Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:28][C:29]([CH3:45])([CH3:44])[CH2:30][O:31][S:32]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33]>>[CH3:28][C:29]([CH3:45])([CH3:44])[CH2:30][O:31][S:32]([C:35]1[CH:36]=[C:37]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[C:10]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=4)[N:9]=3)[CH:3]=2)[CH:38]=[CH:39][CH:40]=1)(=[O:34])=[O:33]
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cc1
Reactant: CC(C)(C)COS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)COS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1

Procedure:
3′-[4-Trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid 2,2-dimethyl-propyl ester was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.3) (1.35 g, 3.02 mmol) and 3-(2,2-dimethyl-propyloxysulfonyl)-benzeneboronic acid (example F.4) (1.31 g, 4.81 mmol) according to the general procedure VI. Obtained as a white solid (1.43 g, 80%). MS (ISP) 594.6 [(M+H)+]; mp 157° C.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([C:28]2[CH:33]=[CH:32][C:31]([N:34]([C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=3)[C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)(=[O:8])[O:5]CC)C.Br[Si](C)(C)C>ClCCl>[CH3:50][O:49][C:46]1[CH:47]=[CH:48][C:43]([N:34]([C:35]2[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=2)[C:31]2[CH:30]=[CH:29][C:28]([N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:16]3[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[CH:14][CH:15]=3)=[CH:33][CH:32]=2)=[CH:44][CH:45]=1
Reactant: CCOP(=O)(CCCOc1ccc(N(c2ccc(OC)cc2)c2ccc(N(c3ccc(OC)cc3)c3ccc(OC)cc3)cc2)cc1)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: COc1ccc(N(c2ccc(OC)cc2)c2ccc(N(c3ccc(OC)cc3)c3ccc(OCCCP(=O)(O)O)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11. To a dry 25 mL round bottom flask under nitrogen was added diethyl3-(4-((4-(bis(4-methoxyphenyl)amino)phenyl)(4-methoxyphenyl)amino)phenoxy)propylphosphonate (0.500 g, 0.718 mmol) and the flask was purged with nitrogen. Dichloromethane (1.00 mL) and bromotrimethylsilane (0.199 g, 2.30 mmol) were added under nitrogen and the mixture was allowed to stir at room temperature overnight. Upon disappearance of the starting material the solvent was removed through nitrogen purge. Residual solvent was removed in vacuo. Anhydrous methanol (8.00 mL) was added to the flask and allowed to stir at room temperature overnight. White solid was filtered from methanol through cannula filtration. Solid was washed using 3×5 mL anhydrous methanol and dried in vacuo. The product was collected under nitrogen atmosphere as a green solid (0.185 g, 40.2%). 1H NMR (400 MHz, (CD3)2SO) δ 9.87 (s, 2H), 6.89 (m, 8H), 6.83 (m, 8H), 6.71 (s, 4H), 3.91 (m, 2H), 3.69 (s, 9H), 1.84 (m, 2H), 1.51 (m, 2H). 13C {1H} NMR (400 MHz, (CD3)2S, δ): 154.98, 154.40, 142.17, 140.91, 140.77, 125.27, 125.19, 122.72, 122.68, 115.37, 114.82, 68.35 (m), 55.24, 23.62 (m). 31P NMR (400 MHz, (CD3)2S, δ): 25.05. HRMS-EI (m/z): [M]+ calcd for C36H37N2O7P, 640.23; found, 640.1). Anal. Calcd for C36H37N2O7P: C, 67.49; H, 5.82; N, 4.37. Found: C, 67.09; H, 6.16; N, 3.99.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:9]2[CH2:12][CH:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10]2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[N:9]2[CH2:10][CH:11]([N:13]([CH3:33])[S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=S(=O)(NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CN(C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)S(=O)(=O)c1ccccc1

