Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:12][CH:9]([CH:10]=[CH2:11])[CH:4]([CH:5]([OH:8])[CH2:6][OH:7])[O:3]1.N1C=CC=CC=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.Cl>C(Cl)(Cl)Cl>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([O:7][CH2:6][CH:5]([OH:8])[CH:4]2[O:3][C:2]([CH3:13])([CH3:1])[O:12][CH:9]2[CH:10]=[CH2:11])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: C=CC1OC(C)(C)OC1C(O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C=CC1OC(C)(C)OC1C(O)COS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 100.6 %

Procedure:
3,4-(Dimethylmethylenedioxy)-5-hexene-1,2-diol (9.77 g) was mixed with 155 ml of pyridine and 52 ml of chloroform, and 11.39 g of p-toluenesulfonyl chloride was added gradually in four portions at 0° C. The mixture was stirred at 0° C. for 6 hours, poured into 6N hydrochloric acid with ice and extracted with diethyl ether. The extract was washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution in sequence, dried with anhydrous ride aqueous solution in sequence, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to afford 17.88 g of 3,4-(dimethylmethylenedioxy)-2-hydroxy-5-hexen-1-yl p-toluenesulfonate having the following properties.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16]>C(O)C.C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:9]=[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]1[OH:16]
Reactant: Nc1ccccc1O
Reactant: O=Cc1ccccn1
Solvent: CCO
Solvent: CC(=O)O
Product: OC1C=CC=CC1=NCc1ccccn1
Reaction time: 12 h
Yield: 100 %

Procedure:
200 μl (2 mmol) of 2-pyridinecarboxaldehyde (reagent 1) and 220 mg (2 mmol) of 2-aminophenol (reagent 2) were dissolved in 10 mL of dry ethanol. One drop of glacial acetic acid was added and the reaction mixture was stirred during 12 h. The solution was filtered on paper and the filtrate was evaporated to dryness. After a chromatography on silica gel (CH2Cl2, 100 ml then AcOEt 200 ml), 394 mg of ligand L1 were obtained as orange solid with a yield of 100%.
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([NH:10][C:11]2[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[CH:6][CH:5]=1)([OH:3])=[O:2].[C:25](Cl)(=[O:28])[CH2:26][CH3:27].O.Cl>N1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2[CH:21]=[C:20]([NH:22][C:25](=[O:28])[CH2:26][CH3:27])[CH:19]=[CH:18][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])=[CH:23][CH:24]=1)([OH:3])=[O:2]
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)c1ccc(N)cc1NC(=O)c1ccc(C(=O)O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1ccc(NC(=O)CC)cc1NC(=O)c1ccc(C(=O)O)cc1
Reaction time: 3 h
Yield: 62.6 %

Procedure:
A solution of 3 g of ethyl 2-(4-carboxybenzamido)-4-aminobenzoate in 30 ml of pyridine was mixed with 3 g of propionyl chloride, and the mixture was held at 40° to 50° C. for a period of 3 hours. Subsequently, 20 ml of water was gradually added to the mixture which was held at the temperature for a period of one hour. After further addition of 100 ml of water, hydrochloric acid was used to control the pH of the reaction mixture between 1 and 2, and the precipitating crystal was filtered, washed with water, and recrystallized from a solvent mixture of ethanol and water to thereby produce 2.2 g of ethyl 2-(4-carboxybenzamido)-4-propionamidobenzoate having a melting point in the range of from 246° to 248° C.
Reaction SMILES: [Na].[CH3:2][C@@H:3]1[C@@H:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:6]2[C:7](Cl)=[N:8][C:9]3[N:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:12]=[CH:11][C:10]=3[C:5]2=[N:4]1.[O-:28][CH2:29][CH2:30][CH3:31].[Na+].[Cl-]>C(O)CC>[CH3:2][C@@H:3]1[C@@H:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:6]2[C:7]([O:28][CH2:29][CH2:30][CH3:31])=[N:8][C:9]3[N:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:12]=[CH:11][C:10]=3[C:5]2=[N:4]1
Reactant: C[C@H]1N=C2c3cnn(-c4ccccc4)c3N=C(Cl)N2[C@@H]1c1ccccc1
Reactant: CCC[O-]
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CCCO
Product: CCCOC1=Nc2c(cnn2-c2ccccc2)C2=N[C@H](C)[C@@H](c3ccccc3)N12

