Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Cl[CH2:16][CH2:17][NH:18][C:19]([NH:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[C:24]([CH3:32])[CH:23]=1)=[O:20].C([O-])(O)=O.[Na+].N[C@H](C(O)=O)CC1C=C2C(C=CC=C2)=CC=1>C1COCC1>[OH:13][C:7]1([C:4]2[CH:3]=[CH:2][C:1]([CH3:14])=[CH:6][CH:5]=2)[CH2:8][CH2:9][N:10]([CH2:16][CH2:17][NH:18][C:19]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[C:24]([CH3:32])[CH:23]=2)=[O:20])[CH2:11][CH2:12]1
Reactant: Cc1ccc(C2(O)CCNCC2)cc1
Reactant: Cc1cc(NC(=O)NCCCl)c2ccccc2n1
Agent: N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C2(O)CCN(CCNC(=O)Nc3cc(C)nc4ccccc34)CC2)cc1
Temperature: 70 °C
Reaction time: 144 h

Procedure:
To a solution of 4-p-tolyl-piperidin-4-ol (0.03 mmol) in dry THF (1 mL) is added 1-(2-chloro-ethyl)-3-(2-methyl-quinolin-4-yl)-urea (0.03 mmol), solid NaHCO3 (2.5 mg), and Nal (1 mg). The flask is tightly sealed, and shaken at 70° C. for 6 days. The reaction mixture is evaporated, taken up in aqueous formic acid, and purified by preparative HPLC to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[N:19]=[C:20]([CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[N:21]([CH3:22])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:36]C1C=CC2C3N(CC(C)C)C(C)=NC=3C=NC=2C=1)C1C=CC=CC=1.C1C=C(Cl)C=C(C(OO)=O)C=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N+:15]([O-:36])=[CH:14][C:13]3[N:19]=[C:20]([CH2:23][O:24][CH2:25][CH2:26][O:27][CH3:28])[N:21]([CH3:22])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCOCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1C
Reactant: Cc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COCCOCc1nc2c[n+]([O-])c3ccc(OCc4ccccc4)cc3c2n1C
Reaction time: 3 h

Procedure:
A modification of the general method described in Part B of Example 3 was followed using 8-benzyloxy-2-[2-methoxy(ethoxymethyl)]-1-methyl-1H-imidazo[4,5-c]quinoline (5.4 g, 14 mmol) in lieu of 7-benzyloxy-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline. Dichloromethane (100 mL) was used as the solvent, and after three hours an analysis by TLC indicated the reaction was incomplete. Additional mCPBA (0.5 equivalents) was added, and the reaction was terminated after one additional hour. After the work-up the product was purified by column chromatography on silica gel (eluting with 90:10 dichloromethane:methanol to provide 1.5 g of 8-benzyloxy-2-[2-methoxy(ethoxymethyl)]-1-methyl-5-oxido-1H-imidazo[4,5-c]quinoline as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:24][CH3:25])[C:5]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12].Br[CH:27]([CH3:42])[CH2:28][CH2:29][CH2:30][N:31]1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41]>CCN(CC)CC>[CH3:25][O:24][C:4]1[C:5]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]2[C:11](=[C:2]([NH:1][CH:27]([CH3:42])[CH2:28][CH2:29][CH2:30][N:31]3[C:35](=[O:36])[C:34]4=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]4[C:32]3=[O:41])[CH:3]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12]
Reactant: CC(Br)CCCN1C(=O)c2ccccc2C1=O
Reactant: COc1cc(N)c2nccc(C)c2c1OCCCCc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(NC(C)CCCN2C(=O)c3ccccc3C2=O)c2nccc(C)c2c1OCCCCc1ccccc1
Reaction time: 1.5 h
Yield: 109.7 %

