Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]#[N:8].[Cl:9][CH2:10][C:11]#N.[ClH:13]>O1CCOCC1>[Cl:13][C:7]1[C:6]2[CH:5]=[CH:4][S:3][C:2]=2[N:1]=[C:11]([CH2:10][Cl:9])[N:8]=1
Reactant: Cl
Reactant: N#CCCl
Reactant: N#Cc1ccsc1N
Solvent: C1COCCO1
Product: ClCc1nc(Cl)c2ccsc2n1
Temperature: 2 °C
Reaction time: 15 h

Procedure:
1. 17.3 g of 2-aminothiophene-3-carbonitrile are dissolved in 150 ml of dioxan. 13.3 g of chloroacetonitrile are added thereto, the mixture is cooled to 2° C., hydrogen chloride is introduced for 7 h. and the mixture is subsequently stirred at room temperature for 15 h. The reaction mixture is evaporated in a vacuum. The residue is suspended in 500 ml of water and the crystals am filtered off. There are obtained 26.2 g of crude 4-chloro-2-(chloromethyl)thieno[2,3-d]pyrimidine. Pure product of m.p. 66°-68° C. is obtained after recrystallization from hexane.
Reaction SMILES: [CH:1]([C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH3:15])[C:6]([O:16][CH3:17])=[CH:5][CH:4]=1)=[O:2].P([O-])(O)(O)=[O:19].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O1CCCC1.O>[CH2:12]([O:11][C:9]([C:8]1[C:7]([O:14][CH3:15])=[C:6]([O:16][CH3:17])[CH:5]=[CH:4][C:3]=1[C:1]([OH:19])=[O:2])=[O:10])[CH3:13]
Reactant: O=P([O-])(O)O
Reactant: CCOC(=O)c1c(C=O)ccc(OC)c1OC
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(=O)O)ccc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
A solution of ethyl 6-formyl-2,3-dimethoxybenzoate (5.24 g, 22 mmol), sodium dihydrogen phosphate (3.60 g, 30 mmol) and 2-methyl-2-butene (10.3 ml, 96.8 mmol) in t-butanol (20 ml), tetrahydrofuran (20 ml) and water (20 ml) was stirred at room temperature for 10 min. To the obtained mixture was added sodium chlorite (6.76 g, 74.8 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-n-hexane to give 2-(ethoxycarbonyl)-3,4-dimethoxybenzoic acid (4.51 g, 80.7%) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SiH:8]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[O:9]C(C)C)=[CH:4][CH:3]=1.[Na].[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.[CH3:26]COCC>CN(C)C=O.C(OCC)(=O)C>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([Si:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([OH:9])[CH2:26][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)=[CH:18][CH:17]=1
Reactant: CCOCC
Reactant: CC(C)O[SiH](c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O[Si](Cn1ccnc1)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 19 %

Procedure:
A mixture of 5.5 g (15.3 mmol) of chloromethyl[bis(4-chlorophenyl](2-propoxy)silane and 1.5 g (17 mmol) of imidazole sodium salt in dimethylformamide was warmed to 80° to 90° for 2 hours, cooled, diluted with ethyl acetate, washed three times with water and once with brine, dried over magnesium sulfate, and evaporated to leave a viscous oil. Trituration with ether gave 1.0 g (19%) of the title compound as a colorless solid: m.p. 131°-133°; nmr (CD3SOCD3) 4.1 (2H, s), 6.8 (1H, s), 6.9 (1H, s), 7.4 (4H, d), 7.6 (5H, d).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22]Cl)([C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[C:31]1([CH3:37])C=CC=CC=1>O>[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][O:4][C:5]([O:20][CH2:21][CH2:22][N:28]2[CH2:37][CH2:31][N:25]([CH3:24])[CH2:26][CH2:27]2)([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])[CH2:27][CH2:26]1
Reactant: O=C(c1ccccc1)C(OCCCl)(OCCCl)c1ccccc1
Reactant: CN1CCNCC1
Reactant: Cc1ccccc1
Solvent: O
Product: CN1CCN(CCOC(OCCN2CCN(C)CC2)(C(=O)c2ccccc2)c2ccccc2)CC1

