Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.O>C(O)C>[O:11]1[CH:12]=[CH:13][CH:14]=[C:10]1[C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccco2)cc1
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2ccco2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a suspension of 2-(4-nitrophenyl)furan (0.378 g, 2 mmol, prepared according to the method of Heterocycles, 1990, 31, 1951) in ethanol (20 mL) was heated to 70° C. and added stannous chloride dihydrate (2.26 g, 10 mmol) and the mixture was stirred for 2 hours. The reaction mixture was cooled to room temperature and poured into water (50 mL), the whole was extracted with ethyl acetate (30 mL×2). The organic layer was dried over Na2SO4, filtered through celite and concentrated to give the crude subtitle compound (0.35 g). MS (EI): m/z 159 (M+)
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16].[Cl:19][CH:20]([F:23])[CH2:21]Cl>CO>[Cl:19][CH:20]([F:23])[CH2:21][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16]
Reactant: NS(=O)(=O)c1ccccc1S
Reactant: FC(Cl)CCl
Solvent: CO
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccccc1SCC(F)Cl
Reaction time: 24 h

Procedure:
A mixture of 217.8 g of the triethylamine salt of 2-mercaptophenylsulfonamide obtained in accordance with Example P6 and 101 g of 1,2-dichloro-1-fluoroethane in 950 ml of methanol is stirred in an autoclave for 24 hours at a temperature of from +65° C. to +70° C. and for a further 24 hours at from +95° C. to +100° C. The reaction mixture is then concentrated by evaporation and the residue is stirred with water. By extracting with ethyl acetate, washing with water, drying over sodium sulfate, concentrating by evaporation and purifying the residue by chromatography with methylene chloride, 99.5 g (49.2% of the theoretical yield) of 2-(2-chloro-2-fluoroethylthio)-phenylsulfonamide having a melting point of from +88° C. to +89° C. are obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([C@H:10]1[CH2:15][C@H:14]([NH:16][CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12][N:11]1[C:28](=[O:37])[C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[CH:30]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:38]I>COCCOC>[CH2:3]([C@@H:10]1[CH2:15][C@@H:14]([N:16]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][CH:19]=2)[CH3:38])[CH2:13][CH2:12][N:11]1[C:28](=[O:37])[C:29]1[CH:30]=[C:31]([Cl:36])[CH:32]=[C:33]([Cl:35])[CH:34]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@@H](NCc2ccnc3ccccc23)C[C@@H]1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CN(Cc1ccnc2ccccc12)[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
13.4 mg (0.446 mmol) of an 80% strength suspension of sodium hydride in mineral oil (suspended in hexane and decanted) are added in one portion to a solution of 150 mg (0.297 mmol) of (2S*,4R*)-2-benzyl-1-(3,5-dichlorobenzoyl)-N-(4-quinolylmethyl)-4-piperidinamine in 2 ml of 1,2-dimethoxyethane at 0° C. After 10 minutes at 0° C., the mixture is left to stir at RT for 30 minutes, again cooled to 0° C., and 22 μl (0.357 mmol) of methyl iodide are added. The mixture is then stirred at RT for 96 hours. The solvent is stripped off in a rotary evaporator, and the residue is chromatographed on silica gel with toluene/ethyl acetate (1:1). The title compound ##STR78## is obtained (20 mg, 13%) as white foam. TLC: toluene/ethyl acetate (1:1) Rf =0.45; FD-MS: M+ =517, 519.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)[CH2:3][OH:4].[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.Cl>N1C=CC=CC=1>[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([O:4][CH2:3][C:2]([CH3:22])([CH3:1])[CH2:5][O:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:9]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: CC(C)(CO)COCc1ccc(F)c(Oc2ccccc2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(C)(C)COCc2ccc(F)c(Oc3ccccc3)c2)cc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 53.1 %

