Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[C:12]=2[OH:19])[CH:3]=1.CN.[C:22]([BH3-])#[N:23].[Na+].[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30]>C(OCC)(=O)C.C(O)(=O)C.CO>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:23][CH3:22])[C:12]=2[OH:19])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1O
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1cccc(Oc2cc(Cl)ccc2C#N)c1O
Yield: 61.4 %

Procedure:
4-Chloro-2-(3-formyl-2-hydroxyphenoxy)-benzonitrile (0.30 g, 1.10 mmol), methylamine (2M in methanol, 2.5 mL, 5.0 mmol) and sodium cyanoborohydride (0.10 g, 1.6 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (35 mL) for 19 h. The solvent was removed in vacuo. The residue was treated with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. To the ethyl acetate layer was added fumaric acid (0.12 g, 1.03 mmol) and the solvent removed in vacuo. The residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 4-chloro-2-[2-hydroxy-3-(methylaminomethyl)phenoxy]-benzonitrile fumarate (256 mg, 58%) as a white solid.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.Br[C:16]1[CH:21]=[CH:20][C:19]([C:22]([OH:28])([CH3:27])[C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>O.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(C)C=CC=CC=1>[CH3:1][C@@H:2]1[N:7]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:28])([CH3:27])[C:23]([F:25])([F:26])[F:24])=[CH:18][CH:17]=2)[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: CC(O)(c1ccc(Br)cc1)C(F)(F)F
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Temperature: 100 °C
Yield: 67.3 %

Procedure:
A 100 mL round-bottomed flask was charged with tert-butyl (3S)-3-methyl-1-piperazinecarboxylate (10.0 g, 49.9 mmol), 2-(4-bromophenyl)-1,1,1-trifluoro-2-propanol (13.43 g, 49.9 mmol, Example 27, step 1), sodium tert-butoxide (10.56 g, 110 mmol) and 100 mL of toluene. To this was added dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (1.864 g, 3.99 mmol, Strem Chemical Inc, Newburyport, Mass.), tris(dibenzylideneacetone)dipalladium (0) (1.83 g, 2.00 mmol, Strem Chemical Inc, Newburyport, Mass.). The mixture was heated at 100° C. for 12 h then diluted with water (100 mL) and extracted with EtOAc (2×200 mL). The combined extracts were dried (MgSO4) and purified by column chromatography (330 g of silica, 0 to 50% EtOAc in hexanes) to give tert-butyl (3S)-3-methyl-4-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-1-piperazinecarboxylate (13.05 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]=2[O:3]1.[Cl:22][C:23]1[CH:24]=[C:25]2[C:30](=O)[O:29][C:27](=[O:28])[C:26]2=[CH:32][C:33]=1[Cl:34].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[OH-].[Na+]>O1CCCC1.O>[Cl:22][C:23]1[CH:24]=[C:25]2[C:26](=[CH:32][C:33]=1[Cl:34])[C:27](=[O:28])[N:19]([C:14]1[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]3[O:3][C:2]([CH3:21])([CH3:1])[CH:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:5]=3[C:13]=1[CH3:20])[C:30]2=[O:29]
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccccc1)C(C)(C)O2
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C)c(N2C(=O)c3cc(Cl)c(Cl)cc3C2=O)c(C)c2c1OC(C)(C)C2c1ccccc1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
To a solution of 2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine (1.00 g, 3.56 mmol) in tetrahydrofuran (30 ml) was added under an argon atmosphere 4,5-dichlorophthalic anhydride (850.6 mg, 3.92 mmol) and the mixture was refluxed with heating for 13 hours. The reaction mixture was cooled down to room temperature and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC) hydrochloride (760.0 mg, 3.96 mmol) and 1-hydroxy-1H-benzotriazole (HOBT) monohydrate (602.6 mg, 3.93 mmol) were added to the mixture. The resulting mixture was refluxed with heating for 3 hours and then cooled down to room temperature. Water and an 8 N aqueous solution of sodium hydroxide were added into the reaction mixture and the product was extracted twice with ethyl acetate. The combined extracts were washed with an aqueous, saturated solution of sodium hydrogen carbonate, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was crystallized from ethyl acetate to obtain 1.16 g (68% yield) of the title compound. Melting point: 178-181° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[OH:20][CH2:21][CH:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)=[CH:27][C:26]=1[F:41])[CH2:23][OH:24]>CN(C=O)C.O>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH:15][C:32]([NH:31][C:28]3[CH:29]=[CH:30][C:25]([CH:22]([CH2:21][OH:20])[CH2:23][OH:24])=[C:26]([F:41])[CH:27]=3)=[O:33])=[CH:12][C:11]([C:16]([F:17])([F:18])[F:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1ccc(C(CO)CO)c(F)c1)Oc1ccccc1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)Nc1ccc(C(CO)CO)c(F)c1
Reaction time: 16 h
Yield: 35.7 %

