Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:11][C:12]([OH:30])([CH2:17][C:18]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])([CH3:20])[CH3:19])[C:13]([F:16])([F:15])[F:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[O:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[C:42](Cl)=[O:43]>ClCCl>[F:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH3:29])=[C:21]([C:18]([CH3:20])([CH3:19])[CH2:17][C:12]([OH:30])([C:13]([F:14])([F:15])[F:16])[CH2:11][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([C:42]([C:38]3[O:37][CH:41]=[CH:40][CH:39]=3)=[O:43])[CH2:3][CH2:2]2)[CH:26]=1
Reactant: O=C(Cl)c1ccco1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CCNc2ccccc21)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CN1CCN(C(=O)c2ccco2)c2ccccc21)C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h
Yield: 23.8 %

Procedure:
To a solution of 2-(3,4-dihydro-2H-quinoxalin-1-ylmethyl)-1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-ol (0.50 g, 0.117 mmol) in dichloromethane (10 mL) was added pyridine (0.24 mL, 0.129 mmol) and 2-furoyl chloride (0.012 mL, 0.129 mmol). The reaction was stirred at room temperature for 14 hours. The reaction mixture was diluted with dichloromethane, washed with two 25 mL portions of a saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and the solvent was evaporated in vacuo. Purification by flash column chromatography (5% MeOH/CH2Cl2) yielded the title compound as a white solid (14.5 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[C:7]3[S:8][CH:9]=[CH:10][C:11]=3[C:12](=O)[C:2]1=2.[CH2:15]([Mg]Br)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl[Sn]Cl>C1COCC1>[CH2:15]([C:6]1[C:7]2[S:8][CH:9]=[CH:10][C:11]=2[C:12]([CH2:5][CH2:4][CH2:3][CH2:2][CH2:12][CH2:11][CH2:7][CH3:6])=[C:2]2[S:1][CH:5]=[CH:4][C:3]=12)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCC[Mg]Br
Reactant: O=C1c2ccsc2C(=O)c2ccsc21
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Product: CCCCCCCCc1c2ccsc2c(CCCCCCCC)c2ccsc12
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a 100 mL flask under nitrogen was added 4,8-dihydrobenzo[1,2-b:4,5-b′]dithiophene-4,8-dione (1.1 g, 5.0 mmol) and anhydrous THF (10 mL). The mixture was heated to reflux and octylmagnesium bromide (20 mmol, 10 mL, 2.0 M in Et2O) was added dropwise. After refluxing for 2 hours more, SnCl2 solution (7.3 g in 19 mL 10% HCl) was slowly added dropwise. The mixture was kept at 60° C. for 1 hour. After cooling down, the organic phase was separated. The water phase was extracted with ether once and the organic phases were combined and dried over Na2SO4. Purification by column chromatography with hexane as eluent gave a yellow oil (780 mg, yield 37.6%). 1H NMR (CDCl3, 500 MHz) δ=7.48 (d, J=5.5 Hz, 2H), 7.47 (d, J=5.5 Hz, 2H), 3.20 (t, J=7.5 Hz, 4H), 1.75-1.88 (m, 4H), 1.43-1.54 (m, 4H), 1.21-1.42 (bs, 16H), 0.90 (t, J=7.0 Hz, 6H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl.[NH2:14][OH:15].[OH-].[K+].Cl>C(O)C.O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=[N:14][OH:15])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: NO
Reactant: CCCCCC(=O)CCCCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCC(CCCCC)=NO
Temperature: 0 °C
Yield: 100.2 %