Procedure:
A stirred mixture of 8-amino-6-methoxy-4-methyl-5-(4-phenylbutoxy)quinoline (12.8 g, 0.038 mol) and 4-bromo-1-phthalimidopentane (BPP) (22.6 g, 0.076 mol) was heated at 135°-140° C. while Et3N (7 ml) was added in small portions during 1 hr. After 1.5 h at 135°-140° C., second portions of BPP (11.3 g) and Et3N (3.5 ml) were added and heating was continued for 2 h. Third portions of BPP (11.3 g) and Et3N (3.5 ml) were introduced and heating was continued for another 2 h. The mixture was allowed to cool and thoroughly extracted with Et2O (total, ca. 600 ml). The extract was treated with charcoal and then with saturated ethereal hydrogen chloride (250 ml). The resulting dark red semi-solid mass was separated by decantation and basified with ethereal Et3N. Concentration of the ethereal solution left a brown oil which was dissolved in CHCl3, placed on a silica gel column (200 g) and eluted with CHCl3. The first fractions were combined on the basis of TLC and concentrated to give 23 g of 6-methoxy-4-methyl-8-(1-methyl-4-phthalimidobutylamino)-5-(4-phenylbutoxy) quinoline as an oil which was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][O:8][Si:9]([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH3:28])[CH:4]=1.C([Li])(CC)C.C(N1CCCCC1)=[O:35]>O1CCCC1>[Si:9]([O:8][CH2:7][C:6]1[CH:26]=[CH:27][C:3]([CH:2]=[O:35])=[CH:4][C:5]=1[CH3:28])([C:22]([CH3:25])([CH3:24])[CH3:23])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cc(CBr)ccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=CN1CCCCC1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 113 %

Procedure:
To a stirred solution of (4-bromomethyl-2-methyl-benzyloxy)-tert-butyl-diphenyl-silane (3 g, 6.83 mmol) in tetrahydrofuran is added sec-butyl lithium at −78° C. under nitrogen atmosphere. The reaction mixture is warmed to 0° C. and stirred for 30 min. The reaction mixture is cooled to −78° C., N-formyl piperidine (1.13 mL, 10.24 mmol) is added, and the reaction mixture is stirred for 3 hours at room temperature. The reaction mixture is quenched with water at 0° C. and extracted with EtOAc (50 mL×3). The combined organic layer is washed with brine solution, dried over magnesium sulphate, and concentrated under vacuum to give the title compound (3 g, 46%). ESI/MS m/z 389.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:17][C@H:18]1[CH2:24][CH2:23][CH2:22][C@@H:21]([CH3:25])[CH2:20][NH:19]1.[Cl-].[NH4+]>C(#N)C>[Cl:9][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:19]2[CH2:20][C@H:21]([CH3:25])[CH2:22][CH2:23][CH2:24][C@@H:18]2[CH3:17])[C:7]=1[F:8]
Reactant: Fc1c(Cl)ncnc1Cl
Reactant: C[C@@H]1CCC[C@H](C)NC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: C[C@@H]1CCC[C@H](C)N(c2ncnc(Cl)c2F)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
Into 3 ml of acetonitrile were added 0.2 g of 4,6-dichloro-5-fluoropyrimidine, 0.50 g of potassium carbonate and 0.27 g of cis-2,6-dimethylhexahydro-1H-azepine hydrochloride, and the mixture was stirred for 2 hours at 60° C. The reaction mixture was cooled to near room temperature, a saturated ammonium chloride aqueous solution was added therein, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.3 g of 1-(6-chloro-5-fluoropyrimidin-4-yl)-cis-2,6-dimethylhexahydro-1H-azepine
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[C:14]([S:18]([C:21]3[CH:25]=[C:24]([C:26]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[NH:27])[S:23][C:22]=3[S:36][CH3:37])(=[O:20])=[O:19])[CH:15]=[C:16]([Br:17])[C:11]=2[N:10]=[CH:9]1)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>CO>[C:32]([O:31][C:29](=[O:30])[NH:28][C:26]([C:24]1[S:23][C:22]([S:36][CH3:37])=[C:21]([S:18]([C:14]2[CH:15]=[C:16]([Br:17])[C:11]3[N:10]=[CH:9][NH:8][C:12]=3[CH:13]=2)(=[O:19])=[O:20])[CH:25]=1)=[NH:27])([CH3:35])([CH3:34])[CH3:33]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cc(Br)c2ncn(C(=O)OC(C)(C)C)c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cc(Br)c2nc[nH]c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
A solution of 4-bromo-6-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-benzoimidazole-1-carboxylic acid tert-butyl ester ((from above step b) 1.00 g, 1.58 mmol) in MeOH (10 mL) was treated with aqueous Na2CO3 (0.340 g, 3.17 mmol in 2 mL water). The reaction mixture was stirred at room temperature 30 min., and solvents were removed in vacuo. The residue was taken up in EtOAc and washed with water (1×50 mL) and brine (1×50 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to afford the product {[4-(7-bromo-3H-benzoimidazole-5-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.755 g, 90%) as a brown solid. 1H NMR (MeOD): δ 8.48 (s, 1H), 8.32 (m, 1H), 8.20 (s, 1H), 8.03 (d, 1H, J=1.6 Hz), 2.63 (s, 3H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1.[Cl:16]C1C=CC=CC=1C=O.FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:16]
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Reactant: O=Cc1ccccc1Cl
Agent: O=Cc1ccc(F)cc1
Product: COC(=O)C(=O)C(Cl)c1ccccc1Cl