Procedure:
A mixture of 2,2-dimethyl-3-(4-fluoro-3-phenoxybenzyloxy)propan-1-ol (5 g), p-toluenesulphonyl chloride (3.75 g) and pyridine (10 cm3) was stirred at the ambient temperature (ca. 20° C.) for 24 hours. The mixture was poured into dilute aqueous hydrochloric acid solution and hhe aqueous mixture extracted with ethyl acetate (3×250 cm3). The combined organic layers were washed with brine, then dried over anhydrous magnesium sulphate. Evaporation of the solvent under reduced pressure gave a dark oil (4 g) which was purified by column chromatography on a silica gel support, eluting with petroleum ether (boiling range (60°-80° C.) containing 20% by volume ethyl acetate, to give the title compound (3.9 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:41]>CC(O)C>[ClH:41].[F:1][C:2]1[C:3]([CH2:25][NH:26][CH3:27])=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)n1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cccc(OC)n2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methoxypyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (136 mg) in 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 62 mg, 51%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.P(Cl)(Cl)Cl>O>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:12]([C:3]2[C:2]([OH:1])=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[N:10]3)=[CH:5][CH:4]=2)=[O:14])=[CH:18][CH:17]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(O)c1ccc2cccnc2c1O
Solvent: ClP(Cl)Cl
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1ccc2cccnc2c1O
Reaction time: 8 h
Yield: 21.3 %

Procedure:
A solution of 8-hydroxyquinoline-7-carboxylic acid (0.250 g) of Preparation 1 and 4-chlorobenzylamine (0.187 g) in 25 mL xylenes is heated to reflux. To this is added dropwise PCl3 (0.073 g). Refluxing is continued overnight. The reaction is then cooled and water is added to destroy excess PCl3. The resulting solid is collected and recrystallized from EtOAc/hexanes to yield 0.088 g of the title product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[SH:15]>[OH-].[Na+].C(I)CCC>[CH2:10]([S:15][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])[C:2]=1[Cl:1])[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(S)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCI
Product: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Cl
Reaction time: 50 h

Procedure:
To a stirred solution of 4-chloro-3-mercapto-5-sulfamylbenzoic acid (5.5 g) in 1 N sodium hydroxide (29.5 ml), butyl iodide (2.1 ml) is added. After additional stirring for 50 hours precipitates the sodium salt of 3-butylthio-4-chloro-5-sulfamylbenzoic acid which is collected and washed with ice water. The sodium salt is suspended in water (25 ml) and 1 N hydrochloric acid added slowly until a pH value of 1. The precipitate is collected by filtration and recrystallized from aqueous ethanol to yield 3-butylthio-4-chloro-5-sulfamylbenzoic acid with a melting point of 202° - 203° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].Cl>CN(C)C=O>[C:16]([O:15][C:14]([NH:13][CH2:12][CH2:11][C:3]1[CH:4]=[CH:5][C:6]([CH:8]([CH3:9])[CH3:10])=[CH:7][C:2]=1[O:1][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:20])([CH3:18])([CH3:17])[CH3:19]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)c1ccc(CCNC(=O)OC(C)(C)C)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cc(C(C)C)ccc1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl N-[2-(2-hydroxy-4-isopropylphenyl)ethyl]-carbamate (0.234 g) and 0.116 g of potassium carbonate were suspended in 5 mL of N,N-dimethylformamide. To the stirred suspension was added dropwise 0.126 mL of ethyl 4-bromobutyrate at room temperature, and the mixture was stirred at room temperature for 16 hours. To the reaction mixture were added 10 mL of 1 mol/L hydrochloric acid and then 20 mL of water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate-hexane) to give 0.283 g of ethyl 4-[2-(2-tert-butoxycarbonylaminoethyl)-5-isopropylphenoxy]-butyrate.
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:7][C:6]=1[F:31])([OH:4])=[O:3].[CH:32]([C:34]1[N:35]=[C:36]([NH:39][C:40](=[O:42])[CH3:41])[S:37][CH:38]=1)=O.CC(C)([O-])C.[K+].O>CN(C)C=O>[C:40]([NH:39][C:36]1[S:37][CH:38]=[C:34]([CH:32]=[CH:9][C:8]2[CH:29]=[CH:30][C:5]([C:2]([OH:4])=[O:3])=[C:6]([F:31])[CH:7]=2)[N:35]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)Nc1nc(C=O)cs1
Reactant: O=C(O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1F
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1nc(C=Cc2ccc(C(=O)O)c(F)c2)cs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
To a solution of (4-carboxy-3-fluorobenzyl)(triphenyl)phosphoniumbromide (2.037 g, 4.112 mmol) and N-(4-formyl-1,3-thiazol-2-yl)acetamide (599.5 mg, 3.523 mmol) in anhydrous N,N-dimethylformamide (15 ml) was added potassium tert-butoxide (1.180 g, 10.52 mmol), and the mixture was stirred at room temperature for 3 hr. Water (150 ml) was added to the reaction mixture, and the mixture was washed 3 times with ethyl acetate. While stirring, 1M hydrochloric acid (10.5 ml) was added to the aqueous layer. The precipitated solid was collected by filtration and washed with water. The solid was dried under reduced pressure to give 4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]vinyl}-2-fluorobenzoic acid (753.9 mg, 2.461 mmol, yield 69.9%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](N)[S:9][CH:10]=1)=[O:5])[CH3:2].N([O-])=O.[Na+].[ClH:16]>O.Cl[Cu]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Cl:16])[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(N)n1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1csc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The free based 2-amino-thiazole-4-carboxylic acid ethyl ester (306 mg, 1.78 mmol) and CuCl (238 mg, 2.4 mmol) were suspended in conc. HCl (8 ml) and the mixture cooled on a salt/ice bath. A pre-cooled solution of NaNO2 (166 mg, 2.4 mmol) in water (2 ml) was added over a period of 10 min. The mixture was allowed to warm to room temperature over 1 h and was stirred for a further 1 h. Water was added and the aqueous layer extracted with EtOAc (3×10 ml). The combined EtOAc layers were washed with brine, dried (Na2SO4), filtered and the solvent removed in vacuo to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[ClH:12].Cl.[Cl:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][SH:29])[CH2:22][CH2:21]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:14].[ClH:12].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[SH:29][CH2:28][CH2:27][CH2:26][N:23]2[CH2:24][CH2:25][N:20]([CH2:19][C:18]3[CH:17]=[CH:16][C:15]([Cl:14])=[CH:31][CH:30]=3)[CH2:21][CH2:22]2)[OH:11])[CH:6]=[CH:7][CH:8]=1
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: COc1cccc(N=C=O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(NC(O)=[SH]CCCN2CCN(Cc3ccc(Cl)cc3)CC2)c1
Yield: 63.3 %