Procedure:
To a stirred solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (153 mg, 0.4918 mmol, 1.0 eq) in DMF (5 mL) was added TEA (0.205 mL, 1.4754 mmol, 3.0 eq) followed by phenyl 4-(1,3-dihydroxypropan-2-yl)-3-fluorophenylcarbamate (150 mg, 0.4918 mmol, 1.0 eq) at RT and the mixture stirred for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL). The organic layer was washed with water (10 mL) and brine (5 mL), dried over anhydrous Na2SO4, and evaporated under vacuum. The crude product was purified by neutral alumina column chromatography using MeOH/CHCl3 (1:19) as eluent to get 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(4-(1,3-dihydroxypropan-2-yl)-3-fluorophenyl)urea (85.5 mg; 36%) as off white solid; TLC system: MeOH/CHCl3 (1:9); Rf: 0.5).
Reaction SMILES: [NH2:1][C:2]1(C(OCC)=O)[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:6]2[C:16]([CH3:20])=[C:17]([CH3:19])[S:18][C:5]=2[N:4]2[C:21]([CH3:24])=[N:22][N:23]=[C:3]12.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>C(O)C.O>[NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[C:6]2[C:16]([CH3:20])=[C:17]([CH3:19])[S:18][C:5]=2[N:4]2[C:21]([CH3:24])=[N:22][N:23]=[C:3]12
Reactant: CCOC(=O)C1(N)N=C(c2ccc(Cl)cc2)c2c(sc(C)c2C)-n2c(C)nnc21
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1sc2c(c1C)C(c1ccc(Cl)cc1)=NC(N)c1nnc(C)n1-2
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.5 %

Procedure:
Ethyl (6-amino-4-(4-chlorophenyl)-2,3,9-trimethyl-6H- thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)- carboxylate (11 g) was dissolved in a mixed solution of ethanol (250 ml) and water (80 ml). Barium hydroxide octahydrate (8.4 g) was added and the mixture was stirred at room temperature for 24 hours. The solvent was distilled away under reduced pressure, and water (100 ml) was added. The pH of the mixture was adjusted to 2 with 1N hydrochloric acid and stirred for 20 minutes. The mixture was neutralized with an aqueous solution of sodium hydrogencarbonate and extracted twice with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was subjected to silica gel column chromatography. The solvent was distilled away, the resulting residue was crystallized from diisopropyl ether, and the crystals were filtrated to give 7 g of 6-amino-4-(4-chlorophenyl)-2,3,9- trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine, melting point 192°-197° C. with decomposition.
Reaction SMILES: [N:1]1([C:7]([NH:9][CH:10]([CH2:14][S:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:17])=[O:16])[C:11]([OH:13])=O)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.OC(C(F)(F)F)=O.[NH2:32][CH2:33][CH:34]([OH:46])[CH2:35][NH:36][S:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:39])=[O:38].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[C:40]1([S:37]([NH:36][CH2:35][C:34](=[O:46])[CH2:33][NH:32][C:11]([CH:10]([NH:9][C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:8])[CH2:14][S:15]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:16])=[O:17])=[O:13])(=[O:39])=[O:38])[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: NCC(O)CNS(=O)(=O)c1ccccc1
Reactant: O=C(O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1)CNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.7 %