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester but using 2-chlorobenzaldehyde instead 4-fluorobenzaldehyde.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][C:12]1[CH:13]=[C:14]([C:23]([O:25][CH3:26])=[O:24])[N:15]([CH2:18][C@H:19]2[CH2:21][C@@H:20]2[CH3:22])[C:16]=1[CH3:17].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.O>[CH:8]([C:13]1[C:12]([CH3:11])=[C:16]([CH3:17])[N:15]([CH2:18][C@H:19]2[CH2:21][C@@H:20]2[CH3:22])[C:14]=1[C:23]([O:25][CH3:26])=[O:24])=[O:9]
Reactant: COC(=O)c1cc(C)c(C)n1C[C@H]1C[C@@H]1C
Reactant: CN(C)C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1c(C=O)c(C)c(C)n1C[C@H]1C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
Phosphorous oxychloride (2.15 g, 14 mmol) was added to a solution of dimethylformamide (1.10 g, 15 mmol) in toluene (2 ml) and the mixture was stirred at room temperature for 30 minutes. To this mixture was added a solution of methyl 4,5-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrole-2-carboxylate (2.21 g, 10 mmol) in toluene (6 ml) and the mixture was then heated at 80° C. for 10 hours. After this time, the reaction mixture was poured into water and neutralized with saturated aqueous sodium hydrogencarbonate solution. The organic layer was separated and was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated in vacuo. The residue was chromatographed on a column using ethyl acetate/hexane=10/1 as the eluant to afford the title compound (1.95 g, 78.2%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[NH:9][N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:12]=2)[N:3]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C:27]1[C:28]([C:37]2[CH:44]=[CH:43][C:40]([CH:41]=O)=[CH:39][CH:38]=2)=[N:29][C:30]2[N:31]([N:33]=[C:34]([CH3:36])[N:35]=2)[CH:32]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C.C(N(CC)CC)C>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C:27]1[C:28]([C:37]2[CH:38]=[CH:39][C:40]([CH2:41][N:16]3[CH2:17][CH2:18][CH:13]([C:11]4[N:12]=[C:8]([C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=5)[NH:9][N:10]=4)[CH2:14][CH2:15]3)=[CH:43][CH:44]=2)=[N:29][C:30]2[N:31]([N:33]=[C:34]([CH3:36])[N:35]=2)[CH:32]=1
Reactant: Cc1cccc(-c2nc(C3CCNCC3)n[nH]2)n1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccc(F)cc3F)cn2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Cc1cccc(-c2nc(C3CCN(Cc4ccc(-c5nc6nc(C)nn6cc5-c5ccc(F)cc5F)cc4)CC3)n[nH]2)n1
Reaction time: 1 h

