Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:14]2[CH2:18][CH2:17][CH2:16][C:15]2([F:20])[F:19])[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:14]2[CH2:18][CH2:17][CH2:16][C:15]2([F:19])[F:20])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(c1ccc(Cl)cc1)C1CCCC1(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C(c1ccc(Cl)cc1)C1CCCC1(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.70 g (8.92 mmol) of ethyl (4-chlorophenyl)(2,2-difluorocyclopentyl)acetate (diastereomer mixture) were dissolved in 10 ml of methanol, 10 ml of THF and 5 ml of water, and 7.13 g (89.18 mmol) of 50% strength aqueous sodium hydroxide solution were added at RT. The reaction mixture was stirred at RT overnight. The mixture was then diluted with water and acidified with hydrochloric acid. The aqueous phase was extracted three times with ethyl acetate, the combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure and the residue was dried under high vacuum. This gave 2.39 g of the title compound (97.6% of theory, diastereomer ratio about 1:1).
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)=[O:5].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][C:21]=1[F:28].O>C1COCC1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:4]([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7]2)=[O:5])=[CH:22][C:21]=1[F:28]
Reactant: Fc1cc([Mg]Br)ccc1Cl
Reactant: CON(C)C(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)c2ccc(Cl)c(F)c2)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 65.5 %

Procedure:
(R)-tert-Butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (1.107 g, 4.285 mmol) was dissolved in THF (21.4 mL, 0.2M), cooled to 0° C., and degassed with N2. 4-Chloro-3-fluorophenylmagnesium bromide (0.5M in THF; 17.14 mL, 8.571 mmol) was added drop wise by syringe, and the reaction was then stirred at 0° C. for 1.5 hours. Water (10 mL) was then added to quench the reaction. The mixture was concentrated by rotovap to remove the bulk of the THF. The remaining mixture was diluted to 50 mL with water and extracted with 4/1 dichloromethane/isopropyl alcohol (2×50 mL). The combined organics were washed with water (100 mL), were isolated, dried over sodium sulfate, filtered and concentrated. The crude product was loaded onto an SP1 samplet and purified by silica gel chromatography using a gradient from 2% to 50% ethyl acetate in hexanes. Product containing fractions were pooled and concentrated to afford (R)-tert-butyl 3-(4-chloro-3-fluorobenzoyl)pyrrolidine-1-carboxylate as an oil (920 mg, 65% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C[O-].[Na+].[I-].[K+].Br[CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18]>CO.C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)=[CH:23][CH:22]=2)[C:17]([O:19][CH3:20])=[O:18])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Cl
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C(Oc1ccc(Cl)c(C)c1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 3.565 g of 4-chloro-3-methylphenol, 1.188 g of sodium methoxide and 50 mg of potassium iodide in 40 ml of methanol is added 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate in 10 ml of benzene. The mixture is refluxed overnight and poured into 100 ml of water. The mixture is extracted with `× 75 ml of ether and the combined extracts are washed with 50 ml of 5% NaOH, 50 ml of water, 50 ml of saturated brine and dried (MgSO4). Evaporation of the solvent yields a yellow oil. Chromatography on 100 g of silica gel yields a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:7]2O)[CH3:2].P(Cl)(Cl)([Cl:22])=O.N>>[Cl:22][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH2:1][CH3:2])[N:5]=2)[N:10]=[CH:9][C:8]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2ccc(OCC)nc2c1O
