Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[N:12]=[C:11]([C:21]([OH:23])=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:28]([N:30]([CH2:34][CH3:35])[CH2:31][CH2:32]O)[CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[N:12]=[C:11]([C:21]([O:23][CH2:29][CH2:28][N:30]([CH2:34][CH3:35])[CH2:31][CH3:32])=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CCO
Reactant: O=C(O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCN(CC)CCOC(=O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Temperature: 25 °C

Procedure:
To 4-benzyloxy-5,7-dichloroquinoline-2-carboxylic acid (1.7 g), was added thionyl chloride (10 ml) and the mixture was heated to reflux for 2 hours. The mixture was cooled to room temperature, excess thionyl chloride removed under reduced pressure to give an off white solid, to which was added dry tetrahydrofuran (20 ml). The solution was cooled to 0° C. and N,N-diethylethanolamine (2.1 ml) added dropwise. The reaction was left to warm to room temperature over 1 hour, poured into 10% sodium carbonate (100 ml) and extracted with ethyl acetate (3×100 ml). The organic layers were combined and washed with water (2×100 ml), brine (2×50 ml) and dried over magnesium sulphate. The solvent was removed under reduced pressure and the crude product purified by column chromatography to give 2-diethylaminoethyl 4-benzyloxy-5,7-dichloroquinoline-2-carboxylate (1.1 g). δ (360 MHz, DMSO-d6), 0.99 (1H, t, CH2CH3), 2.54 (4H, q, CH2CH3), 2.81 (2H, t, CH2N), 4.41 (2H, m, CO2CH2), 5.50 (2H, s, OCH2), 7.41 (3H, m, o,p-ArH). 7.60 (2H, d, m-ArH), 7.71 (1H, s, 3-H), 7.86 (1H, d, 6-H) and 8.12 (1H, d, 8-H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].CO.[CH:20]([NH2:24])([CH2:22][CH3:23])[CH3:21]>C(N(CC)CC)C>[Cl:11][C:6]1[N:5]=[C:4]([CH3:12])[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]([NH:24][CH:20]([CH3:21])[CH2:22][CH3:23])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CCC(C)N
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1NC(C)CC

Procedure:
139.5 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester (0.5 Mol.) are dissolved in about 500 ml. methanol. 60 g. of triethylamine are added and the solution is heated at reflux temperature. At this point, 36.5 g. of sec. butylamine are added dropwise. After the addition is completed, heating is continued for ten minutes. The solvent is then removed in vacuo and 500 ml. of ethyl acetate are added to the residue. The triethylamine hydrochloride is filtered off and the solvent evaporated. The resulting yellow oil, 6-chloro-2-methyl-4-(1-methylpropyl)amino-5-nitropyridine-3-carboxylic acid, ethyl ester is recrystallized with methanol, yield: 107 g. (68%); m.p. 33°-35° (methanol).
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@@H:10]([C@@H:21]([O:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][N:33]=2)[CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[C:27]([Si:24]([CH3:26])([CH3:25])[O:23][CH2:22][C@@H:21]([C@@H:10]1[C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:12][NH:8][CH2:9]1)[O:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][N:33]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](Oc1ccc(Cl)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@H](Oc1ccc(Cl)cn1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 100 °C
Yield: 83 %

Procedure:
To a solution of 2-[(R)-1-[(3R,4S)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-pyridine 570 mg (0.96 mmol) dissolved in toluene (4 mL) was added 0.31 mL (2.89 mmol) of 1-chloroethyl chloroformate and 0.491 mL (2.89 mmol) of Hunig base subsequently, and the mixture was heated at 100° C. for 40 minutes, then concentrated in vaccuo. The residue was dissolved in methanol (5 mL) and stirred at room temperature over night. The mixture was concentrated in vaccuo and diluted with ethyl acetate, then washed with aq. sodium bicarbonate solution twice. The separated organic layer was dried over sodium sulfate and concentrated in vaccuo after filtration yielded 0.40 g (83%) of the title compound as a light brown oil. ES-MS m/e: 501.2 (M+H+).
Reaction SMILES: Cl[S:2]([C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)(=O)=O.CCO.[Sn].Cl>C(Cl)Cl>[CH3:17][C:10]([O:9][C:8]1[CH:7]=[CH:6][C:5]([SH:2])=[CH:19][CH:18]=1)([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Sn]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1ccc(S)cc1
Yield: 72.2 %

