Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:13])=[CH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:1][C:2]1([CH3:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:4](=[O:5])[CH2:3]1
Reactant: CC(C)=CC(=O)Nc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC1(C)CC(=O)Nc2ccccc21
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
To 40 g (0.22 mol) of 3-methylcrotonoanilide, heated in the molten state at 130° C., was added 33.4 g (0.25 mol) of aluminum chloride, portionwise, over a 30 minute period. Heating was continued at 130° C. for a further 30 minutes, and then the temperature was lowered to 85° C. and a further 5 g (0.038 mol) of aluminum chloride was added. The temperature was maintained at 85° C. for 1 hour and then the reaction mixture was treated cautiously with 500 g of ice. The resulting mixture was extracted with ether and the ether extracts were dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silicic acid, eluting with ether:hexane (1:2), and the product containing fractions were combined and evaporated in vacuo. This afforded 23.7 g (59% yield) of the title compound, mp 111°-112° C.
Reaction SMILES: C(OC([NH:8][CH:9]([CH3:29])[CH:10]([C:12]1([C:25](OC)=[O:26])[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[OH:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+].O(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O>C(Cl)Cl>[OH:11][CH:10]1[C:12]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:25](=[O:26])[NH:8][CH:9]1[CH3:29]
Reactant: COC(=O)C1(C(O)C(C)NC(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1NC(=O)C2(CCN(C(=O)OC(C)(C)C)CC2)C1O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 1-tert-butyl 4-methyl 4-(2-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)piperidine-1,4-dicarboxylate (8000 mg, 19.2 mmol) in DCM (190 mL) was added TFA (44.4 mL, 576 mmol) at 0° C. and the resulting solution was stirred for 2 h. After removing the volatiles, high vacuum was applied briefly to remove excess TFA, and the residue was dissolved in MeOH (190 mL), and K2CO3 (26.5 g, 192 mmol) was added. The reaction mixture was heated at 60° C. for 2 h. After cooling to room temperature, saturated NaHCO3 solution (60 mL) was added, followed by (BOC)2O (12.6 g, 57.6 mmol). The reaction mixture was stirred overnight, and extracted with DCM. The organic layer was dried with MgSO4, and concentrated to give the crude product, which was purified by column chromatography (0-20% MeOH/DCM, monitored at 210 nM) to give the title compound. LC/MS: [(M+1)]+=285
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH:13]([C:20]([O:22][CH3:23])=[O:21])[C:14]2=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]2[OH:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCc2c(OCc3ccccc3)cccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCc2c(OCc3ccccc3)cccc2C1O
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
A solution of 7.95 g of 5-(benzyloxy)-2-(methoxycarbonyl)-1-tetralone in 80 ml of methanol was ice-cooled and 0.97 g of sodium borohydride was added in five portions. After stirring for 30 minutes, an ice bath was removed and the mixture was further stirred for 30 minutes. The reaction solution was diluted with iced water, extracted with diethyl ether, washed with water and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressured. The residue was purified by silica gel column chromatography to obtain 5.96 g of the desired compound as a colorless oily substance.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10]([C:14]2[NH:19][C:18](=[O:20])[C:17]3=[CH:21][N:22]=[C:23](I)[N:16]3[N:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.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>[CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10]([C:14]2[NH:19][C:18](=[O:20])[C:17]3=[CH:21][N:22]=[C:23]([C:29]4[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=4)[N:16]3[N:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccccc2)CC1c1nn2c(I)ncc2c(=O)[nH]1
Reactant: OB(O)c1ccc(F)cc1
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: [K+]
Solvent: Cc1ccccc1
Product: CC1CN(Cc2ccccc2)CC1c1nn2c(-c3ccc(F)cc3)ncc2c(=O)[nH]1
Temperature: 100 °C
Yield: 86.5 %

