mg, 0.890 mmol) of diethylazodicarboxylate was added, and the reaction mixture was kept at 0°-5° C. for 3 h until TLC analysis showed the reaction to be complete. For isolation of the products the reaction mixture was chromatographed directly on silica gel column, using ethyl acetate-hexane, 1:3 to yield 3-[tert-butyldimethylsilyloxy)methyl]-6-[[3-(N,N-dimethylamino)-phenyloxy]methyl]-1,2-dithiin (115 mg, 41.1%); 1H-NMR (CDCl3) δ7.3 (bs, 1 H), 7.1 (bs, 1 H), 6.60 (d, J=2.4, 1 H), 6.52 (bd, J=7.27 1 H), 6.42 (d, J=6.0, 1 H), 6.34 (d, J=6.0, 1 H), 4.60 (s, 2 H), 4.26 (s, 2 H), 2.65 (s, 6 H), 0.88 (s, 9 H), 0.07 (s, 6 H).
Reaction SMILES: [C:1]([O:4][C@:5]1([C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[CH2:18][CH2:17]3)[CH2:14][CH2:13]1)[C:6](=[O:12])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].[C:32]([O-])(=O)C.[Na+].P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl.COCOC>[C:1]([O:4][C@:5]1([C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:31])[CH2:22][CH2:23]2)[C:18](=[CH2:32])[CH2:17]3)[CH2:14][CH2:13]1)[C:6](=[O:12])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: COCOC
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(OC(C)=O)C(=O)COC(C)=O)[C@@]2(C)CCC(=O)C=C12
Yield: 58.9 %

Procedure:
A solution of 2.0 g of 17,21-diacetoxy-4-pregnene-3,20-dione in 60 ml of methylene chloride and 60 ml of formaldehyde dimethylacetal is refluxed for 30 hours with 2.0 g of sodium acetate and 12.6 g of phosphorus pentachloride. The mixture is worked up analogously to Example 9, thus isolating 1.21 g of 17,21-diacetoxy-6-methylene-4-pregnene-3,20-dione, mp 227°-228° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14]C)=[O:12].[Mg].ClCCl.[NH4+].[Cl-]>CO>[CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C1Nc2ccccc2C1C
Temperature: 25 °C

Procedure:
Ethyl 3-methylindole-2-carboxylate (4.06 g, 20 mmol) was dissolved in methanol (50 ml) and magnesium shavings (2.431 g, 100 mmol) were then added with stirring, at room temperature under a nitrogen atmosphere. After the reaction started, a water bath was used to maintain the reaction temperature between 15-20° C. After the end of the reaction, dichloromethane (200 ml) was added to the mixture, followed by NH4Cl solution (200 ml). The organic phase was separated out and the aqueous phase was extracted with dichloromethane (3×50 ml). The combined organic phases were dried over magnesium sulphate and the solvent was removed to give a brown oil.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=[O:17])[NH:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH:28]([N:30]([CH2:39][C@@H:40]([CH2:44][CH2:45][CH2:46][CH3:47])[C:41](F)=[O:42])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:29]>CN(C=O)C.C(OCC)(=O)C>[CH:28]([N:30]([CH2:39][C@@H:40]([CH2:44][CH2:45][CH2:46][CH3:47])[C:41]([N:12]1[C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][CH2:15][N:11]1[C:9]([O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:10])=[O:42])[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:29]
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)N1
Reactant: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
To a solution of 1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid 91.52 g, 6.1 mmol) and DIPEA (3.15 g, 24.4 mmol) in DMF (8 mL) was added (2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)hexanoyl fluoride (10) (1.7 g, 6.1 mmol) in DMF. The reaction mixture was stirred at rt overnight and LC/MS indicated completion of the reaction. The mixture was diluted with ethyl acetate (20 mL), and washed with 5% aqueous citric acid, brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:1) followed by DCM/MeOH (200:1) to provide the title compound (0.48 g, 32%). LCMS: (M+H)+: 512.0. 1H NMR (300 MHz, CDCl3) δ ppm 0.79 (t, J=6.0 Hz, 3H), 1.10 (m, 4H), 1.40 (m, 1H), 1.57 (m, 1H), 1.77 (m, 1H), 2.17 (m, 1H), 2.97 (m, 2H), 3.25-3.69 (m, 1H), 4.13 (m, 3H), 4.56-4.93 (m, 2H), 5.12 (s, 2H), 7.34 (m, 10H), 7.74 (s, 0.3H), 8.36 (s, 0.6H).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]=[C:13]([C:18]4[CH:28]=[CH:27][C:21](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])=[CH:20][CH:19]=4)[NH:12][C:11]=3[N:10]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[C:9]2=[O:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:37]1COC[CH2:38]1.C(O)C.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH2:37]([O:25][C:24](=[O:26])/[CH:23]=[CH:22]/[C:21]1[CH:20]=[CH:19][C:18]([C:13]2[NH:12][C:11]3[N:10]([CH2:29][CH:30]4[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]4)[C:9](=[O:36])[N:8]([CH2:7][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[C:16](=[O:17])[C:15]=3[N:14]=2)=[CH:28][CH:27]=1)[CH3:38]
Reactant: O=C(O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Reactant: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)/C=C/c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)cc1
Reaction time: 3.75 h
Yield: 72 %

