Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([NH2:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12][CH3:13].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].Cl.O1CCOCC1>CCOCC.COCCOCCOC.C1COCC1>[ClH:1].[CH2:2]([NH2:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[CH3:13]
Reactant: CC#CCCCCCCCCCN
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: COCCOCCOC
Product: C/C=C/CCCCCCCCCN
Temperature: 150 °C
Yield: 44.5 %

Procedure:
10-Dodecyn-1-amine hydrochloride (2.0 g, 9.2 mmol) and 1 ml THF were added to 30 ml diglyme. Lithium aluminum hydride (2 g, 53 mmol) were added and the mixture was heated at 150° C. for 96 hours. The mixture was cooled and 15% aqueous NaOH was added and the mixture was extracted with Et2O. The extracts were dried over Na2SO4, filtered, and the solvent was evaporated. The residue was chromatographed on silica gel eluting with CH2Cl2 -MeOH-NH4OH (150:90:1) to obtain an oil. The oil was dissolved in Et2O, 9 ml 1N HCl-dioxane solution were added, and solvent was evaporated to leave the title compound (0.9 g, 45% yield): C12H25N·HCl (219.80); 1H-NMR (CDCl3) δ8.3 (br s,3), 5.41 (m,2), 2.99 (m,2), 1.97 (m,2), 1.8 (m,2), 1.64 (d,3), 1.4-1.2 (m,12). Anal. calcd.: C, 65.57; H, 11.92; N, 6.37; found: C, 65.56; H, 11.55; N, 6.15.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[NH:15]([C:22]1[CH:30]=[C:29]([C:31](O)=[O:32])[C:28]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:27][C:23]=1[C:24](O)=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ClC1C=CC(NC2C=C(C(O)=O)C(NC3C=CC(Cl)=CC=3)=CC=2C(O)=O)=CC=1>>[CH:38]1[CH:39]=[C:40]2[C:31]([C:29]3[C:28]([NH:34][C:35]2=[CH:36][CH:37]=1)=[CH:27][C:23]1[C:24]([C:21]2[C:16]([NH:15][C:22]=1[CH:30]=3)=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:25])=[O:32]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: O=C(O)c1cc(Nc2ccc(Cl)cc2)c(C(=O)O)cc1Nc1ccc(Cl)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 85 °C

Procedure:
382 parts of polyphosphoric acid, containing 85.0% P2O5, are introduced into a pressure vessel. Then 68.7 parts of 2,5-dianilinoterephthalic acid and 7.6 parts of 2,5-di(4-chloro-anilino)terephthalic acid are introduced with stirring at from 80 to 90° C. and the mixture is heated at 125° C. for 1 hour during which ring closure takes place to form the quinacridone. The reaction mixture is then introduced into a second pressure vessel where it is hydrolyzed under pressure and with stirring with a mixture of 1718 parts of 30% phosphoric acid at 140° C. During this hydrolysis the temperature rises to 155° C. The mixture is stirred at 155° C. for 0.5 hour. Then it is cooled to 60° C. and the mixed crystal pigment is filtered off with suction, washed to neutrality with water and dried at 80° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]([F:21])=[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])[CH:7]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>C1C=CC=CC=1>[C:23]([NH:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]([F:21])=[C:6]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])[CH:7]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Solvent: c1ccccc1
Product: CC(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
00 g of 3-(5-amino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione was dissolved in 5 ml of benzene. To the obtained solution, 0.61 ml of acetic anhydride was added and the resultant solution was refluxed for one hour. After distilling off benzene, the obtained crude product was washed with hexane to obtain 3-(5-acetylamino-4-chloro-2 fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H) -pyrimidinedione as white crystals.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:38])[C:17]2[CH:22]=[N:21][C:20](S(C)(=O)=O)=[N:19][C:18]=2[N:27]([C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[CH2:34][CH2:33][CH2:32]3)[CH:28]=1)=[O:14])[CH3:11]>>[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:38])[C:17]2[CH:22]=[N:21][C:20]([NH:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[N:19][C:18]=2[N:27]([C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[CH2:34][CH2:33][CH2:32]3)[CH:28]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: NCCN1CCOCC1
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCCN3CCOCC3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(Step F) the title compound was prepared from 2-morpholin-4-yl-ethylamine (4.8 μL, 0.036 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(Step E), 15 mg, 0.036 mmol). 15.5 mg of 8-indan-5-yl-2-(2-morpholin-4-yl-ethylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.24 (s, 1H), 8.45 (s, 1H), 7.34 (d, 1H), 7.22 (s, 1H), 7.15 (d, 1H), 6.19 (br, 1H), 4.36 (q, 2H), 3.65 (m, 4H), 3.24 (m, 2H), 2.99 (m, 4H), 2.30-2.60 (m, 6H), 2.17 (m, 2H), 1.37 (t, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H29N5O4: 464.22 (M+H). Found: 464.4.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[S:33](=[O:35])(=[O:34])[NH:32][C:31](=[O:36])[CH2:30]2)=[CH:25][CH:24]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[O:4].C(N(CC)C(C)C)(C)C.[CH3:46][O:47][C:48](=[O:60])[C@@H:49]([N:57]=[C:58]=[O:59])[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C)C=O>[CH2:50]([C@@H:49]([C:48](=[O:60])[O:47][CH3:46])[NH:57][C:58](=[O:59])[NH:1][C@@H:2]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]2[S:33](=[O:35])(=[O:34])[NH:32][C:31](=[O:36])[CH2:30]2)=[CH:27][CH:28]=1)[C:3](=[O:4])[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[C:12]=1[C:13]([O:15][CH3:16])=[O:14])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)N=C=O
Reactant: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@@H](N)Cc1ccc(C2CC(=O)NS2(=O)=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)cc1)NC(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.5 %

