Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg]Cl.[O:4]=[C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]>O1CCCC1>[OH:4][C:5]1([CH3:1])[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC1CCCCC1=O
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCCCC1(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 21.8 %

Procedure:
A solution of methyl magnesium chloride (3M in tetrahydrofuran, 19 ml, 57 mmol) was added to a solution of tert-butyl 2-oxocyclohexylcarbamate (4.0 g, 18.8 mmol) (Synth. Commun. (1992), 22(20), 3003–12) in tetrahydrofuran (80 ml) at −78° C. The mixture was allowed to warm to ambient temperature and was stirred for 3 h. The mixture was quenched by the addition of saturated ammonium chloride solution (20 ml) and was partitioned between water and diethyl diethyl ether. The organic phase was washed with water, brine, dried over MgSO4, and the solvent removed under reduced pressure to give a white solid which was purified by flash column chromatography using ethyl acetate:cyclohexane (98:2 to 70:30) as eluant to give the less polar diastereoisomer of tert-butyl 2-hydroxy-2-methylcyclohexylcarbamate (940 mg) as a white solid.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([NH:19][C:20]([N:22]1[CH2:31][CH2:30][C:29]2[CH:28]=[N:27][C:26]([NH:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[N:25][C:24]=2[CH2:23]1)=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=1)(C(C)(C)C)(C)C.C1COCC1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[Cl:18][C:13]1[CH:12]=[C:11]([C@H:10]([NH:19][C:20]([N:22]2[CH2:31][CH2:30][C:29]3[CH:28]=[N:27][C:26]([NH:32][CH:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[N:25][C:24]=3[CH2:23]2)=[O:21])[CH2:9][OH:8])[CH:16]=[CH:15][C:14]=1[F:17]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](NC(=O)N1CCc2cnc(NC3CCOCC3)nc2C1)c1ccc(F)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@H](CO)c1ccc(F)c(Cl)c1)N1CCc2cnc(NC3CCOCC3)nc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)—N-(2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethyl)-2-(tetrahydro-2H-pyran-4-ylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxamide (0.250 g, 0.443 mmol) and THF (5 mL) at RT was added TBAF (0.532 mL, 0.532 mmol) and the reaction was stirred for 1 h at RT, poured into water and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (500:20 to 500:30) to afford 0.100 g (50.2%) of I-46: 1H NMR (400 MHz, d6-DMSO) δ 8.08 (s, 1H), 7.52 (d, 1H), 7.32 (d, 2H), 6.91-6.86 (m, 2H), 4.85 (br s, 1H), 4.74 (m, 1H), 4.40-4.30 (m, 2H), 3.87-3.84 (m, 3H), 3.58-3.54 (m, 4H), 3.38-3.31 (m, 2H), 2.56-2.54 (m, 2H), 1.81-1.78 (m, 2H), 1.53-1.46 (m, 2H); MS m/z (APCI-pos) M+1=450.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[C:18]1([C:24]2[CH:35]=[CH:34][C:27]([C:28](N(OC)C)=[O:29])=[CH:26][CH:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:24]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:25]=[CH:26][C:27]([C:28]([C:2]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[O:29])=[CH:34][CH:35]=1
Reactant: CON(C)C(=O)c1ccc(-c2ccccc2)cc1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: [Li]CCCC
Product: COc1ccc(C(=O)c2ccc(-c3ccccc3)cc2)c(C(=O)O)c1

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with 4-phenyl-N-methoxy-N-methylbenzamide.
Reaction SMILES: [O:1]=[S:2]1(=[O:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[BH4-].[Na+].Cl>O>[O:1]=[S:2]1(=[O:9])[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1
Reactant: O=C1CCS(=O)(=O)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: O=S1(=O)CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 104.1 %

