Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11](=[S:13])[NH:10][C:9](=[O:14])[C:8]=2[CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:16]([CH2:24][CH2:25][CH2:26][CH2:27]C1C=C(S([O-])(=O)=O)C=CC=1C)[Si](C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[OH:16][CH2:24][CH2:25][CH2:26][CH2:27][N:12]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:8]([CH3:15])[C:9](=[O:14])[NH:10][C:11]1=[S:13]
Reactant: Cc1c(-c2ccccc2)[nH]c(=S)[nH]c1=O
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1CCCCO[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)n(CCCCO)c(=S)[nH]c1=O
Reaction time: 1.5 h
Yield: 4.1 %

Procedure:
To 2 ml of dimethyl sulfoxide, 468 mg (2.0 mmol) of 6-phenylthiothymine, 358 mg (1.0 mmol) of 4-(t-butyldimethylsiloxy)-butyl-p-toluenesulphonate and 276 mg (2.0 mmol) of potassium carbonate were added and heated to react for 4 hours at 80° C. The reaction mixture was concentrated under reduced pressure, added with methanol and filtered. The filtrate was concentrated under reduced pressure, added with 20 ml of tetrahydrofuran and 1 ml of 1N hydrochloric acid and stirred for 90 minutes. The reaction mixture was concentrated under reduced pressure and adsorbed on a silica gel column and eluted with 2% methanol/chloroform. The eluate was concentrated and crystallized from acetone/hexane to obtain 12.0 mg of the target compound (Yield: 4%).
Reaction SMILES: [CH2:1]([N:5]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]I)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([N:5]([C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH2:13][NH:38][C:39]2[N:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:15])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CI)C(=O)O)cc1
Reactant: Nc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CNc2ccccn2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-iodoacetyl-L-lysine (200 mg, 0.38 mmol, example 105, step B) by following the indications of general procedure H using DIEA (0.19 mL, 1.09 mmol) and 2-aminopyridine (170 mg, 1.31 mmol). The crude material was purified by preparative HPLC. The product was isolated as a solid (88 mg, 47% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:65][C:66]1[CH:67]=[C:68]([CH:70]=[CH:71][CH:72]=1)[NH2:69]>C(Cl)Cl>[Cl:65][C:66]1[CH:67]=[C:68]([NH:69][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])[CH:70]=[CH:71][CH:72]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1cccc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2cccc(Cl)c2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (0.150 mL, 0.855 mmol) and 3-chloro-aniline (Aldrich, 44 mg, 0.32 mmol). The mixture was stirred at rt for 1.5 hr. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (20 g column, 0-10% EtOAc/methylene chloride) to give a white solid. 48 mg.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.OS(O)(=O)=O.O=S(=O)=O>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([NH2:6])=[CH:8][C:9]=1[S:1]([OH:3])(=[O:5])=[O:2]
Reactant: Cc1ccc(N)cc1
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: Cc1ccc(N)cc1S(=O)(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
107 parts of fused p-toluidine are added dropwise over 30 minutes to 183 parts of 100% sulfuric acid, while keeping the temperature at 75°-80° C. After stirring for 15 minutes the p-toluidine is completely dissolved. This sulfuric acid solution is then run into 260 parts of 66% oleum over 30 minutes, while keeping the temperature at 40°-50° C. by cooling with an ice bath. Stirring is continued for 30 minutes at 45°-50° C., after which time no more educt can be detected by HPLC. The batch is poured into 500 parts of ice/water and the precipitated 4-methylaniline-3-sulfonic acid is filtered with suction and washed with 500 parts of ice/water, affording 248 parts of moist 70.0% 4-methylaniline-3-sulfonic acid, corresponding to a yield of 93%, based on p-toluidine. No more p-toluidine and no more 4-methylaniline-2-sulfonic acid is detectable by HPLC (<0.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH2:26])=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH:26][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:10])=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)Nc2ccc(Cl)cc2)sc1C(=O)NCc1ccccc1
Yield: 62 %