Agent: N
Product: CCOC(=O)c1cnc2ccc(OCC)nc2c1Cl
Temperature: 25 °C

Procedure:
Ethyl 6-ethoxy-4-hydroxy-1,5-naphthyridine-3-carboxylate (3.0 g) was added to phosphorus oxychloride (25 ml), with stirring, at ambient temperature. The mixture was heated at 50° C. for 45 minutes. The mixture was cooled to 10° C. and added to ice/water at less than 5° C. The mixture was then basified with concentrated aqueous ammonia solution SG 0.88 at less than 5° C. The mixture was extracted with dichloromethane to give ethyl 4-chloro-6-ethoxy-1,5-naphthyridine-3-carboxylate, m.p. 61°-64° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[C:16]([O:19][CH3:20])[N:17]=[CH:18][C:11]=3[N:10]=[C:9]2[CH3:21])=[CH:4][CH:3]=1.Br.Br[CH2:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:20][O:19][C:16]1[N:17]=[CH:18][C:11]2[N:10]=[C:9]([CH3:21])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:7][CH:6]=3)[C:13](=[O:14])[C:12]=2[CH:15]=1
Reactant: COc1cc2c(=O)n(-c3ccc(O)cc3)c(C)nc2cn1
Reactant: BrCCCN1CCCC1
Agent: Br
Product: COc1cc2c(=O)n(-c3ccc(OCCCN4CCCC4)cc3)c(C)nc2cn1

Procedure:
The title compound was synthesized as a white solid (m.p.:123-126° C.) by the method according to Example 63, using 3-(4-hydroxyphenyl)-6-methoxy-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one synthesized in Example 197 and 1-(3-bromopropyl)pyrrolidine hydrobromide as starting materials, followed by recrystallization (ethyl acetate/diethyl ether).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]([NH2:16])(=[O:15])[CH3:14].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.O1CCOCC1>[C:13]([NH:16][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:15])[CH3:14]
Reactant: CC(N)=O
Reactant: COC(=O)c1cc(C)nc(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(C)nc(NC(C)=O)c1
Temperature: 150 °C
Yield: 88.5 %

Procedure:
A mixture of methyl 2-chloro-6-methylisonicotinate (2.00 g, 10.8 mmol), acetamide (1.27 g, 21.6 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.20 g, 0.22 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.37 g, 0.65 mmol), tripotassium phosphate (2.74 g, 12.9 mmol) and 1,4-dioxane (26 mL) is heated by microwave irradiation at 150° C. for 1 hr. After cooling to room temperature, the mixture is filtered through a pad of celite. The filtrate is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (4:11:3) to give 1.99 g (89% yield) of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[CH3:10][C@@H:11](O)[CH2:12][CH:13]=[CH2:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][C@H:13]([CH2:12][CH:11]=[CH2:10])[CH3:14]
Reactant: C=CC[C@@H](C)O
Reactant: Oc1cc(F)ccc1Br
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC[C@H](C)Oc1cc(F)ccc1Br
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a solution of 2-bromo-5-fluorophenol (1.46 g, 7.64 mmol, 1 equiv), (R)-pent-4-en-2-ol (0.94 mL, 9.17 mmol, 1.2 equiv), and PPh3 (2.40 g, 9.17 mmol, 1.2 equiv) in THF (26 mL) was added DIAD (1.78 mL, 9.17 mmol, 1.2 equiv). After stirring 2 h, the yellow solution was diluted with ether, washed with 1 N NaOH, dried (MgSO4), and concentrated in vacuo. The crude product was purified by flash column chromatography (hexane) to provide the product (1.18 g, 60%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.49 (dd, J=8.7, 6.3 Hz, 1H), 6.67 (dd, J=10.6, 2.8 Hz, 1H), 6.62-6.56 (m, 1H), 5.91 (ddt, J=17.1, 10.1, 7.1 Hz, 1H), 5.22-5.12 (m, 2H), 4.49-4.38 (m, 1H), 2.62-2.52 (m, 1H), 2.49-2.40 (m, 1H), 1.39 (d, J=6.1 Hz, 3H).