Procedure:
The procedure described in Example 2 was followed, using 1.3 g of 3-methoxyphenyl isocyanate, 3.0 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.9 g of triethylamine and 50 ml of methylene chloride, to give 1.35 g (32% of theory) of N-(3-methoxyphenyl)-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as an off-white crystalline solid, M.p. 238°-240° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][O:6][CH:5]([CH2:8][OH:9])[CH2:4][O:3]1.[CH3:11][S:12](Cl)(=[O:14])=[O:13].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:11][S:12]([O:9][CH2:8][CH:5]1[CH2:4][O:3][C:2]([CH3:10])([CH3:1])[CH2:7][O:6]1)(=[O:14])=[O:13]
Reactant: CC1(C)COC(CO)CO1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)COC(COS(C)(=O)=O)CO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
(5,5-Dimethyl-1,4-dioxan-2-yl)methanol (740 mg, 5.06 mmol) and TEA (0.988 mL, 7.09 mmol) were dissolved in DCM (20 mL). At 0° C. MsCl (0.473 mL, 6.07 mmol) was added dropwise. After the addition the solution was warmed to ambient temperature and stirred for 1 hr. Saturated NaHCO3 solution was added and the two layers were separated. The aqueous layer was extracted three times with DCM. The organic layers were combined, dried over Na2SO4 and concentrated. The resulting residue was purified on a silica gel column (heptane:EtOAc 4:1 to 1:1) to give the product as a colorless oil (805 mg, 71%). 1H NMR (400 MHz, CDCl3) δ ppm 4.18-4.19 (2H, m), 3.71-3.76 (1H, m), 3.66 (1H, t, J=10.8 Hz), 3.52-3.57 (2H, m), 3.37 (1H, d, J=11.6 Hz), 3.03 (3H, s), 1.28 (3H, s), 1.09 (3H, s).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[N:15]=2)[CH2:10]1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>C1COCC1>[OH:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:16]1[N:15]=[C:14]([N:11]2[CH2:12][CH2:13][C@@H:9]([NH:8][C:33](=[O:34])[O:35][CH2:36][CH3:37])[CH2:10]2)[C:23]2[C:18](=[CH:19][C:20]([CH3:24])=[CH:21][CH:22]=2)[N:17]=1
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)N[C@@H]1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)C1
Temperature: -55 °C
Yield: 86.3 %

