Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[N:4]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=3)[N:23]=[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:21]=2[CH3:37])[CH2:3]1.Cl[C:40]1[CH:45]=[C:44]([CH3:46])[N:43]=[C:42]([NH2:47])[N:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:30][C:26]1[CH:25]=[C:24]2[C:29]([C:20]([N:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:40]5[CH:45]=[C:44]([CH3:46])[N:43]=[C:42]([NH2:47])[N:41]=5)[CH:6]=4)[C:2]([CH3:38])([CH3:1])[CH2:3]3)=[C:21]([CH3:37])[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[N:23]2)=[CH:28][CH:27]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2ccc3c(c2)N(c2c(C)c(-c4ccccn4)nc4cc(F)ccc24)CC3(C)C)nc(N)n1
Temperature: 120 °C

Procedure:
Prepared according to procedure P using 4-(3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl)-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (70 mg, 0.14 mmol) (described herein), 4-chloro-6-methylpyrimidin-2-amine (21.7 mg, 0.15 mmol), bis(triphenylphosphine)palladium(ii) chloride (9.6 mg, 0.014 mmol), and sodium carbonate (43.7 mg, 0.41 mmol) in 1,4-dioxane (3.1 mL) and water (0.79 mL), and heating in a microwave at 120° C. for 60 min. After purification 4-(1-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-6-methyl-2-pyrimidinamine was obtained as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.75 (1H, d, J=4.3 Hz), 7.76-7.96 (4H, m), 7.34-7.46 (2H, m), 7.28 (1H, br. s.), 7.21-7.26 (1H, m), 6.66-6.76 (1H, m), 6.58 (1H, d, J=1.2 Hz), 5.19 (2H, br. s.), 3.74-3.90 (2H, m), 2.35-2.41 (3H, m), 2.28-2.35 (3H, m), 1.55-1.61 (3H, m), 1.49-1.55 (3H, m). Mass Spectrum (ESI) m/e=491 (M+1).
Reaction SMILES: [CH2:1]=O.[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[CH:9]([O:12][C:13]([NH:15][CH2:16][CH2:17][S:18][C:19]1[N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[CH:22]=[CH:21][CH:20]=1)=[O:14])([CH3:11])[CH3:10]>C(O)(=O)C>[CH:9]([O:12][C:13]([NH:15][CH2:16][CH2:17][S:18][C:19]1[N:24]2[C:25]([CH2:1][N:3]3[CH2:8][CH2:7][O:6][CH2:5][CH2:4]3)=[CH:26][N:27]=[C:23]2[CH:22]=[CH:21][CH:20]=1)=[O:14])([CH3:11])[CH3:10]
Reactant: C=O
Reactant: C1COCCN1
Reactant: CC(C)OC(=O)NCCSc1cccc2nccn12
Solvent: CC(=O)O
Product: CC(C)OC(=O)NCCSc1cccc2ncc(CN3CCOCC3)n12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 50.1 %

Procedure:
To a solution of an aqueous 37% formalin solution (210 mg, 2.59 mmoles) in acetic acid (2 ml) was added morpholine (226 μl, 2.59 mmoles) under ice-cooling and the mixture was stirred at room temperature for 45 minutes. 5-[2-(isopropyloxycarbonylamino)ethylthio]imidazo[1,2-a]pyridine (651 mg, 2.33 mmoles) was added, followed by stirring at 60° C. for 2 hours. After the solvent was distilled off, the residue was diluted with chloroform, washed in turn with aqueous 1N NaOH and saturated saline, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography [eluent: ethanol/ethyl acetate=1:10] to obtain 442 mg of the desired product (50.1%, light brown solid).
Reaction SMILES: C(O[C:6]([C:8]1[C:9]([OH:23])=[C:10]2[CH:22]=[CH:21][S:20][C:11]2=[C:12]([C:14]#[C:15][Si](C)(C)C)[N:13]=1)=[O:7])CCC.C[O-].[Na+].CO.[NH2:29][CH2:30][C:31]([OH:33])=[O:32]>>[C:14]([C:12]1[N:13]=[C:8]([C:6]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:7])[C:9]([OH:23])=[C:10]2[CH:22]=[CH:21][S:20][C:11]=12)#[CH:15]
Reactant: CCCCOC(=O)c1nc(C#C[Si](C)(C)C)c2sccc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C#Cc1nc(C(=O)NCC(=O)O)c(O)c2ccsc12
Reaction time: 18 h
Yield: 101.4 %