Reaction SMILES: N1(O[C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)C2C=CC=CC=2N=N1.[NH2:20][C:21]1[CH:26]=[CH:25][O:24][CH2:23][CH:22]=1.C(N(CC)CC)C>CN(C)C=O>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([NH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:19])=[CH:17][CH:16]=1
Reactant: NC1=CCOC=C1
Reactant: Nc1ccc(C(=O)On2nnc3ccccc32)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccc(C(=O)NC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.3 %

Procedure:
To a mixture of 1.1441 g (4.5 mmole) of 4-amino-benzoic acid benzotriazol-1-yl ester and 8 mL of dry dimethylformamide was added 0.6575 g (6.5 mmole) of 4-amino-pyran followed by 0.4554 g (0.45 mmole) of triethylamine. The mixture stirred at room temperature for 90 minutes. Volatiles were removed under reduced pressure and the residue taken up in ethyl acetate, and the organic layer washed once with 100 mL of 0.5 M sodium carbonate, twice with 75 mL water, and then 75 mL brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.5378 g 4-amino-N-(tetrahydro-pyran-4-yl)-benzamide, which was used without further purification.
Reaction SMILES: [C:1]([NH:6][C:7]1[S:18][C:10]2[CH2:11][N:12]([C:15](=[O:17])[CH3:16])[CH2:13][CH2:14][C:9]=2[C:8]=1[C:19]([O:21]CC)=O)([O:3]CC)=O.[NH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[O:39][CH3:40])[CH2:29][CH2:28]1>>[OH:3][C:1]1[N:24]([CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][N:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])[CH2:31][CH2:32]2)[C:19](=[O:21])[C:8]2[C:9]3[CH2:14][CH2:13][N:12]([C:15](=[O:17])[CH3:16])[CH2:11][C:10]=3[S:18][C:7]=2[N:6]=1
Reactant: COc1ccccc1N1CCN(CCN)CC1
Reactant: CCOC(=O)Nc1sc2c(c1C(=O)OCC)CCN(C(C)=O)C2
Product: COc1ccccc1N1CCN(CCn2c(O)nc3sc4c(c3c2=O)CCN(C(C)=O)C4)CC1

Procedure:
2.5 g (7.3 mmol) of 2-carboethoxyamino-3-carboethoxy-6-acetyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine were heated with 1.7 g (7.3 mmol) of 1-(2-aminoethyl)-4-(2-methoxyphenyl)piperazine at 180° C. for 2 h under nitrogen while stirring the melt efficiently. After cooling, the crude product was purified by column chromatography (silica gel, mobile phase methylene chloride/ methanol 95/5). 0.7 g (20%) of product with melting point 135-137° C. was isoldted.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)(O)=O.[NH3:40]>C(Cl)(Cl)Cl>[NH2:40][CH2:1][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:38][CH:39]=1
Reactant: N
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(CCN)cc2)c1

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester. (31 mg) and a saturated ammonia solution in chloroform (0.1 ml) according to an analogous synthetic method to Example 806, the title compound (0.7 mg) was obtained.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:6]=1B(O)O.CCO.[CH3:21][O:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=1>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:21][O:22][C:23]([C:24]1[CH:25]=[C:26]([C:6]2[CH:7]=[CH:8][C:9]([O:13][CH3:14])=[C:10]([O:11][CH3:12])[C:5]=2[O:4][CH3:3])[CH:27]=[CH:28][CH:29]=1)=[O:31]
Reactant: COC(=O)c1cccc(Br)c1
Reactant: COc1ccc(B(O)O)c(OC)c1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COC(=O)c1cccc(-c2ccc(OC)c(OC)c2OC)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