Procedure:
To a 3-L three-neck round-bottom flask equipped with an overhead mechanical stirrer, addition funnel and a N2 inlet was added ethyl 2-[4-(chlorosulfonyl)phenoxy]-2-methylpropanoate (53 g, 0.173 moles, 1 eq) and absolute EtOH (500 ml). Tin powder (325 mesh, 123.06 g, 1.04 moles, 6 eq) was added as a solid. The overhead stirrer was adjusted so that the rotor is as close as possible to the bottom of the round-bottom flask and stirring speed was accelerated to a very high setting before adding the HCl to prevent the clumping of the tin metal. Hydrogen chloride (4N in dioxane, 300 ml) was added dropwise over the course of 1 hour. The reaction mixture was refluxed for 4 hours at which point the hot ethanolic solution was poured into a 2-L Erlenmeyer flask containing CH2Cl2 (1 L) and ice. After stirring for 10 minutes the biphasic mixture was filtered through Celite. After transferring to a separatory funnel the phases were separated and the aqueous fraction was washed with CH2Cl2 (2×100 ml). The combined organic fractions were dried over Na2SO4, filtered and concentrated in vacuo. A bright yellow oil with a white precipitate suspended resulted. This yellow mixture was dissolved in a minimum amount of CH2Cl2 and filtered once again through Celite to yield 30 g (75%) of a bright yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:20])[C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1)(=[O:23])[CH3:22]>>[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]([CH3:20])[C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)=[CH:27][CH:26]=1)(=[O:23])[CH3:22]
Reactant: Cc1cc(OCCCCCl)cc2c1NC(=O)OC2(C)C
Reactant: CC(=O)Nc1ccc(S)cc1
Product: CC(=O)Nc1ccc(SCCCCOc2cc(C)c3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and 4-acetamido-thiophenol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:13].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][C:21]=1[C:30]([F:33])([F:32])[F:31]>N1C=CC=CC=1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH2:10][CH2:11][C:12]([N:14]([CH2:15][CH3:16])[CH2:17][CH3:18])=[O:13])=[C:2]([NH:1][S:26]([C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:30]([F:33])([F:31])[F:32])[CH:22]=2)(=[O:28])=[O:27])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCN(CC)C(=O)CCSc1ccc(Cl)cc1N
Solvent: c1ccncc1
Product: CCN(CC)C(=O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Yield: 85 %

Procedure:
Following General Procedure B, the title compound (999 mg, 85%) was prepared from 3-((2-amino-4-chlorophenyl)thio)-N,N-diethylpropanamide (635 mg, 2.22 mmol) and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (619 mg, 2.22 mmol) in pyridine (6 ml).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH3:12][NH2:13]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:13][CH3:12]
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Solvent: CCO
Product: CNc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (25 g) in EtOH (100 ml) was added methylamine (40% in MeOH, 34.8 ml) at room temperature. The mixture was stirred at room temperature for 1 h. After being stirred, the reaction mixture was cooled to 0° C., and the precipitate was collected by filtration and washed with EtOH (0° C.) and IPE. The solid was dried to give the title compound (24.8 g) as a yellow solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[NH:16][CH2:15]2.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>C1COCC1>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:21])[N:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH2:15]2
Reactant: COc1ccc(CBr)cc1
Reactant: O=C1NCc2cc(Cl)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN2Cc3cc(Cl)ccc3C2=O)cc1
Reaction time: 0.17 h
Yield: 104.3 %