Procedure:
Under an N2 atmosphere at RT, triethylamine (174 μL, 1.25 mmol) was added to a solution of (R)-2-(4-(3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (200 mg, 0.62 mmol) in THF (6.0 mL). After cooling the mixture to −55° C., ethyl chloroformate (59 μL in 600 μL THF, 0.62 mmol) was slowly added, and the reaction was warmed to RT over a period of 30 minutes. The mixture was quenched with H2O and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-20% EtOAc in a 1:1 mixture of CH2Cl2 and hexanes gave (R)-ethyl 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (compound 2) (210 mg, 86%). 1H NMR (400 MHz, DMSO-d6) δ 8.42 (dd, J=7.8, 1.5 Hz, 1H), 8.18 (d, J=8.7 Hz, 1H), 7.59-7.58 (m, 2H), 7.38-7.33 (m, 2H), 6.94-6.90 (m, 2H), 4.27-4.12 (m, 3H), 4.04-3.98 (m, 3H), 3.87-3.86 (m, 1H), 2.50 (s, 3H), 2.26-2.18 (m, 1H), 2.05-1.99 (m, 1H), 1.16 (t, J=7.3 Hz, 3H) ppm. LC/MS: m/z 393.3 (M+H)+ at 2.31 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>C1COCC1>[CH:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][C:18](=[O:19])[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)c1ccccc1N
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)c1ccccc1NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 33.9 %

Procedure:
To a stirred solution of 2-isopropylaniline (200 mg, 1.5 mmol) in THF (9 mL) was added pyridine (0.24 mL, 3.0 mmol), then phenyl chloroformate (0.28 mL, 2.2 mmol) at rt. Some solid precipitated out. The mixture was stirred at rt for 4.5 h. Water was added to the reaction and it was extracted with EtOAc. The organic solution was washed with water (5 mL) and dried over MgSO4 and then filtered. The filtrate was concentrated in vacuo and crystallized from EtOAc-hexanes (1:9 v/v) to afford the title compound (130 mg, 34%). 1H-NMR (DMSO-d6) δ 9.45 (s, 1H), 7.44 to 7.36 (m, 2H), 7.35 to 7.28 (m, 2H), 7.25 to 7.14 (m, 5H), 3.27 (m, 1H), 1.17 (d, J=6.9 Hz, 2H); TLC Rf=0.33 (9:1 v/v hexanes-EtOAc).
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[CH3:17])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:16])/[CH2:9][CH2:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13].[SH:18][CH2:19][CH2:20][OH:21].C(N(CC)CC)C>CO>[OH:1][CH2:2]/[CH:3]=[C:4](/[CH3:17])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:16])/[CH2:9][CH2:10][C:11](=[O:15])[CH:12]([CH3:14])[CH2:13][S:18][CH2:19][CH2:20][OH:21]
Reactant: C=C(C)C(=O)CC/C(C)=C/CC/C(C)=C\CO
Reactant: OCCS
Solvent: CO
Solvent: CCN(CC)CC
Product: C/C(=C/CO)CC/C=C(\C)CCC(=O)C(C)CSCCO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 300 mg (0.0013 mol) of (6E,10Z)-12-hydroxy-2,6,10-trimethyl-1,6,10-dodecatrien-3-one in 10 ml of methanol is treated with 0.27 ml of 2-mercapto-ethanol and 0.53 ml of triethylamine. The solution is stirred at room temperature for 18 hours under argon. After removing the solvent on a rotary evaporator the residue is treated with water and methylene chloride. After extraction the organic phase is dried and freed from solvent on a rotary evaporator. The residue is chromatographed on silica gel with ether-methanol 50:1. There is obtained (6E,10Z)-12-hydroxy-1-[(2-hydroxyethyl)thio]-2,6,10-trimethyl-6,10-dodecadien-3-one which has the following absorption bands in the IR spectrum: 3369 cm-1, 1708 cm-1, 1667 cm-1, 1450 cm-1, 1044 cm-1, 1055 cm-1.
Reaction SMILES: C([O:4][CH:5]1[CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6]1)(=O)C.[CH2:12]([N:19]1[C:27]2[C:26](=[O:28])[N:25]([CH3:29])[C:24](=[O:30])[N:23]([CH3:31])[C:22]=2[N:21]=[C:20]1Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>CC(O)C>[CH2:12]([N:19]1[C:27]2[C:26](=[O:28])[N:25]([CH3:29])[C:24](=[O:30])[N:23]([CH3:31])[C:22]=2[N:21]=[C:20]1[N:7]1[CH2:6][CH:5]([OH:4])[CH2:11][NH:10][CH2:9][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)OC1CNCCNC1
Reactant: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2)n(C)c1=O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2c(nc(N3CCNCC(O)C3)n2Cc2ccccc2)n(C)c1=O
Yield: 97 %