Procedure:
To a solution of methyl 2-[4-({(2S)-2-amino-3-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoyl}amino)butoxy]-6-hydroxybenzoate (8.0 mg, 0.015 mmol) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (0.008 mL, 0.045 mmol) and (S)-2-isocyanato-3-phenyl-propionic acid methyl ester (3.5 mg, 0.017 mmol) and stirred overnight at room temperature. The product was purified by preparative LCMS to afford the desired product (1.9 mg, 17%). LCMS found for C35H41N4O11S (M+H)+: m/z=725.1
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([C:12]2([CH3:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:21]1([OH:27])C=CC=CC=1.C(Cl)(Cl)Cl.Cl>C(O)C.O>[C:1]([C:5]1[CH:10]=[C:9]([CH:21]=[O:27])[C:8]([OH:11])=[C:7]([C:12]2([CH3:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)c(C2(C)CCCCC2)c1
Reactant: Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(C=O)c(O)c(C2(C)CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
4-t-butyl-2-(1-methylcyclohexyl)phenol (7.0 g, 0.028 mole) was dissolved in 10 ml of absolute ethanol in a 100 ml round bottom flask equipped with a water-cooled condenser. Sodium hydroxide (11.4 g, 0.28 mole) was dissolved in 10 ml water and added while still hot to the solution of phenol. Chloroform (6.8 g, 0.057 mole) was added in 2 to 3 ml portions over a 10-minute period. The resulting brown mixture was stirred for 1 hour while it cooled to ambient temperature. The mixture was added to 25 ml of 5M hydrochloric acid. The organic layer was isolated in a separatory funnel and dried over anhydrous magnesium sulfate. The mixture was filtered and rotoevaporated to a thick syrup to an assumed yield of 30% of the crude product with an IR spectrum having the characteristic aldehyde carbonyl stretching frequency. The product was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[N:7]([CH2:9][CH2:10][CH2:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[C:24]([CH:26]3[CH2:29][CH2:28][CH2:27]3)[N:23]=[C:22]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:21]=2)[CH2:16][CH2:15]1)=O)[CH3:8])([CH3:4])([CH3:3])[CH3:2].B>O1CCCC1>[C:1]([O:5][C:6](=[O:34])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[C:24]([CH:26]3[CH2:27][CH2:28][CH2:29]3)[N:23]=[C:22]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:21]=2)[CH2:16][CH2:15]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCCC(=O)N1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1)C(=O)OC(C)(C)C
Agent: B
Solvent: C1CCOC1
Product: CN(CCCCN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1)C(=O)OC(C)(C)C
Yield: 64.5 %