Procedure:
To 1,1-dioxo-tetrahydrothiopyran-4-one (6.3 g, 36 mmol) in H2O (55 mL) was added, in portions, sodium borohydride (720 mg, 18.9 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then the pH was adjusted to 4 with aq. HCl. The reaction mixture was concentrated and suspended in acetone and filtered. The filtrate was concentrated and triturated with ether/hexane to provide 1,1-dioxo-tetrahydrothiopyran-4-ol (5.63 g, 90%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(F)cc1CCc1ccc(F)cc1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(F)cc2CCc2ccc(F)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-fluoro-2-[2-(4-fluorophenyl)ethyl]phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.86-2.98 (4H, m), 5.05 (2H, s), 5.73 (1H, d, J=2.0 Hz), 6.90-78.01 (6H, m), 7.33-7.39 (2H, m), 7.59 (1H, d, J=1.6 Hz), 7.95 (1H, s), 8.56 (1H, d, J=4.4 Hz). [M+H] Calc'd for C24H18F2N4O, 417; Found, 417.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:19]([O:21][CH3:22])=[O:20])=[C:5]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:10]=[CH:9][N:8]=2)[N:6]=1.C(N(CC)C(C)C)(C)C.[Cl:32][C:33]1[C:37]([Cl:38])=[C:36]([CH3:39])[NH:35][C:34]=1[C:40]([NH:42][C@@H:43]1[CH2:48][CH2:47][NH:46][CH2:45][C@@H:44]1[O:49][CH3:50])=[O:41]>CN1CCCC1=O.O>[Cl:32][C:33]1[C:37]([Cl:38])=[C:36]([CH3:39])[NH:35][C:34]=1[C:40]([NH:42][C@@H:43]1[CH2:48][CH2:47][N:46]([C:2]2[S:3][C:4]([C:19]([O:21][CH3:22])=[O:20])=[C:5]([C:7]3[N:12]=[C:11]([N:13]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[CH:10]=[CH:9][N:8]=3)[N:6]=2)[CH2:45][C@@H:44]1[O:49][CH3:50])=[O:41]
Reactant: COC(=O)c1sc(Cl)nc1-c1nccc(N2CCCCC2)n1
Reactant: CO[C@H]1CNCC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OC)C2)nc1-c1nccc(N2CCCCC2)n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a stirred solution of methyl 2-chloro-4-[4-(piperidin-1-yl)pyrimidin-2-yl]-1,3-thiazole-5-carboxylate (Intermediate 67, 30 mg, 0.08 mmol) in N-methylpyrrolidinone (0.5 mL), N,N-diisopropyl ethylamine (23 mg, 0.18 mmol) and 3,4-dichloro-N-[(3S,4R)-3-methoxypiperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (WO2006087543, 27 mg, 0.09 mol) were added at room temperature. The above reaction mixture was heated at 90° C. for 3 h. The reaction mixture was cooled to room temperature, diluted with water (5 mL) and stirred for 1 h. The solid obtained was collected by filtration and dried to obtain methyl 2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-[4-(piperidin-1-yl)pyrimidin-2-yl]-1,3-thiazole-5-carboxylate 35 mg (66%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:27][CH3:28])=[C:14]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=2)[CH2:10]1)(=O)[CH3:7].[C:29]([C:31]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[CH:34][C:32]=1[NH2:33])#[N:30].[OH-].[Na+]>C(Cl)Cl.O>[CH2:20]([O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:27][CH3:28])[CH2:10][N:9]([C:6](=[N:33][C:32]1[CH:34]=[C:35]([O:40][CH3:41])[C:36]([O:38][CH3:39])=[CH:37][C:31]=1[C:29]#[N:30])[CH3:7])[CH2:18][CH2:17]2)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1cc(N)c(C#N)cc1OC
Reactant: COc1cc2c(cc1OCc1ccccc1)CCN(C(C)=O)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(C#N)c(N=C(C)N2CCc3cc(OCc4ccccc4)c(OC)cc3C2)cc1OC
Temperature: 25 °C
Yield: 72.8 %

Procedure:
Phosphorus oxychloride (3.24 ml) was added over 1 minute to a stirred solution of N-acetyl-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline (10 g) in methylene chloride (100 ml) at 10°. After stirring for twenty minutes at room temperature, a solution of 2-cyano-4,5-dimethoxyaniline (5.72 g) in methylene chloride (80 ml) was added and the resulting suspension was heated at reflux for 16 hours. The reaction mixture was then allowed to cool, water (60 ml) was added followed by 40% sodium hydroxide to pH 8-9 with stirring for five minutes. The organic layer was then separated and the aqueous phase extracted with methylene chloride (3×50 ml). The combined organic layers were washed (H2O), dried (MgSO4) and evaporated. The residue was chromatographed on silica (Merck Art.9385) under medium pressure, eluting with methylene chloride containing gradually increasing amounts of methanol (0-10%). Some impure product-containing fractions were re-chromatographed on silica but using methylene chloride containing 2-4% methanol. The pure product-containing fractions were combined, evaporated, and the residue recrystallised from ethyl acetate to give the title compound as a colourless powder (11.02 g), m.p. 164°-5° (d).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26](=O)[CH3:27])=[CH:22][CH:21]=2)[CH2:15][CH2:14]1.[OH-:29].[K+].Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:26]([C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:16]3[CH2:17][CH2:18][O:13][CH2:14][CH2:15]3)=[CH:25][CH:24]=1)[CH:27]=[C:5]2[C:6]([OH:11])=[O:29]
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: [OH-]
Reactant: CC(=O)c1ccc(CN2CCOCC2)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(-c2ccc(CN3CCOCC3)cc2)nc2ccc(F)cc12
Temperature: 125 °C
Yield: 75.1 %