Procedure:
[1,4]Diazepan-6-ol acetate (2B) (116 mg, 0.49 mmol) and 7-benzyl-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione (100 mg, 0.33 mmol) were dissolved in 2-propanol (20 ml) and triethylamine (0.68 ml, 4.9 mmol) and the mixture was subjected to micro waves (150° C., 6 bar, 300 W, 8 hours). The solvents were evaporated and the remaining was redissolved in dichloromethane (20 ml) and water (20 ml). The aqueous layer was acidified with potassium hydrogen sulfate until pH=2. The aqueous layer was separated and aqueous sodium hydroxide was added until pH=12. The aqueous layer was extracted with 3×50 ml of dichloromethane, and the combined organic material were added excess trifluoroacetic acid, and evaporated, to afford 123 mg of the title compound as a brown oil in 75% yield.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH:10]=2)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=CC=1Cl.Cl.Cl[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]Cl.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]([C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH:10]=2)=[C:4]([N:8]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(N)c1C1=CC(C)(C)CC(C)(C)C1
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cc1cccc(N2CCNCC2)c1C1=CC(C)(C)CC(C)(C)C1
Temperature: 200 °C
Reaction time: 0.83 h
Yield: 73.5 %

Procedure:
To a mixture of 3-methyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenylamine (663 mg, 2.72 mmol) produced in Example (71b) and 1,2-dichlorobenzene (3 mL) was added bis(2-chloroethyl)amine hydrochloride (632 mg, 3.54 mmol), followed by stirring for 5 hours and 50 minutes at an external temperature of 200° C. under a nitrogen atmosphere. During the reaction, a nitrogen stream was passed through the reactor several times. The reaction mixture was cooled to room temperature, chloroform and saturated solution of sodium hydrogencarbonate were added, and the filtrate obtained by filtration through Celite was extracted with chloroform. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 625 mg of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:29])=[C:24](B(O)O)[CH:25]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:22]3[CH:21]=[C:20]([F:19])[CH:25]=[CH:24][C:23]=3[CH3:29])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: Cc1ccc(F)cc1B(O)O
Product: CCCNC(=O)c1nnc2c(-c3cc(F)ccc3C)cccc2c1N
Yield: 86.5 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (150 mg, 0.485 mmol) and 5-fluoro-2-methyl-phenylboronic acid (154 mg, 1.000 mmol) were reacted to afford the title compound (142 mg, 86% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.53 (br, 1H), 7.91 (m, 1H), 7.77-7.63 (m, 2H), 7.26 (m, 1H), 7.07-6.97 (m, 2H), 3.45 (apparent quartet, J=7.0 Hz, 2H), 2.01 (s, 3H), 1.65 (apparent sextet, J=7.0 Hz, 2H), 0.99 (t, J=7.0 Hz, 3H). MS APCI, m/z=339 (M+H). HPLC 1.77 min.