Procedure:
To a solution of 5.11 g of 6-undecanone in 20 ml of ethanol were successively added a solution of 3.47 g of hydroxylamine hydrochloride in 6 ml of water and a solution of 4.77 g of potassium hydroxide in 6 ml of water. The resulting mixture was heated under reflux for 3 hours. The reaction mixture was then poured into 150 ml of ice-containing water. The resulting aqueous mixture was made acidic by addition of 2N hydrochloric acid, and extracted with benzene. The organic layer was washed with saturated aqueous sodium chloride and evaporated under reduced pressure to remove the solvent. There was obtained 5.57 g (corresponding to theoretical amount) of 6-undecanone oxime as a pale yellow solid,
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]3)[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([NH:32][C:33]([O:35][CH2:36][CH:37]2[C:49]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=3[C:43]3[C:38]2=[CH:39][CH:40]=[CH:41][CH:42]=3)=[O:34])[C:29](O)=[O:30])=[CH:23][CH:22]=1)(=[O:20])[NH2:19].O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH:48]1[C:49]2[CH:37]([CH2:36][O:35][C:33](=[O:34])[NH:32][CH:28]([CH2:27][C:24]3[CH:23]=[CH:22][C:21]([C:18](=[O:20])[NH2:19])=[CH:26][CH:25]=3)[C:29](=[O:30])[N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]3[C:9]3[NH:10][CH:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=3)[C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:44]=2[CH:45]=[CH:46][CH:47]=1
Reactant: c1ccc(-c2c[nH]c(C3CCCCN3)n2)cc1
Reactant: NC(=O)c1ccc(CC(NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(CC(NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCCCC2c2nc(-c3ccccc3)c[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 138 mg (0.5 mmol) of 2-(4-Phenyl-1H-imidazol-2-yl)-piperidine, 215 mg (0.5 mmol) of 3-(4-Carbamoyl-phenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionic acid, 135 mg (1.0 mmol) of hydroxybenzotriazole hydrate, 115 mg (0.6 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added 2 mL of dimethylformamide. The resulting mixture was allowed to stir at room temperature under argon overnight. The mixture was then partitioned between ethyl acetate and water. The organic layer was separated, dried over MgSO4 and concentrated to a yellow oil which was used for the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH3:20].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH3:20])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCCNS(=O)(=O)c1ccccc1
Yield: 48.8 %

Procedure:
Using the general method of Example 232, 1-(4-aminobutyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (0.50 g, 1.9 mmol) was reacted with benzenesulfonyl chloride (0.24 mL, 1.9 mmol) to provide 0.38 g of N-[4-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzenesulfonamide as brown granules, m.p. 215.4–216.0° C. Analysis: Calculated for C21H23N5O2S: % C, 61.59; % H, 5.66; % N, 17.10. Found: % C, 61.24; % H, 5.65; % N, 16.95.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:14]([CH2:22][C:23](OCC)=[O:24])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:14]([CH2:22][C:23]([NH:1][C:2]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:24])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CCOC(=O)c1cc(Cl)ccc1N
Product: CCOC(=O)c1cc(Cl)ccc1NC(=O)CC(=O)c1ccccc1
Yield: 49.1 %

Procedure:
To 6.0 grams of ethyl 2-amino-5-chlorobenzoate is added 6.4 grams of ethyl benzoylacetate, the mixture is heated at 180° to 190° C. for ten hours, cooled, crystals separated out therefrom are collected by filtration, and washed with methanol to give 5.1 grams of ethyl 2-benzoylacetylamino-5-chlorobenzoate, colorless needles. To 200 ml of ethanol is added 640 mg of metal sodium, then 4.8 grams of ethyl 2-benzoylacetylamino-5-chlorobenzoate is added thereto, the mixture is heated to reflux for two hours, cooled, poured into ice water, adjusted to pH 3 with 10% hydrochloric acid, crystals separated out therefrom are collected by filtration, and recystallized from dimethylformamide and methanol to give 1.9 grams of 3-benzoyl-6-chloro-4-hydroxy-2-quinoline, pale yellow needles, melting at above 300° C.
Reaction SMILES: [C:1]1([C:7](=[O:18])/[CH:8]=[C:9](\[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](#[N:22])[CH2:20][CH3:21]>CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:20]([C:19]1[C:8]([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:18])=[C:9]([CH3:10])[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:22]=1)[CH3:21]
Reactant: C/C(=C/C(=O)c1ccccc1)Nc1ccccc1
Reactant: CCC#N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: CCc1nn(-c2ccccc2)c(C)c1C(=O)c1ccccc1