Procedure:
Following the procedure as described in Example 4, making variations only as required to use 4-chlorophenyl isocyanate in place of phenyl isocyanate to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 62% yield; m.p.>300° C.; 1H NMR (DMSO-d6, 300 MHz) δ 9.14 (s 1H), 8.47 (t, J=6.0 Hz, 1H), 7.51-7.48 (m, 2H), 7.35-7.17 (m, 8H), 4.35 (d, J=5.7 Hz, 2H), 2.43 (s, 3H); 13C NMR (DMSO-d6, 75 MHz) δ 162.2, 140.1, 138.1, 129.2, 128.7, 127.7, 127.1, 126.8, 120.7, 43.0, 39.1; MS (ES+) m/z 401.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH2:14]([N:26]=[C:27]=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CCOCC>[CH2:14]([NH:26][C:27]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]([CH3:12])[CH2:11][C:2]1([CH3:13])[CH3:1])=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC1CC(C)(C)Nc2ccccc21
Reactant: CCCCCCCCCCCCN=C=O
Solvent: CCOCC
Product: CCCCCCCCCCCCNC(=O)N1c2ccccc2C(C)CC1(C)C
Temperature: -70 °C
Reaction time: 168 h
Yield: 66 %

Procedure:
0.1 mole of 2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline is dissolved in 50 ml of ether and the solution is mixed with 0.1 mole of n-dodecyl isocyanate. A spatula tip of diazadicyclooctane is then added, the mixture is left to stand for 7 days at 20° to 25° C. and cooled at -70° C. and the precipitate which has separated out is filtered off. N-n-Dodecylaminocarbonyl-2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline with a melting point of 48°-50° C. is obtained.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[Cl:11][CH2:12][C:13](Cl)=[O:14]>>[Cl:11][CH2:12][C:13]([NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:10])=[O:9])=[O:14]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(Cl)CCl
Product: O=C(CCl)Nc1ccccc1C(=O)O

Procedure:
Anthranilic acid shown by formula (10) is reacted with chloroacetyl chloride to obtain N(chloroacetyl)anthranilic acid shown by formula (15). This reaction is suitably carried out by heating under reflux in a solvent such as benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7][N:8]2[CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:4][CH:3]=1
Reactant: CC(C)CCBr
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CCn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 110.7 %

Procedure:
A mixture of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (200 mg, 0.81 mmol) and potassium carbonate (214 mg, 2.02 mmol) in N,N-dimethylformamide (2 mL) was stirred at 25° C. for 30 min. This mixture was then treated with 1-bromo-3-methylbutane (0.15 mL, 1.21 mmol) and then heated at 60° C. for 5 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (1×50 mL), water (2×50 mL), and a saturated aqueous sodium chloride solution (1×50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford 1-[6-chloro-1-(3-methyl-butyl)-1H-indol-3-yl]-2,2,2-trifluoro-ethanone (284.9 mg) as dark yellow solid which was used without further purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]#[C:13][C:14]([CH2:18][F:19])([OH:17])[CH2:15][F:16].N1C=CC=CC=1>C(=O)([O-])[O-].[Ba+2].[Pd+2].C(=O)([O-])[O-].C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1/[CH:12]=[CH:13]\[C:14]([CH2:18][F:19])([OH:17])[CH2:15][F:16]
Reactant: OC(C#Cc1cc(C(F)(F)F)ccc1Cl)(CF)CF
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: OC(/C=C\c1cc(C(F)(F)F)ccc1Cl)(CF)CF
Temperature: 25 °C
Reaction time: 240 h
Yield: 98.2 %