Procedure:
180 mg (0.57 mmol) 2-Methyl-6-(5-piperidine-4-yl-2H-[1,2,4]triazole-3-yl)-pyridine×2HCl are dissolved in 4.8 mL NMP. After addition of 0.19 mL triethylamine the reaction mixture is stirred for one hour. 200 mg (0.57 mmol) 4-[6-(2,4-Difluorophenyl)-2-methyl-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]-benzaldehyde and 0.06 mL acetic acid are added. The reaction mixture is stirred over night at room temperature. 133 mg (0.63 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for 5 hours. The reaction mixture is treated with saturated NaHCO3. The precipitate is filtered off, washed with water and dried. After chromatography of the precipitate on silica gel (dichloromethane/methanol) 99.7 mg (28.7%) of the desired product are obtained.
Reaction SMILES: [N+]([C:4]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]=1[C:16]([OH:18])=[O:17])([O-])=O.C(OC(=O)C)(=O)C.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1.[OH-].[K+].Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.CC(C)=O.O>[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([S:33][C:4]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:6]3[C:7]([O:18][C:16](=[O:17])[C:5]=23)=[O:9])=[CH:29][CH:28]=1
Reactant: Cc1ccc(S)cc1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C(=O)O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(Sc2cc([N+](=O)[O-])cc3c2C(=O)OC3=O)cc1
Reaction time: 1.5 h

Procedure:
46.05 g (0.180 mol) of 3,5-dinitrophthalic acid are kept under reflux with 26 g (0.25 mol) of acetic anhydride in 210 ml of toluene for one hour. The mixture is filtered hot and the filtrate is evaporated. The residue is dissolved under reflux together with 27.4 g (0.221 mol) of p-thiocresol and 34.7 g (0.34 mol) of acetic anhydride in 4.6 liters of methylene chloride. This solution is added dropwise, at 20°-27° C., with vigorous stirring, to a solution of 1.9 g (8.5 mmols) of benzyltriethylammonium chloride in 190.4 g of 50% potassium hydroxide solution (1.7 mols). After the dropwise addition (135 minutes), the mixture is stirred thoroughly for 90 minutes and acidified with concentrated hydrochloric acid, with cooling. The mixture is converted to two clear phases with the addition of water and acetone; the organic phase is separated off, dried over sodium sulfate and evaporated. The residue is heated under reflux with 36.7 g of acetic anhydride in 200 ml of toluene, the mixture is filtered hot and the filtrate is evaporated. The above reaction is repeated with the residue, using 21.8 g (0.214 mol) of acetic anhydride, 19.9 g (0.161 mol) of p-thiocresol, 2.4 g of benzyltriethylammonium chloride and 285 g of 30% NaOH solution. After thorough stirring, the mixture is acidified and the organic phase is separated off, dried over sodium sulfate and evaporated. The residue is converted to the anhydride with 52.1 g of acetic anhydride and 250 ml of toluene. After recrystallisation from methylene chloride/n-pentane, 20.83 g (39% of theory) of 3-(p-methylphenylthio)-5-nitrophthalic anhydride are obtained; melting point: 180°-2° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].Cl[C:39]1[CH:44]=[C:43]([O:45][CH3:46])[N:42]=[C:41]([O:47][CH3:48])[N:40]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][C:39]3[CH:44]=[C:43]([O:45][CH3:46])[N:42]=[C:41]([O:47][CH3:48])[N:40]=3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Reactant: COc1cc(Cl)nc(OC)n1
Product: COc1cc(Oc2cc3c(cc2OC)CCN(CC(=O)NC2CCc4ccccc42)C3Cc2ccc(OC)c(OC)c2)nc(OC)n1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 4-chloro-2,6-dimethoxy-pyrimidine
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[CH2:3][Mg]Br.[CH3:8][S:9][C:10]1[N:15]=[C:14]([CH3:16])[C:13]([C:17]2[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=2[F:25])=[C:12](Cl)[N:11]=1>C1(C)C=CC=CC=1>[CH3:8][S:9][C:10]1[N:15]=[C:14]([CH3:16])[C:13]([C:17]2[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=2[F:25])=[C:12]([CH2:1][CH:2]([CH3:3])[CH2:6][CH3:7])[N:11]=1
Reactant: CCC(C)C[Mg]Br
Reactant: CSc1nc(C)c(-c2c(F)cc(F)cc2F)c(Cl)n1
Solvent: Cc1ccccc1
Product: CCC(C)Cc1nc(SC)nc(C)c1-c1c(F)cc(F)cc1F
Reaction time: 2 h