Procedure:
N,N'-Carbonyldiimidazole (Lancaster Synthesis, 908 mg, 5.6 mmol) was added to a pale yellow slurry of (E)-4-[1,3 bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl]cinnamic acid (from step (d) example 1, 1.962 g, 4.0 mmol) in anhydrous DMF (15 mL)-THF (15 mL) under nitrogen. The slurry was stirred for 3.75 h, during which time it became bright yellow as a gas evolved. Absolute ethanol (460 mL, 8 mmol) was then added, followed by DBU (Aldrich, 837 mL, 5.6 mmol). Addition of the base produced a deep red reaction mixture and caused almost complete dissolution of the acyl imidazole. After stirring for 18 h, the reaction mixture was treated with an additional equivalent of absolute ethanol (230 mL, 4 mmol). The orange solution was stirred for 2.5 h before volatiles were removed at 1Torr. The resulting brown mixture was chromatographed on silica gel, eluting with a gradient from 0-6% methanol in dichloromethane. The title compound eluted in 0-1% methanol in dichloromethane as an off-white solid (1.643 g, 79%). Recrystallization from dichloromethane-hexanes provided a white powder (1.501 g, 72%), m.p. >300° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:54]([CH2:56][CH2:57][NH:58][CH2:59][CH2:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)#[N:55]>O1CCCC1>[C:54]([CH2:56][CH2:57][N:58]([CH2:59][CH2:60][CH2:61][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)[C:18](=[O:20])[C@H:9]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])#[N:55]
Reactant: N#CCCNCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)N(CCC#N)CCCc1ccccc1
Reaction time: 8 h