Procedure:
To a solution of compound 6 (500 mg, 1.14 mmol) and 4-fluorophenylboronic acid (300 mg, 2.14 mmol) in 30 mL of toluene was added K2CO3 (1.0 g, 7.24 mmol). The resulting mixture was degassed by purging with nitrogen for 15 min, before Pd(PPh3)4 (120 mg, 0.10 mmol) was added. The resulting suspension was bubbled with nitrogen for 10 minutes. The reaction mixture was heated to 100° C. for 18 hours and then cooled to room temperature. After removal of the solvent, the residue was purified by chromatography on silica gel column (eluted with PE/EtOAc=5:1 to 1:2) to afford compound 10 (398 mg, 86% yield) as a white solid. LC-MS: m/z 404.31 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 8.34˜8.31 (m, 2H), 7.95 (s, 1H), 7.38 (m, 4H), 7.31 (m, 1H), 7.16 (m, 2H), 3.85 (d, J=12.4 Hz, 1H), 3.63 (d, J=12.4 Hz, 1H), 3.44˜3.40 (m, 1H). 3.05 (d, J=10 Hz, 1H), 2.84 (m, 1H), 2.61 (m, 1H), 2.50˜2.47 (m, 1H), 1.99 (m, 1H), 1.22 (d, J=6.8 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[OH-].[Na+].C1C=CC=CC=1>CS(C)=O>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([O:11][C:8]2[CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]([OH:1])=[CH:10][CH:9]=2)=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: O=C(O)c1cc(O)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CS(C)=O
Product: O=C(O)c1cc(Oc2ccc([N+](=O)[O-])cc2)ccc1O

Procedure:
77 g of 2,5-dihydroxybenzoic acid and 78.5 g of p-chloronitrobenzene were dissolved in 300 ml of dimethyl sulphoxide under a nitrogen atmosphere, and 40 g of sodium hydroxide and 225 ml of benzene were added to the resulting solution. The mixture was then distilled under reflux at 90° to 95° C on a water separator until no more water was separated off (about 2 hours). The benzene was distilled off in a water jet vacuum, the residue poured into 2.5 liters of water, the mixture acidified with concentrated hydrochloric acid while stirring vigorously, the crude, pale brown 5-(4-nitrophenoxy)-salicylic acid which was precipitated was filtered off under suction and washed acid free with water. Drying in vacuo at 80° C gave 126 g (92% of the theoretical yield) of 5-(4-nitrophenoxy)-salicylic acid, recrystallised from methanol (and active carbon, optionally with a little water added) 120 g (87% of the theoretical) of yellow crystals melting at 193° to 194° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]([NH:10][C:11]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=2)[C:17]([CH3:42])=[C:16]3[CH3:43])=[O:12])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:44]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH3:42][C:17]1[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[C:30]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:25][CH:24]=2)[C:19]2[C:15]([C:16]=1[CH3:43])=[CH:14][C:13]([C:11](=[O:12])[NH:10][C@H:8]([C:4]1[CH:3]=[C:2]([CH3:44])[CH:7]=[CH:6][CH:5]=1)[CH3:9])=[CH:21][CH:20]=2
Reactant: CB1OB(C)OB(C)O1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(Br)c3)cc12
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: [K+]
Solvent: C1COCCO1
Product: Cc1cccc([C@H](C)NC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1
Temperature: 100 °C

Procedure:
A mixture of (S)-tert-butyl 4′-((5-((1-(3-bromophenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (24 mg, 0.038 mmol), trimethylboroxine (10 μL, 0.072 mmol), Pd(PPh3)4 (11 mg, 0.0095 mmol) and K2CO3 (15 mg, 0.11 mmol) in Dioxane (0.7 ml) were heated in a Biotage Microwave reactor at 100° C. for 2 h. The solvent was removed and the residue was purified by reverse phase prep-HPLC (MeOH/Acetonitrile/water) to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH2:21]([O:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Nc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: c1ccc(COc2ccc(Nc3ccccc3)cc2)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 4-hydroxy-N-phenyl-aniline (30 g; 162 mmol) in acetonitrile (400 mL) there are added 58 g of Cs2CO3 (178 mmol) and stirring is carried out for 15 minutes at ambient temperature. Benzyl bromide (22.5 mL; 178 mmol) is then added dropwise and then the reaction mixture is refluxed for 4 hours. After filtering and rinsing with acetonitrile, the filtrate is concentrated and purified by chromatography over silica gel using petroleum ether and ethyl acetate as eluants. The title product is then obtained in the form of a colourless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]=[C:5]([OH:28])[CH2:6][CH:7]([C:9]1[N:10]([CH:25]([CH3:27])[CH3:26])[C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5](=[O:28])/[CH:6]=[CH:7]/[C:9]1[N:10]([CH:25]([CH3:26])[CH3:27])[C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: COC(=O)C=C(O)CC(O)c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)CC(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1 g of crude 5-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxypent-2-enoic acid methyl ester in 50 ml of toluene are introduced into a 100 ml three-necked round-bottomed flask equipped with a magnetic stirrer, thermometer, reflux condenser and nitrogen delivery line, 48 mg (0.025 mmol) of toluene-4-sulfonic acid are added and the mixture is stirred for 4 hours under reflux. The mixture is then cooled to room temperature, washed once with 25 ml of saturated sodium hydrogen carbonate solution and twice with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated by evaporation. The crude product is purified by means of flash chromatography (hexane/ethyl acetate=9:1). An orange resin is obtained which, according to NMR, is the product in a keto-enol equilibrium of approximately 3:1.
Reaction SMILES: B(Br)(Br)Br.[CH:5]1([C:8]2[N:12]=[C:11]([CH:13]=[CH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([O:23]C)[CH:16]=3)[O:10][N:9]=2)[CH2:7][CH2:6]1>ClCCl>[CH:5]1([C:8]2[N:12]=[C:11]([CH:13]=[CH:14][C:15]3[CH:16]=[C:17]([OH:23])[C:18]([OH:21])=[CH:19][CH:20]=3)[O:10][N:9]=2)[CH2:7][CH2:6]1
Reactant: COc1ccc(C=Cc2nc(C3CC3)no2)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(C=Cc2nc(C3CC3)no2)cc1O
Reaction time: 0.62 h