Procedure:
13.1 g of {4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-4-oxo-butyl}-methyl-carbamic acid tert-butyl ester (27.66 mmol) were dissolved in 250 ml of tetrahydrofuran. 44.9 g of borane in tetrahydrofuran (522.44 mmol) were added dropwise within 25 min. and then the reaction mixture was heated to reflux for 1.5 h. The reaction mixture was poured onto water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using dichloromethane-methanol (0-5%) as eluent. Fractions containing the product were combined and the solvent evaporated to yield 8.2 g of the title compound.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)=[O:5].[CH:15]1([NH2:18])[CH2:17][CH2:16]1>O>[CH:15]1([NH:18][C:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:17][CH2:16]1
Reactant: NC1CC1
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Solvent: O
Product: CCOC(=O)C=C(CC(=O)OCC)NC1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.1 %

Procedure:
To 30.33 g (0.15 mol) of diethyl acetonedicarboxylate was added dropwise 11.8 g (0.19 mol) of cyclopropylamine at such a rate that reaction temperature was kept below 48° C. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into H2O, extracted twice with ether, dried (MgSO4) and concentrated in vacuo affording 34.42 g of a light yellow oil. Crude was kugelrohr distilled at 53 Pa and collected at a pot temperature of 102°-104° C. to give 23.73 g (66%) of enamine diester as a light yellow oil, nD25 1.5025.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[CH2:24]([CH:31]1[CH2:36][NH:35][CH2:34][CH2:33][NH:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CS(C)=O>[CH2:24]([CH:31]1[NH:32][CH2:33][CH2:34][N:35]([C:18]2[C:19]([F:21])=[CH:20][C:10]3[C:11]([CH:17]=2)=[N:12][C:13]2[N:14]([CH3:16])[CH:15]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:7](=[O:23])[C:8]=2[CH:9]=3)[CH2:36]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc(CC2CNCCN2)cc1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C)c2nc3cc(N4CCNC(Cc5ccccc5)C4)c(F)cc3cc2c1=O
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 82.6 %

Procedure:
A suspension of 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.3 g) and (RS)-2-benzylpiperazine (1.3 g) in dimethyl sulphoxide (25 cc) is heated to approximately 90° C. with stirring for 1 hour 45 minutes. After cooling to a temperature in the region of 20° C., the reaction mixture is treated with water (100 cc) and extracted with trichloromethane (3×30 cc). The combined organic extracts are washed with water (3×30 cc), dried over magnesium sulphate, filtered and concentrated to dryness at approximately 50° C. under reduced pressure (20 kPa). After 1 recrystallization in a mixture of dimethylformamide (4 cc) and ethanol (1 cc), (RS)-8-(3-benzyl-1-piperazinyl)-3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.6 g) is obtained in the form of a yellow solid, m.p. 190° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](OC)=[O:21])=[CH:16][C:15]=2[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.CO.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:15]=2[CH3:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: CCOCC
Solvent: CO
Product: Cc1cc(CO)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Yield: 55.3 %

