Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].C([N-]C(C)C)(C)C.[Li+].CON(C)[C:28](=[O:44])[CH:29]([O:42][CH3:43])[C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>C1COCC1>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:28](=[O:44])[CH:29]([O:42][CH3:43])[C:30]3[CH:31]=[CH:32][C:33]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[CH:34][CH:35]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)o2)cc(OC)c1Br
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 59 %

Procedure:
To a solution of 2-(4-bromo-3,5-dimethoxyphenyl)furan (0.203 g, 0.72 mmol) in anhydrous THF (2 mL) under argon in an oven-dried flask cooled to −78° C. was added a solution of lithium diisopropylamide (2.0 M in THF/heptane/ethylbenzene; 0.4 mL, 0.8 mmol) dropwise. After stirring for 35 min at −78° C., a solution of N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide (0.315 g, 1.1 mmol) in THF (2 mL) was added dropwise. After stirring for 25 min, the mixture was allowed to warm to room temp while stirring for 2 hrs. The reaction was quenched with the addition of saturated aqueous NH4Cl then brine and EtOAc were added. The layers were separated and the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography (35-65% EtOAc-hexanes) provided an oil that was triturated with MeOH-Et2O (1:1) with sonication. The solid was collected on a Büchner, rinsed with MeOH-Et2O (1:1) and dried in vacuo to give 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanone as a yellow solid. A second batch was collected from MeOH-Et2O (˜10%) to give additional product (0.220 g total, 59% yield). MS: m/z 516.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].[Br:12]Br>C(Cl)(Cl)(Cl)Cl>[Br:12][C:8]1[C:3]([O:2][CH3:1])=[C:4]([OH:11])[C:5]([O:9][CH3:10])=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: COc1cccc(OC)c1O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)c(OC)c1O
Reaction time: 2 h
Yield: 66.1 %

Procedure:
To a stirring solution of 2,6-dimethoxy-phenol (2 g, 12.98 mmol) in CCl4 (70 mL) at −10° C. was added bromine (2.07 g, 12.98 mmol) and stirred for 2 h. The reaction mixture was diluted with CCl4, washed with water and the combined CCl4 layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 3-Bromo-2,6-dimethoxy-phenol as a solid (2 g, 66%).
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[S:4].[CH:6]([CH:8]([CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[N:19][CH:20]=1)[C:9](OCC)=O)=[O:7]>C(O)C>[N:17]1[CH:16]=[C:15]([CH2:14][C:8]2[C:6](=[O:7])[NH:2][C:3](=[S:4])[NH:5][CH:9]=2)[CH:20]=[N:19][CH:18]=1
Reactant: CCOC(=O)C(C=O)Cc1cncnc1
Reactant: NC(N)=S
Agent: [Na]
Solvent: CCO
Product: O=c1[nH]c(=S)[nH]cc1Cc1cncnc1
Reaction time: 18 h
Yield: 33.7 %

Procedure:
Sodium (0.25 g) was dissolved in ethanol (5 ml), thiourea (0.77 g) added, and the mixture stirred under reflux for 1 hour. A solution of ethyl 2-formyl-3-(5-pyrimidyl)propionate (1.99 g) in ethanol (5 ml) was added slowly, and reflux continued for 18 hours. The solvent was evaporated, and the residue taken up in water and washed with dichloromethane. The aqueous solution was acidified to pH 5, and the precipitate filtered off, washed with water and dried to obtain 5-(pyrimid-5-ylmethyl)-2-thiouracil (0.71 g). 1H-NMR (d6-DMSO) δ3.58 (2H,s), 7.54 (1H,s), 8.70 (2H,s) and 9.02 (1H,s). MPt 265-6° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].O1[CH2:8][CH2:7][CH2:6][CH2:5]1.[C:9](=[S:11])=[S:10].C(Cl)C=CC>O>[CH2:5]([S:10][C:9](=[S:11])[N:2]([CH3:3])[CH3:1])[CH:6]=[CH:7][CH3:8]
Reactant: S=C=S
Reactant: CNC
Reactant: C1CCOC1
Agent: CC=CCCl
Solvent: O
Product: CC=CCSC(=S)N(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
12.0 Grams of a 50% dimethylamine aqueous solution was added to 30 ml of tetrahydrofuran, and to this mixture being maintained a temperature at 0°-5° C., was added dropwise 5.0 gr of carbon disulfide under agitation over the period of 30 minutes. Thereafter, the reaction mixture was maintained at a room temperature and further 5.4 gr of crotyl chloride was added dropwise thereto over the period of 30 minutes, and this was followed by 3-hour agitation at the same temperature to complete the reaction. The reaction mixture was poured into water and the separated organic substance was extracted twice with 30 ml of toluene, washed with diluted hydrochloric acid and further washed with water, and then toluene was removed by distillation to obtain 10.2 gr of the desired product having the following physical properties.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[C:15]([NH:18][C@H:19]([C:27](O)=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:17])[CH3:16].CN1CCOCC1>CC(N(C)C)=O.CN(C)C=O>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH:6][C:27](=[O:28])[C@H:19]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[NH:18][C:15](=[O:17])[CH3:16]
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(C)=O
Temperature: 0 °C
Reaction time: 12 h
Yield: 84.6 %