Procedure:
51 mg sodium was dissolved in 5 ml n-propanol. 670 mg of the above product (2R-trans)-2,7-dihydro-2-methyl-3,7-diphenyl-5-chloro-3H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine dissolved in 15 ml n-propanol was added to the propoxide solution with stirring. After 1 hour the reaction was poured into 200 ml saturated NaCl and the extracts were dried over MgSO4, filtered and concentrated to yield an oil which was purified by radial chromatography (30-50-70-90% ethanol/hexane, 2 mm plate) to yield 600 mg of (2R-trans)-2,7-dihydro-2-methyl-3,7-diphenyl-5-propoxy-3H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].Cl[C:6]([O:8][CH:9]([Cl:11])[CH3:10])=[O:7].N1C=CC=CC=1>C(OCC)C>[C:6](=[O:7])([O:4][CH:1]([CH3:3])[CH3:2])[O:8][CH:9]([Cl:11])[CH3:10]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CC(C)O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)OC(=O)OC(C)Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 87.7 %

Procedure:
0.66 g of isopropanol was added to 1.43 g of 1-chloroethyl chloroformate, and the solution was cooled to 0° C. in an ice-water bath. The mixture of 0.84 g of pyridine and 10 ml ethyl ether was added dropwise into the solution. The solution was reacted for 1 hour at that temperature, following 4 hours at room temperature. The reaction was stopped and the mixture was filtered, and the filtrate was washed respectively with 10% hydrochloric acid and water once. The organic phase was dried and concentrated to give 1.461 g of a light yellow liquid 1-chloroethyl isopropyl carbonate with a yield of 87.7%. The crude was directly used in the next reaction without purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11]O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: CSc1ccc(CCCO)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1ccc(CCCBr)cc1
Reaction time: 18 h
Yield: 89.4 %

Procedure:
Compound 96-1 (940 mg) was dissolved in methylene chloride (20 ml), triphenylphosphine (1.43 g) and N-bromosuccinimide (966 mg) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 18 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (1.13 g) as a colorless oil.
Reaction SMILES: [CH:1]1([C@@H:6]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:7]([OH:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH3:22][C:23]([CH3:25])=[CH2:24]>ClCCl>[CH:1]1([C@@H:6]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:7]([O:9][C:23]([CH3:25])([CH3:24])[CH3:22])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C(C)C
Reactant: Cc1ccc([C@@H](C(=O)O)C2CCCC2)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: Cc1ccc([C@@H](C(=O)OC(C)(C)C)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
160 g (732.9 mmol) of (2S)-cyclopentyl-(4-methylphenyl)acetic acid were initially charged in 480 ml of dichloromethane, and 2.1 ml of sulfuric acid and 172 ml (1722.4 mmol) of condensed 2-methylprop-1-ene were added at 10° C. The mixture was stirred at RT overnight. If required, the addition of sulfuric acid and 2-methylprop-1-ene was repeated until all the starting material had been consumed. After the reaction had ended, 21 g of potassium carbonate were added and the mixture was stirred for another 2-3 h (evolution of gas). The mixture was then diluted with 700 ml of water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 4:1). This gave 172 g (85% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:48]1([NH:51][CH2:52][C@@H:53]2[C@@H:57]([OH:58])[CH2:56][CH2:55][NH:54]2)[CH2:50][CH2:49]1>CN(C=O)C>[CH:48]1([NH:51][CH2:52][C@@H:53]2[C@@H:57]([OH:58])[CH2:56][CH2:55][N:54]2[C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:12])=[O:11])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:32])[CH2:50][CH2:49]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: O[C@H]1CCN[C@@H]1CNC1CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CC[C@H](O)[C@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (250 mg, 0.5 mmol), HOBt (81 mg, 1.2 eq.), EDC (115 mg, 1.2 eq.), TEA (0.17 mL, 2.5 eq.) and (2R,3S)-2-cyclopropylaminomethyl-pyrrolidin-3-ol (312 mg, 4 eq.) in DMF (10 mL) was stirred at rt for overnight. The reaction was concentrated, washed with water, sodium bicarbonate and brine, dried and concentrated. The residue was purified on a silica gel column to give 100 mg of the titled compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]([F:6])=[C:3]([F:5])[F:4].[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8]>>[Cl:1][CH:2]([F:6])[C:3]([N:9]([CH2:10][CH3:11])[CH2:7][CH3:8])([F:5])[F:4]
Reactant: CCNCC
Reactant: FC(F)=C(F)Cl
Product: CCN(CC)C(F)(F)C(F)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
Chlorotrifluoroethylene (454 g; 3.91 mole) is bubbled into diethylamine (350 g; 4.8 mole) over about 6 hours while the temperature is maintained at 30°-45° C. by use of an ice bath. The mixture is stirred overnight at room temperature and then distilled in vacuo to give 415 g (2.2M) of N-(2-chloro-1,1,2-trifluoroethyl)-diethylamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:26]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]=CCCCC)=[CH:10][CH:9]=1)=[O:6].O.I([O-])(=O)(=O)=[O:35].[Na+]>C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[CH:26]=1)[C:5]([NH:7][C:8]1[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11]([CH:18]=[O:35])=[CH:10][CH:9]=1)=[O:6]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCCC=Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)c2ccccc12
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(NC(=O)c2cc(F)cc(N3CCOCC3)c2)c2ccccc12
Reaction time: 1.5 h
Yield: 45.3 %