Procedure:
According to AVV A, (Z)-1-phenyl-3-phenylamino-but-2-ene-1-one (237.3 mg, 1.0 mmol, 1.0 equiv.) was stirred with Cu(OAc)2 (544.9 mg, 3.0 mmol, 3.0 equiv.) into propionitrile (3.0 ml, 41.9 mmol, 41.9 equiv.) for 24 hours at 120° C. After the dark-brown bluish raw product (330.0 mg) was purified by means of column chromatography (silica gel (50 g), pentane/EtOAc 98:2→60:40→0:100), the desired product was obtained in the form of a yellow oil (126.2 mg, 0.43 mmol, 43%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=[O:7])#[N:2].[OH:16]O.[OH-].[Na+].Cl>>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=[O:7])(=[O:16])[NH2:2]
Reactant: OO
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)Oc1ccc(C(=O)O)cc1C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
3-Cyano-4-isopropoxy-benzoic acid (50 mg, 0.24 mmol), hydrogen peroxide (280 μL of 30% w/v, 2.4 mmol), and 10% NaOH (240 μL of 10% w/v, 0.61 mmol) were combined and stirred at room temperature for 16 h. The mixture was acidified with 4M HCl and was extracted with ethyl acetate (2×7 mL). The combined organics were washed with brine, dried over sodium sulfate and evaporated to give 3-carbamoyl-4-isopropoxy-benzoic acid (45 mg, 83%). ESI-MS m/z talc. 223.1, found 224.3 (M+1)+; Retention time: 1.49 minutes (4 min run).
Reaction SMILES: O1CCOCC1.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[S:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:10][CH:9]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(N(CC)CC)C>[C:21]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[S:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:12][CH:13]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(C2SC(=O)NC2=O)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C1NC(=O)C(c2ccc(NC(=O)c3ccccc3)cc2)S1
Temperature: 0 °C
Yield: 93.3 %

Procedure:
Into 20 ml of dioxane were dissolved 0.5 g of 5-(4-aminophenyl) thiazolidine-2,4-dione, and, after added 0.34 g of benzoyl chloride and further added dropwise 0.24 g of triethylamine, the mixture was refluxed for 1 hour. After cooling by standing, the reaction mixture was poured into 150 ml of ice water and the crystals deposited were collected by filtration, washed with water and dried. These were recrystallized from chloroform to obtain 0.70 g of title compound.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:19])(=[O:18])[C:7]1[CH:17]=[C:14]([O:15][CH3:16])[C:12]([OH:13])=[C:9]([O:10][CH3:11])[CH:8]=1.[CH3:20]O>>[OH:13][C:12]1[C:14]([O:15][CH3:16])=[CH:17][C:7]([C:6]([O:19][CH3:20])=[O:18])=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1cc(C(=O)O)cc(OC)c1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(OC)c(O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Concentrated sulphuric acid (3 mL), was added dropwise to a solution of 81 (20.24 g, 102.1 mmol) in refluxing methanol (70 mL). The reaction mixture was heated at reflux for a further 5 hours and then cooled to room temperature and concentrated to a third of its original volume. The concentrate was poured onto crushed ice (c. 150 mL) and allowed to stand for 30 minutes. The aqueous mixture was extracted with ethyl acetate (3×100 mL) and the combined organic phase washed with distilled water (3×100 mL), brine (3×100 mL) and dried over anhydrous MgSO4. Removal of ecxess solvent under reduced pressure afforded the product as a yellow solid, 121 (18.39 g, 86.7 mmol; 1H NMR (270 MHz, CDCl3) δ 3.9 (s, 3H), 3.95 (s, 3H), 3.975 (s, 3H), 6.1 (s, 1H), 7.3 (s, 2H); 13C NMR (67.8 MHz, CDCl3) δ 166.9, 146.6, 139.2, 121.0, 106.6, 56.4, 52.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](O)=[CH:10][C:11](=O)[C:12]([F:15])([F:14])[F:13].[NH2:18][NH2:19]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:19][N:18]=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=1
Reactant: NN
Reactant: O=C(C=C(O)c1ccc(F)cc1F)C(F)(F)F
Solvent: CC(=O)O
Product: Fc1ccc(-c2cc(C(F)(F)F)n[nH]2)c(F)c1
Temperature: 95 °C
Yield: 93.1 %

Procedure:
At 24° C., 15.0 g (0.06 mole) of the product of step A was dissolved in 50 mL glacial acetic acid and treated with 2 mL (0.064 mole) anhydrous hydrazine, added over a period of 5 minutes. The reaction was heated to 95° C. for 30 minutes. The reaction was cooled and poured into 300 mL ice water. The slurry was filtered and the cake washed with water and air dried to give 13.86 g (94%) of 5-(2,4-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazole as a white solid, mp 157-158° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])=[CH:5][CH:4]=1)[CH3:2].CC(C)([O-])C.[K+].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[CH2:37][CH2:38]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:30])([CH3:27])([CH3:26])[CH3:25]>CC(N(C)C)=O>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[CH2:37][CH2:38][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCCCN2C(=O)OC(C)(C)C)cc1
Reactant: CCc1ccc(CCc2ccccc2O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCc1ccc(CCc2ccccc2OCCC2CCCCN2C(=O)OC(C)(C)C)cc1
Yield: 99.3 %