Procedure:
A mixture of 4-hydroxy-7-trimethylsilanylethynyl-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester (70 mg, 0.2 mmol) and a 0.5 M solution of sodium methoxide in methanol (10 ml, 5 mmol) was refluxed with stirring for 1 h before glycine (375 mg, 5 mmol) was added. Refluxing and stirring was continued for 18 h before the mixture was concentrated in vacuo. The residue was dissolved in water (20 ml), and the pH of the solution was adjusted to 2-3 by addition of 6 N aqueous HCl. The resulting suspension was extracted with ethyl acetate (1×20 ml). The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound as a tan solid (56 mg); MS-(+)-ion: M+1=277.1.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[Br:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([S:18]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]2[CH2:27][OH:28])(=[O:20])=[O:19])=[C:13]([CH3:29])[CH:12]=1.CCOC(C)=O.CCCCCC>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[Br:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([S:18]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]2[CH2:27][O:28][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])(=[O:19])=[O:20])=[C:13]([CH3:29])[CH:12]=1
Reactant: Cc1cc(Br)cc(C)c1S(=O)(=O)N1CCCCC1CO
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(Br)cc(C)c1S(=O)(=O)N1CCCCC1COCC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
180 ml of 50% sodium hydroxy solution and 180 ml of tert-butyl bromoacetate were added to a solution of 18 g of (1-(4-bromo-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methanol, and stirring was carried for 10 minutes. 1.815 g of tetra-n-butylammonium hydrogen sulfate were then added, and stirring was carried out for a further 45 minutes at room temperature. The progress of the reaction was monitored by thin-layer chromatography (20% EtOAc/hexane). When the reaction was complete, 400 ml of ethyl acetate were added, and the phases were separated. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica; 5% EtOAc/hexane). tert-butyl 2-((1-(4-bromo-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetate was obtained in a yield of 78.2% (18 g).
Reaction SMILES: [Si:1]([C:8]1[C:9]([CH:21]=O)=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([N:18]([CH3:20])[CH3:19])=[CH:13][CH:12]=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:23](#[N:27])[CH2:24][C:25]#[N:26].N1CCCCC1>CCO>[CH3:19][N:18]([CH3:20])[C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH:21]=[C:24]([C:23]#[N:27])[C:25]#[N:26])[C:8]([Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:17]2
Reactant: CN(C)c1ccc2cc(C=O)c([Si](C)(C)C(C)(C)C)cc2c1
Reactant: N#CCC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: CN(C)c1ccc2cc(C=C(C#N)C#N)c([Si](C)(C)C(C)(C)C)cc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
415.7 mg (1.2616 mmol) of the compound 14 was dissolved in 9 mL of EtOH, and then added with 83.4 mg (1.2616 mmol) of malononitrile and 1 mL (12.616 mmol) of piperidine, and stirred for 3 hours at room temperature. When the reaction was completed, EtOH was removed by vacuum-distillating, and then the mixture was separated and purified by a column chromatography (eluent: EtOAc/n-hexane(v/v)=¼) without an additional extraction process to obtain 333.4 mg (70%) of an orange solid compound 15. 1H NMR (CDCl3, 300 MHz, 293K): δ 8.70(s, 1H), 8.24(s, 1H), 7.70-7.67(d, 1H), 7.02-6.98(dd, 1H), 6.88(s, 1H), 6.60-6.59(d, 1H), 3.14(s, 6H), 1.05(s, 9H), 0.31(s, 6H). 13C NMR(CDCl3, 75 MHz, 293K): δ 154.13, 152.53, 151.30, 140.20, 131.43, 131.09, 121.46, 119.27, 115.40, 114.88, 114.30, 111.78, 103.41, 40.29, 25.79, 18.38, −4.23. HRMS: m/z calcd. for C22H27N3OSi 377.1923 found 377.1923.
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:6]=2[CH:5]=[C:4]([CH3:18])[CH:3]=1.C(N(C(C)C)CC)(C)C.[O:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([CH:31]4[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[C:4]([CH3:18])[CH:3]=1
Reactant: Cc1cc(F)c2[nH]c(=O)n(C3CCNCC3)c2c1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(F)c2[nH]c(=O)n(C3CCN(C4CCOCC4)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
4-Fluoro-6-methyl-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one (12.5 mmol, 3.6 g) (D5a) was dissolved in dichloromethane (50 ml), diisopropylethylamine (3 eq., 37.6 mmol, ˜6.4 ml), and tetrahydro-4H-pyran-4-one (4 eq., 50 mmol, ˜5 g) were added in that order at room temperature; sodium triacetoxyborohydride (3 eq., 37.6 mmol, ˜8 g) was added at room temperature and the mixture was stirred at room temperature for one overnight. The reaction mixture was diluted with dichloromethane (100 ml) and quenched with NaHCO3 (saturated aqueous solution); methanol was added to dissolve the solid which developed in the organic layer; the two phases were separated and the aqueous phase was extracted with dichloromethane (2×); the combined organics were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated to afford 3.8 g, 92%. The material was triturated with diethyl ether and filtered to afford 3.6 g title compound. This was dissolved in MeOH/DCM and 2 eq of HCl (1M in Et2O) were added. The mixture was stirred at room temperature for 10 minutes, solvent was evaporated and the solid was triturated with Et2O to afford another batch, 3.8 g, pale grey solid.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([N+:16]([O-])=O)[C:9]=2[CH3:19])[CH2:5][C:4](=[O:20])[C:3]=1[C:21](=[O:25])[CH2:22][CH2:23][CH3:24].[OH-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C>[OH:20][C:4]1[CH2:5][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([NH2:16])[C:9]=2[CH3:19])[CH2:7][C:2](=[O:1])[C:3]=1[C:21](=[O:25])[CH2:22][CH2:23][CH3:24]
Reactant: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)c([N+](=O)[O-])c2C)CC1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)c(N)c2C)CC1=O
Reaction time: 1 h
Yield: 30.4 %