Procedure:
0.38 g of L-phenylalanine methyl ester hydrochloride (1.8 mmol), 0.37 g of N-acetyl-L-phenylalanine (1.7 mmol) and 1.6 ml of N-methylmorpholine (14.6 mmol) are dissolved in 30 ml of dimethylacetamide and cooled to 0° C. 1.2 ml of CPA from example 2 (50% in dimethylformamide, 1.9 mmol) are then added. The mixture is stirred at 0° for another 1 h and at room temperature for 12 h. The solution is concentrated by evaporation and extracted with ethyl acetate and 1N HCl solution, sat. NaHCO3, sat. NaCl and dist. water. The organic phase is dried over magnesium sulfate, filtered off and concentrated by evaporation. 0.53 g of the white N-acetyl-L-phenylalaninyl-L-phenylalanine methyl ester is obtained (84%).
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.C1(C)[C:11]([S:16]([O:19][C:20]2[CH2:26][CH:25]3[N:22]([C:23](=[O:27])[CH2:24]3)[C:21]=2[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])(=[O:18])=[O:17])=CC=CC=1>>[CH3:11][S:16]([O:19][C:20]1[CH2:26][CH:25]2[N:22]([C:23](=[O:27])[CH2:24]2)[C:21]=1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])(=[O:17])=[O:18]
Reactant: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1
Agent: CS(=O)(=O)OS(C)(=O)=O
Product: CS(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1

Procedure:
By substituting an equivalent amount of methanesulfonic anhydride for p-toluenesulfonic anhydride of Example 18, benzyl 3-methanesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate is obtained. Hydrogenolysis of this material by the method described in Example 19 affords sodium 3-methanesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([OH:6])=[O:5].[CH2:20](Br)[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22].C(N(CC)CC)C>C(OCC)(=O)C>[OH:1][CH:2]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][C:4]([O:6][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22])=[O:5]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCCCCCCCCCCCCC(O)CC(=O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCC(O)CC(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a suspension of (±)-3-hydroxyhexadecanoic acid (500 mg, 1.84 mmol) in ethyl acetate (3.6 ml) were added phenacyl bromide (421 mg, 2.12 mmol) and triethylamine (294 mg, 2.12 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was washed with water, saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then dried over magnesium sulfate. Magnesium sulfate was filtered off and the filtrate was concentrated under reduced pressure to obtain 678 mg of the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][NH:54][CH2:55][CH:56]([C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=2)[F:57])=[CH:51][CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:66]=[CH:65][C:52]([CH2:53][N:54]([CH2:55][CH:56]([C:58]2[CH:59]=[CH:60][C:61]([Cl:64])=[CH:62][CH:63]=2)[F:57])[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:51][CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)c1ccc(CNCC(F)c2ccc(Cl)cc2)cc1
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CC(F)c2ccc(Cl)cc2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 22.6 %

Procedure:
To a solution of 15 mg (0.08 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 24 mg of TBTU (0.08 mmol) in 1.5 ml DMF, were added 0.066 ml (0.38 mmol) of N,N-diisopropylethyl amine in 1 ml DMF. After stirring for 5 min at rt, 25 mg (0.08 mmol) of [rac]-(4-tert-butyl-benzyl)-[2-(4-chloro-phenyl)-2-fluoro-ethyl]-amine were added. After stirring for 17 h at rt, the reaction mixture was diluted with 40 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; heptane/EtOAc 4:1) to give 9 mg (21%) of a light yellow solid. MS (ISP): 497.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:10]=CC(S(C)(=O)=O)=C[C:3]=1C(O)=O.[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([OH:27])=[O:26])=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].IC(C)C>C(O)(C)C>[Cl:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH:2]([CH3:10])[CH3:3])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18]([OH:20])=[O:19]
Reactant: O=C(O)c1cc(S(=O)O)ccc1Cl
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Solvent: CC(C)I
Solvent: CC(C)O
Product: CC(C)S(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Yield: 42 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 2-Chloro-5-methanesulfonyl-benzoic acid from 2-Chloro-5-sulfino-benzoic acid and 2-iodopropane in 20 ml isopropanol/20 ml water and obtained in 42% yield. MS (m/e): 261.1 (MH−, 100%).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:31])[N:10]([C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][CH3:29])=[O:27])=[CH:20][C:19]=2[OH:30])[CH:15]=[CH:16][CH:17]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(O)(=O)C>CO.C(OCC)(=O)C.[Pd]>[CH2:1]([NH:8][C:9](=[O:31])[N:10]([C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][C:19]=2[OH:30])[CH:15]=[CH:16][CH:17]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C/C(=O)OC)cc2O)c1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Yield: 50.7 %