Procedure:
Sodium bis(trimethylsilyl) amide (2 mL, 2 M in THF, 2 mmol) was added dropwise at 0° C. to a solution of 5-chloro-2,3-dihydro-isoindol-1-one (0.34 g, 2 mmol) in THF (10 mL). After stirring for 10 min, 1-bromomethyl-4-methoxy-benzene (0.52 g, 2.6 mmol) was added dropwise. The resulting reaction mixture was allowed to stir at room temperature for 48 hours before quenching with saturated aqueous ammonium chloride solution. After extraction with EtOAc, the organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give the crude product (0.6 g, 100%) as a yellow oil. MS: 288.0 (M+H+). It was used directly in the next step, without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([N:18]3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.N.O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]([CH3:23])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:18])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(C(=O)n3ccnc3)ncn2-c2cccc(Cl)c2C1=O
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CN1Cc2c(C(N)=O)ncn2-c2cccc(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7 g (20.5 mmol) of 1-[[7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl]carbonyl]imidazole are suspended in 20 ml of N,N-dimethylformamide, whereupon the suspension is treated with 3.5 ml (about 46 mmol) of a 25 percent aqueous ammonia solution, the mixture is stirred at room temperature for 1 hour and then poured into 10 ml of water. The product is filtered off under suction after 1 hour, rinsed with water and dried at 80° in a high vacuum. There is obtained 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide of melting point 266°-268°.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:14][CH2:15][C@H:16]3[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]3)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9]([OH:11])=O)[CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[N:35]1([S:39]([NH2:42])(=[O:41])=[O:40])[CH2:38][CH2:37][CH2:36]1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[N:35]1([S:39]([NH:42][C:9](=[O:11])[C:8]2[CH:12]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:5]([O:14][CH2:15][C@H:16]3[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]3)=[CH:6][C:7]=2[F:13])(=[O:41])=[O:40])[CH2:38][CH2:37][CH2:36]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: C[C@H]1CC[C@H](COc2cc(F)c(C(=O)O)cc2C2CC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[C@H]1CC[C@H](COc2cc(F)c(C(=O)NS(=O)(=O)N3CCC3)cc2C2CC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 5-cyclopropyl-2-fluoro-4-((trans-4-methylcyclohexyl)-methoxy)benzoic acid (0.255 g, 0.83 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.242 g, 1.26 mmol) and 4-dimethylaminopyridine (0.242 g, 1.98 mmol) in anhydrous dichloromethane (22 mL) was added azetidine-1-sulfonamide (0.173 g, 1.27 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The mixture was poured into 5% aqueous hydrochloric acid (50 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (4×50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL); dried over anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was purified by column chromatography (0% to 40% ethyl acetate in hexanes) to afford the title compound (0.114 g, 33%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.66 (d, J=16.7 Hz, 1H), 7.59 (d, J=9.1 Hz, 1H), 6.57 (d, J=14.5 Hz, 1H), 4.25 (t, J=7.7 Hz, 4H), 3.83 (d, J=6.1 Hz, 2H), 2.27 (q, J=7.7 Hz, 1H), 2.11-2.02 (m, 1H), 1.92-1.75 (m, 5H), 1.41-1.29 (m, 1H), 1.25-0.90 (m, 10H), 0.70-0.64 (m, 2H); MS (ES−) m/z 423.26 (M−1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.[OH-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[C:14]1([S:20]([NH:1][CH2:2][C@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@H]1CC[C@H](CNS(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
trans-4-(Aminomethyl)cyclohexane carboxylic acid (15.2 g, 0.097 mol) was dissolved in a 2N NaOH solution (96.5 mL, 2 equivalents). The solution was brought to 10° C., benzenesulfonyl chloride (17.1 g, 0.097 mol) was added dropwise and then the mixture was stirred overnight at room temperature. The mixture was diluted with water, the solution was washed with ether, and then the aqueous portion was acidified with 12N HCl to give an oily precipitate. The precipitate was extracted with CH2Cl2, and the extracts were dried (Na2SO4) and concentrated under reduced pressure to give trans-4-(Benzenesulfonylamino-methyl)-cyclohexanecarboxylic acid as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([OH:24])([C:20]([F:23])([F:22])[F:21])[CH2:6][C:7]([C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18])([CH3:9])[CH3:8])C>C(O)C>[F:16][C:14]1[CH:13]=[CH:12][C:11]([N+:17]([O-:19])=[O:18])=[C:10]([C:7]([CH3:9])([CH3:8])[CH2:6][C:5]([OH:24])([C:20]([F:22])([F:23])[F:21])[C:4]([OH:25])=[O:3])[CH:15]=1
Reactant: CCOC(=O)C(O)(CC(C)(C)c1cc(F)ccc1[N+](=O)[O-])C(F)(F)F
Solvent: CCO
Product: CC(C)(CC(O)(C(=O)O)C(F)(F)F)c1cc(F)ccc1[N+](=O)[O-]
Reaction time: 48 h