Procedure:
By carrying out the operation according to the procedure of Example 24, but starting with 0.21 g of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-phenylsulfonamide, 17 mg of 80% sodium hydride and introducing iodomethane in two portions at an interval of 3 hours. 80 mg of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-methylphenylsulfonamide are thus obtained in the form of a white lacquer [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 2.70 (s: 3H); 3.03 (broad t, J=7.5 Hz: 2H); 3.37 (broad t, J=7.5 Hz: 2H); 3.94 (mt: 1H); 4.28 (s: 1H); from 7.20 to 7.35 (mt: 8H); from 7.45 to 7.65 (mt: 3H); 7.74 (broad d, J=8 Hz: 2H)].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:7]=[C:6]([OH:29])[CH:5]=1.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:5]=[C:6]([O:29][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:7]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:9]=1
Reactant: BrCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCc2ccccc2)cc(C(=O)OC)c1
Yield: 75.5 %

Procedure:
A mixture of 50.9 g (0.12 mol) of 3-hydroxy-5-(octadecyloxy)benzoic acid methyl ester, 21.6 ml (0.18 mol) of benzyl bromide and 50 g (0.36 mol) of potassium carbonate in 750 ml of DMF was stirred and heated at 85° for 65 hours. The reaction mixture was filtered and the filtrate was concentrated at reduced pressure. The residue was recrystallized from methylene chloride-methanol to give 46.3 g (75% yield, mp 61°-63°) of 3-(octadecyloxy)-5-(phenylmethoxy)benzoic acid methyl ester. The structure was confirmed by the nmr spectrum.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:15]([Cl:16])=[CH:14][C:13]([OH:17])=[CH:12][C:11]=1[Cl:18])(=[O:3])[CH3:2].[Cl:19][C:20](Cl)([Cl:24])[CH2:21][CH2:22]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([Cl:18])=[CH:12][C:13]([O:17][CH2:22][CH:21]=[C:20]([Cl:24])[Cl:19])=[CH:14][C:15]=1[Cl:16])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCOc1c(Cl)cc(O)cc1Cl
Reactant: ClCCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 80 °C
Yield: 78.4 %

Procedure:
A solution of 25.3 grams (0.086 mole) of 4-(2,6-dichloro-4-hydroxyphenoxy)butyl acetate in 250 mL of DMF was stirred, and 19.5 grams (0.1 mole) of 1,1,1,3-tetrachloropropane was added, followed by 18 grams (0.13 mole) of potassium carbonate. Upon completion of addition the reaction mixture was heated at 80° C. during a 17 hour period. After this time the reaction mixture was cooled to ambient temperature, stirred with 350 mL of water and extracted with four 150 mL portions of diethyl ether. The combined extracts were washed with two 100 mL portions of water, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 1:1 methylene chloride:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 27.1 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: O.C(O)(=O)C[C:4]([CH2:9][C:10]([OH:12])=O)([C:6](O)=O)O.S(O)(O)(=O)=O.C([NH:22][C:23](=[NH:27])[NH:24][CH2:25][CH3:26])C.OS(O)(=O)=O.O=S(=O)=O.[CH2:37](C(C)=O)[CH:38](C)C>O.N>[OH:12][C:10]1[CH:9]=[C:4]([CH3:6])[N:22]=[C:23]([N:24]([CH2:25][CH3:26])[CH2:37][CH3:38])[N:27]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CCNC(=N)NCC
Reactant: CC(=O)CC(C)C
Agent: N
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O
Product: CCN(CC)c1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of citric acid monohydrate (126.0 g) and diethylguanidine sulphate (82.0 g) was added to 15% oleum (250 ml), keeping the temperature below 30° C by external cooling. After stirring at the ambient temperature for 15 minutes to complete solubilisation the solution was heated at 70° C for 80 minutes, cooled by external cooling to 0° C, and carefully diluted with water (350 ml) and with ammonia solution (s.g. 0.880, 600 ml). The resulting slurry was heated to reflux, methyl isobutyl ketone (10 ml) being added to prevent excessive frothing. Refluxing was continued for 16 hours, after which the mixture was cooled to 70°-80° C and methyl isobutyl ketone (600 ml) added to dissolve the precipitate. The ketonic phase was separated, washed with water (2 × 100 ml) whilst still hot, and then cooled and dried over anhydrous magnesium sulphate. Evaporation of the solvent yielded chromatographically pure 4-hydroxy-2-diethylamino-6-methylpyrimidine, melting point 133°- 135° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]([C:17]1[CH:18]=[C:19]([NH:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[CH:20]=[CH:21][CH:22]=1)#[N:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([NH:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:15]#[N:16])[CH:18]=2)[CH:25]=1
Reactant: N#Cc1cccc(Nc2cccc(C(=O)O)c2)c1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cccc(Nc2cccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)c2)c1
Yield: 37.1 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-3-(3-cyanophenylamino)benzamide was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.030 g; 0.130 mmol), 3-(3-cyanophenylamino)benzoic acid (0.037 g; 0.155 mmol), HATU (0.064 g; 0.169 mmol) and N,N-diisopropylethylamine (0.060 mL; 0.324 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.020 g (37%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[CH:15][N:14](/[CH:17]=[CH:18]\[C:19]([NH:21][NH2:22])=[O:20])[N:13]=2)[CH:5]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:7]=1.[CH3:23]OC(OC)OC.CS(O)(=O)=O.CCOC(C)=O.CCCCCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[CH:15][N:14](/[CH:17]=[CH:18]\[C:19]3[O:20][CH:23]=[N:22][N:21]=3)[N:13]=2)[CH:5]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:7]=1
Reactant: COC(OC)OC
Reactant: CC(C)Oc1cc(Cl)cc(-c2ncn(/C=C\C(=O)NN)n2)c1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)Oc1cc(Cl)cc(-c2ncn(/C=C\c3nnco3)n2)c1
Temperature: 70 °C
Yield: 1050.7 %