Procedure:
A solution of 3-hydroxy-5-(2,4,6-trimethyl-3-nitrophenyl)-2-butyrylcyclohex-2-en-1-one (3.3 g, 0.01 mole) and sodium hydroxide (38 g) in 50% aqueous ethanol (120 ml) was stirred and heated under reflux. Sodium dithionite (9.6 g, 0.05 mole) was added in portions over a period of 30 minutes to the solution and refluxing was continued for 1 hour. The reaction mixture was filtered while still hot and the filtrate was diluted with water (100 ml), neutralized with hydrochloric acid and finally extracted with dichloromethane (2×100 ml). Evaporation of the dichloromethane layer gave 3-hydroxy-5-(3-amino-2,4,6-trimethylphenyl)-2-butyrylcyclohex-2-en-1-one (0.96 g, 32%) as an orange oil. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm); 1.00 (3H, t); 1.5 (2H, m); 2.14 (3H,s); 2.22 (3H, s); 2.30 (3H, s); 2.4-4.0 (7H, m); 6.78 (1H, s); exchangeable protons not observed.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH2:10][N+:11]([O-:13])=[O:12])[CH:4]=1.[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH:15]=[CH2:16].N12CCCN=C1CCCCC2>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([N+:11]([O-:13])=[O:12])[CH2:16][CH2:15][C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[CH:7][CH:8]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COc1cccc(CC[N+](=O)[O-])c1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cccc(CC(CCC(=O)OC(C)(C)C)[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 76.2 %