Procedure:
To a cooled solution of 0.79 mL of 1M boron tribromide (0.79 mmol) in 2 mL dichloromethane, 0.1 g (0.34 mmol) of cyclopropyl-5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1,2,4]oxadiazole (compound of Example 36) dissolved in 1 mL of dichloromethane was added, over a period of 15-20 min at −40° C. to −45° C. The reaction mixture was stirred at −40° C. to −45° C. for 30-45 min and allowed to attain 25° C. to 30° C. slowly, over a period of 1 h. The reaction mixture was further stirred at 25° C. to 30° C. for 4-5 h. After the completion of the reaction, the reaction mixture was quenched with 10 mL of chilled 5% sodium bicarbonate solution, below 20° C. (pH: 8-9). 10 mL of ethyl acetate was added to the reaction mass to dissolve the solid and stirred for 10-15 min. The organic layer was separated and the aqueous layer was washed with 10 mL of 10% sodium chloride solution. The organic layer was collected and distilled to obtain a crude material, which was purified by column chromatography (silica gel, chloroform-methanol) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5](OS(C(F)(F)F)(=O)=O)[N:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:20][C:21]1[S:22][CH:23]=[C:24]([CH3:26])[N:25]=1>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:20][C:21]3[S:22][CH:23]=[C:24]([CH3:26])[N:25]=3)[N:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1csc(N)n1
Reactant: O=S(=O)(Oc1nccc2ccc(Cl)nc12)C(F)(F)F
Product: Cc1csc(Nc2nccc3ccc(Cl)nc23)n1

Procedure:
The title compound, MS: m/e=277 (M+H+), was prepared in accordance with the general method of example 1 from trifluoro-methanesulfonic acid 2-chloro-[1,7]naphthyridin-8-yl ester (Example G) and 2-amino-4-methylthiazole.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][CH:20]([C:24]([NH:26][CH2:27][C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=1)=[O:25])[C:21](O)=[O:22]>>[Cl:34][C:32]1[CH:33]=[C:28]([CH:29]=[C:30]([Cl:35])[CH:31]=1)[CH2:27][NH:26][C:24](=[O:25])[CH:20]([CH3:19])[C:21]([NH:1][CH:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:22]
Reactant: CC(C(=O)O)C(=O)NCc1cc(Cl)cc(Cl)c1
Reactant: CN1C(=O)C(N)c2ccccc2-c2ccccc21
Product: CC(C(=O)NCc1cc(Cl)cc(Cl)c1)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
The title compound, MS: m/e=496.2 (M+H+), was prepared in analogy to example 16 from 7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and 2-methyl-N-(3,5-dichloro-benzyl)-malonamic acid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:15])[CH:12]([CH3:14])[CH3:13].[Br:16]Br.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:16][C:12]([CH3:13])([CH3:14])[C:11]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[C:7]([Cl:8])[C:2]=1[Cl:1])=[O:15]
Reactant: COc1ccc(C(=O)C(C)C)c(Cl)c1Cl
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C(=O)C(C)(C)Br)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of 2',3'-dichloro-4'-methoxyisobutyrophenone (45 g., 0.183 mole) in acetic acid (150 ml.) is treated during one-half hour with bromine (30 g., 0.187 mole). The reaction mixture is stirred 10 minutes, then poured into ice water (600 ml.) containing sodium bisulfite (2 g.). The 2-bromo-2',3'-dichloro-4'-methoxyisobutyrophenone (IV) which separate (48 g.) melts at 72°-73°C. after recrystallization from hexane.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:6]=1[C:7]([C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)=[O:8].[OH-].[Na+]>C(O)(=O)C.O>[CH3:1][C:2]1[NH:3][CH:4]=[N:5][C:6]=1[C:7]([C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)=[O:8]
Reactant: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C(=O)c1ccc2cccnc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1[nH]cnc1C(=O)c1ccc2cccnc2c1
Temperature: 25 °C

