Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:7]([S:11][CH3:12])=[C:8](Br)[N:9]=1)[CH2:2][CH3:3].C1COCC1.C([Li])CCC.ClC(OCC)=O>CCCCCC.O>[CH2:1]([S:4][C:5]1[N:6]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:18])[CH3:19])[C:7]([S:11][CH3:12])=[CH:8][N:9]=1)[CH2:2][CH3:3]
Reactant: CCCSc1nc(Br)c(SC)n1COCC[Si](C)(C)C
Agent: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCCSc1ncc(SC)n1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
7.94 g of the product obtained in Stage C above is introduced at ambient temperature into 80 cm3 of anhydrous THF, followed by cooling down to -78° C. and 13.75 cm3 of a 1.6M n-butyllithium solution in hexane is added. After 10 minutes, 15 cm3 of ethyl chloroformate is added, followed by agitation for another 15 minutes at -78° C. 60 cm3 of water is added, the reaction medium is left to return to ambient temperature, the THF is evaporated off, 10 cm3 of 32% soda is added to destroy the excess ethyl chloroformate, followed by extraction with 3×200 cm3 of AcOEt, washing with 2×80 cm3 of water, drying, filtering and evaporating.
Reaction SMILES: [CH:1]([NH:4][S:5](Cl)(=[O:7])=[O:6])([CH3:3])[CH3:2].[C:9]([NH:13][C:14](=[NH:19])[O:15][CH:16]([CH3:18])[CH3:17])([O:11][CH3:12])=[O:10].C(N(CC)CC)C>O1CCCC1>[C:9]([NH:13][C:14](=[N:19][S:5](=[O:7])(=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])[O:15][CH:16]([CH3:17])[CH3:18])([O:11][CH3:12])=[O:10]
Reactant: COC(=O)NC(=N)OC(C)C
Reactant: CC(C)NS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)NC(=NS(=O)(=O)NC(C)C)OC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
95 parts of isopropylaminosulfonyl chloride were stirred into a mixture of 96 parts of N-carbomethoxy-O-isopropylisourea and 73 parts of triethylamine in 700 parts of tetrahydrofuran in the course of 25 minutes, at 10°-15° C. After having been stirred for one hour at 25° C., the reaction mixture was extracted once with water and once with 0.5 N hydrochloric acid, dried and concentrated under reduced pressure. This gave 130 parts of N-carbomethoxy-N'-isopropylsulfamyl-O-isopropylisourea, of melting point 62°-64° C. 33.7 parts of this product were cyclized by means of 17.6 parts of 50% strength by weight sodium hydroxide solution in 30 parts of water in the course of 5 minutes at from 55° to 60° C. Extraction with ether, acidification, washing with water and drying gave 22 parts of 6-isopropyl-3-isopropoxy-5,6-dihydro-1,2,4,6-thiatriazin-5-one-1,1-dioxide, of melting point 164°-167° C. This constitutes active ingredient No. 4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH:28]1(S(Cl)(=O)=O)[CH2:32]C[CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([S:23]([CH:26]5[CH2:30][CH2:29][CH2:28][CH2:32]5)(=[O:24])=[O:25])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)C1CCCC1
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Product: O=S(=O)(C1CCCC1)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 20 %

Procedure:
According to the procedure for compound 398 using cyclopentanesulfonyl chloride (97 mg, 0.57 mmol) afforded 9.7 mg (20% yield) of 403, as a solid.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Cl:12][CH:13]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])[C:14](Cl)=[O:15]>ClCCl>[C:1]([O:5][C:14](=[O:15])[CH:13]([Cl:12])[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(Cl)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)C(Cl)c1ccc(Cl)cc1Cl
Yield: 82.6 %

Procedure:
While stirring and with ice cooling, a solution of 17.6 g of t-butanol and 19.2 ml of pyridine in 60 ml of dichloromethane is dripped into a solution, cooled at 5° C., of 62 g of α-chloro-α-(2,4-dichlorophenyl)-acetyl chloride in 60 ml of dichloromethane in such a manner that the temperature of the reaction mixture stays below 10° C. After all the solution has been dripped in, the mixture is stirred overnight at room temperature, is then diluted with 100 ml of dichloromethane and extracted 5 times, each time with 100 ml of water. The organic phase is dried over magnesium sulfate and distilled after the solvent has been evaporated. There is obtained 58 g of α-chloro-α-(2,4-dichlorophenyl)-acetic acid t-butyl ester as a colorless oil; b.p. 98°-103° C./0.13 mbar.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([Br:13])[CH:7]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC#N>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:8]([Br:13])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(O)c(Br)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(OCc2ccccc2)c(Br)c1
Temperature: 25 °C