Procedure:
Following a procedure similar to that described in Example 40(a), 1.00 g of 2-[2-(4-ethylphenyl)ethyl]phenol (prepared as described in Preparation 26), 0.496 g of potassium t-butoxide and 1.70 g of 1-t-butoxycarbonyl-2-[2-(p-toluenesulfonyloxy)ethyl]piperidine were reacted in 20 ml of dimethylacetamide. The mixture was then worked up as described in Example 40(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.92 g (yield 99%) of the title compound as a colorless oil.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([NH2:13])=[CH:8][CH:9]=2)[CH2:4]1.Cl.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](SCC)=[NH:21]>C(O)C>[ClH:1].[ClH:1].[CH3:2][N:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([NH:13][C:20]([C:16]3[S:15][CH:19]=[CH:18][CH:17]=3)=[NH:21])=[CH:8][CH:9]=2)[CH2:4]1
Reactant: CN1CCc2ccc(N)cc2C1
Reactant: CCSC(=N)c1cccs1
Agent: Cl
Solvent: CCO
Product: CN1CCc2ccc(NC(=N)c3cccs3)cc2C1
Temperature: 0 °C

Procedure:
2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-ylamine hydrochloride (34.66 g) in 95% ethanol (600 ml) was warmed to 65° C. to dissolve most of the solids, and the mixture was then allowed to cool with stirring. The next day, the fine suspension of solids was treated with 2-thiophenecarboximidothioic acid, ethyl ester, hydrochloride (41 g) and stirred at 23° C. All solids had dissolved by 2 h, and by 4 h new solids had precipitated. The mixture was treated with concentrated hydrochloric acid (2 ml). The mixture was cooled to 0° C. and stirred for 30 minutes. The solids were filtered off, washed with ethanol (2×50 ml), and air dried to provide N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-thiophenecarboximidamide dihydrochloride, m.p. 142-146° C.; MS m /z 272 [M+H]+.
Reaction SMILES: Br.Br[CH:3]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1)=O.[NH2:22][C:23]([NH2:25])=[S:24].C(N(CC)CC)C>C(#N)C>[CH3:13][C:12]([C:9]1[CH:10]=[CH:11][C:6]([C:4]2[N:22]=[C:23]([NH2:25])[S:24][C:3]=2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:7][CH:8]=1)([CH3:15])[CH3:14]
Reactant: NC(N)=S
Reactant: CC(C)(C)c1ccc(C(=O)C(Br)c2ccncc2)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)c1ccc(-c2nc(N)sc2-c2ccncc2)cc1
Yield: 70 %

Procedure:
To a solution of 2-bromo-1-[4-(1,1-dimethylethyl)phenyl]-2-(4-pyridyl)ethanone hydrobromide (5.0 g, 12 mmol) and thiourea (0.95 g, 13 mmol) in acetonitrile (60 mL) was added dropwise triethylamine (1.8 ml, 13 mmol) and the mixture was refluxed for 3 h. The solvent was evaporated under reduced pressure and saturated aqueous sodium hydrogencarbonate solution was added to the residue. The precipitated solid was collected by filtration. The obtained crude crystal was recrystallized from ethanol to give the title compound (2.6 g, 8.4 mmol, yield 69%).
Reaction SMILES: [OH2:1].[CH2:2]([O:5][C:6]1[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][C:11]=1[Br:12])[CH:3]=[CH2:4]>OS(O)(=O)=O>[Br:12][C:11]1[CH:10]=[CH:9][C:8]([O:13][CH3:14])=[C:7]2[C:6]=1[O:5][CH2:2][CH:3]([OH:1])[CH2:4]2
Reactant: C=CCOc1cc(OC)ccc1Br
Reactant: O
Agent: O=S(=O)(O)O
Product: COc1ccc(Br)c2c1CC(O)CO2
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a mixture of H2SO4 (6.9 ml) and water (6.1 ml) at room temperature was added Tl2O3 (2.38 g, 5.22 mmol). The mixture was stirred for 30 min and water (37 ml) was added, thereafter the temperature was raised to 60° C. and 3-allyloxy-4-bromoanisol (2.16 g, 8.89 mmol) was added. The mixture was stirred at 60° C. for 4.5 hours. Another portion of Tl2O3 (1.0 g, 2.19 mmol) stirred for 30 min at 20° C. in H2SO4 (2.6 ml) and H2O (3 ml) was added and the reaction mixture was stirred for another 17 hours at 60° C. After cooling the mixture was extracted with chloroform. The organic layer was washed with water, dried (MgSO4) and evaporated. After chromatography (SlO2) with ether as eluant, 552 mg (24%) of 8-bromo-5-methoxy-3-chromanol was isolated. An analytic sample of the product was obtained from recrystallization in light petroleum-ether, m.p. 115°-117° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:26]([NH2:28])[CH3:27]>O1CCCC1>[CH2:26]([NH:28][C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH3:27]
Reactant: Clc1nc(NCC2(c3ccccc3)CCCCC2)c2ccccc2n1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNc1nc(NCC2(c3ccccc3)CCCCC2)c2ccccc2n1
Temperature: 60 °C