Procedure:
At 50° C., 70 ml (0.035 mol) of a 0.5 M solution of 2-methylbutylmagnesium bromide (in tetrahydrofuran) were added to 9.1 g (30 mmol) of 2-methylthio-4-methyl-5-(2,4,6-trifluorophenyl)-6-chloropyrimidine (Example 1.1.) and about 200 mg of bisdiphenylphosphinoferrocenepalladium dichloride in 90 ml of toluene. After about 2 hours, an additional about 200 mg of bisdiphenylphosphinoferrocenepalladium dichloride and, a little at a time, a further 50 ml of a 0.5 M solution of 2-methylbutyl-magnesium bromide (in tetrahydrofuran) were added. The reaction was monitored by HPLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:15]3[CH:16]=[CH:17][C:18]([O:20]C)=[CH:19][C:14]=3[S:13][N:12]=2)=[O:10])=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].B(Br)(Br)Br.O.CCOC(C)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:15]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:14]=3[S:13][N:12]=2)=[O:10])=[CH:4][C:3]=1[C:22]([F:24])([F:23])[F:25]
Reactant: COc1ccc2c(C(=O)Nc3ccc(F)c(C(F)(F)F)c3)nsc2c1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(F)c(C(F)(F)F)c1)c1nsc2cc(O)ccc12
Temperature: 45 °C
Reaction time: 72 h

Procedure:
A suspension of 252 mg (0.68 mMol) 6-methoxy-benzo[d]isothiazole-3-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide in 15 ml CH2Cl2 is cooled in an ice-bath, then 20 ml of a 1 M solution of BBr3 in CH2Cl2 are added. The suspension is stirred for 3 days at 45° C., the resulting solution is cooled, poured into water and EtOAc, the aq. layer is separated off and extracted twice with EtOAc. The organic layers are washed twice with water and sat. NaHCO3, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; acetone/hexane 1:95→2:3) gives the title compound: MS: [M−1]=355; TLC(hexane/acetone 2:1): Rf=0.46.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[N:17][C:18]([NH:21][C:22]3[N:23]=[CH:24][C:25]4[CH:31]=[CH:30][C:29](=[O:32])[N:28]([CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)[C:26]=4[N:27]=3)=[CH:19][CH:20]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>C(Cl)Cl>[ClH:1].[CH:33]1([N:28]2[C:26]3[N:27]=[C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([N:12]5[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]5)=[CH:16][N:17]=4)[N:23]=[CH:24][C:25]=3[CH:31]=[CH:30][C:29]2=[O:32])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4ccc(=O)n(C5CCCCC5)c4n3)nc2)CC1
Agent: Cl
Solvent: ClCCl
Product: O=c1ccc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
HCl gas was bubbled through a solution of 4-[6-(8-cyclohexyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (105 mg, 0.21 mmol) in CH2Cl2 (3 mL) at room temperature until a solid was formed. The mixture was stirred at room temperature for 6 hours and the solid formed was collected by filtration. The solid was hygroscopic. It was recrystalized from MeOH with addition of a few drops of water to yield 8-cyclohexyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt (40 mg, 35%). mp: 228–230° C. Anal Calc'd for C22H27N7O2O HCl 3.5 H2O: C, 48.80; H, 6.70; N, 18.11; Cl, 13.09. Found: C, 48.88; H, 6.39; N, 17.95; Cl, 12.88.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8]/[N:9]=[C:10](/[CH:18]1[CH2:21][N:20]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:19]1)\[CH2:11][CH2:12][CH:13](OC)OC)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O>[C:1]([O:5][C:6]([NH:8][N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:18]1[CH2:21][N:20]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:19]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(CC/C(=N\NC(=O)OC(C)(C)C)C1CN(C(=O)OCc2ccccc2)C1)OC
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nn1cccc1C1CN(C(=O)OCc2ccccc2)C1
Yield: 99.7 %