Procedure:
The intermediate 4-(4-methoxycarbonyl-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (1.42 g) described in Preparation Example 97 was dissolved in diethyl ether (18 mL), 0.99M diisobutylaluminum hydride (9 mL) was added under cooling to −78° C., and the mixture was stirred while rising the temperature to room temperature. The mixture was further stirred at room temperature for 2 hr, methanol (0.7 mL) was added, and aqueous solution (5 mL) of Rochelle salt was added. The precipitate was collected by filtration from the reaction mixture, and the filtrate was concentrated. The obtained residue was purified by column chromatography (ethyl acetate:hexane) to give 4-(4-hydroxymethyl-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (720 mg). The obtained 4-(4-hydroxymethyl-2-methylphenyl)piperazine-1-carboxylic acid tert-butyl ester (720 mg) was dissolved in chloroform (6 mL), 4N hydrogen chloride/ethyl acetate solution (2.3 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with aqueous potassium carbonate solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give the title compound (654 mg).
Reaction SMILES: S([CH:5](C)[C:6]([O:8][C:9](=[O:16])[CH:10]([S:12]([OH:15])(=[O:14])=[O:13])[CH3:11])=[O:7])(O)(=O)=O.O1[C:22](=O)[CH2:21][CH2:20]S1(=O)=O.C(C1C(=O)OS(=O)(=O)C1)C(C)C.CC1C(=O)OS(=O)(=O)C1>>[CH2:11]([C:10]1([S:12]([OH:15])(=[O:13])=[O:14])[CH2:5][C:6](=[O:7])[O:8][C:9]1=[O:16])[CH2:20][CH2:21][CH3:22]
Reactant: CC(C(=O)OC(=O)C(C)S(=O)(=O)O)S(=O)(=O)O
Reactant: O=C1CCS(=O)(=O)O1
Agent: CC(C)CC1CS(=O)(=O)OC1=O
Agent: CC1CS(=O)(=O)OC1=O
Product: CCCCC1(S(=O)(=O)O)CC(=O)OC1=O

Procedure:
sulfopropionic anhydride, i.e., 1,2-oxathiolane-5-one-2,2-dioxide of the formula: ##STR7## 4-methyl-1,2-oxathiolane-5-one-2,2-dioxide 4-isobutyl-1,2-oxathiolane-5-one-2,2-dioxide
Reaction SMILES: [Si]([O:18][C:19]1[CH:54]=[CH:53][C:22]([O:23][CH2:24][C@@H:25]([OH:52])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([S:36][CH:37]3[CH2:42][CH2:41][N:40]([C:43]([NH:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:44])[CH2:39][CH2:38]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl.C(Cl)(Cl)Cl.CO>[C:46]1([NH:45][C:43]([N:40]2[CH2:41][CH2:42][CH:37]([S:36][C:33]3[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:52])[CH2:24][O:23][C:22]4[CH:53]=[CH:54][C:19]([OH:18])=[CH:20][CH:21]=4)=[CH:31][CH:32]=3)[CH2:38][CH2:39]2)=[O:44])[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(SC3CCN(C(=O)Nc4ccccc4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(Nc1ccccc1)N1CCC(Sc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 69.7 %

Procedure:
4-{[4-(2-{[(2S)-3-(4-([tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)phenyl]sulfanyl}-N-phenyl-1-piperidinecarboxamide (0.25 g, 0.33 mmol) was reacted according to Procedure H (eluant: 12:3:1 dichloromethane-chloroform-methanol) to give the title compound (0.12 g, 0.23 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]([CH2:18][S:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=3)([OH:17])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1)#[N:2].CO.[OH-].[Na+:33]>O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][C:14]([CH2:18][S:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([O-:26])=[O:25])=[CH:28][CH:29]=3)([OH:17])[CH2:15][CH2:16]2)=[CH:7][CH:8]=1)#[N:2].[Na+:33]
Reactant: COC(=O)c1ccc(SCC2(O)CCN(CCc3ccc(C#N)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1ccc(CCN2CCC(O)(CSc3ccc(C(=O)[O-])cc3)CC2)cc1

Procedure:
The compound (248 mg) obtained in Example 42 was suspended in a 50% mixture of methanol and water (10 mL) and was further mixed with 2 N sodium hydroxide solution (0.3 mL), followed by heating under reflux for ten hours. The solvent was removed under reduced pressure, and the residue was crystallized from ethyl acetate. The crystals were collected by filtration, and dried to yield the titled compound (200 mg) as crystals.
Reaction SMILES: Cl.Cl.Cl.Br[C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]3[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[N:14]=3)[S:10][C:9]=2[CH:31]=1.[Br:32]C1C2SC=CC=2C=CC=1>>[Br:32][C:31]1[C:9]2[S:10][C:11]([C:13]3[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[N:14]=3)=[CH:12][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cnc(NCCCN2CCN(C)CC2)nc1-c1cc2ccc(Br)cc2s1
Reactant: Brc1cccc2ccsc12
Agent: Cl
Product: Cc1cnc(NCCCN2CCN(C)CC2)nc1-c1cc2cccc(Br)c2s1