Procedure:
With stirring, 23.6 g (0.067 mole) of benzil-di-(2-chloroethyl)ketal and 120 g (1.2 moles) of N-methylpiperazine are kept for 3 hours at 95° C. After cooling, 250 ml of toluene are added and the reaction mixture is poured into water. The aqueous layer is extracted with toluene and the toluene layer is subsequently washed neutral with water. The toluene layer is dried over Na2SO4, concentrated and dried in a high vacuum.
Reaction SMILES: [Pd:1].[N+:2]([O-:5])([OH:4])=[O:3]>>[N+:2]([O-:5])([O-:4])=[O:3].[Pd+2:1].[N+:2]([O-:5])([O-:4])=[O:3]
Reactant: O=[N+]([O-])O
Reactant: [Pd]
Product: O=[N+]([O-])[O-]
Product: [Pd+2]
Reaction time: 8 h

Procedure:
An organic liquid solution of palladium nitrate was prepared by dissolving 350 g of palladium metal in 500 mL of commercially available concentrated nitric acid. The reaction was stirred overnight and any unreacted metal was removed by filtration. The solution was then standardized. The palladium concentration was determined by weighing a 1 mL aliquot of solution and then firing the aliquot at 1000° C. for 15 minutes. After cooling, the residual metal was weighed and the percent metal of the solution was determined as well as the molarity. The hydrogen ion concentration was determined by complexing the palladium ions with an added 5 g of sodium chloride to a 1 mL aliquot of solution. The hydrogen ions were then titrated with 0.1 molar solution of sodium hydroxide using a pH meter to indicate the endpoint. In a typical experiment, the palladium concentration was about 3.5 molar and the acid concentration was about 1 to 2 molar.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:27][C:26]2[N:22]([C:23]([C@H:28]3[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]3)=[N:24][N:25]=2)[C:21]2[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:20]=2[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:27][C:26]2[N:22]([C:23]([CH:28]3[CH2:29][CH2:30][C:31](=[O:34])[CH2:32][CH2:33]3)=[N:24][N:25]=2)[C:21]2[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:20]=2[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](O)CC2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCC(=O)CC2)C1
Temperature: -50 °C
Reaction time: 0.08 h
Yield: 89.4 %

Procedure:
To a solution of oxalyl chloride (0.11 ml, 1.3 mmol) in dichloromethane (8 ml) was added dimethylsulfoxide (0.21 ml, 2.6 mmol) at −60° C. The mixture was stirred for 5 minutes at −50° C. A solution of cis/trans-8-chloro-1-(4-hydroxy-cyclohexyl)-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester (0.046 g, 1.1 mmol) in dichloromethane (3 ml) was added at −65° C. Stirring for 30 minutes was followed by addition of triethylamine (0.77 ml, 5.5 mmol). The cooling bath was removed 5 minutes after completed addition, and the reaction mixture was stirred for 1 h. The reaction mixture was washed with one portion of aqueous saturated ammonium chloride solution. The aqueous layer was extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash-chromatography with n-heptane/ethyl acetate as eluent gave the title compound (0.41 g, 90%) as white solid. MS m/e: 417 ([[M+H]]+)
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([C:22]3[N:23](CC4C=CC=CC=4)[N:24]=[N:25][C:26]=3[C:27]([F:30])([F:29])[F:28])=[O:21])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7]>CO.C(O)(=O)C.[Pd]>[CH3:1][CH:2]([CH3:38])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([C:22]3[NH:23][N:24]=[N:25][C:26]=3[C:27]([F:29])([F:28])[F:30])=[O:21])[CH2:18][CH2:19]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3c(C(F)(F)F)nnn3Cc3ccccc3)CC2)nn1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3[nH]nnc3C(F)(F)F)CC2)nn1
Reaction time: 8 h
Yield: 36.3 %