Procedure:
In a 20 ml microwave vial, 5-fluoroisatin (650 mg, 4 mmol) was suspended in ethanol (7 ml), then, 1-[4-(morpholinomethyl)phenyl]ethanone (preparation 6) (863 mg, 4 mmol) was added followed by water (7 ml). To this suspension potassium hydroxide (2.21 g, 39 mmol) was added at room temperature. The microwave vial was sealed and the reaction mixture was heated at 125° C. for 20 min under microwave irradiation. The resulting solution was diluted with water (50 ml) and adjusted to pH 7-8 with 10% HCl. The resulting precipitate was filtered and washed with water (50 ml) and ethyl acetate (100 ml) to obtain the desired product as an off-white solid (1.1 g, Yield: 76%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1.[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1>CC#N>[CH3:17][O:16][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1)[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10]2
Reactant: COc1ccc2nc(Cl)c(C(F)(F)F)nc2c1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CC#N
Product: CCOC(=O)C1CCN(c2nc3ccc(OC)cc3nc2C(F)(F)F)CC1
Temperature: 150 °C
Yield: 88.5 %

Procedure:
2-chloro-6-methoxy-3-(trifluoromethyl)quinoxaline (Intermediate 11, 240 mg) was suspended in MeCN (1.5 mL) with ethyl piperidine-4-carboxylate (173 mg) and TEA (205 mg) in a sealed microwave tube and heated at 150° C. with microwave for three hours. The resultant mixture was purified by silica gel column chromatography to afford 310 mg of ethyl 1-(6-methoxy-3-(trifluoromethyl)quinoxalin-2-yl)piperidine-4-carboxylate.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[O:5][C:6]([C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:8]=1.[CH3:23][C:24]1[NH:25][CH:26]=[CH:27][N:28]=1>CN(C)C=O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[N:8]=[C:4]([N:25]3[CH:26]=[CH:27][N:28]=[C:24]3[CH3:23])[O:5][C:6]=2[C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:11]=1
Reactant: CCOC(=O)C(=O)c1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
Sodium hydride(oil, 60%, 710 mg) was gradually added to a mixture of ethyl 2-[2-chloro-4-(4-chlorophenyl)-5-oxazolyl]-2-oxoacetate(4.63 g), 2-methylimidazole(1.45 g) and N,N-dimethylformamide(50 ml) at 0° C. After stirring for 1 hour at room temperature, the reaction mixture was poured into ice water to give ethyl 2-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]-2-oxoacetate(3.12 g, 59%). This was recrystallized from ethyl acetate-hexane to give colorless prisms. mp 126-127° C.
Reaction SMILES: [C:1]([O:20]C)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:22](OC)(=O)[CH2:23]CCCCCC/C=C\CCCCCCCC>>[CH3:22][CH2:23][CH2:18][CH2:17][CH2:16]/[CH:15]=[CH:14]\[CH2:13]/[CH:12]=[CH:11]\[CH2:10]/[CH:9]=[CH:8]\[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:20])=[O:19]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCCCC(=O)O

Procedure:
Methyl ester of DGLA is recovered preferably by extracting the above-mentioned treated solution with an organic solvent such as hexane, an ether such as ethyl ether, or an ester such as ethyl acetate. Next, the resulting extract is dried on, for example, anhydrous sodium sulfate, and the solvent is distilled off preferably under reduced pressure to obtain a mixture comprising fatty acid esters. This mixture contains, in addition to the desired fatty acid HGLA methyl ester, other fatty acid methyl esters, such as methyl parmitate, methyl stearate, methyl oleate and the like. To isolate methyl ester of DGLA from the mixture of these fatty acid methyl esters, column chromatography, low temperature crystallization, the urea-inclusion method, the liquid/liquid countercurrent chromatography method, and the like can be used alone or in combination.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH:16]=[CH2:17])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])C=C>>[Si:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15]/[CH:16]=[CH:17]/[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: C=CCc1ccccc1O[Si](C)(C)C(C)(C)C
Reactant: C=CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)/C=C/Cc1ccccc1O[Si](C)(C)C(C)(C)C
Yield: 90.7 %