Procedure:
2.4 g of 4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleric acid-ethyl ester is dissolved in 30 ml of ethanol and purified with 60 ml of 1 M sodium hydroxide solution. After 2 days at room temperature, it is concentrated by evaporation, the residue is dissolved in water, acidified at 0° C. and extracted with ethyl acetate. The ethyl acetate phase is washed neutral with water, dried (Na2SO4) and concentrated by evaporation. After crystallization from diisopropyl ether, 4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleric acid with a flash point of 130–131° C. is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[CH2:11]([O:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=1Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CO>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.C1(C)C=CC=CC=1>[CH2:11]([O:18][C:19]1[C:20]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][CH:28]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: COC(=O)c1ccc(OCc2ccccc2)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OCc2ccccc2)c(-c2ccc(O)cc2)c1
Temperature: 70 °C
Reaction time: 48 h
Yield: 68.6 %

Procedure:
(4-Hydroxyphenyl)boronic acid (5.0 g, 36.3 mmol), methyl 4-benzyloxy-3-bromobenzoate (7.0 g, 21.8 mmol) and cesium carbonate (18.0 g, 55.2 mmol) were added to a mixed solution of methanol (50 mL) and toluene (100 mL), the air was substituted with argon gas, and tetrakis(triphenylphosphine)palladium(0) (0.45 g, 0.39 mmol) was added. The reaction mixture was stirred under an argon atmosphere at 70° C. for 2 days. After cooling the reaction mixture, the insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:5-2:1), and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (5.0 g, yield 69%) as colorless prism crystals.
Reaction SMILES: C([O:9][CH2:10][C:11]1[N:20]=[C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:32][CH3:33])[CH:17]=2)[N:12]=1)(=O)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C.C(O)C>[OH:9][CH2:10][C:11]1[N:20]=[C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:32][CH3:33])[CH:17]=2)[N:12]=1
Reactant: COc1ccc2nc(COC(=O)c3ccccc3)nc(NCc3ccc4c(c3)OCO4)c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc2nc(CO)nc(NCc3ccc4c(c3)OCO4)c2c1
Yield: 89.5 %