(The following reaction is done in an N2 atmosphere.) To a solution of 2,3,4-Trimethoxyphenylboronic acid (32) (1.40 g, 6.60 mmol) in toluene (15.0 mL) is added EtOH (2.0 mL), Pd(PPh3)4 (208 mg, 0.18 mmol) and Na2CO3.10H2O (4.81 g, 16.80 mmol) in water (5.2 mL). The resulting mixture is carefully degassed (5 times alternating vacuum and flushing with N2). A solution of Methyl-3-bromobenzoate (9) (1.29 g, 6.00 mmol) in toluene (9.0 mL) is added by syringe, the resulting mixture is again carefully degassed and stirred overnight at 100° C. Partition the mixture between brine/EtOAc (1+1), separate layers, extract the aqu. layer with EtOAc (3×), wash the combined organic layer with brine, dry with Na2SO4 and remove solvent. Purify crude product by preparative radial chromatography (silica gel, EtOAc/CyH 1+5) to obtain 2′,3′,4′-Trimethoxy-biphenyl-3-carboxylic acid methyl ester (33) as a yellowish oil (1.07 g, 58%). 1H NMR (400 MHz, CDCl3): 3.66 (s, 3H); 3.89 (s, 3H); 3.92 (s, 6H); 6.74 (d, 1H, J=8.6 Hz); 7.03 (d, 1H, J=8.6 Hz); 7.44 (t, 1H, J=7.8 Hz); 7.70 (d, 1H, J=7.6 Hz); 7.97 (d, 1H, J=7.8 Hz); 8.15 (br.s 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](SC)=[C:13]2[C:18](=[O:19])[O:17][C:16]([CH3:21])([CH3:20])[O:15][C:14]2=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[NH4+:26]>C1COCC1.Cl[Hg]Cl>[NH2:26][C:12]([NH:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[C:13]1[C:18](=[O:19])[O:17][C:16]([CH3:21])([CH3:20])[O:15][C:14]1=[O:22]
Reactant: COc1ccc(NC(SC)=C2C(=O)OC(C)(C)OC2=O)cc1OC
Reactant: [NH4+]
Agent: Cl[Hg]Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(NC(N)=C2C(=O)OC(C)(C)OC2=O)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A mixture of 5-[(3,4-dimethoxy-phenylamino)-methylsulfanyl-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (1.0 g, 2.8 mmol), 30% ammonium hydroxide (8.5 mL), HgCl2 (0.75 g, 2.8 mmol) in THF (5 mL) was stirred at room temperature for 30 minutes. The mixture was extracted with DCM and water (3×) and dried with Na2SO4. Concentration in vacuo afforded 5-[amino-(3,4-dimethoxy-phenylamino)-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione as a white solid (0.90 g, 97% yield) and this compound was used without further purification. LCMS: m/z 321 (M−H)−.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](Cl)=[O:18].N1C=CC=CC=1.O>C1COCC1>[I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([O:13][CH3:12])[CH:15]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: NNC(=O)c1ccc(I)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(C(=O)NNC(=O)c2ccc(I)cc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-Iodobenzohydrazide (5.0 g, 19.1 mmol) in dry THF (80.0 ml) was slowly added 3-methoxybenzoyl chloride (3.5 g, 20.5 mmol) at 0° C. under nitrogen. During addition of 3-methoxybenzoyl chloride the white solid was appeared. After addition of 3-methoxybenzoyl chloride, the reaction was warmed up to room temperature. The reaction mixture was stirred for 18 hours at room temperature and then pyridine (5.0 ml) was added and stirred for additional 2 h. Water (300.0 ml) was added to reaction mixture. The white solid was obtained and collected by filtration. After dried under vacuum, product was obtained as white powder in 7.2 g (94.7%). 1H NMR (400 MHz, DMSO-d6, δ): 10.60 (s, 1H, NH), 10.52 (s, 1H, NH), 7.91 (d, J=8.0 Hz, 2H), 7.68 (d, J=8.0 Hz, 2H), 7.50 (d, J=8.0 Hz, 1H), 7.45 (d, J=2.4 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.15 (dd, J1=8.0 Hz, J2=2.4 Hz, 1H), 3.81 (s, 3H, OCH3).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]=[CH2:7])=[O:3].[OH:8][C@H:9]1[CH2:13][NH:12][C@H:11]([C:14]([OH:16])=[O:15])[CH2:10]1.[OH-].[Na+].[Na+].[Cl-]>C1COCC1.O.CCOC(C)=O>[CH2:5]([O:4][C:2]([N:12]1[CH2:13][C@H:9]([OH:8])[CH2:10][C@H:11]1[C:14]([OH:16])=[O:15])=[O:3])[CH:6]=[CH2:7]