Procedure:
Using the method of [4-(6-bromobenzo[b]thiophen-2-yl)-5-methylpyrimidin-2-yl]-[3-(4-methylpiperazin-1-yl)-propyl]-amine tri-hydrochloride, the title compound is prepared from 7-bromobenzo[b]thiophene and isolated as a solid. ES+(m/z) 460 (79Br) and 462 (81Br) [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1Cl.[C:11]([O-])([O-])=[O:12].[K+].[K+]>CO>[Cl:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1[O:12][CH3:11]
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cnn(C)c(=O)c1Cl
Reaction time: 1 h
Yield: 93.8 %

Procedure:
10 g (55.8 mmoles) of intermediate 3a are placed in the presence of 115 g (837 mmoles) K2CO3 in 725 mL MeOH. The reaction medium is agitated for 1 h under reflux then filtered through celite. The filtrate is concentrated to dryness and the residue solubilized in CH2Cl2 and washed with water. After drying over Na2SO4, the organic phases are evaporated and the residue obtained is purified by silica gel flash chromatography (CH2Cl2—AcOEt, gradient 100:0 to 60:40 over 45 min). 9.14 g of intermediate 4b are thus obtained in the form of a white solid (yield 94%). TLC silica gel 60 F 254 Merck, CH2Cl2—AcOEt: 50:50, Rf=0.36.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[CH:11]=[C:10]([C:25]([OH:27])=O)[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH:51]1[CH2:55][CH2:54][CH:53]([N:56]2[CH2:61][CH2:60][O:59][CH2:58][CH2:57]2)[CH2:52]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:25]([N:51]3[CH2:55][CH2:54][CH:53]([N:56]4[CH2:57][CH2:58][O:59][CH2:60][CH2:61]4)[CH2:52]3)=[O:27])[CH:11]=[C:12]([C:14]([NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[O:24])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: C1CC(N2CCOCC2)CN1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3ccc(C)nc3)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(C(=O)N3CCC(N4CCOCC4)C3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-((6-methylpyridin-3-yl)methylcarbamoyl)-biphenyl-3-carboxylic acid (55 mg, 0.15 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (58 mg, 0.30 mmol), 1-hydroxybenzotriazole hydrate (23 mg, 0.15 mmol), and CH2Cl2 (3 mL) were added 4-(pyrrolidin-3-yl)morpholine (48 mg, 0.30 mmol) and N,N-diisopropylethylamine (53 μL, 0.30 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 30-60% MeCN/water[10 mM Et2NH]) to afford a white foam.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.Cl.[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19]CO>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])=[O:8])=[CH:11][CH:12]=1
Reactant: COCCOCCO
Reactant: COC(=O)c1ccc(O)cc1
Agent: Cl
Agent: [Na]
Product: COCCOCCOC(=O)c1ccc(O)cc1
Temperature: 130 °C

Procedure:
In a first step, an amount of 1 g (43 mmol) of sodium was dissolved in 25 of ml 2-(2-methoxyethoxy)ethanol. To the resulted solution an amount of 3 g (22 mmol) of methyl 4-hydroxybenzoate was added and the mixture was heated to 130° C. for 24 hours; after cooling to room temperature, it was acidified with a hydrochloric acid solution (3N) and extracted with ethyl acetate. The removal of the solvent under reduced pressure and column chromatography of the residue (silica gel, hexane:ethyl acetate 3:1) afforded 2-(2-methoxyethoxy)ethyl 4-hydroxybenzoate, in the form of a colourless oil in essentially quantitative yield.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[CH2:26]Br>>[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([Cl:31])[CH:30]=1)[CH2:26][N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20]
Reactant: Clc1cc(Cl)cc(CBr)c1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(Cl)cc(Cl)c2)c1
Yield: 63.6 %

Procedure:
5-isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3,5-dichlorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (283 mg, yield: 63.6%).