Procedure:
A solution of benzyl 3-[(1E)-N-(tert-butoxycarbonyl)-4,4-dimethoxybutanehydrazonoyl]azetidine-1-carboxylate (2.47 g, 5.67 mmol) and AcOH (30 mL) was stirred (40° C.) for 18 h. The mixture was concentrated and the residue was dissolved in EtOAc (75 mL) and washed with saturated, aqueous NaHCO3 (75 mL). The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated to afford the desired product (2.1 g) which was used without further purification. ES-MS m/z 272.01 [M+H]+, HPLC RT (min) 3.50.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=O.Cl.[NH2:18][OH:19].N1C=CC=CC=1.C(Cl)Cl>CCCCCC>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=[N:18][OH:19]
Reactant: NO
Reactant: COc1cccc(C(=O)c2sccc2Br)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1cccc(C(=NO)c2sccc2Br)c1
Yield: 85.4 %

Procedure:
Stir a mixture of (3-bromothiophen-2-yl)-(3-methoxyphenyl)methanone (7 g, 0.024 mol), hydroxylamine hydrochloride (3.09 g, 0.048 mol) and pyridine (40 mL) overnight at room temperature, and then heat the mixture (100° C.–105° C.) for four hours. TLC (DCM) shows that the reaction is complete. Quench the reaction mixture with water and extract with ether (three times). Wash the ether phase with HCl (3N) and water, dry (MgSO4), filter and concentrate to yield an oil that solidifies. Recrystallize the solid from ether:hexane to obtain the title compound (6.4 g, 87% Yield), m.p. 102–103° C.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13]Cl>>[OH:4][CH2:3][CH2:2][N:1]([CH2:13][C:12]1[CH:15]=[CH:16][CH:17]=[C:10]([O:9][CH3:8])[CH:11]=1)[CH2:5][CH2:6][OH:7]
Reactant: COc1cccc(CCl)c1
Reactant: OCCNCCO
Product: COc1cccc(CN(CCO)CCO)c1

Procedure:
2-[(2-Hydroxy-ethyl)-(3-methoxy-benzyl)-amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (3.1 g, 29.5 mmol) and 3-methoxybenzyl chloride (5 g, 31.9 mmol). Yield 9.28 g, (99%); yellow oil; MS: 226 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](B(O)O)[CH:6]=[CH:5]2.Cl[C:16]1[N:17]=[CH:18][C:19]([C:22]([O:24]C)=[O:23])=[N:20][CH:21]=1>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:16]1[N:17]=[CH:18][C:19]([C:22]([OH:24])=[O:23])=[N:20][CH:21]=1)[CH:6]=[CH:5]2
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: OB(O)c1ccc2cc(O)ccc2c1
Product: O=C(O)c1cnc(-c2ccc3cc(O)ccc3c2)cn1

Procedure:
Followed the two step procedure described for Example 7 starting from 6-hydroxynaphthalen-2-ylboronic acid and methyl 5-chloropyrazine-2-carboxylate. 1H-NMR (MeOD-d4 500 MHz): 9.31 (s, 2H), 8.64 (s, 1H), 8.19-8.21 (d, J=9.0 Hz, 1H), 7.90-7.91 (d, J=8.5 Hz, 1H), 7.80-7.82 (d, J=8.5 Hz, 1H), 7.15-7.18 (t, J=2.0, 10.0 Hz, 2H). MS (ESI): m/z=267.0 [M+1]+.