Procedure:
(2-chloro-quinazolin-4-yl)-(1-phenyl-cyclohexylmethyl)-amine (0.052 g; 0.15 mmol) was treated with 1 mL of a 2 M solution of ethylamine in tetrahydrofuran. The reaction vessel was tightly sealed and the reaction mixture was heated at 60° C. for 24 h. The volatile components were removed under vacuum and the crude residue was purified directly be preparative HPLC to give 0.020 g of N2-ethyl-N4-(1-phenyl-cyclohexylmethyl)-quinazoline-2,4-diamine as a white solid. LCMS m/z=361.2 (M+H)+
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH:12]2[C:14]([NH:16][NH2:17])=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:18]1[C:27]2[C:22](=[C:23]([C:28](=O)[CH3:29])[CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][N:19]=1>ClCCCl.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:13][CH:12]2[C:14]([NH:16]/[N:17]=[C:28](/[C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[C:22]=2[CH:21]=[CH:20][N:19]=[CH:18]3)\[CH3:29])=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1cccc2cnccc12
Reactant: CC(C)(C)c1ccc(C2CC2C(=O)NN)cc1
Solvent: ClCCCl
Solvent: O
Product: C/C(=N\NC(=O)C1CC1c1ccc(C(C)(C)C)cc1)c1cccc2cnccc12
Yield: 45.2 %

Procedure:
A solution of 2-(4-tert-butylphenyl)cyclopropanecarbohydrazide (200 mg, 0.86 mmol) and 1-(isoquinolin-5-yl)ethanone (147 mg, 0.86 mmol) in 1,2-dichloroethane (10 mL) was stirred at room temperature for 2 h. The reaction mixture was then diluted with water (5 mL) and the organic layer was separated, washed brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was purified via silica gel column chromatography to afford (E)-2-(4-tert-butylphenyl)-N′-(1-(isoquinolin-5-yl)ethylidene)cyclopropanecarbohydrazide (150 mg, 45%) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:4][CH:3]=1.[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][NH2:26])[CH3:22].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:26][CH2:25][CH2:24][N:23]([CH2:27][CH3:28])[CH2:21][CH3:22])=[O:18])=[CH:19][CH:20]=2)=[N:4][CH:3]=1
Reactant: O=C(O)c1ccc(Nc2ncc(Br)n3ccnc23)cc1
Reactant: CCN(CC)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)CCNC(=O)c1ccc(Nc2ncc(Br)n3ccnc23)cc1
Yield: 69 %

Procedure:
In the same way as described in for Compound 90, step 3, using 4-(5-bromo-imidazo[1,2-a]pyrazin-8-ylamino)-benzoic acid (0.593 g 1.78 mmol), N,N diethylethane-1,2-diamine (0.30 mL, 2.14 mmol), DIPEA (0.48 mL, 2.68 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.68 g, 1.78 mmol) in DMF. The title compound (0.53 g, 69%) is obtained after purification by silica gel column chromatography eluting with DCM followed by 95:5 DCM:NH3 (7M in MeOH). LCMS: Rt 2.21 min (96%).
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:28][CH:29]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>ClCCl.CO>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:28][CH:29]=2)=[O:23])=[CH:16][CH:17]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(Oc3ccccc3)nc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(Oc3ccccc3)nc2)cc1)C(=O)O
Yield: 67.6 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-butyl-3-[4-[2-(2-phenoxypyridine-5-carbonylamino)ethoxy]phenyl]propionate (215 mg), which is the product of Example 55, was reacted with aqueous sodium hydroxide solution (1N, 1.32 ml) and the reaction mixture was treated to afford the crude free acid which was subjected to chromatography on a silica gel thin layer plate using dichloromethane/methanol=10/1 as the eluant to give the title compound (137 mg) as colorless crystals.