Procedure:
6-[4-(3-benzyl-5-trifluoromethyl-3H-[1,2,3]triazole-4-carbonyl)piperazin-1-yl]pyridazine-3-carboxylic acid (3-methylbutyl)amide (0.4 g, 0.75 mmol) was dissolved in 10 mL of MeOH with 3 drops of acetic acid and 0.2 g of 10% Pd/C was added. The reaction mixture was kept under normal pressure of H2 at ambient temperature overnight. After filtration the reaction mixture was evaporated under reduced pressure and the residue was recrystallized from 3 mL of EtOH to give 120 mg (36% yield) of 6-[4-(5-trifluoromethyl-3H-[1,2,3]triazole-4-carbonyl)-piperazin-1-yl]pyridazine-3-carboxylic acid (3-methylbutyl)amide as a white powder. 1H NMR (500 MHz, Acetone-d6) 88.18, 7.91, 7.32, 3.92-3.72, 3.45, 1.67, 1.52, 0.92.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C@@H:14]([CH2:22][C:23]1[CH:24]=[N:25][C:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:27][CH:28]=1)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(N(CC)CC)C.[NH2:44][C@@H:45]1[CH2:60][C:59]2=[CH:61][CH:62]=[C:56]([CH:57]=[CH:58]2)[O:55][CH2:54][CH2:53][CH2:52][CH2:51][O:50][CH2:49][C@H:48]([CH:63]([CH3:65])[CH3:64])[NH:47][C:46]1=[O:66]>CN(C=O)C>[C:33]([O:32][C:30]([NH:29][C:26]1[N:25]=[CH:24][C:23]([CH2:22][C@H:14]([NH:13][C:1]([NH:44][C@@H:45]2[CH2:60][C:59]3=[CH:58][CH:57]=[C:56]([CH:62]=[CH:61]3)[O:55][CH2:54][CH2:53][CH2:52][CH2:51][O:50][CH2:49][C@H:48]([CH:63]([CH3:64])[CH3:65])[NH:47][C:46]2=[O:66])=[O:2])[C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[CH:28][CH:27]=1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](N)C(=O)N1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C[C@H](N)C(=O)OC(C)(C)C)cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(=O)OC(C)(C)C)C(=O)N1
Reaction time: 8 h

Procedure:
112 mg (0.69 mmol) of 1,1′-carbonyldiimidazole were added to a mixture of 234 mg (0.69 mmol) of tert-butyl (S)-2-amino-3-(6-tert-butoxycarbonylaminopyridin-3-yl)-propionate and 106 μl (77 mg, 0.76 mmol) of triethylamine in 2.5 ml of DMF. The solution was stirred at RT for 1 h, before a solution of 222 mg (0.69 mmol) of (9S,12R)-12-amino-9-isopropyl-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18),15-trien-11-one (1-1E) in 2.5 ml of DMF was added. The mixture was left to stand overnight and then concentrated and partitioned between water and ethyl acetate. The organic phase was separated off, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC. The required fractions were combined, freed of acetonitrile, made slightly alkaline with sodium bicarbonate and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH3:11][Si](C=[N+]=[N-])(C)C.CCOCC>C1C=CC=CC=1.CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1ccc(C(=O)O)nc1
Solvent: CCOCC
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc(N)cn1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
5-Amino-pyridine-2-carboxylic acid 1 (5.4 mmol) is dissolved in benzene:MeOH 3:1 (40 mL) and cooled in an ice-bath to 0° C. To the solution is slowly added 2M TMSCH2N2 in Et2O solution (6.5 mmol). After the addition is complete, the reaction mixture is warmed to it and stirred for 6 h. After removing the solvent in vacuum, methyl 5-aminopicolinate 2 is obtained and used in the next step without further purification. MS (m/z) (M+1)+: 153.1.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[OH-:11].[Na+].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19](N2CCOCC2)C#N)[CH:14]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([CH2:4][C:3]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=2[Cl:1])=[O:11])[CH:14]=1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: N#CC(c1cccnc1)N1CCOCC1
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Product: O=C(Cc1ccc(Cl)cc1Cl)c1cccnc1