Procedure:
A solution of Boc-homophenylalanine (136 mg, 0.49 mmol), diisopropylethylamine (169 μl mg, 0.97 mmol), and tetrahydrofuran (3 ml) was treated with PyBrop (248 mg, 0.63 mmol) at 0° C. (2-cyanoethyl)-3-phenylpropylamine (109 mg, 0.58 mmol) in tetrahydrofuran (2 ml) was added dropwise and the reaction mixture was stirred overnight. The solid was filtered and rinsed with ethyl acetate, and the filtrate was concentrated and purified by chromatography to give Boc-homophenylalanine (2-cyanoethyl)-3-phenylpropylamide. A mixture of above product (200 mg), 10% palladium-on-carbon (20 mg), and methanol (40 ml) was hydrogenated on a Parr hydrogenator (40 psi) overnight. The catalyst was removed by filtration through Celite and the filtrate was concentrated in vacuo. The residue was then treated with trifluoroacetic acid for 30 min. The solvent was removed in vacuo and the product was purified by reverse phase HPLC to give white solid: 1H NMR (400 MHz, D2O) δ1.8-2.1 (m, 6H), 2.5-2.8 (m, 4H), 3.0-3.3 (m, 4H), 3.3-3.7 (m, 2H), 4.0-4.1 (m, 1H), and 7.3-7.5 (m, 10H).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11](O)=[O:12])=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]1[C@@H:41]2[C@@H:36]([CH2:37][CH2:38][CH2:39][CH2:40]2)[CH2:35][CH2:34][NH:33]1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:7]2[O:6][C:5]([C:3](=[O:4])[C:2]([CH3:21])([CH3:1])[CH3:20])=[C:9]([CH2:10][C:11]([N:33]3[CH2:34][CH2:35][C@H:36]4[C@H:41]([CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:32]3)=[O:12])[C:8]=2[CH:14]=1
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Reactant: C1CC[C@@H]2CNCC[C@@H]2C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)N3CC[C@@H]4CCCC[C@@H]4C3)c2c1
Temperature: 40 °C

Procedure:
Dissolve a mixture of 17 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 12.3 mg cis-decahydroisoquinoline followed by 23.0 mg EDC and 35 μL DIEA. This solution was heated at 40° C. for 2 hours. It was purified directly on RP-HPLC using 65-100% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.41 min. (m/Z=412.3, 328.2, 434.2).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH2:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[Br:16][C:17]1[S:18][C:19]([C:23](O)=[O:24])=[C:20]([CH3:22])[N:21]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>O1CCCC1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:23]([C:19]2[S:18][C:17]([Br:16])=[N:21][C:20]=2[CH3:22])=[O:24])[CH2:4][CH2:3]1
Reactant: CN1CCC(N)CC1
Reactant: Cc1nc(Br)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(Br)sc1C(=O)NC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 87 %

Procedure:
To a stirred mixture of 1-methyl-4-aminopiperidine (125 μL, 114 mg, 1 mmol) and triethylamine (570 μL, 414 mg, 4.1 mmol) in anhydrous tetrahydrofuran (1.0 mL), 2-bromo-4-methyl-thiazole-5-carboxylic acid (266 mg, 1.2 mmol), (3-dimethylaminopropyl)-ethyl-carbodiimide hydrochloride (232 mg, 1.2 mmol) and 1-hydroxy-benzotriazole (164 mg, 1.2 mmol) were sequentially and the mixture was stirred at room temperature for 22 h. After dilution with dichloromethane (20 mL), the mixture was washed with water (3×10 mL), dried over MgSO4 and concentrated. In this manner the title compound (277 mg, 0.87 mmol, 87%) was obtained as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([O:5][OH:6])([CH3:4])[CH3:3].[OH-:7].[Na+].Cl[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11]>O>[C:10](=[O:7])([O:12][CH:13]([CH3:15])[CH3:14])[O:11][O:6][O:5][C:2]([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)OC(=O)Cl
Reactant: [OH-]
Reactant: CC(C)(C)OO
Agent: [Na+]
Solvent: O
Product: CC(C)OC(=O)OOOC(C)(C)C
Reaction time: 0.83 h

Procedure:
129 parts (1 mol) of TBHP-70, 92 parts of water and 172 parts of LUP were fed into a 1-l glass beaker. 170 parts (1 mol) of 25% aqueous caustic soda was added dropwise to the beaker over a period of 20 minutes while keeping the contents at 25° C. on an ice-water bath. After the completion of the dropwise addition, the temperature of the contents was lowered to 10° C., followed by the dropwise addition thereto of 126 parts (1 mol) of isopropyl chloroformate over a period of 50 minutes. The obtained mixture was stirred for 50 minutes. 250 parts of 5% aqueous caustic soda was added to the formed organic layer to transfer unreacted materials from the organic layer to the aqueous layer. The resulting organic layer was thrice washed with 250 parts of water and dehydrated with a dehydrating agent to obtain 334 parts of t-butylperoxy isopropyl carbonate diluted with LUP to 50% (hereinafter abbreviated to "TBIC-LUP 50") as a final product.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4](Br)[N:3]=1.[C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)#[N:18].[OH-].[K+]>>[C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:4]2[N:3]=[C:2]([NH2:1])[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=2)[CH2:21][CH2:20]1)#[N:18]
Reactant: COc1cc2nc(Br)nc(N)c2cc1OC
Reactant: N#CN1CCNCC1
Agent: [K+]
Agent: [OH-]
Product: COc1cc2nc(N3CCN(C#N)CC3)nc(N)c2cc1OC