Procedure:
In a 25-mL, 3N round-bottomed flask equipped with nitrogen inlet, and a rubber septum, (Z)-3-(3-(3-chloro-5-isopropoxyphenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (0.3 g, 1.0 eq.) was dissolved in THF (7.5 mL, 25V) and trimethylorthoformate (0.109 g, 1.1 eq) and added Methanesulphonic acid (0.053 g, 0.5 eq) was added into it. The Reaction mixture was refluxed at 70° C. for 2-3 h. The progress of the reaction was followed by TLC analysis on silica gel with 50% EtOAc-hexane as mobile phase. SM Rf=0.40 and Product Rf=0.5. Reaction mixture was poured into ice water (10 mL) slurry and compound was extracted with EtOAc (3×15 mL). The combined organic layers was washed with brine solution (3×15 mL), dried over MgSO4, filtered, and concentrated by rotary evaporation (25° C., 20 mmHg) to afford 0.28 g of Crude compound. evaporation (25° C., 20 mmHg) to afford 3.25 g of a yellow oil. The resulting crude compound was subjected to column purification. The crude reaction mixture was purified by column chromatography using silica 60/120 using ethyl acetate:hexane as mobile phase. The column (5×10 cm) was packed in hexane and started eluting in ethyl acetate in gradient manner starting with fraction collection (25-mL fractions) from 35% to 40% ethyl acetate in hexane. Compound started eluting with 35% ethylacetate in hexane. Fraction containing such TLC profile was collected together to obtain pure compound (50 mg), Yield (16.18%). 1H NMR (400 MHz, CDCl3) δ 10.3 (s, 1H), 8.50 (s, 1H), 8.46 (s, 1H), 7.74 (s, 1H), 7.63 (s, 1H) 7.50-7.53 (d, J=12 Hz, 1H) 7.01 (s, 1H) 6.27-6.30 (d, J=12 Hz, 1H) 4.65-4.71 (m, 1H) 1.39-1.40 (d, J=4 Hz, 6H) LCMS C11H7ClF3N3 (331.76)[M+1] found 331.85 at 3.910. (LCMS 99.67%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].F[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([CH3:34])[CH:26]=3)[CH:22]=[CH:21][N:20]=2)=[C:11]([O:35][CH3:36])[CH:10]=1.ClC1C(C2C3C(=CC=CC=3)N(C)C=2)=NC(NC2C=C([N+]([O-])=O)C(F)=CC=2OC)=NC=1.CCN(C(C)C)C(C)C>FC(F)(F)CO>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][N:5]([CH3:6])[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]([CH3:34])[CH:26]=3)[CH:22]=[CH:21][N:20]=2)=[C:11]([O:35][CH3:36])[CH:10]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Reactant: CNCCN(C)C
Agent: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Solvent: OCC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 140 °C
Yield: 62 %