Procedure:
A solution of (8) in acetic acid/water (12 mL/8 mL) was heated at 110° C. for 1.5 h. The reaction was cooled to room temperature. Crushed ice was added, and basification of reaction with NaOH (s) to pH˜6 was followed. The aqueous layer was extracted with chloroform/isopropanol (3:1, 200 mL). The pooled organic layers were dried over magnesium sulfate. The mixture was filtered, and the solvents were removed under vacuum. The residue was purified by chromatography on silica gel with 3% saturated ammonia methanol in dichloromethane to give (5-methyl-1H-imidazol-4-yl)(quinolin-7-yl)methanone (9) as a white solid (0.53 g, 2.24 mmol, 35% over 3 steps).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[N:19]=[N:20][C:21]([CH2:24][NH2:25])=[CH:22][CH:23]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O.O>[NH2:25][CH2:24][C:21]1[N:20]=[N:19][C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:26])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[CH:23][CH:22]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccc(CN)nn3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2ccc(CN)nn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Yield: 39 %

Procedure:
To a solution of [6-(6-aminomethyl-pyridazin-3-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.28 g, 0.78 mmol) in THF:H2O (1:1, 6 mL) at 0° C. was added a solution of LiOH (0.056 g, 2.35 mmol) in water (1 mL). The solution was allowed to warm to room temperature over 3 hours then acidified to pH 2 with 1N HCl at 0° C. and concentrated in vacuo. The residue was purified by preparative HPLC to give [6-(6-aminomethyl-pyridazin-3-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (0.1 g, 38%). 1H NMR (400 MHz, DMSO): δ 8.78 (brs, 2H), 7.93 (d, J=9.2 Hz, 1H), 7.53 (d, J=9.2 Hz, 1H), 7.34 (s, 1H), 7.09 (s, 1H), 5.51 (d, J=8.8 Hz, 1H), 4.27 (d, J=5.2 Hz, 2H), 3.06 (d, J=14.8 Hz, 1H), 2.28 (s, 3H), 2.16-2.10 (m, 1H). MS (ESI) m/z=330 [M+H]+.
Reaction SMILES: [CH2:1]([N:9]1[C:13](=[O:14])[CH:12]=[CH:11][S:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>C(OCC)C.O1CCCC1>[CH2:1]([NH:9][C:13](=[O:14])/[CH:12]=[CH:11]\[S:10][C:21](=[O:24])[CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCn1sccc1=O
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCNC(=O)/C=C\SC(=O)CC
Temperature: 0 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a cooled (0° C.), stirred solution of 21.3 g (0.10 mol) of 2-octyl-4-isothiazolin-3-one in 400 ml of anhydrous ethyl ether was added dropwise 30 ml (0.03 mol) of a 1.0M solution of lithium aluminum hydride in tetrahydrofuran over a 20 min period. After the addition the mixture was stirred at 0° C. for 1 hr. Over a 15 min period 8.96 ml (0.10 mol) of propionyl chloride was added. After this addition the mixture was allowed to warm to room temperature. After 12 hr the reaction mixture was a white solid suspended in an orange solution. The mixture was filtered and the filtrate was diluted with 300 ml of ethyl acetate and washed once with 300 ml of 10% aqueous hydrochloric acid. The organic layer was set aside and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water until the washes were neutral in pH, washed with brine, and dried over anhydrous magnesium sulfate. Filtration and removal of solvents gave N-octyl-cis-3-(propanoylthio)acrylamide as an oil which crystallized upon standing. These crude crystals were recrystallized from ethyl ether/hexane to give 16 g (59% yield) as white crystals, m.p. 68°-70° C., and is reported in Table 1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.B.C1COCC1.[Li]C(C)(C)C.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH:30]=[O:31])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH:30]([OH:31])[C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: c1cocn1
Agent: B
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ncco2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
To a solution of oxazole (420 mg, 6.08 mmol) in THF (15 mL) was added BH3-THF (1.0M in THF, 6.69 mL, 6.69 mmol). The mixture was stirred at room temperature for 1 hour. After cooling to −78° C., t-BuLi (1.7M, 4.29 mL, 7.30 mmol) was introduced to the mixture and stirred at this temperature for 30 min. 4-Formyl-piperidine-1-carboxylic acid tert-butyl ester (1.30 g, 6.08 mmol) was added dropwise and the mixture was stirred at −78° C. for 3 hours. Work-up and purification gave 4-(hydroxy-oxazol-2-yl-methyl)-piperidine-1-carboxylic acid tert-butyl ester as a white foam (1.227 g, 71%).
Reaction SMILES: N[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.N([O-])=O.[Na+].O(CC)C([S-])=[S:18].[K+]>Cl.O>[SH:18][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCOC(=S)[S-]
Reactant: Nc1cnc2ccccc2c1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: Sc1cnc2ccccc2c1
Temperature: 0 °C