Procedure:
2-[(Morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionic acid (50 mg, 0. 14 mmol), N-(3-amino-2-hydroxy-propyl)-benzenesulfonamide TFA salt (60 mg, 0.17 mmol), EDC (100 mg, 0.52 mmol), and HOBt (100 mg, 0.64 mmol) were combined. DMF (3 mL) was added and then 4-methylmorpholine (0.3 mL). The mixture was stirred at ambient temperature for 3 hours. After dilution with ethyl acetate (100 mL) the solution was washed with 1N HCl, saturated aqueous NaHCO3 and brine, dried with MgSO4 and evaporated under vacuum. The residue was dissolved in acetone (5 mL). Jones reagent was added until the orange color persisted. The mixture was stirred for 2 hours, quenched with isopropanol, and diluted with ethyl acetate (100 mL). The solution was washed with water, saturated aqueous NaHCO3 and brine, dried with MgSO4 and evaporated under vacuum. The crude product was recrystallized from ethyl acetate/diethyl ether to give morpholine-4-carboxylic acid [1-(3-benzenesulfonylamino-2-oxo-propylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide as white solid (19 mg); 1H NMR: (DMSO) 8.17 (t, J=5.7 Hz, 1H), 7.93 (t, J=5.9 Hz, 1H), 7.76–7.48 (m, 5H), 7.36–7.29 (m, 5H), 7.05 (d, J=8.1 Hz, 1H), 4.68–4.59 (m, 1H), 4.45 (s, 2H), 3.89 (d, J=5.7 Hz, 2H), 3.79–3,75 (m, 2H), 3.56–3.22 (m, 10H); MS: (M+H)+ 567.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[OH:13])[C:7](O)=[O:8])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][C:27]([NH2:29])=[NH:28]>>[C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[OH:13])[C:7]([NH:28][C:27]([NH2:29])=[NH:26])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C(=O)O)ccc1O
Reactant: N=C(N)N
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(=O)c1cc(C(=O)NC(=N)N)ccc1O

Procedure:
1.0 eq. of 3-acetyl-4-hydroxybenzoic acid was reacted in accordance with Variant A with 1.1 eq. of carbonyldiimidazole and 5 eq. of guanidine. Colorless crystals, mp 218°-221° C.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][C:7](=[O:9])[CH:6]([C:10](=[O:13])[CH2:11][CH3:12])[C:5](=[O:14])[CH2:4]1)=O.[NH2:15]OS(O)(=O)=O>O>[O:14]=[C:5]1[CH:6]([C:10](=[O:13])[CH2:11][CH3:12])[C:7](=[O:9])[CH2:8][CH:3]([C:1]#[N:15])[CH2:4]1
Reactant: NOS(=O)(=O)O
Reactant: CCC(=O)C1C(=O)CC(C=O)CC1=O
Solvent: O
Product: CCC(=O)C1C(=O)CC(C#N)CC1=O
Reaction time: 8 h
Yield: 77 %

Procedure:
30.7 g (0.16 mol) of 5-formyl-2-propionylcyclohexane-1,3-dione in 150 ml of distilled water were initially taken, and 21.0 g (0.19 mol) of hydroxylamine-O-sulfonic acid were added at room temperature. Stirring was then carried out overnight at room temperature. The precipitate was filtered off under suction, washed with water and dried. 23.8 g (71% of theory) of 3,5-dioxo-4-propionylcyclohexanenitrile of melting point 70-74° C. were obtained.
Reaction SMILES: Cl[CH2:2][O:3][C:4]([O:6][CH:7]([CH2:24][O:25][C:26](=[O:39])[C@H:27]([CH:36]([CH3:38])[CH3:37])[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][O:9][C:10](=[O:23])[C@H:11]([CH:20]([CH3:22])[CH3:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:5].[Na+].[I-:41]>C(#N)C>[I:41][CH2:2][O:3][C:4]([O:6][CH:7]([CH2:24][O:25][C:26](=[O:39])[C@H:27]([CH:36]([CH3:38])[CH3:37])[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:8][O:9][C:10](=[O:23])[C@H:11]([CH:20]([CH3:22])[CH3:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:5]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)OC(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)OC(=O)OCI
Yield: 92 %