Procedure:
The representative procedure was followed using tert-butyl(2-allylphenoxy)dimethylsilane (124 mg, 0.50 mmol), tert-butyl acrylate (128 mg, 1.00 mmol) and Grubbs-2 catalyst (8.5 mg, 0.01 mmol). Column chromatography on silica gel (eluting with 3% EtOAc/hexanes) afforded the product as a colorless oil (158 mg, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=3)[O:15][C:16]=2[CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=3)[O:15][C:16]=2[CH3:17])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(Cl)cc3)c(C)o2)cc1
Agent: Cl
Product: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(Cl)cc1
Yield: 100.2 %

Procedure:
Method C. Reaction of benzoate 19 (217 mg, 0.53 mmol) and 6 M HCl (5 mL) gave acid 20 (208 mg, 100%) as a white solid: mp (H2O) 268-271° C.; 1H NMR [(CD3)2SO] δ 13.18 (br s, 1 H, CO2H), 8.04 (dd, J=8.6, 1.8Hz, 2 H, H-2, H-6), 7.90 (br dd, J=8.6, 1.8Hz, 2 H, H-3, H-5), 7.81 (ddd, J=8.7, 2.4, 2.0 Hz, 2 H, H-2′, H-6′), 7.70 (ddd, J=8.7, 2.4, 2.0Hz, 2 H, H-3′, H-5′), 4.74 (s, 2 H, CH2SO2), 2.21 (s, 3 H, CH3); MS m/z 393.2 (MH+, 100%), 393.0 (MH+, 35%). Anal. calcd for C18H14ClNO5S: C, 55.18; H, 3.60; N, 3.57. Found: C, 55.22; H, 3.41; N, 3.47%.
Reaction SMILES: BrCCO.FC1C=CC=CC=1C1C2C=C([N+]([O-])=O)C=CC=2N(C)C(=O)C(C)(C)N=1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[C:43]2[CH:44]=[C:45]([N+:48]([O-:50])=[O:49])[CH:46]=[CH:47][C:42]=2[N:41](CCO)[C:40](=[O:54])[C:39]([CH3:56])([CH3:55])[N:38]=1>CCOCC.CCCCCC>[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[C:43]2[CH:44]=[C:45]([N+:48]([O-:50])=[O:49])[CH:46]=[CH:47][C:42]=2[NH:41][C:40](=[O:54])[C:39]([CH3:56])([CH3:55])[N:38]=1
Reactant: CC1(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2N(CCO)C1=O
Agent: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Agent: OCCBr
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2NC1=O

Procedure:
From 25 g (0.073 mol) of 5-(o-chlorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one and 2-bromoethanol there is obtained, in analogy to the details in paragraph (c) of Example 1, with a reaction period of 7 days, 5-(o-chlorophenyl)-1,3-dihydro-1-(2-hydroxyethyl)-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 124°-125° (ether/n-hexane).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][CH2:28][C@@H:27]([CH2:31][O:32][Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])[CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[CH:40]([Si:33]([CH:34]([CH3:36])[CH3:35])([CH:37]([CH3:39])[CH3:38])[O:32][CH2:31][C@@H:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:26]1)([CH3:41])[CH3:42]
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CC(C)[Si](OC[C@@H]1CCCN(c2nnc3ccc(F)cn23)C1)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[Si](OC[C@@H]1CCCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 57.1 %

Procedure:
To a solution of Intermediate A (140 mg, 0.860 mmol) in dry DMF (2 mL) at RT under Ar was added NaH (60% dispersion in oil, 49.0 mg, 1.23 mmol) (CARE: gas evolution) and the resulting brown suspension was stirred at RT for 45 min. A solution of Intermediate 77b (333 mg, 0.819 mmol) in dry DMF (2 mL) was added and the resulting dark brown solution stirred at 60° C. under Ar for 2.5 h. The solution was concentrated in vacuo, redissolved in MeOH (2 mL) and AcOH (0.100 mL), then applied to and SCX-2 cartridge, and washed with MeOH (100 ml). The product was eluted with 2M NH3 in MeOH (75 mL); concentration in vacuo left a viscous dark brown oil. FCC, using 2-7% [2M NH3 in MeOH] in DCM, gave the title compound as a yellow-brown viscous oil (257 mg, 57%). LCMS (Method 3): Rt 3.27 min, m/z 550 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[CH:16]([O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23])([CH3:18])[CH3:17]>O1CCOCC1.N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]([NH:14][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[O:19][CH:16]([CH3:17])[CH3:18])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: COC(=O)c1ccc(N)c(C(=O)OC)c1
Reactant: CC(C)Oc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(NC(=O)c2ccccc2OC(C)C)c(C(=O)OC)c1
Yield: 69.3 %