Procedure:
N1,N1,N2-trimethylethane-1,2-diamine (80 mg, 0.79 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 129, (which may be prepared by the method described for Intermediate 87); 350 mg, 0.79 mmol) and DIPEA (0.342 mL, 1.97 mmol) in 2,2,2-trifluoroethanol (5 mL). The mixture was heated in a microwave at 140° C. for 1 h. The cooled reaction mixture was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M methanolic ammonia and appropriate fractions were combined and concentrated in vacuo onto silica. Purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 gave the title compound (230 mg, 62%) as an orange solid; 1H NMR: 2.16 (6H, s), 2.45-2.49 (2H, t, obscured by DMSO peak), 2.86 (3H, s), 3.26 (2H, t), 3.87 (3H, s), 3.95 (3H, s), 6.85 (1H, s), 7.11 (1H, t), 7.21 (1H, d), 7.25 (1H, t), 7.52 (1H, d), 8.10 (1H, s), 8.31 (1H, d), 8.33 (1H, s), 8.36 (1H, d), 8.62 (1H, s); m/z: ES+ MH+ 476.40.
Reaction SMILES: CO[C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CO>[N:10]1([C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: C1COCCN1
Reactant: CCC(=O)CC(=O)OC
Solvent: CO
Product: CCC(=O)CC(=O)N1CCOCC1

Procedure:
50.0 g (384 mmol) of 3-oxovaleric acid methyl ester and 35.1 g (403 mmol) of morpholine were heated for 9 h at 110° C., whereby the methanol formed was removed via a distillation bridge. The reaction mixture was then freed of volatile constituents on a rotary evaporator and purified by column chromatography (silica gel, eluent: gradient of ethyl acetate to ethanol). The pure product fractions were freed from solvent on a rotary evaporator and yielded 39.7 g (60%) of a viscous, colorless, clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C@@H:10]([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.I[CH2:14][CH3:15].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([CH2:14][CH3:15])[C@@H:10]([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: CCI
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCN1c2cc(Cl)nc(=O)n2C[C@@H]1C
Temperature: 90 °C
Reaction time: 1 h
Yield: 139.2 %

Procedure:
To a solution of (S)-7-chloro-2-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (50.0 mg, 0.269 mmol) and iodoethane (63.0 mg, 0.404 mmol) in acetonitrile (1 ml) was added Cs2CO3 (176 mg, 0.539 mmol). The reaction mixture was stirred at 90° C. for 1 h, filtered and concentrated to give crude product (80 mg) as a brown solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][C:20]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:14]=[C:13]1[CH2:33][O:34][CH2:35][CH3:36])(C)(C)C.[ClH:38]>C(O)C>[ClH:38].[ClH:38].[CH2:26]([O:25][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH2:7])[C:13]([CH2:33][O:34][CH2:35][CH3:36])=[N:14][C:15]=3[CH:16]=[N:17][C:18]=2[CH:19]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCN
Temperature: 25 °C

Procedure:
tert-Butyl[4-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate (21.0 g) was dissolved in ethanol (100 mL) and concentrated hydrochloric acid (13.0 mL). The reaction was heated at reflux for 1 hour and then cooled to ambient temperature. A tan precipitate formed. The solid was filtered and dried under vacuum for 16 hours to yield 12.1 g of 4-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butylamine dihydrochloride as a beige solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[NH2:11])=[CH:3][CH:2]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2/[CH:8]=[CH:7]/[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1C=Cc1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2ccccc2/C=C/c2ccncc2)cc1
Yield: 21.1 %

Procedure:
Using 4.93 g of 2-[2-(4-pyridyl)ethenyl]aniline and 5.70 g of p-methoxybenzenesulfonyl chloride, the reaction and after-treatment procedure of Example 1 was otherwise carried out to give a crystal crop. This crystal crop was recrystallized from ethanol to provide 1.94 g of the title compound (light yellowish white prisms). m.p. 207-209° C.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:20]([NH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:12])=[O:21]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: Cc1ccccc1N=C=O
Product: Cc1ccccc1NC(=O)Nc1ccc([N+](=O)[O-])cc1O
Yield: 66.1 %