Procedure:
In a flask fitted with stirrer, thermometer, and drying tube is placed 100 ml. of chloroform, 12.0 g. (0.05 mole) of 4-amino-2-bromo-6,7-dimethoxyquinazoline (prepared by the method of U.S. Pat. No. 3,511,836) and 5.8 g. (0.052 mole) of 1-cyanopiperazine. The mixture is maintained at 50° C. for 24 hours after which 2N potassium hydroxide solution is added at room temperature to adjust to pH 9.5. The organic layer is separated and the aqueous phase extracted again with chloroform and the combined extracts are evaporated to dryness to obtain 2-(4-cyanopiperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:24]([O:26][CH3:27])=[O:25])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:23])[C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:28]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>C(Cl)(Cl)Cl.CO>[C:1]([O:5][C:6]([NH:8][CH:9]([C:24]([O:26][CH3:27])=[O:25])[CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:23])[C:20]([OH:22])=[O:21])=[CH:17][C:18]=1[Cl:28])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)C(CCOc1ccc(C(=O)C(=O)O)cc1)NC(=O)OC(C)(C)C
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)C(CCOc1ccc(C(=O)C(=O)O)cc1Cl)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18.7 h
Yield: 118 %

Procedure:
DL-p-(3-tert-Butoxycarbonylamino-3-methoxycarbonylpropoxy)phenylglyoxylic acid (750 mg.) was dissolved in a mixture of chloroform (15 ml.) and methanol (10 ml.), and to the solution was added 1,3,5-trichloroisocyanuric acid (180 mg.) in the course of 5 minutes, whereafter the mixture was stirred at ambient temperature for 18.7 hours. The insoluble materials were filtered off from the reaction mixture and the filtrate was evaporated to dryness under reduced pressure. The resultant residue was dissolved in ethyl acetate, and the solution was washed with water and then dried over magnesium sulfate. This solution was evaporated to dryness under reduced pressure to give a residue, which was subjected to column chromatography on silica gel (11 g.). Elution was carried out with a mixture of chloroform and methanol (99:1 by volume) and the fractions containing a desired compound were collected. The solvent was removed by evaporation from the eluate under reduced pressure to give DL-p-(3-tert-butoxycarbonylamino-3-methoxycarbonylpropoxy)-3-chlorophenylglyoxylic acid (380 mg.).
Reaction SMILES: CS(N)(=O)=O.[N:6]1([S:10]([NH2:13])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1.C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[Cl:41][C:42]1[C:43]([F:52])=[CH:44][C:45]([F:51])=[C:46]([CH:50]=1)[C:47](O)=[O:48]>>[N:6]1([S:10]([NH:13][C:47](=[O:48])[C:46]2[CH:50]=[C:42]([Cl:41])[C:43]([F:52])=[CH:44][C:45]=2[F:51])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Reactant: NS(=O)(=O)N1CCC1
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(F)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with azetidine-1-sulfonamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-chloro-2,4-difluorobenzoic acid, the title compound was obtained as a colorless powder (7.0 g, 70%): 1H NMR (300 MHz, DMSO-d6) δ 12.07 (br s, 1H), 7.99 (t, J=7.6 Hz, 1H), 7.71 (t, J=9.8 Hz, 1H), 4.03 (t, J=7.7 Hz, 4H), 2.20-2.10 (m, 2H); MS (ES−) m/z 309.1, 311.1 (M−1).
Reaction SMILES: [CH3:1][C:2]1[N:29]=[C:5]2[NH:6][C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.I[CH:31]([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)(=O)C>[CH3:1][C:2]1[N:29]=[C:5]2[N:6]([CH:31]([CH3:33])[CH3:32])[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C)nn12
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C(C)C)c2nc(C)nn12
Temperature: 100 °C
Reaction time: 5 h
Yield: 28 %