Procedure:
A solution of 5.89 g (13.87 mmol, 1 eq) of methyl (E)-3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]acrylate in 10 ml of methanol and 10 mL of ethyl acetate in the presence of 3 mL of acetic acid and 1.0 g (17% by mass) of 10% palladium-on-charcoal is stirred for 12 hours at room temperature under a hydrogen atmosphere. The palladium is filtered off through Celite and the solvents are evaporated off. The residue is chromatographed on silica gel (7/3 heptane/ethyl acetate) and crystallized from pentane. 3.0 g of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate are obtained in solid form. Yield=60%
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][Br:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: BrCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCCCCCCCCCCCCCBr)cc2)cc1
Yield: 70.1 %

Procedure:
An acetone solution of 90 m moles(21.8 g) of 4'-hydroxybiphenyl-4-carboxylic acid ethyl ester obtained in Example 24, 0.15 mole(57.6 g) of 1,16-dibromohexadecane, and 0.4 mole(55.3 g) of potassium carbonate was refluxed for four hours. The reaction solution was filtered. The filtrate was concentrated, and then purified by column chromatography to obtain 34.4 g of 4'-(16-bromohexadecyloxy)biphenyl-4-carboxylic acid ethyl ester. (yield: 70%)
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)=[O:28].[CH3:37][NH:38][CH3:39]>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][C:27](=[O:28])[N:2]([CH3:1])[C@H:3]2[CH2:4][CH2:5][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:38]([CH3:39])[CH3:37])[CH2:7][CH2:8]2)=[CH:31][CH:32]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CNC
Reactant: CN[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCCCC[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1

Procedure:
In analogy to examples 29.10 and 29.11, trans-Methansulfonic acid 5-(4-methyl amino-cyclohexyl)-pentyl ester.Trifluoroacetic acid salt and 4-chlorophenyl chloroformate were reacted, followed by treatment with dimethylamine to give trans-Methyl-{4-[5-(dimethylamino)-pentyl]-cyclohexyl}-carbamic acid 4-chloro-phenyl ester, MS: 381 (MH+, 1Cl).
Reaction SMILES: [Cl:1][C:2](=[CH2:6])[C:3]([OH:5])=[O:4].CS(O)(=O)=O.[CH3:12][C:13](=[CH2:15])[CH3:14].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2](=[CH2:6])[C:3]([O:5][C:13]([CH3:15])([CH3:14])[CH3:12])=[O:4]
Reactant: C=C(Cl)C(=O)O
Reactant: C=C(C)C
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=C(Cl)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 30 h