Procedure:
Compound 2.1 was prepared by a modification of the published procedure of Albert and Barlin (J. Chem. Soc. 2384-2396 (1959)). 3-Aminoquinoline (15.0 g, 105 mmol) was suspended in a mixture of 10N HCl (40 mL), ice (21 g) and water (100 mL) at 0-5° C., before sodium nitrite (7.6 g, 110 mmol) was added slowly. The mixture was then added portionwise to another solution of potassium ethyl xanthate (20.8 g, 125 mmol) in water (60 mL) at 45° C. The mixture was heated for 1 h before cooling off. The mixture was then extracted with ether. The ethereal solution was washed with 2N NaOH solution, water, and brine before drying over magnesium sulfate. After filtration, the removal of the solvent gave a brown oil (15 g), which was then dissolved in ethanol (150 mL) and refluxed with KOH (25 g) under nitrogen overnight. The ethanol solvent was then removed under vacuum, and the residue was separated between water and ether. The ethereal solution was discarded. The aqueous solution was acidified to pH=˜4, before it was extracted with ether. Then ethereal solution was washed with brine, dried over magnesium sulfate, filtered and concentrated under vacuum to give crude product (7.5 g) as a brown oil. Subsequent flash chromatography with eluent (0%-5%-10% ethyl acetate/dichloromethane) produced 3-mercaptoquinoline (2.1) (5.35 g, 32% yield) as a solid. 1H NMR (DMSO) δ 9.02 (1H, d, J=2.3 Hz), 8.63 (1H, d, J=2.2 Hz), 7.95-8.05 (2H, m), 7.75-8.02 (1H, m), 7.60-7.67 (1H, m).
Reaction SMILES: [CH3:1][CH:2]([N:11]1[C:15](=[O:16])[CH:14]=[C:13](Cl)[NH:12]1)[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([Cl:10])[CH:4]=1.[NH3:18]>C(O)C>[NH2:18][C:13]1[NH:12][N:11]([CH:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([CH3:9])=[C:5]([Cl:10])[CH:4]=2)[C:15](=[O:16])[CH:14]=1
Reactant: N
Reactant: Cc1ccc(C(C)n2[nH]c(Cl)cc2=O)cc1Cl
Solvent: CCO
Product: Cc1ccc(C(C)n2[nH]c(N)cc2=O)cc1Cl
Temperature: 150 °C

Procedure:
0.2 mol of 1-(α-methyl-3-chloro-4-methylbenzyl)-3-chloropyrazol-5-one was dissolved in 100 ml of ethanol, 17 g of ammonia were added and the mixture was heated to 150° C for 2 hours in a stirred autoclave. After concentrating the reaction solution, the crude product was obtained. It was recrystallized twice from ethanol.