Procedure:
A mixture of 4-(2-chloro-5-trifluoromethylphenyl)-1-fluoro-2-fluoromethyl-3-butyn-2-ol (44.5 g), 5% palladium-barium carbonate (6.6 g), pyridine (2.3 g) and ethyl acetate (500 ml) was stirred under a hydrogen atmosphere at room temperature for 10 days. The catalyst was filtered off from the reaction mixture; subsequent concentrating under reduced pressure gave 4-(2-chloro-5-trifluoromethylphenyl)-1-fluoro-2-fluoromethyl-3-cis-buten-2-ol (44.0 g).
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]=[CH:7]1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A suspension of 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 7.8 mmol) in pyridine (1 L) was warmed to 60° C. to dissolve the starting material. The solution was cooled to about 30° C. and then benzoyl chloride (1.1 g, 7.8 mmol) diluted with pyridine (100 mL) was slowly added. After 1 hour analysis by high performance liquid chromatography (HPLC) indicated that some starting material remained. Additional benzoyl chloride (0.3 g) was added and the reaction was warmed to 50° C. overnight. The reaction mixture was concentrated under vacuum. The resulting residue was combined with chloroform (200 mL) and 1% sodium carbonate (200 mL). The organic layer was separated and then concentrated under vacuum. The resulting residue was combined with propyl acetate (30 mL) and heated on a steam bath to dissolve the residue. The solution was allowed to cool. The resulting precipitate was isolated by filtration to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzamide as a solid, m.p. 210-212° C. Analysis: Calculated for C21H21N5O: %C, 70.18; %H, 5.89: %N, 19.48; Found: %C, 69.49; %H, 5.97; %N, 19.64. 1H NMR (500 MHz, DMSO-d6) δ8.48 (t, J=6.0 Hz, 1H), 8.22 (s, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.43 (m, 3H), 7.21 (t, J=8.0 Hz, 1H), 6.62 (broad s, 2H), 4.64 (t, J=7.0 Hz, 2H), 3.30 (q, J=6.0 Hz, 2H), 1.92 (quintet, J=7.0 Hz, 2H), 1.58 (quintet, J=7.0 Hz, 2H); MS (EI) m/e 359.1746 (359.1746 calcd for C21H21N5O).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:8]([OH:14])[C:9]([CH3:13])([CH3:12])[CH2:10][Cl:11])=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:8]([O:14][C:22](=[O:24])[CH3:23])[C:9]([CH3:12])([CH3:13])[CH2:10][Cl:11])=[CH:20][CH:21]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(CCl)C(O)C(Oc1ccc(Cl)cc1)n1cncn1
Product: CC(=O)OC(C(Oc1ccc(Cl)cc1)n1cncn1)C(C)(C)CCl
Temperature: 100 °C
Yield: 65 %

Procedure:
23.1 g (0.07 mol) of 1-(4-chlorophenoxy)-1-(1,2,4-triazol-1-yl)-3,3-dimethyl-4-chloro-butan-2-ol were dissolved in 100 ml of acetic anhydride and the solution was heated to 100° C. for 12 hours. Thereafter, it was concentrated by distilling off excess acetic anhydride in vacuo. The oil which remained was taken up in 150 ml of diisopropyl ether and the product was allowed to crystallize out at 0° C. 17 g (65% of theory) of 1-(4-chlorophenoxy)-1-(1,2,4-triazol-1-yl)-2-acetoxy-3,3-dimethyl-4-chloro-butane of melting point 111°-117° were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][C:17]3[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:18]=3[CH3:26])[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]>CC(O)=O.CO.[Fe]>[NH2:23][C:21]1[CH:20]=[CH:19][C:18]([CH3:26])=[C:17]([NH:16][C:14]2[CH:15]=[C:10]([NH:9][C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)[N:11]=[CH:12][N:13]=2)[CH:22]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(N)cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.3 %