Procedure:
A solution of 2-O-chloromethoxycarbonyl-1,3-di-O-(N-tertbutoxycarbonyl-L-valyl)propane-1,2,3-triol (7.86 g, 13.5 mmol) and NaI (8.09 g, 54.0 mmol) in 135 mL dry acetonitrile was refluxed at 80° C. for 4 h under N2. The reaction mixture was concentrated under vacuum, and then partitioned between 150 mL diethyl ether and 50 mL H2O. The aqueous layer was reextracted with 2×25 mL ether. The combined organic phases were washed successively with 25 mL aqueous Na2S2O3 and 50 mL brine, dried over Na2SO4, and concentrated. Flash column chromatography (silica gel, 2/1 hexane-ethyl acetate gave 8.38 g (92%) title product (alternative name: 2-iodomethoxycarbonyloxy-1,3-bis-(N-tert-butoxycarbonyl-L-valyloxy)propane or 1,3-bis(N-tert-butoxycarbonyl-L-valyloxy)-2-propyl iodomethyl carbonate) as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:13][C:14]1[CH:19]=[C:18](F)[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].[H-].[Na+]>CN(C=O)C>[F:13][C:14]1[CH:19]=[C:18]([CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22])[O:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@H](Oc2ccc([N+](=O)[O-])c(F)c2)CC1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl 4-hydroxycyclohexanecarboxylate (20.7 g, 120.19 mmol) and 2,4-difluoronitrobenzene (19.125 g, 120.19 mmol) in DMF at 5° C. was added NaH (5.05 g, 126.2 mmol) in one portion, resulting in a slow exotherm to 10° C. The reaction was stirred at 5° C. for 1 hour then allowed to warm to ambient temperature and stirred for 24 hr. The reaction was cooled to 0° C. and quenched with water (˜400 mL). The mixture was extracted with EtOAc (3×˜150 mL), the organic layers combined, washed with brine (2×˜100 mL), dried (MgSO4), filtered and evaporated to an orange oil (36 g). The crude residue was purified by preparative HPLC (silica, 4:1 ethyl acetate:isohexane) to give the title compound (4.5 g, 12%) as a pale orange oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])=S)=[CH:6][CH:5]=1.[S]>CCO>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]2[NH:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCCCNC(=S)Nc2ccccc2N)cc1
Agent: [S]
Solvent: CCO
Product: COC(=O)c1ccc(OCCCNc2nc3ccccc3[nH]2)cc1

Procedure:
A mixture of 36-4 (2.5 g, 7.0 mmol), HgO (3.0 g, 13.9 mmol), sulfur (42 mg) and EtOH (50 mL) was refluxed for 2.5 h. Filtration and concentration gave a brown gum which was purified by flash chromatography (silica, 9:1 CH2Cl2 /CH3OH) to provide 36-5 as a tan solid.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][N:10]=[C:9]([NH:19][CH3:20])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([O:25][C:26](=[O:34])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32]Br)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26](=[O:34])[CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][N:19]([C:9]1[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][N:10]=1)[CH3:20])([CH3:24])([CH3:23])[CH3:22]
Reactant: CNc1ncc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)COCCCCBr
Product: CN(CCCCOCC(=O)OC(C)(C)C)c1ncc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
In the same manner as in Example 22, except that 4,5-diphenyl-2-(methylamino)pyrimidine was used in place of 5,6-diphenyl-2-(methylamino)pyrazine and 2-(4-bromobutyloxy)acetic acid tert-butyl ester was used in place of 2-(4-bromobutyloxy)acetic acid methyl ester, the desired compound was prepared as a pale yellow oily substance.
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.[NH2:12][CH2:13][C:14]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:12][CH2:13][C:14]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15]2)[CH:3]=1
Reactant: CCOC(=O)C1(CN)CC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1(CNc2cc(Br)ccc2[N+](=O)[O-])CC1
Yield: 80.8 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (792 mg, 3.6 mmol) in tetrahydrofuran (30 mL) was added ethyl 1-(aminomethyl)cyclopropanecarboxylate (441 mg, 3.0 mmol) and potassium carbonate (621 mg, 4.5 mmol). The reaction mixture was stirred at reflux for 15 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic phase was separated, concentrated and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give ethyl 1-((5-bromo-2-nitrophenylamino)methyl)cyclopropanecarboxylate as a light yellow solid (832 mg, 67%).
Reaction SMILES: [CH:1]1([C:7]2[C:16]([NH:17][C:18](=[O:20])[CH3:19])=[C:15]([Cl:21])[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]=2[OH:22])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.FC(F)(F)C(O)=O>>[C:18]([NH:17][C:16]1[C:7]2[CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]3[O:22][C:8]=2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][C:15]=1[Cl:21])(=[O:20])[CH3:19]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)c(C2CC=CCC2)c1O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c2c1OC1CCCCC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.2 g of methyl 3-(3-cyclohexenyl)-4-acetylamino-5-chlorosalicylate and 5 ml trifluoroacetic acid are stirred at room temperature overnight. The acid is removed under vacuum and the residue diluted with ether, washed with sodium bicarbonate, then water, dried and evaporated to dryness to give crude methyl 1-acetylamino-2-chloro-5a,6,7,8,9,9a-hexahydrodibenzofuran-4-carboxylate. This product is purified by flash chromatography using 10% ethyl acetate/hexane to give pure product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH:30]=2)[CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:8]2.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)[CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:18][CH:19]=1)[CH2:8]2
Reactant: [H][H]
Reactant: COc1cc(C2=CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Agent: [Pd]
Solvent: CO
Product: COc1cc(C2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reaction time: 18 h
Yield: 41.4 %