Procedure:
125 g of 2,4-dichlorobenzyl chloride are added at room temperature to a mixture of 700 g of 50% sodium hydroxide, 23 g of tetrabutylammonium iodide and 130 g of α-(3-pyridyl)-4-morpholineacetonitrile. After 2 hours the mixture is extracted with diethyl ether. After evaporation of the ether, the crude product, α-(2,4-dichlorobenzyl)-α-(3-pyridyl)-4-morpholineacetonitrile (m.p. 130°-132°), remains behind. The crude product is taken up in 300 ml of concentrated hydrochloric acid and the solution is heated to reflux temperature for 12 hours. The reaction mixture is made basic and extracted with ethyl acetate, and the organic phase is washed, dried over anhydrous sodium sulfate and concentrated. Crystallization from ethyl acetate/n-hexane yields 2,4-dichlorobenzyl 3-pyridyl ketone of melting point 78°-79°.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[N:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].CN(C=O)C.[NH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[OH:30].C(N(CC)CC)C>O>[OH:30][C:21]1[CH:22]=[CH:23][C:24]([C:26]([F:27])([F:28])[F:29])=[CH:25][C:20]=1[NH:19][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][N:10]=[CH:11][C:3]=1[C:2]([F:13])([F:12])[F:1]
Reactant: O=C(Cl)c1ccncc1C(F)(F)F
Reactant: Nc1cc(C(F)(F)F)ccc1O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C(F)(F)F)ccc1O)c1ccncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.72 g of 3-trifluoromethyl isonicotinic acid and 4 ml of thionyl chloride was heated to reflux for 1.5 hours. The reaction mixture was cooled to room temperature, and the reaction mixture was concentrated under reduced pressure to give 3-trifluoromethyl isonicotinic acid chloride. A mixture of the resultant 3-trifluoromethyl isonicotinic acid chloride and 4 ml of DMF was added dropwise to a mixture of 0.66 g of 2-amino-4-trifluoromethylphenol, 0.76 g of triethylamine, 4 ml of DMF while ice-cooling. The reaction mixture was stirred at room temperature for one hour and stirred while heating at 50° C. for 2.5 hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give 0.62 g of N-[2-hydroxy-5-(trifluoromethyl)phenyl]-3-(trifluoromethyl)isonicotinamide.
Reaction SMILES: C(O)CO.[S:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([CH:14](C#N)[C:15]([O:17]C(C)(C)C)=[O:16])[C:8]=2[CH:7]=[CH:6]1.[OH-].[K+].O>C1(C)C=CC=CC=1>[S:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([CH2:14][C:15]([OH:17])=[O:16])[C:8]=2[CH:7]=[CH:6]1
Reactant: CC(C)(C)OC(=O)C(C#N)c1cccc2sccc12
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)Cc1cccc2sccc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To ethylene glycol (1.0 mL) solution of 0.25 g of tert-butyl 2-(1-benzothiophen-4-yl)-2-cyanoacetate were added 1.0 mL of aqueous solution of 40% (w/w) potassium hydroxide and 0.3 mL of water, which was then stirred at 95 to 105° C. for 1 hour. To the reaction mixture were added water and toluene, and the aqueous layer was separated. The pH was adjusted to 2 with 6 mol/L hydrochloric acid, to which was added ethyl acetate. The organic layer was separated, and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. To the resultant residue was added cyclohexane. The precipitate was collected by filtration to provide 0.15 g of 2-(1-benzothiophen-4-yl)acetic acid as white solid form.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([CH2:22][C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)[CH:12]2[C:21]3[N:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1.O.[NH2:34][NH2:35].C(=O)(O)[O-].[Na+]>C(O)C>[NH:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[CH2:22][N:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([NH:34][NH2:35])=[O:2])=[CH:9][CH:8]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1
Reactant: NN
Reactant: COC(=O)c1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Temperature: 80 °C
Yield: 63.2 %