Procedure:
To a stirred room temperature solution of 3-fluoro-N-(4-hex-1-enyl-naphthalen-1-yl)-5-morpholin-4-yl-benzamide (2.7 g, 6.25 mmol) THF (15 ml) and water (5 ml) is added osmium tetroxide (2.5% in t-butanol) (1000 and sodium periodate (6 g) in portions over 30 minutes. After 1.5 hours, the mixture is diluted with ethyl acetate (200 ml) and washed with water (2×100 ml). The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is purified by column chromatography on silica gel eluting with 25-30% ethyl acetate in hexanes to give 3-fluoro-N-(4-formyl-naphthalen-1-yl)-5-morpholin-4-yl-benzamide as a tan powder (1.072 g). Mp: 204-5° C. 1H NMR 400 MHz (CDCl3) δ 10.3(s, 1H), 9.41(d, 1H, J=8.8 Hz), 8.47(d, 2H, J=7.6 Hz), 8.02(d, 1H, J=8 Hz), 7.92(d, 1H, J=8.4 Hz), 7.65-7.76(m, 2H), 7.31(s, 1H), 7.05(d, 1H, J=8 Hz), 6.79(d, 1H, J=11.6 Hz), 3.88(t, 4H, J=5.2 Hz), 3.27(t, 4H, J=5.2 Hz). MS: 379 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[C:32]4[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=4)[N:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)=[O:14])[CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[K+]>CO>[OH:5][C:4]([C:6]1[CH:7]=[C:8]([NH:12][C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]3[C:32]4[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=4)[N:26]=[CH:25][CH:24]=3)=[CH:20][CH:21]=2)=[O:14])[CH:9]=[CH:10][CH:11]=1)=[O:3]
Reactant: CCOC(=O)c1cccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cccc(C(=O)O)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.4 %

Procedure:
N-(3-Ethoxycarbonylphenyl)-N'-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}urea (190 mg) obtained in Example 197 was dissolved in methanol (3 ml), 35% aqueous potassium hydroxide (5 ml) was added, and the admixture was stirred at room temperature for 30 minutes. After removing methanol by reduced-pressure distillation and neutralizing using dilute hydrochloric acid, the separated crystals were filtered to obtain 67 mg of the title compound (yield: 38%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]>>[CH3:20][O:19][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[N:10]([C:8]3[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([C:29]4[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[C:31]([O:32][CH3:33])[CH:30]=4)[N:7]=3)[CH:11]=[N:12][C:13]=2[CH:18]=1
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: COc1ccc(-c2nc(-n3cnc4cc(OC)c(OC)cc43)sc2C(=O)O)cc1OC
Yield: 59.8 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3,4-dimethoxyphenylboronic acid (27.3 mg, 0.15 mmol) gave 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-(3,4-dimethoxy-phenyl)-thiazole-5-carboxylic acid (26.4 mg, 60%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.45 (br.s., 1 H); 8.83 (s, 1 H); 7.86 (s, 1 H); 7.66 (d, 1 H); 7.60 (dd, 1 H); 7.40 (s, 1 H); 7.08 (d, 1H); 3.87 (s, 3 H); 3.85 (s, 3 H); 3.84 (s, 3 H); 3.82 (s, 3 H). MS m/z 442 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:27]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClCCCl>[Br:27][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=3)([C:14]([F:17])([F:15])[F:16])[O:11][N:10]=2)=[CH:3][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: FC(F)(F)C1(c2cc(Cl)c(Cl)c(Cl)c2)CC(c2ccc(CBr)c(Cl)c2)=NO1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 26.2 g of 3-(3-chloro-4-methylphenyl)-5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 200 mL of 1,2-dichloroethane, 12.1 g of N-bromosuccinimide and 0.81 g of α,α′-azobisisobutyronitrile were added and the resultant reaction mixture was stirred at 80° C. for 3 hours. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature and was washed with water (70 mL×2). Subsequently, the washed reaction mixture was dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order and the solvent was distilled off under reduced pressure to obtain 34.1 g of a crude objective substance as a brown oily substance. This substance was used in the next process as it was without being further purified.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][C:12]([CH3:14])=O.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>CCCCCC>[CH:12]([NH:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:14])[CH3:11]
Reactant: CC(C)=O
Reactant: NNC(=O)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: CC(C)NNC(=O)c1ccccc1
Yield: 71.1 %