Procedure:
Synthesis of N-(5-Amino-2-methylphenyl)-N′-(3-chloro-4-fluorophenyl)-pyrimidine-4,6-diamine (Int-F) A mixture of 4-(3-chloro-4-fluorophenyl)-6-chloropyrimidin-4-ylamine (IR-4) (1.2 g, 4.6 mmol), 2-methyl-5-nitroaniline (0.85 g, 5.5 mmol) and 1 mL of concentrated HCl in 10 mL of n-butanol was heated at 120° C. for 16 h. With stirring, 5 mL of EtOAc was added to the reaction mixture. The light yellow colored product that precipitated was filtered and dried under vacuum to give N-(3-chloro-4-fluorophenyl)-N′-(2-methyl-5-nitrophenyl)pyrimidine-4,6-diamine. MS (APCI) (m/z): 374/376 (M+1). A mixture of N-(3-chloro-4-fluorophenyl)-N′-(2-methyl-5-nitrophenyl)pyrimidine-4,6-diamine (0.55 g, 1.5 mmol) and iron powder (35 mesh, 0.5 g, 5 eq) in 5 mL of HOAc and 2 mL of MeOH was heated at reflux for 2 h. The solvent was removed in vacuo and the dark colored residue was mixed with 150 mL of CH2Cl2 and 15 mL of sat. K2CO3 solution and was stirred at room temperature for 30 min. The organic layer was dried (MgSO4), was concentrated, and was then purified by flash chromatography (silica gel, MeOH/NH4OH/CH2Cl2) to afford 0.115 g of N-(5-amino-2-methylphenyl)-N′-(3-chloro-4-fluorophenyl)pyrimidine-4,6-diamine as a light colored solid. (Int-F) MS (m/z): 344/346 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(S(C)(=O)=O)cc1C(=O)O
Reaction time: 2 h

Procedure:
Combine methyl 2-methoxy-5-methylsulfonylbenzoate (2.24 g, 9.2 mmol) and a 1 M aqueous potassium hydroxide solution (10 mL, 10 mmol). Heat to reflux. After 2 hours, filter while still hot, cool in an ice bath, and acidify by dropwise addition of a 1 M aqueous hydrochloric acid solution (11 mL) to give a solid. Collect the solid by filtration, rinse with water, and dry to give the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=O)(=[O:3])[CH3:2].[NH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH2:14][CH2:15]2>O=P(Cl)(Cl)Cl>[C:1]([N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH2:14][CH2:15]2)(=[O:3])[CH3:2]
Reactant: Nc1cccc2c1CCC2
Reactant: CC(=O)N1CCNC1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)N1CCN=C1Nc1cccc2c1CCC2
Reaction time: 40 h
Yield: 34.6 %

Procedure:
140.9 g (1.1 moles) of 1-acetyl-2-imidazolidinone (melting point 186°-187° C.) are introduced into 1,320 ml of POCl3 and 133.2 g (1 mole) of 4-amino-indan are added dropwise, with vigorous stirring, under conditions such that the internal temperature does not rise above 50° C. After completion of the addition, stirring is continued for 40 hours at 50° C. The excess POCl3 is then distilled off as completely as possible under reduced pressure on a rotary evaporator and the distillation residue is added to 5 l of ice water whilst keeping the temperature at ≤15° C. by further addition of ice. The pH is brought to 11 by means of 25% strength sodium hydroxide solution, whilst cooling with ice, the mixture is repeatedly extracted with chloroform, the combined chloroform phases are again washed with 1 liter of 2 N sodium hydroxide solution and are then washed neutral with water and dried over anhydrous sodium sulfate, and the chloroform is distilled off. The residue is recrystallized from isopropanol. 84.3 g of pure 1-acetyl-(4-indanylamino)-2-imidazoline of melting point 180.5°-182° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4][NH2:5].[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1>>[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])=[CH:10][CH:9]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COC(=O)CN
Product: COC(=O)CNCc1ccc(O)cc1
Yield: 40 %