Procedure:
32 g of α-chloroacrylic acid was dissolved in 600 ml of dichloromethane and, to this, 20 ml of methanesulphonic acid and 300 ml of isobutylene were added at −5° C. After stirring for 30 hours at room temperature, the reaction liquid was poured into 500 ml of saturated aqueous sodium bicarbonate solution and the dichloromethane layer separated off. After drying with anhydrous sodium sulphate, the solvent was distilled off and t-butyl α-chloroacrylate obtained. 10 g of the t-butyl α-chloroacrylate obtained plus 200 mg of azobisisobutyronitrile were dissolved in 100 ml of toluene and reaction carried out at 80° C. Poly-t-butyl α-chloroacrylate was obtained. The molecular weight of the copolymer obtained determined by gel permeation chromatography (GPC) was, by polystyrene conversion, a number average molecular weight of 215,000 and a weight average molecular weight of 537,000. The polymer obtained was irradiated with an electron beam, and the value of the main chain scission efficiency Gs calculated from the number average molecular weight determined by GPC was 3.8.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].S(O)(O)(=O)=O.[NH2:18][C:19]1[NH:20][CH:21]=[CH:22][N:23]=1.CCN(C(C)C)C(C)C.[CH3:33][C:34]1[C:35]([CH2:41][N:42]([CH2:49][C:50]2[C:55]([CH:56]([CH3:58])[CH3:57])=[CH:54][CH:53]=[CH:52][N:51]=2)[CH:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[N:36][CH:37]=[C:38]([CH3:40])[CH:39]=1>CN(C=O)C>[NH:20]1[CH:21]=[CH:22][N:23]=[C:19]1[NH:18][C:1]([N:46]1[CH2:47][CH2:48][CH:43]([N:42]([CH2:41][C:35]2[C:34]([CH3:33])=[CH:39][C:38]([CH3:40])=[CH:37][N:36]=2)[CH2:49][C:50]2[C:55]([CH:56]([CH3:58])[CH3:57])=[CH:54][CH:53]=[CH:52][N:51]=2)[CH2:44][CH2:45]1)=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cnc(CN(Cc2ncccc2C(C)C)C2CCNCC2)c(C)c1
Reactant: Nc1ncc[nH]1
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc(CN(Cc2ncccc2C(C)C)C2CCN(C(=O)Nc3ncc[nH]3)CC2)c(C)c1
Temperature: 60 °C
Reaction time: 22 h
Yield: 10.1 %

Procedure:
A solution of 1,1′-carbonyldiimidazole (0.1054 g, 0.65 mmol), 2-aminoimidazole sulfate (0.0859 g, 0.65 mmol), and DIPEA (0.45 mL, 2.60 mmol) in DMF (7 mL) was stirred at room temperature for 4 hours. (3,5-Dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine (0.2301 g, 0.65 mmol) was added and stirred at 60° C. for 22 hours, then concentrated. Saturated NaHCO3 (15 mL) was added and extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. Purification of the crude material by column chromatography on silica gel (50:1:1 CH2Cl2-MeOH—NH4OH) followed by radial chromatography on silica (100:1:1 CH2Cl2-MeOH—NH4OH) provided 30.2 mg (10%) COMPOUND 348 as a yellow solid. 1H NMR (CDCl3) δ 0.93 (d, 6H, J=9.0 Hz), 1.61-1.72 (m, 2H), 1.93 (d, 2H, J=11.1 Hz), 2.16 (s, 3H), 2.28 (s, 3H), 2.68-2.79 (m, 4H), 3.80 (d, 4H, J=18.3 Hz), 4.33 (d, 2H, J=12.9 Hz), 6.70 (s, 2H), 7.12-7.16 (m, 1H), 7.24 (s, 1H), 7.50 (d, 1H, J=7.5 Hz), 8.18 (s, 1H), 8.32 (d, 1H, J=4.5 Hz). 13C NMR (CDCl3) 18.29, 18.46, 23.60, 27.39, 27.59, 44.78, 54.32, 57.40, 123.16, 132.26, 133.21, 133.85, 139.06, 144.40, 145.46, 146.07, 146.64, 154.49, 155.70, 156.31. ES-MS m/z 463.1 (M+H). Anal. Calcd. for C26H35N7O.0.3CH2Cl2: C, 64.85; H, 7.37; N, 20.13. Found: C, 64.72; H, 7.63; N, 19.74.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([NH2:16])[S:8][C:7]=1[NH2:17])=[O:5])[CH3:2].[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O.FC(F)(F)C(O)=O>C(O)(C)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([N:16]=[CH:23][C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)[S:8][C:7]=1[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N)sc(N)c1C(=O)OCC
Reactant: O=Cc1cccs1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(N)sc(N=Cc2cccs2)c1C(=O)OCC
Yield: 81 %