Procedure:
A mixture of 4′-[(2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.8 g), 2-iodopropane (0.4 mL), potassium carbonate (0.55 g) and N,N-dimethylacetamide (10 mL) was stirred at 100° C. for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.24 g, 28%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:13]([O:19][CH2:20][C:21]([CH3:27])([CH3:26])[CH2:22][N:23]([CH3:25])[CH3:24])(=[O:18])[CH2:14][C:15]([CH3:17])=O.[NH2:28]/[C:29](/[CH3:35])=[CH:30]\[C:31]([O:33][CH3:34])=[O:32]>CC(O)C>[CH3:17][C:15]1[NH:28][C:29]([CH3:35])=[C:30]([C:31]([O:33][CH3:34])=[O:32])[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:2]=2[Cl:1])[C:14]=1[C:13]([O:19][CH2:20][C:21]([CH3:27])([CH3:26])[CH2:22][N:23]([CH3:25])[CH3:24])=[O:18]
Reactant: O=Cc1cccc([N+](=O)[O-])c1Cl
Reactant: CC(=O)CC(=O)OCC(C)(C)CN(C)C
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)(C)CN(C)C)C1c1cccc([N+](=O)[O-])c1Cl
Yield: 20.8 %

Procedure:
A mixture of 185.5 mg of 2-chloro-3-nitrobenzaldehyde, 236.5 mg of 3-(N,N-dimethylamino)-2,2-dimethylpropyl acetoacetate and 126.5 mg of methyl 3-aminocrotonate in 2 ml of 2-propanol was reacted and then purified in the same way as in Referetial Example 6, (ii) to yield 100 mg of the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=3[CH3:11])[CH2:20][CH2:21]2)=[O:10])=[N:6][CH:7]=1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(Br)cn1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Yield: 101.5 %

Procedure:
Using 5-bromopyridine-2-carboxylic acid (5 g) and 1-(2,4-dimethylphenyl)piperazine (4.8 g) and by the reaction and treatment in the same manner as in Preparation Example 109, the title compound (9.4 g) was obtained.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:12]([N:13]=[C:14]=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.Cl.[N:17]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[C@@H:19](O)[CH2:18]2.CN(C)C=[O:29]>C(OCC)(=O)C>[N:17]12[CH2:18][CH:19]([CH2:21][CH2:22]1)[C@H:20]([O:15][C:14](=[O:29])[NH:13][C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH2:23][CH2:24]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C=Nc1ccccc1-c1ccccc1
Reactant: CN(C)C=O
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1-c1ccccc1)O[C@@H]1CCN2CCC1C2
Yield: 99 %

Procedure:
2-Biphenyl isocyanate (1.00 g, 5.12 mmol) and (R)-(−)-3-quinuclidinol hydrochloride (921 mg, 5.63 mmol) were heated together in N,N-dimethylformamide (2.06 mL) at 110° C. for 12 h. The reaction mixture was cooled and diluted with ethyl acetate (15 mL) and then washed with saturated aqueous sodium bicarbonate (2×10 mL). The organic layer was extracted with 1 M hydrochloric acid (3×20 mL) and the combined aqueous extracts were made basic to pH 8-9 with potassium carbonate. The aqueous layer was then extracted with ethyl acetate (3×20 mL) and the combined organic layers were dried (magnesium sulfate) and solvent was removed under reduced pressure to give the title compound as a yellow oil (1.64 g, 99% yield).