Procedure:
A solution of benzoylhydrazine (10 g, 73.45 mmol) in hexane (200 ml) was treated with acetone (54 mL, 734.5 mmol) and refluxed overnight. The precipitate was collected by suction filtration to afford a white solid which was treated with TFA (200 ml) and triethylsilane (24 mL, 149.24 mmol) at 60° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between DCM and 1N NaOH. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the product as a white solid (9.31 g, 71%).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH2:8])=[N:5][N:4]=1)[CH3:2].N1C=CC=CC=1.[C:15]1([O:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[C:15]1([O:21][C:22](=[O:23])[NH:8][C:6]2[S:7][C:3]([CH2:1][CH3:2])=[N:4][N:5]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCc1nnc(N)s1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1nnc(NC(=O)Oc2ccccc2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5-Ethyl-[1,3,4]thiadiazol-2-ylamine (2.5 g, 19.4 mmol) and pyridine (1.72 ml, 21.3 mmol) in dichloromethane (70 ml) is cooled to −70° C. and treated with a solution of phenylchloroformate (2.45 ml, 19.6 mmol) in dichloromethane (10 ml) dropwise. The reaction mixture is allowed to warm to ambient temperature and stirred for 3 hours during which a precipitate forms. The precipitate is collected by filtration, and dried under vacuum to afford (5-Ethyl-[1,3,4]thiadiazol-2-yl)-carbamic acid phenyl ester as white solid. [M+H] 250.15
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].[OH-].[K+].[CH3:7][N:8]1[C:12](Cl)=[C:11]([Cl:14])[C:10]([Cl:15])=[N:9]1.O>CS(C)=O>[CH3:7][N:8]1[C:12]([S:4][CH2:1][CH2:2][CH3:3])=[C:11]([Cl:14])[C:10]([Cl:15])=[N:9]1
Reactant: Cn1nc(Cl)c(Cl)c1Cl
Reactant: CCCS
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCSc1c(Cl)c(Cl)nn1C
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A stirred mixture of 4.9 g (0.064 moles) propanthiol and 3 g (0.054 moles) potassium hydroxide in 50 ml dimethylsulfoxide was heated (at about 120° C.) for thirty minutes. Then 10 g (0.054 moles) 1-methyl-3,4,5-trichloropyrazole was added in one portion. Heating (at about 120° C.) of the stirred reaction mixture was continued for about 6 hours. The reaction mixture was allowed to cool. The reaction mixture was added to water (about 50 ml); the resulting mixture was extracted with ether. The etheral phase was separated, washed with water twice, and dried over magnesium sulfate. The solvent was then stripped. The product was distilled out at 124° C. under high vacuum and heat.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]#[C:8][C:9]([OH:11])=O.ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[N:34]=[CH:33][C:32]([C:38]#[N:39])=[C:31]2[NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([Br:47])[CH:42]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[Br:47][C:43]1[CH:42]=[C:41]([NH:40][C:31]2[C:30]3[C:35](=[CH:36][CH:37]=[C:28]([NH:27][C:9](=[O:11])[C:8]#[C:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:29]=3)[N:34]=[CH:33][C:32]=2[C:38]#[N:39])[CH:46]=[CH:45][CH:44]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: COCCOCC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COCCOCC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 37.5 %