Procedure:
To a suspension of (3-bromo-4-hydroxy-phenyl)-acetic acid ethyl ester (0.100 g, 0.39 mmol) and cesium carbonate (0.376 g, 1.16 mmol) in MeCN was added benzyl bromide (0.06 mL, 0.46 mmol), and the reaction was stirred at room temperature until no starting material was seen by analytical tlc. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][S:11]([NH2:14])(=[O:13])=[O:12])([O-:3])=[O:2].C(N=[C:20]=[O:21])CCC.C1N2CCN(CC2)C1.C(Cl)(Cl)=O>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][S:11]([N:14]=[C:20]=[O:21])(=[O:12])=[O:13])([O-:3])=[O:2]
Reactant: CCCCN=C=O
Reactant: NS(=O)(=O)Cc1ccccc1[N+](=O)[O-]
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Product: O=C=NS(=O)(=O)Cc1ccccc1[N+](=O)[O-]

Procedure:
A solution of 9.0 g of the product of Example 3, 4.2 g of butyl isocyanate and 0.1 g of DABCO in 80 ml of dry xylenes was heated to 136°. To this solution was added 3.0 ml of liquid phosgene at such a rate as to maintain the temperature between 125° and 136°. This addition required about 21/2 hours. The solution was cooled to 25°, filtered under nitrogen and stripped in vacuo to give crude 2-nitrophenylmethanesulfonyl isocyanate as a viscous, moisture-sensitive oil showing a sulfonyl isocyanate peak in the infrared at 2230 cm-1.
Reaction SMILES: [C:1]([N:8]1C=CN=C1)(N1C=CN=C1)=[S:2].[CH2:13]([O:20]CC1C=CC=CC=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Na].N.FC(F)(F)S(Cl)(=O)=O.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1>[C:1](=[S:2])([O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH2:8]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: c1ccc(COCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: N
Agent: O=S(=O)(Cl)C(F)(F)F
Solvent: C1CCOC1
Product: NC(=S)OCc1ccccc1

Procedure:
To a stirred solution of 1,1′-thiocarbonyldiimidazole (0.01 mol), in THF is added sodium benzyloxide (0.01 mol), and the mixture is stirred for from 1 minute to about 24 hours. To the mixture is added ammonia gas, and the mixture is stirred at atmospheric pressure or shaken at from atmospheric pressure to about 75 psi. Reaction progress may be followed by TLC or HPLC. (Alternatively, the imidazolyl leaving groups may be first activated (sequentially) by sulfonylation on nitrogen by pretreatment before each displacement with a suitable sulfonylating reagent such as trifluoromethanesulfonyl chloride or para-toluenesulfonyl chloride. This allows displacement of imidazolyl under less rigorous reaction conditions.) When a sufficient amount of desired product is formed, the mixture is partitioned between ethyl acetate and water, or optionally the mixture is first rotary evaporated, and the residue is so partitioned. The organic layer is washed with brine, dried over sodium sulfate, and rotary evaporated to give thiocarbamic acid, benzyl ester, which may be purified, if needed or desired, by chromatography on silica gel or crystallization.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C@@H:3]([O:5][C:6](=O)[O:7]C1C=CC([N+]([O-])=O)=CC=1)[CH3:4].[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[C:32]3[CH2:38][C@H:37]([CH:39]4[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]4)[O:36][C:33]3=[CH:34][N:35]=2)=[CH:26][CH:25]=1)(=[O:23])=[O:22].C(N(CC)C(C)C)(C)C>O1CCCC1>[F:1][C:2]([F:19])([F:18])[C@@H:3]([O:5][C:6]([N:42]1[CH2:43][CH2:44][CH:39]([C@@H:37]2[O:36][C:33]3=[CH:34][N:35]=[C:30]([C:27]4[CH:28]=[CH:29][C:24]([S:21]([CH3:20])(=[O:22])=[O:23])=[CH:25][CH:26]=4)[CH:31]=[C:32]3[CH2:38]2)[CH2:40][CH2:41]1)=[O:7])[CH3:4]
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@H](OC(=O)N1CCC([C@H]2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ncc3O2)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Carbonic acid 4-nitro-phenyl ester (S)-2,2,2-trifluoro-1-methyl-ethyl ester (85 mg) is added to a solution of (R)-5-(4-methanesulfonyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (100 mg) and N,N-diisopropyl-ethylamine (60 μL) in tetrahydrofuran (2 mL) at room temperature. The solution is stirred at room temperature overnight and then washed with 1 N aqueous NaOH solution (3×), water, and brine. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:1→1:3) to give the title compound. LC (method 1): tR=1.00 min; Mass spectrum (ESI+): m/z=499 [M+H]+.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O-:16])[N:10]=[CH:9]2)C=CC=CC=1.[Na+].[Cl-].[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH3:40])=[CH:34][CH:33]=1>>[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][O:16][CH2:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][NH:8][CH:12]=2)=[CH:34][CH:33]=1
Reactant: CCCc1ccc(C)cc1
Reactant: [O-]CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [Na+]
Product: Cc1ccc(CCCOCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of sodium 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanolate and 5 mmol of 3-(4-methylphenyl)propane chloride are treated as described in Example 5.
Reaction SMILES: [CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6]([C:12]([O:14]CC3C=CC=CC=3)=[O:13])/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9][OH:10]>C(O)C.[Pd]>[CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6]([C:12]([OH:14])=[O:13])/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9][OH:10]
Reactant: O=C(OCc1ccccc1)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Agent: [Pd]
Solvent: CCO
Product: O=C(O)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21