Procedure:
1.5 g of 10% palladium/carbon powder was added to a solution of 1.26 g (2.93 mmol) of 2-benzoyloxymethyl-4-(3,4-methylenedioxybenzyl)amino-6-methoxyquinazoline in an ethyl acetate/ethanol (20 ml-20 ml) mixture. The obtained mixture was stirred at room temperature in a stream of hydrogen for 24 hours and filtered through Celite. The filter cake was washed with hot ethyl acetate/ethanol. The filtrate and the washings were distilled under a reduced pressure to remove the solvent. Thus 0.89 g of the title compound was obtained as a pale-yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:23])[N:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][S:19][CH2:20][CH2:21]Cl)[CH2:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[Na+].[I-].[CH2:26]([NH:28][CH2:29][CH2:30][OH:31])[CH3:27]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:23])[N:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][S:19][CH2:20][CH2:21][N:28]([CH2:26][CH3:27])[CH2:29][CH2:30][OH:31])[CH2:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](CSCCCl)CC1
Reactant: CCNCCO
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCN(CCO)CCSC[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 94 mg (0.25 mmol) of trans-[4-(2-Chloro-ethylsulfanylmethyl)-cyclohexyl]-methyl-carbamic acid 4-chloro-phenyl ester in 1 ml DMA was treated with a catalytic amount of NaI and with 0.05 ml (0.5 mmol) of 2-ethylaminoethanol and stirred at RT for 16 h. The reaction mixture was stirred for 1 week, adding every day twice 0.05 ml (0.5 mmol) of 2-ethylaminoethanol. The solution was concentrated and the residual oil was extracted with aqueous sat. NaHCO3/Et2O (3×). The organic phases were washed with aqueous 10% NaCl solution and dried over Na2SO4 to yield after flash column chromatography on silica gel (CH2Cl2/MeOH 95:5) 40 mg (39%) of trans-(4-{2-[Ethyl-(2-hydroxy-ethyl)-amino]-ethylsulfanylmethyl}-cyclohexyl)-methyl-carbamic acid 4-chloro-phenyl ester, MS: 429 (MH+, 1Cl).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N=C=NC(C)C)(C)C.[Cl:21][C:22]1[CH:38]=[CH:37][C:25]([CH2:26][N:27]2[CH2:31][CH2:30][C@@H:29]([NH:32][C:33](=[O:36])[CH2:34][NH2:35])[CH2:28]2)=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[Cl:21][C:22]1[CH:38]=[CH:37][C:25]([CH2:26][N:27]2[CH2:31][CH2:30][C@@H:29]([NH:32][C:33](=[O:36])[CH2:34][NH:35][C:4](=[O:6])[C:3]3[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=3[NH2:1])[CH2:28]2)=[CH:24][CH:23]=1
Reactant: NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: ClC(Cl)Cl
Product: Nc1ccc(Cl)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-Amino-5-chlorobenzoic acid (0.060 mL) and diisopropylcarbodiimide (0.060 mol) were added to a chloroform (2 mL) solution of (R)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine (0.050 mmol). The resulting reaction solution was stirred at room temperature for 15 hours. The mixture solution was loaded onto a Varian™ SCX column and washed with methanol (15 mL). The obtained crude product was eluted with a solution of 2 M NH3 in methanol (5 mL) and concentrated to thereby afford (R)-1-(4-chlorobenzyl)-3-[N-[2-amino-5-chlorobenzoyl]glycyl]amino]pyrrolidine (Compd. No. 1084) (12.7 mg, 60%). The purity was determined by RPLC/MS (87%). ESI/MS m/e 421.0 (M++H, C20H22Cl2N4O2).
Reaction SMILES: B([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(O)O.Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=2)[C:7]([OH:9])=[O:8])[CH:15]=1
Reactant: Brc1cccnc1
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1cccc(-c2cccnc2)c1
Yield: 83.7 %

Procedure:
To a solution of 3-boronobenzoic acid (1.5 g, 9 mmol) and 3-bromopyridine (1.5 g, 9.9 mmol) in acetonitrile (40 mL) and water (40 mL), potassium carbonate (5.5 g, 40 mmol), Bis(triphenylphosphine)palladium(II) chloride (400 mg, 0.37 mmol) was added. The mixture was stirred under reflux overnight. Then the hot suspension was filtered and concentrated to half of the original volume and washed with dichloromethane. The aquatic phase was adjusted to pH=3 with hydrochloric acid (1 M) and filtrated, washed with water. The residue was dried in vacuum to obtain 1.5 g of 3-(pyridin-3-yl)benzoic acid. Yield: 83%. LC-MS (ESI) m/z: 200 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:16]/[C:17](/[CH3:24])=[CH:18]\[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:17]([CH3:24])=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(N=C=O)ccc1Cl
Reactant: CCOC(=O)/C=C(/C)N
Product: CCOC(=O)C=C(C)NC(=O)Nc1ccc(Cl)c(C(=O)OCC)c1

Procedure:
using ethyl 2-chloro-5-isocyanatobenzoate and ethyl 3-aminocrotonate there is obtained ethyl 2-chloro-5-{3-[2-(ethoxycarbonyl)-1-methylvinyl]ureido}-benzoate,