Procedure:
To a solution of 0.56 g (3.54 mmol) of 4-(2-methoxy-ethoxy)-but-2-ynoic acid and 0.46 g (3.4 mmol) of isobutyl chloroformate in 12 ml of tetrahydrofuran was added at 0° C. with stirring 0.36 g (3.54 mmol) of N-methylmorpholine. After 15 min, 1.0 g (2.95 mmol) of 6-amino-4-[(3-bromophenyl)amino]-quinoline-3-carbonitrile was added. After stirring 3 hr at 0° C. and 17 hr at room temperature, the mixture was poured into a saturated solution of sodium bicarbonate. The mixture was extracted with ethyl acetate and the organic layer was dries over magnesium sulfate. The solvent was remove and the residue was purified by chromatography on silica gel eluting with chloroform-ethyl acetate mixtures to give 0.53 g of 4-(2-Methoxy-ethoxy)-but-2-ynoic acid[4-(3-bromo-phenylamino)-3-cyano-quinolin-6-yl]-amide as a yellow powder: mass spectrum (electrospray, m/e,): M+H 480.9.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1>C(O)(=O)C>[CH3:8][C:7]1[C:2]([N:1]2[CH:12]=[CH:16][CH:15]=[CH:14]2)=[C:3]([OH:9])[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(O)c1N
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: Cc1cccc(O)c1-n1cccc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 82.5 %

Procedure:
A round bottom flask was charged with 2-amino-3-methyl-phenol (2.5 g, 20.3 mmol) and acetic acid (37.5 mL) which provided a very dark solution. Stirring was commenced and the vessel was charged with 2,5-dimethoxytetrahydrofuran (2.6 mL, 20.3 mmol) added neat dropwise over a period of 2 minutes. The dark mixture was then heated at 100° C. for 3 h then 80° C. for 12 hours. The solvent was evaporated under vacuum and the crude residue purified by column chromatography using a gradient of 0.5-50% EtOAc in hexanes to yield 3-methyl-2-(1H-pyrrol-1-yl)phenol (2.9 g, 83%). ESI-MS m/z calc. 173.1, found 174.3 (M+1)+. Retention time: 1.31 minutes (3 min run).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][CH:12]([CH3:17])[C:11]=2[CH:18]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1>>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][CH:12]([CH3:17])[C:11]=3[CH:18]=2)=[CH:22][CH:21]=1
Reactant: CC1OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: Cc1ccc(S)cc1
Product: Cc1ccc(SCCCCOc2ccc3c(c2)C(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4-methyl-4H-3,1-benzoxazin-2-one and 4-methyl-thiophenol.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][B-:5]([F:8])([F:7])[F:6].[CH3:9][N:10]([CH3:37])[C:11]1[CH:36]=[CH:35][C:14]([CH:15]=[N:16][N+:17]2[CH:21]=[CH:20][N:19]([N:22]=[CH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=3)[C:18]=2SC)=[CH:13][CH:12]=1.CN(C)C=O>C(OCC)C>[F:4][B-:5]([F:8])([F:7])[F:6].[CH3:9][N:10]([CH3:37])[C:11]1[CH:36]=[CH:35][C:14]([CH:15]=[N:16][N+:17]2[CH:21]=[CH:20][N:19]([N:22]=[CH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=3)[C:18]=2[N:2]([CH3:3])[CH3:1])=[CH:13][CH:12]=1
Reactant: CNC
Reactant: CSc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(C)c1ccc(C=Nn2cc[n+](N=Cc3ccc(N(C)C)cc3)c2N(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Gaseous dimethylamine is passed through a mixture of 2.47 g of 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2(methylthio)imidazolium tetrafluoroborate and 30 ml of absolute dimethylformamide until a weight increase of 0.4 g (corresponding to 1.8 equivalents) is achieved and the mixture is subsequently stirred at room temperature overnight. From the resulting reddish solution, there is obtained by the addition of diethyl ether a crystalline precipitate which is removed by filtration under suction and washed twice with water and ethanol each time. After re-precipitation from dimethylformamide/diethyl ether, there is obtained 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-(dimethylamino)imidazolium tetrafluoroborate as a yellow solid of melting point 248°-252° (decomposition).