Procedure:
To a stirred solution of 4-{[(1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzoic acid methyl ester (AMD9711) (140 mg, 0.33 mmol) in dry ethanol (3 mL) was added hydrazine monohydrate (0.5 mL, 10.3 mmol) and the resulting mixture was heated at 80° C. for 24 h. Saturated aqueous sodium bicarbonate (5 mL) was added, the phases separated and the aqueous layer extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification of the crude material by radial chromatography (1 mm plate, 75:1:1 CH2Cl2-MeOH-NH4OH) afforded the title compound (89 mg, 61%) as a white solid. 1H NMR (CDCl3) δ1.64-1.68 (m, 1H), 1.94-2.04 (m, 2H), 2.20-2.24 (m, 1H), 2.66-2.72 (m, 1H), 2.78-2.83 (m, 1H), 3.73 (s, 2H), 3.93 (d, 1H, J=16 Hz), 4.00-4.12 (m, 3H), 4.15 (d, 1H, J=16 Hz), 7.14-7.18 (m, 3H), 7.40 (d, 2H, J=8 Hz), 7.50 (br d, 1H, J=7 Hz), 7.58 (d, 2H, J=8 Hz), 7.62 (br d, 1H, J=7 Hz), 8.06 (s, 1H), 8.66 (dd, 1H, J=5, 1 Hz); 13C NMR (CDCl3) δ21.2, 23.6, 29.0, 48.7, 53.7, 60.4, 111.4, 118.4, 121.5, 122.3, 126.9, 128.6, 131.5, 134.7, 137.3, 143.5, 146.8, 155.8, 157.1, 168.4. ES-MS m/z 427 (M+H). Anal. Calcd. for C25H26N6O.0.5CH2Cl2: C, 65.31; H, 5.80; N, 17.92. Found: C, 65.22; H, 5.77; N, 17.97.
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15](Cl)(=[O:18])[CH2:16][CH3:17].C(N(CC)CC)C>O1CCCC1>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:15](=[O:18])[CH2:16][CH3:17]
Reactant: NC1CCc2oc3ccccc3c2C1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 18.9 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol), propionyl chloride (0.47 mL, 5.3mmol), and triethylamine (2.1 mL, 15 mmol) in tetrahydrofuran (20 mL) provided N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-propionamide (0.23 g). Mp 164-165° C.; Anal. Calcd. for C15H17NO2: C, 74.05; H, 7.04; N, 5.76; Found: C, 74.09; H, 7.09; N, 5.78.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]2[NH:13][CH2:12][CH:11]([CH2:14][CH3:15])[O:10]2)[CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.[F:24][C:25]([F:33])([F:32])[CH:26]([CH3:31])[CH2:27][C:28](Cl)=[O:29].[OH-].[Na+]>C(Cl)Cl.O>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]2[N:13]([C:28](=[O:29])[CH2:27][CH:26]([C:25]([F:33])([F:32])[F:24])[CH3:31])[CH2:12][CH:11]([CH2:14][CH3:15])[O:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCC1CNC(c2cccc(C(F)(F)F)c2)O1
Reactant: CC(CC(=O)Cl)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCC1CN(C(=O)CC(C)C(F)(F)F)C(c2cccc(C(F)(F)F)c2)O1
Reaction time: 8 h