Procedure:
Prepared as in example 10-10a from glycine methyl ester and 4-hydroxybenzaldehyde. Yield 40%. MS M+H calculated 196.1. Found 196.1
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>C1(C)C=CC=CC=1>[C:6]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH:2]([N:13]([CH:14]([CH3:19])[CH3:15])[CH3:11])[C:1]([OH:5])=[O:4])=[CH:16][CH:15]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: O=CC(=O)O
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)N(C)C(C(=O)O)c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 62 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with glyoxylic acid (618 mg, 6.72 mmol), toluene (20 mL), N,N-isopropylmethylamine (486 mg, 6.60 mmol) and 4-(tert-butoxycarbonylamino) phenylboronic acid (1.58 g, 6.66 mmol). The reaction was sealed with a plastic cap under a nitrogen atmosphere and stirred at room temperature for 7 d. After this time, the reaction was concentrated under reduced pressure. The resulting residue was subjected to flash chromatography to afford 25 in 62% yield (1.34 g) as a light brown solid: mp 320° C. dec, 1H NMR (300 MHz, DMSO-d6) δ 9.42 (s, 1H), 7.42 (d, 2H, J=8.7 Hz), 7.37 (d, 2H, J=8.7 Hz), 4.23 (s, 1H), 3.28 (m, 1H), 3.17 (s, 1H), 2.23 (s, 3H), 1.47 (s, 9H), 1.15 (d, 3H, f=6.6 Hz), 1.11 (d, 3H, J=6.6 Hz); MS (ESI+) m/z 323 (M+H).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[C:5]([O:10][CH3:11])(=[O:9])[C:6]([CH3:8])=[CH2:7]>CO>[CH3:11][O:10][C:5](=[O:9])[CH:6]([CH3:8])[CH2:7][NH:4][CH2:1][CH:2]=[CH2:3]
Reactant: C=CCN
Reactant: C=C(C)C(=O)OC
Solvent: CO
Product: C=CCNCC(C)C(=O)OC
Yield: 78.1 %

Procedure:
A solution of 11.42 g (0.20 mole) of allylamine, 24.03 g (0.24 mole) of methyl methacrylate and 100 mL of methanol in a pressure bottle, was heated at 90 degrees for 43 hours. After cooling the mixture was concentrated, then vacuum distilled under vaccuum to give 24.55 g (rac)-2-methyl-3-(2-propenylamino)-propanoic acid methyl ester as colorless oil. b.p. 70 degrees, 5 mm Hg.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][C:14]1([CH3:18])[CH2:17][O:16][CH2:15]1>ClCCl.N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][C:14]2([CH3:18])[CH2:17][O:16][CH2:15]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(CO)COC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Temperature: 20 °C

Procedure:
4-Toluenesulfonyl chloride (20 g, 105 mmol) was dissolved in a mixture of dichloromethane (DCM) (50 ml) and pyridine (50 ml) and cooled in an ice bath. 3-(hydroxymethyl)-3-methyloxetane (100 mmol, 9.9 mL) was added dropwise. The temperature was increased to 20° C. overnight. The solution was diluted with DCM (100 mL) and extracted with water. The organic phase was dried over magnesium sulfate and filtered. The volatile solvents were removed by evaporation. The remaining material was concentrated several times with toluene to remove the residual pyridine and then with chloroform to remove the residual toluene. Yield: 22 g of a white crystalline solid (92%). TLC: Rf(petroleum ether/ethyl acetate, 1:1) 0.56.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[CH3:18][S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:17][CH2:16][CH2:15][NH:14][C:4]1[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:29]2[CH2:28][CH2:27][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19][CH3:18])[CH2:31][CH2:30]2)[N:3]=1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Reactant: CSc1ccccc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CSc1ccccc1N1CCN(c2nc(NCCO)nc(NCCO)c2C#N)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-(2-methylsulfanyl-phenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 60° C. to yield the 2,4-bis-(2-hydroxy-ethylamino)-6-[4-(2-methylsulfanyl-phenyl)-piperazin-1-yl]-pyrimidine-5-carbonitrile as a yellowish lyophilisate; MS: [M+H]+=430.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[C:14]1([S:20]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH:10]=[O:11])=[CH:2]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reaction time: 0.5 h

Procedure:
A stirred solution of 1H-indole-3-carboxaldehyde (1 g, 6.89 mmol), in DMF (25 mL) was treated with sodium hydride (0.357 g, 60% in mineral oil, 8.95 mmol) under nitrogen at room temperature, stirred for 30 minutes, treated with benzene sulfonyl chloride (1.09 mL, 8.25 mmol), stirred at room temperature for 3-5 hrs. After the completion of reaction (T. L. C.), the reaction mixture was quenched with 25 mL ice-cold water and diluted with 25 mL ethyl acetate. The organic phase was separated, washed sequentially with water and brine, dried over anhydrous MgSO4 and concentrated in vacuo. The resultant residue was purified by flash chromatography (silica gel, EtOAc/Hexane, 2/8) to afford the title compound as an off-white foam, which was latter identified by IR, NMR and mass spectral data.