Reactant: C=CCOC(=O)Cl
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
A solution of allyl chloroformate (29.2 mL, 33.2 g, 275 mmol) in THF (30 mL) was added dropwise to a suspension of trans-4-hydroxy-L-proline (11) (30 g, 229 mmol) in a mixture of THF (150 mL) and H2O (150 mL) at 0° C. (ice/acetone), whilst maintaining the pH at 9 with 4 N NaOH. After stirring at 0° C. for 1 hour at pH 9, the aqueous layer was saturated with NaCl, and the mixture diluted with EtOAc (100 mL). The aqueous layer was separated, washed with EtOAc (100 mL) and the pH adjusted to 2 with conc. HCl. The resulting milky emulsion was extracted with EtOAc (2×100 mL), washed with brine (200 mL), dried (MgSO4), filtered and evaporated in vacuo to give the allyl carbamate 12 as a clear viscous oil (42.6 g, 87%): [α]20D=−62.1° (c=0.69, MeOH); 1H NMR (270 MHz, CDCl3+DMSO-d6)(Rotamers) δ 5.98-5.81 (m, 1H, NCO2CH2CH═CH2), 5.40-5.14 (m, 2H, NCO2CH2CH═CH2), 4.64-4.42 (m, 4H, NCO2CH2CH═CH2, NCH2CHOHCH2 and CHCO2H), 3.82-3.51 (m, 2H, NCH2CHOHCH2), 2.34-2.08 (m, 2H, NCH2CHOHCH2); 13C NMR (67.8 MHz, CDCl3+DMSO) (Rotamers) δ 175.0 and 174.5 (CO2H), 155.1 and 154.6 (NC═O), 132.9 and 132.8 (NCH2CH2CH═CH2), 117.6 and 116.7 (NCO2CH2CH═CH2), 69.5 and 68.8 (NCH2CHOH), 65.9 and 65.8 (NCO2CH2CH═CH2), 58.0 and 57.7 (CHCO2H), 55.0 and 54.5 (NCH2CHOH), 39.3 and 38.3 (NCH2CHOHCH2); MS (EI), m/z (relative intensity) 215 (M+., 10) 197 (12), 170 (M-CO2H, 100), 152 (24), 130 (M-CO2C3H5, 97), 126 (34), 112 (50), 108 (58), 86 (11), 68 (86), 56 (19); IR (Neat) 3500-2100 (br, OH), 2950, 1745 and 1687 (br, C═O), 1435, 1415, 1346, 1262, 1207, 1174, 1133, 1082, 993, 771 cm−1; exact mass calcd for C9H13NO5 m/e 215.0794, obsd m/e 215.0791.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([OH:18])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:21]1([C:24](=[N:26]O)[NH2:25])[CH2:23][CH2:22]1>CN(C)C=O>[Br:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:18][N:26]=[C:24]([CH:21]4[CH2:23][CH2:22]4)[N:25]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(C(=O)O)ncn2-c2cccc(Br)c2C1=O
Reactant: NC(=NO)C1CC1
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3nc(C4CC4)no3)ncn2-c2cccc(Br)c2C1=O
Reaction time: 2 h

Procedure:
6.2 g (18 mmol) of 7-bromo-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid in 90 ml of N,N-dimethylformamide are stirred at 70° for 2.5 hours with 2.92 g (18 mmol) of N,N'-carbonyldiimidazole. 1.80 g (18 mmol) of cyclopropanecarboxamidoxime are subsequently added thereto and the mixture is stirred at 100° for a further 2 hours. The solution is evaporated, the residue is treated with 70 ml of acetic acid and the mixture is stirred at 120° for 5 hours. The reaction mixture is evaporated and the residue is partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulphate and evaporated. By chromatography on silica gel while eluting with ethyl acetate and recrystallization from acetonitrile there is obtained 7-bromo-4,5-dihydro-3-(3-cyclopropyl-1,2,4-oxadiazol-5yl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 187°-189°.