Procedure:
In a round bottom flask (50 mL), 2,5-diamino-thiophene-3,4-dicarboxylic acid diethyl ester (50 mg) was added to 20 mL isopropanol to which was added 2-thiophenecarboxaldehyde (24 mg) and a catalytic amount of trifluoroacetic acid (TFA). The mixture was refluxed for 20 hours. Complete removal of the solvent provides an orange solid which was purified by flash chromatography (SiO2), yielding the title compound as an orange solid (81%). M.p.: 114°-116° C. 1H-NMR (300 MHz, [D] acetone): δ=8.24 (s, 1H), 7.63 (d, 1H, 3J=5.0 Hz), 7.52 (dd, 1H, 3J=3.7 Hz and 4J=0.7 Hz), 7.48 (s, 2H), 7.14 (dd, 1H, 3J=5.0 Hz and 3.7 Hz), 4.32 (q, 2H, 3J=7.2 Hz), 4.19 (q, 2H, 3J=7.1 Hz), 1.37 (t, 3H, 3J=7.1 Hz), 1.26 (t, 3H, 3J=7.1 Hz). 13C-NMR (300 MHz, [D] acetone): δ=165.0, 164.3, 161.1, 161.0, 146.1, 143.2, 132.8, 132.1, 130.5, 128.4, 101.8, 61.0, 60.0, 14.3, 14.1.
Reaction SMILES: [CH:1]([S:4]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)=[O:5])([CH3:3])[CH3:2].[CH2:11]([N:14]([CH2:18][CH2:19][CH3:20])[C:15](Cl)=[O:16])[CH2:12][CH3:13].O1CCCC1>C(N(CC)CC)C>[CH2:11]([N:14]([CH2:18][CH2:19][CH3:20])[C:15]([N:8]1[CH:9]=[N:10][C:6]([S:4]([CH:1]([CH3:3])[CH3:2])=[O:5])=[N:7]1)=[O:16])[CH2:12][CH3:13]
Reactant: CC(C)S(=O)c1nc[nH]n1
Reactant: CCCN(CCC)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)n1cnc(S(=O)C(C)C)n1

Procedure:
A mixture of 6.4 g. 3-isopropylsulphinyl-1,2,4-triazole, 8.0 ml. dipropylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 10 ml. dry triethylamine was refluxed under anhydrous conditions for 2 hours. The cooled reaction mixture was filtered and the filtrate distilled under reduced pressure to give 1-dipropylcarbamoyl-3-isopropylsulphinyl-1,2,4-triazole as an oily residue which subsequently solidified, m.p. 15° - 20°C. Elemental analysis satisfactory.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[CH2:14][CH2:15][CH3:16].ClC1C2C(=CC=CC=2)N=CC=1NC=O.Cl.[C:33]1([O:39][NH2:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl.C(ON)C>C(O)(C)C>[O:39]([N:40]1[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=[C:13]1[CH2:14][CH2:15][CH3:16])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NOc1ccccc1
Reactant: CCCC(=O)Nc1cnc2ccccc2c1Cl
Agent: CCON
Agent: Cl
Agent: O=CNc1cnc2ccccc2c1Cl
Solvent: CC(C)O
Product: CCCc1nc2cnc3ccccc3c2n1Oc1ccccc1
Yield: 37.2 %

Procedure:
The method of Part B of Example 20 was followed using N-(4-chloroquinolin-3-yl)butyramide (3.5 g, 14 mmol) in lieu of 4-chloroquinolin-3-ylformamide and O-phenylhydroxylamine hydrochloride (2.3 g, 16 mmol) in lieu of O-ethylhydroxylamine hydrochloride in isopropanol (100 mL). Chromatographic purification was carried out eluting with 5% methanol in dichloromethane containing 2 mL of aqueous ammonium hydroxide per liter of eluent to provide 1.58 g of 1-phenoxy-2-propyl-1H-imidazo[4,5-c]quinoline as a brown, foamy solid.
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][CH3:20])[CH:4]([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[S:13])=[CH:7][CH:6]=1)[CH3:2].[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH2:30]>C(#N)C>[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH:30][C:12]([NH:11][C:8]1[CH:7]=[CH:6][C:5]([CH:4]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[CH:3]([CH2:1][CH3:2])[CH2:19][CH3:20])=[CH:10][CH:9]=1)=[S:13]
Reactant: CCC(CC)C(c1ccc(N=C=S)cc1)n1ccnc1
Reactant: Nc1nc2ccccc2s1
Solvent: CC#N
Product: CCC(CC)C(c1ccc(NC(=S)Nc2nc3ccccc3s2)cc1)n1ccnc1
Yield: 8.2 %

Procedure:
A mixture of 1-[2-ethyl-1-(4-isothiocyanatophenyl)butyl]-1H-imidazole (0.0123 mol) and 2-benzothiazolamine (0.0148 mol) in acetonitrile (80 ml) was stirred and refluxed for 12 hours. The solvent was evaporated and the residue was taken up in H2O and CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/ NH4OH 97.5/2.5/0.1). The desired fractions were collected and the solvent was evaporated. The residue was purified again by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 85/15/0.1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-butanone and DIPE. The precipitate was filtered off and dried, yielding 0.44 g (9%) (±)-N-(2-benzothiazolyl)-N′-[4-[1-(1H-imidazol-1-yl)-2-ethylbutyl]phenyl]-thiourea (compound 705).