Procedure:
Benzyl clavulanate (100 mgs) in ethanol (5 ml) was hydrogenated over 10% Pd/C (30 mgs) for 45 minutes at ambient temperature and atmospheric pressure. The catalyst was filtered, washed with ethanol and the combined filtrates were evaporated in vacuo to give clavulanic acid as an unstable, viscous oil (58 mgs).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH2:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:34][CH:33]=2)[CH2:30][CH2:31]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NCCCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NCCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(3-phenyl-propyl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][N:4]([CH3:16])[CH2:3]1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([C:26](O)=[O:27])=[N:18]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:9]([N:7]1[CH2:8][CH:2]([NH:1][C:26]([C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:17][N:18]=2)=[O:27])[CH2:3][N:4]([CH3:16])[CH2:5][CH2:6]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: CN1CCN(Cc2ccccc2)CC(N)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN1CCN(Cc2ccccc2)CC(NC(=O)c2n[nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
To a solution of 6-amino-1-benzyl-4-methyl-hexahydro-1H-1,4-diazepine (1.0 g) in dichloromethane (20 ml), 1H-indazole-3-carboxylic acid (740 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (877 mg) are added, and the resulting mixture is stirred at 25° C. for 2 hours. The reaction mixture is washed successively with water and 10% aqueous sodium hydroxide solution, and dried over magnesium sulfate. The solvent is evaporated under reduced pressure, and the residue is chromatographed on silica gel with elution of acetone. Fractions containing the title compound are pooled and evaporated under reduced pressure to give the title compound (0.9 g) as an oil. The free base thus obtained is converted to the hemifumarate of the title compound in a usual manner, m.p. 192-194° C. (recrystallized from ethanol).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7](Cl)[CH:6]=[C:5]([CH3:10])[N+:4]=1[O-:11].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>O>[NH2:2][C:3]1[CH:8]=[C:7]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:6]=[C:5]([CH3:10])[N+:4]=1[O-:11]
Reactant: Cc1cc(Cl)cc(N)[n+]1[O-]
Reactant: C1CCNC1
Agent: Cl
Solvent: O
Product: Cc1cc(N2CCCC2)cc(N)[n+]1[O-]
Temperature: 155 °C
Yield: 51 %