Procedure:
The urea was prepared from 2-hydroxy 4-nitro aniline(308 mg, 2 mmol) and 2-methyl phenylisocyanate(2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.38 g, 53%). EI-MS m/z 288(M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[CH3:16][S-:17].[Na+]>CS(C)=O.O>[CH3:16][S:17][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]1=[O:15]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: C[S-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of N-(3-bromopropyl)phthalimide (500 mg) in DMSO (8 mL) was added sodium thiomethoxide (144 mg) and the reaction stirred at room temperature for 16 h. Then with water (2 mL) was added and the mixture stirred at room temperature for 10 min. The reaction was diluted with water (20 mL) and extracted into ethyl acetate (2×20 mL). The combined organics were washed with aqueous brine solution (2×20 mL), dried (MgSO4) and reduced in vacuo to give 2-(3-methylsulfanyl-propyl)-isoindole-1,3-dione as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:5]([CH3:13])=[CH:4][C:3]=1[CH:14]([CH3:22])[C:15](N1CCCC1)=[O:16].Cl.C1(N=C=NC2CCCCC2)CCCCC1>C(O)(=O)C>[CH3:22][CH:14]1[C:3]2[CH:4]=[C:5]([CH3:13])[C:6]([N:8]3[CH2:12][CH2:11][CH2:10][CH2:9]3)=[CH:7][C:2]=2[O:1][C:15]1=[O:16]
Reactant: Cc1cc(C(C)C(=O)N2CCCC2)c(O)cc1N1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc2c(cc1N1CCCC1)OC(=O)C2C
Reaction time: 1 h

Procedure:
A mixture of 1.8 g (6 mmoles) of 2-[2-hydroxy-5-methyl-4-(pyrrolidin-1-yl)-phenyl]-propionic acid pyrrolidide, 2 ml of glacial acetic acid and 2 ml of concentrated hydrochloric acid is boiled under reflux for 40 minutes. The reaction mixture is concentrated by evaporation in vacuo, water is added to the residue, the pH is adjusted to 5 with dilute sodium hydroxide solution and extraction with ether is carried out 3 times. The combined ethereal extracts are dried over sodium sulphate and concentrated in vacuo to 10 ml. 1.2 g (6 mmoles) of N,N'-dicyclohexylcarbodiimide are added thereto and the mixture is left at room temperature for one hour; the residue is filtered off, subsequently washed with ether, and the filtrate is concentrated by evaporation in vacuo. The residue is chromatographed over silica gel with petroleum ether/ether. Subsequent recrystallisation of the pure fractions from ether/petroleum ether yields 3,5-dimethyl-6-(pyrrolidin-1-yl)-benzofuran-2(3H)-one having a melting point of 68°-69°. The starting material can be obtained, for example, as follows:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[CH:15]=[N:14][C:13](SC)=[N:12][C:11]=3[N:18]=2)[CH:4]=[N:3]1.C(Cl)[Cl:20]>C(#N)C>[Cl:20][C:13]1[N:14]=[CH:15][C:10]2[CH:9]=[CH:8][C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[N:18][C:11]=2[N:12]=1
Reactant: ClCCl
Reactant: CSc1ncc2ccc(-c3cnn(C)c3)nc2n1
Solvent: CC#N
Product: Cn1cc(-c2ccc3cnc(Cl)nc3n2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
7-(1-Methyl-1H-pyrazol-4-yl)-2-(methylthio)pyrido[2,3-d]pyrimidine (Preparation 56, 13 mg, 0.05 mmol), was dissolved in acetonitrile and stirred at 0° C. for 15 minutes followed by the addition of SO2C2 in DCM. After 20 minutes the solution was quenched with NaHCO3 solution at 0° C., the organic solvents were removed in vacuo, and the solids were filtered, washed with water and dried to afford the title compound (7.5 mg, 60%).