Procedure:
Three and eight-tenths grams of 2-(m-trifluoromethylphenyl)-5-ethyl-1,3-oxazolidine was combined with 1.3 g of pyridine in 25 ml of methylene chloride and 2.7 g of 3-trifluoromethylbutyroyl chloride in 10 ml of methylene chloride was added dropwise with stirring. The mixture was allowed to stand overnight and was stand overnight and was worked up with 50 ml of 5% NaOH and 200 ml of water. The mixture was dried and stripped under vacuum on the rotary evaporator. The structure was confirmed by NMR and infrared spectroscopy.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:6][C:7]1[C:16](C(=O)C)=[C:15]2[C:10]([C:11](=[O:27])[C:12]([CH3:26])=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:14]2)=[CH:9][CH:8]=1)[C:4]#[CH:5].[CH:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[CH2:36](O)[CH3:37]>O>[CH3:26][C:12]1[C:11](=[O:27])[C:10]2[C:15](=[C:16]([C:29]3([C:28](=[O:35])[CH:36]=[CH2:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH2:30]3)[C:7]([O:6][CH2:3][C:4]#[CH:5])=[CH:8][CH:9]=2)[O:14][C:13]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCO
Reactant: C#CCOc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(C)=O
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C#CCOc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C1(C(=O)C=C)C=CC=CC1
Temperature: 25 °C

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 7-(prop-2-ynyloxy) -8-acetyl-3-methylflavone (2.49 g, 0.0075 mol) and benzaldehyde (0.8 g, 0.0075 mol) in ethanol 95%. The addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.8 g of product m.p. 157-59° C., 1H-NMR (CDCl3)δ: 2.20 (s, 3H); 2.56 (s, 1H); 4.86 (d, 2H, J=2.2 Hz); 7.05 (d, 1H, J=16 Hz); 7.23 (d, 1H, J=8.9 Hz); 7.31-7.50 (m, 7H); 7.50-7.57 (m, H); 8,34 (d, 1H, J=8.9 Hz).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.[C:14](Cl)(=[O:17])[CH:15]=[CH2:16].O>C(Cl)Cl>[C:14]([O:6][CH2:5][CH2:4][CH2:3][S:2][CH3:1])(=[O:17])[CH:15]=[CH2:16]
Reactant: C=CC(=O)Cl
Reactant: CSCCCO
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCCSC
Temperature: 2.5 °C
Reaction time: 2.5 h
Yield: 60.4 %

Procedure:
To a mixture of 3-methylthio-1-propanol (17) (12.5 g, 117.7 mmol) and triethylamine (17.8 g, 177.0 mmol) in dry CH2Cl2 (110 mL) cooled in an ice bath (0-5° C.), a solution of acryloyl chloride (21.3 g, 235.0 mmol) in dry CH2Cl2 (30 mL) was added drop-wise with stirring over a period of 2.5 hours. The reaction mixture was warmed to a room temperature, and then diluted with more CH2Cl2 (225 mL), and poured into water (250 mL). The CH2Cl2 layer was washed with saturated aqueous NaHCO3 solution (2×175 mL), and water (2.225 mL). Evaporation of the dried (Na2SO4) organic layer gave a yellow oil. Purification by column chromatography, (silica gel, hexanes, 10 wt % ether/hexanes) produced a clear oil compound 18 (11.4 g, 60 wt %), namely 3-methylthio-1-propyl acrylate (18).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1>C(O)C.C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[NH:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1
Reactant: COC(=O)CC[C@H](NC(=O)c1ccc(OCc2ccccc2)cc1)C(=O)OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)CC[C@H](NC(=O)c1ccc(O)cc1)C(=O)OC
Temperature: 22 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
To a solution of 5.0 g of N-(4-benzyloxybenzoyl)-L-glutamic acid dimethyl ester in 175 ml ethanol and 25 ml ethyl acetate were added 0.6 g of 5% Pd/C. The mixture was shaken under a hydrogen atmosphere (3 atm) at 22° C. for 3 hours. The reaction mixture was then filtered through Celite and evaporated to an oil which was dissolved in ethyl acetate and, again, filtered through Celite. The filtrate was evaporated to give 3.8 g of the title compound as an oil: 300-MHz 1H NMR (CDCl3) δ2.10-2.21 (m, 1H), 2.24-2.38 (m, 1H), 2.41-2.58 (m, 2H), 3.65 (s, 3H), 3.79 (s, 3H), 4.76-4.85 (m, 1H), 6.86 (d, J=9 Hz, 2H), 7.11 (d, J=10 Hz, 1H), 7.67 (d, J=9 Hz, 2H), 7.78 (b s, 1H).