Procedure:
A quantity (1.95 g., 0.01 mole) of 2-amino-4-chloro-6-methylpyridine-1-oxide hydrochloride (prepared in Part B, Example 1, above) with 10 ml. pyrrolidine and 10 ml. water was sealed in a reinforced bottle and heated in an oil bath at the temperature 155° C. for 5 hrs. After cooling, this reaction mixture was diluted with water and extracted with three 50-ml. portions of methylene chloride. The methylene chloride extract was dried over anhydrous sodium sulfate, treated with charcoal, and filtered. The methylene chloride was removed from the filtrate by evaporation under reduced pressure, and the residue thus obtained was triturated with acetone and collected on a filter. The solids on the filter were crystallized from about 400 ml. acetonitrile. There was thus obtained 0.98 g. (51% yield) of 2-amino-6-methyl-4-pyrrolidinylpyridine-1-oxide as fine white needles having a melting point at 282° C. (with decomposition). The crystals became pink colored after exposure to light for several days.
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][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1.C(OCC)C>CN(C=O)C.C(OCC)(=O)C>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]([CH3:1])=[C:3]2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1C
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)c1c(C)c2ccccc2n1Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Ethyl 3-methyl-1H-indole-2-carboxylate (480 mg, 2.362 mmol) was dissolved in anhydrous DMF (5 mL), followed by the addition of granular potassium carbonate (408 mg, 2.95 mmol) and p-chlorobenzylchloride (0.38 mL, 2.95 mmol). The reaction was allowed to stir at 60° C. for 24 h, after which time the solution was diluted with a 1:1 solution of ethyl acetate:diethyl ether. The organic phase was washed with 10% aqueous sodium carbonate, dried with magnesium sulfate, and concentrated in vacuo. Purification was accomplished via silica gel flash chromatography (60 g silica, 10% EtOAc/hexanes) to give the title compound as a white powder. (Yield: 510 mg, 1.60 mmol, 66%) 1H NMR (400 MHz, CDCl3) 7.71, 7.34-7.15, 6.95, 5.73, 4.34, 2.63, 1.36
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[C:6]([O:12][CH3:13])[C:5]=1[N:14]=[CH:15]OCC.O.[NH2:21][NH2:22]>C(O)C>[NH2:21][N:22]1[C:3](=[O:2])[C:4]2[C:5](=[C:6]([O:12][CH3:13])[C:7]([Cl:11])=[CH:8][C:9]=2[Cl:10])[N:14]=[CH:15]1
Reactant: NN
Reactant: CCOC=Nc1c(OC)c(Cl)cc(Cl)c1C(=O)OC
Solvent: CCO
Solvent: O
Product: COc1c(Cl)cc(Cl)c2c(=O)n(N)cnc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of the imidate 5-2 (400 mg, 1.31 mmol) in ethanol (12 mL), was added under an argon atmosphere, hydrazine hydrate (1.8 mL, 57.8 mmol). After 15 min, the solution was warmed to room temperature and stirred for a further 2 h. The thick suspension was diluted with ethanol and filtered. The solid was washed with cold ethanol and dried under vacuum to give 3-amino-5,7-dichloro-8-methoxy-3H-quinazolin-4-one (5-3) as a white fluffy solid (289 mg, 85%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][C:17](=[O:20])[CH2:18]Br)[CH3:15]>>[CH2:14]([O:16][C:17](=[O:20])[CH2:18][N:11]1[CH2:12][CH2:13][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]1)[CH3:15]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Product: CCOC(=O)CN1CC[C@@H](NC(=O)OC(C)(C)C)C1

Procedure:
1.1 Using general procedure A, (R)-(+)-3-(tert-butyloxycarbonylamino)-pyrrolidine was alkylated with bromoacetic acid ethyl ester to give ((R)-3-tert-butoxycarbonylamino-pyrrolidin-1-yl)-acetic acid ethyl ester. Off-white solid. MS 273.1 ([M+H]+)
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[C:28]([CH2:30]Br)[CH:27]=[CH:26][C:25]=1[O:32][CH2:33][CH3:34])(=[O:3])[CH3:2].Cl[C:36]1[CH:45]=[C:44]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=[CH:43]2)[C:37]=1[C:46]([O:48][CH3:49])=[O:47].Cl>BrCCBr.C1COCC1.Cl[Si](C)(C)C.[Zn]>[CH2:33]([O:32][C:25]1[CH:26]=[CH:27][C:28]([CH2:30][C:36]2[CH:45]=[C:44]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=[CH:43]3)[C:37]=2[C:46]([O:48][CH3:49])=[O:47])=[CH:29][C:24]=1[C@H:6]1[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7]1)[CH3:34]
Reactant: COC(=O)c1c(Cl)cc2cccccc1-2
Reactant: CCOc1ccc(CBr)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CCOc1ccc(Cc2cc3cccccc-3c2C(=O)OC)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.2 %