Procedure:
Dimethyl-4-amino-isophthalate (10 g) in 10 ml of dioxane and 20 ml of anhydrous pyridine are treated with 20 g of 2-isopropoxy-benzoyl chloride at room temperature, overnight. After dilution with water, the precipitate is collected, dissolved in ethyl acetate, and washed with 5% NaHCO3 and then with water. After evaporation to dryness under vacuum, the material is crystallized from isopropyl ether, yielding dimethyl-4-(2'-isopropoxybenzoylamino)-isophthalate (12.3 g; m.p. 107°-110° C.), which is dissolved in 80 ml of dioxane and treated with 80 ml of 1 N NaOH at room temperature for one night. After acidification with dilute HCl, the precipitate is collected under vacuum and washed with water until neutral. The yield is 10.9 g of 4-(2'-isopropoxybenzoylamino)-isophthalic acid, which are treated with 60 ml of acetic anhydride at 90°-100° C. for 15'. After cooling, dilute with 60 ml of isopropyl ether and filter. The yield is 9 g of 6-carboxy-2-(2'-isopropoxyphenyl)-4H-3,1-benzoxazin-4-one (m.p. 246°-250° C.), which are reacted at room temperature first with 90 ml of 32% ammonium hydroxide and then with 45 ml of 2 N NaOH for 120'. After acidification with 4 N HCl, the precipitate is filtered off and crystallized from ethanol-chloroform to give 6-carboxy-2-(2'-isopropoxyphenyl)-3,4-dihydro-4-oxo-quinazoline (6.6 g; m.p. 316°-318° C.).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].[N+:17]([O-])([OH:19])=[O:18]>O>[C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([N+:17]([O-:19])=[O:18])=[C:10]([O:15][CH3:16])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2c(c1)CCC(NC(C)=O)C2
Solvent: O
Product: COc1cc2c(cc1[N+](=O)[O-])CC(NC(C)=O)CC2

Procedure:
30 g of 2-acetylamino-6-methoxy-1,2,3,4-tetrahydronaphthalene are introduced in small amounts into 600 ml of nitric acid (d=1.38), the temperature being kept between -5° and -10° C. The reaction has ended when total dissolution has taken place. The solution is then poured into 2 liters of water and ice and the solid is filtered off, washed and dried. This gives a mixture of the two mononitro isomers, the one being nitrated in the 5-position and the other in the 7-position, and of the dinitro compound. They are separated on a silica column with a 99/1 methyl ethyl ketone/methanol mixture. The compound nitrated in the 7-position melts at 175° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[C:10](=[O:19])[NH:11][C:12]([CH2:15][CH2:16][CH2:17][CH3:18])=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:26]([O:30][C:31]([C:33]1[C:34]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45]Br)=[CH:41][CH:40]=2)=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[C:26]([O:30][C:31]([C:33]1[C:34]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][N:11]3[C:12]([CH2:15][CH2:16][CH2:17][CH3:18])=[CH:13][CH:14]=[C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:20])[C:10]3=[O:19])=[CH:41][CH:40]=2)=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1ccc(CNC(=O)OC(C)(C)C)c(=O)[nH]1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCc1ccc(CNC(=O)OC(C)(C)C)c(=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 46.5 %

Procedure:
(6-Butyl-2-oxo-1,2-dihydropyridin-3-ylmethyl)carbamic acid t-butyl ester (200 mg, 0.71 mmol) was dissolved in THF (5 mL) and cooled to −5° C. n-Butyllithium (285 μL, 2.5M solution in hexanes, 1 eq) was added, and the mixture was stirred at −5° C. for 5 minutes. 4′-Bromomethylbiphenyl-2-carboxylic acid t-butyl ester (247 mg, 1 eq) was added, and solution was warmed to reflux and stirred for 72 hours. The solution was allowed to cool, the solvent evaporated and the residue purified by silica gel chromatography (3:1 hexanes:EtOAc) to yield intermediate (25a) as a white solid (180 mg, 330 μmol). MS m/z: [M+H+] calcd for C33H43N2O5, 547.7; found 547.3.