Procedure:
7-Methoxy-5-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (17 mg, 0.040 mmol) was stirred in methanol for 20 minutes under argon before a small scoop of palladium on carbon was added and the reaction atmosphere was changed to hydrogen. The reaction was allowed to stir for 18 hours under hydrogen. The reaction was filtered and the solvent was removed under reduced pressure to yield 7.2 mg (42%) of a yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.35 (d, 2H), 7.16 (d, 2H), 6.74 (d, 2H), 4.74 (s, 2H), 4.20 (s, 2H), 3.98 (s, 3H), 3.50 (s, 2H), 2.98-3.01 (m, 2H), 2.53-2.60 (m, 1H), 2.04-2.11 (m, 2H), 1.75-1.87 (m, 5H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1.[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25]Br>>[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25][N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[C:11]=2[N:10]=[C:9]1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: COC(=O)c1cccc2nc(-c3c(F)cccc3F)[nH]c12
Reactant: Fc1cccc(F)c1CBr
Product: COC(=O)c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Yield: 76 %

Procedure:
Methyl 2-(2,6-difluorophenyl)benzimidazole-4-carboxylate (Example 100) (16.15 g, 56.0 mmol) and 2,6-difluorobenzyl bromide (14.67 g, 70.86 mmol, 125 M %) were reacted. The crude product was purified using flash chromatography eluting with 2% methanol/CH2Cl2 and recrystallization from diethylether, yielding white crystals of methyl 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-4-carboxylate (17.63 g, 42.55 mmol, 76% yield). M.p. 184-186° C. 1H NMR (200 MHz, CD2Cl2): δ 7.94 (dd, J=1.1, 7.6 Hz, 1H, H5), 7.72 (dd, J=1.1, 8.2 Hz, 1H, H7), 7.56 (m, 1H, H4′), 7.37 (dd, J=7.6, 8.2 Hz, 1H, H6), 7.26 (m, 1H, H4″), 7.09 (m, 2H, H3′,5′), 6.82 (m, 2H, H3″,5″), 5.39 (s, 2H, CH2PhF2), 3.95 (s, 3H, CO2CH3).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[CH3:11][C:12](=[CH:15]OCC)[CH:13]=O>>[CH3:15][C:12]1[CH:11]=[N:1][C:2]2[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=2[CH:13]=1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: CCOC=C(C)C=O
Product: Cc1cnc2c(c1)C(=O)CC(C)(C)C2
Yield: 60.8 %

Procedure:
A mixture of 3-amino-5,5-dimethylcyclohex-2-enone (27.8g., 0.2 mol.) and 2-methyl-3-ethoxyacrolein (22.8 g., 0.2 mol.), in an apparatus equipped for downward distillation, was heated in an oil bath at 120° until the theoretical quantity of distillate was collected (13 ml.) The cooled residue was diluted with 2N HCl (50 ml.), extracted with ethyl acetate (3 × 50 ml.) and the combined extracts discarded. The aqueous solution was adjusted to pH 9.0 with sodium carbonate and extracted with ethyl acetate (3 × 50 ml.). The combined extracts were dried (MgSO4) and the solvent removed in vacuo and the residual oil distilled to give the title compound as a colourless oil (23 g., 53%) b.p. 83°/0.2 mm Hg. (RT = 2 min., 2% OV17, T=150° C).
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH2:17][O:18][C:19]([O:21]C1C=CC=CC=1)=O)=[C:12]2[N:28]1[CH:32]=[CH:31][N:30]=[CH:29]1)=[O:5].[CH3:38][NH2:39]>CO>[Cl:1][C:2]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH2:17][O:18][C:19](=[O:21])[NH:39][CH3:38])=[C:12]2[N:28]1[CH:32]=[CH:31][N:30]=[CH:29]1)=[O:5]
Reactant: CN
Reactant: O=C(OCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1-n1ccnc1)Oc1ccccc1
Solvent: CO
Product: CNC(=O)OCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1-n1ccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8-(2,6-dichlorobenzoylamino)-3-(phenoxycarbonyloxymethyl)-4-(imidazol-1-yl)quinoline (100 mg) in methanol (4 ml) was dropwise added a solution of 2M solution of methylamine in methanol (4 ml) under ice-cooling, and the mixture was stirred for 1 hour at ambient temperature. The mixture was concentrated in vacuo, and the residue was crystallized from ethanol to give 8-(2,6-dichlorobenzoylamino)-4-(imidazol-1-yl)-3-(methylcarbamoyloxymethyl)quinoline (50 mg).