Procedure:
Two drops of 1,2-dibromoethane was added to a suspension of zinc powder (0.17 g) in THF (5.0 ml) in an argon atmosphere and the mixture was refluxed with heating for five minutes. After cooling to room temperature, two drops of chlorotrimethylsilane was added to the reaction mixture. The mixture was stirred for 15 minutes. Next, (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[5-(bromomethyl)-2-ethoxyphenyl]-D-glucitol (1.4 g) was added to the reaction mixture and the mixture was refluxed with heating for one hour. After cooling to room temperature, tetrakistriphenylphosphine palladium (0) (0.27 g) and methyl 2-chloroazulene-1-carboxylate (0.28 g) were added to the reaction mixture. The mixture was refluxed with heating for six hours. After cooling to room temperature, the reaction mixture was poured into 10% aqueous solution of hydrochloric acid under cooling with ice. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain methyl 2-(4-ethoxy-3-[(2S,3S,4R,5R,6R)-3,4,5-tris(acetyloxy)-6-[(acetyloxy)methyl]tetrahydro-2H-pyran-2-yl]benzyl)azulene-1-carboxylate (0.58 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:31]3[C:26](=[CH:27][C:28]([F:33])=[C:29](F)[CH:30]=3)[C:25](=[O:34])[N:24]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:23]2=[O:43])=[CH:18][CH:17]=1>>[F:33][C:28]1[CH:27]=[CH:26][C:31]([N:22]2[C:19]3[C:20](=[CH:21][C:16]([F:15])=[C:17]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH:18]=3)[C:25](=[O:34])[N:24]([O:35][CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:23]2=[O:43])=[CH:30][CH:29]=1
Reactant: CN1CCNCC1
Reactant: O=c1c2cc(F)c(F)cc2n(-c2ccc(F)cc2)c(=O)n1OCc1ccccc1
Solvent: CCN(CC)CC
Product: CN1CCN(c2cc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3-c2ccc(F)cc2)CC1
Yield: 96.8 %

Procedure:
Using General Method 4, the reaction of N-methylpiperazine (0.14 mL, 1.23 mmol), triethylamine (0.17 mL, 1.23 mmol), and 1-(4-fluorophenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example B-1, 0.163 g, 0.41 mmol) provided 0.19 g of the title compound as a solid.
Reaction SMILES: CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[CH2:14]=[CH:15][C@@H:16]([CH3:37])[C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24]([CH2:25][C@@H:26]([OH:36])[CH2:27][CH2:28]2)=[CH:23][CH2:22]3)[CH2:19][CH2:18]1.C1(=O)CCCCC1.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[CH2:14]=[CH:15][C@@H:16]([CH3:37])[C@@H:17]1[C@:34]2([CH3:35])[C@H:20]([C@H:21]3[C@H:31]([CH2:32][CH2:33]2)[C@:29]2([CH3:30])[C:24](=[CH:25][C:26](=[O:36])[CH2:27][CH2:28]2)[CH2:23][CH2:22]3)[CH2:19][CH2:18]1
Reactant: C=C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)[O-]
Agent: O=S(=O)(O)O
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=C1CCCCC1
Product: C=C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.02 h
Yield: 73.8 %

Procedure:
Aluminum isopropoxide (0.39 g, 1.9 mmol) in 3.6 ml of hot toluene was added to a solution of 21-methylene-20(R)-methylpregn-5-en-3β-ol (208.2 mg, 0.6337 mmol) in cyclohexanone (3.6 ml, 35 mmol) and 18 ml of toluene, and the mixture was refluxed with exclusion of moisture for 2 h. After cooling in ice, 0.92 ml of water and 2.2 ml of 3.6N sulfuric acid were added and the mixture was shaken 1 min. Further water (4.6 ml) was added, the mixture was shaken 5 min., and the aqueous phase was discarded. Volatile components were removed by azeotropic/steam distillation and the resulting aqueous suspension was extracted three times with 5 ml portions of methylene chloride. The combined organic extracts were filtered through a small column of sodium sulfate resting on a bed of diatomaceous earth, all of which was contained in a Pasteur pipette. The residue was washed with 5 ml of methylene chloride and the combined filtrates were concentrated under reduced pressure. Recrystallization of the residual film gave white needles (152.7 mg, 0.4677 mmol, 74%), m.p. 138-139° C. TLC (25% ethyl acetate/hexanes on silica gel) showed a major product at Rf 0.54 with a trace contaminant at Rf 0.71 (starting material Rf 0.36).