Reaction SMILES: [OH-].[K+].[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12](=[O:20])[N:13]([CH3:19])[N:14]=[CH:15][C:16]=1[O:17]C)[CH3:4].Cl>C(OCC)(=O)C.O.O1CCOCC1>[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12](=[O:20])[N:13]([CH3:19])[N:14]=[CH:15][C:16]=1[OH:17])[CH3:4]
Reactant: CCc1ccccc1-c1c(OC)cnn(C)c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1ccccc1-c1c(O)cnn(C)c1=O
Yield: 68.1 %

Procedure:
After 50 mL of water, 4.657 g of potassium hydroxide (content, 85%) and 5 mL of 1,4-dioxane were added to 3.193 g of 4-(2-ethylphenyl)-5-methoxy-2-methyl-3(2H)-pyridazinone (Compound II-1), the mixture was stirred and heated under reflux for 36 hours. After cooling, concentrated hydrochloric acid was added to the reaction mixture to acidify, to which 10 ml of water and 100 ml of ethyl acetate were added. The resulting mixture was filtered to remove insoluble substances and the filtrate was separate to two phase. The organic layer was washed with water and then a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The solid obtained was washed with a mixed solvent of ethyl acetate and hexane (1:2) to yield 2.050 g of the title compound as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([S:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:8]=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[OH:22])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:32][O:33][C:34]([C:36]1[N:37]([CH3:45])[C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:39][CH:40]=1)=[O:35]>C1COCC1.C(OCC)(=O)C.O>[CH3:32][O:33][C:34]([C:36]1[N:37]([CH3:45])[C:38]([S:41]([N:15]2[CH2:16][CH2:17][CH:12]([S:11][C:9]3[CH:8]=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]([OH:22])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=3)[CH2:13][CH2:14]2)(=[O:43])=[O:42])=[CH:39][CH:40]=1)=[O:35]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)n1C
Reactant: CC(C)(C)c1cc(SC2CCNCC2)cc(C(C)(C)C)c1O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(S(=O)(=O)N2CCC(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)n1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.5 %

Procedure:
Alternatively, to a solution of 2,6-di-tert-butyl-4-(piperidin-4-ylsulfanyl)-phenol (Ex. 3d, 48.0 g, 0.15 moles) in THF (1000 mL) was added diisopropylethyl amine (39.0 mL, 0.22 moles) and methyl-5-(chlorosulfonyl)-1-methyl-1H-pyrrole-2-carboxylate (35.5 g, 0.15 moles) and the resulting solution was stirred at room temperature for 5 hours. Upon completion, as determined by HPLC, the reaction was diluted with ethyl acetate (500 mL) and water (500 mL). The layers were cut and the organic layer was washed with 1N HCl (500 mL) and 6% brine (2×500 mL), and concentrated under reduced pressure to afford 77.2 g (98.8%) of 5-[4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-sulfonyl]-1-methyl-1H-pyrrole-2-carboxylic acid methyl ester as a white solid, mp 185-187° C. 1H-NMR (400 MHz, CDCl3): δ 7.23 (s, 2H), 7.17 (d, 1H, J=1.6 Hz), 7.09 (d, 1H, J=2.0 Hz), 5.29 (s, 1H), 3.96 (s, 3H), 3.84 (s, 3H), 3.57 (m, 2H), 2.79 (m, 1H), 2.50 (m, 2H), 1.99 (m, 2H), 1.70 (m, 2H), 1.42 (s, 18H). HRMS (ESI) Calcd. for C26H38N2O5S2, 522.2222 (M+). Found: 522.2228. Anal. Calcd. for C26H38N2O5S2: C, 59.74; H, 7.33; N, 5.36; S, 12.27. Found: C, 59.48; H, 7.50; N, 5.22; S, 12.05.