Procedure:
To a solution of 1-methoxy-3-(2-nitroethyl)benzene (22.59 g) and tert-butyl acrylate (15.98 g) in dichloromethane (180 ml) was added a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (1.90 g) in dichloromethane (45 ml) in an ice bath. After stirring for 18.5 hours at ambient temperature, ice water (70 ml) was added to the solution. The organic layer was separated, washed successively with 1N hydrochloric acid, and brine. The solution was treated with silica gel (70 g) and evaporated in vacuo to give tert-butyl 5-(3-methoxyphenyl)-4-nitrovalerate (29.39 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.O.C(N(CC)CC)C>C(OCC)(=O)C>[N:10]1([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[CH2:11][CH2:12][S:13][CH2:14][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(N2CCSCC2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(N2CCSCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.4 %

Procedure:
Stannous chloride dihydrate (10 g, 44.4 mmol) was added to a solution of 4-(4-nitro-phenyl)-thiomorpholine (2 g, 8.9 mmol) in ethyl acetate and stirred at room temperature for 4 hr. Water was added and the reaction mixture was neutralized with triethyl amine. The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to yield 4-thiomorpholin-4-yl-phenylamine (1.2 g, 60%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])=[N:4][C:5]([CH3:11])=[CH:6][C:7]=1[NH:8][CH2:9][CH3:10].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:32][CH2:33]CCCC.I[CH2:39]CC>C1COCC1>[CH3:1][C:2]1[C:3]([O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])=[N:4][C:5]([CH3:11])=[CH:6][C:7]=1[N:8]([CH2:32][CH3:33])[CH2:9][CH2:10][CH3:39]
Reactant: CCCI
Reactant: CCCCCC
Reactant: CCNc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCN(CC)c1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Reaction time: 0.17 h
Yield: 62.8 %

Procedure:
To a solution of [3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4yl]-ethyl-amine (7.00 g, 24.6 mmol) in 100 ml of dry THF was added 1.0 M lithium bis(trimethylsilyl)amide in hexane (32 ml, 32 mmol) at -78° C. After stirring at that temperature for 10 min, the reaction mixture was treated with iodopropane (13 ml, 125 mmol) at -70° C. After stirring at that temperature for 20 min, the dry ice bath was removed and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to give an oil. The oil residue was purified through silica gel column chromatography using 1:1 chloroform:hexane to chloroform as eluent to give 5.04 g (62.5%) of [3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-propyl-amine as yellow solid; 1H NMR (CDCl3) δ6.88 (s, 2H), 6.41 (s, 1H), 3.11(q,2H), 3.03(dd,2H), 2.30 (s, 3H), 2.25 (s, 3H), 2.19 (s, 3H), 2.07 (s, 6H), 1.55 (m, 2H), 1.08 (t, 3H), 0.90 (t, 3H) ppm. The corresponding HCl salt, white crystals; mp 167-169° C.; 1H NMR (MeOH-d4) δ7.00 (s, 2H), 6.75 (s, 1H), 3.54(q,2H), 3.43 (t, 2H), 2.35 (s, 3H), 2.31 (s, 3H), 2.27 (s, 3H), 2.08 (s, 6H), 1.69 (m, 2H), 1.25 (t, 3H0, 0.94 (t, 3H) ppm;
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1B(O)O.Cl[C:14]1[CH:19]=[C:18](Cl)[N:17]=[CH:16][N:15]=1.[IH:21]>>[I:21][C:14]1[CH:19]=[C:18]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[N:17]=[CH:16][N:15]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: I
Reactant: COc1ccc(B(O)O)c(F)c1
Product: COc1ccc(-c2cc(I)ncn2)c(F)c1

Procedure:
The compound was prepared according to Example 1 using 2-fluoro-4-methoxyphenylboronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: [ClH:1].[OH:2][CH:3]([C:15]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19](=[O:26])[NH:20]2)[CH:4]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][CH3:6].[CH3:27][O-:28].[Na+].[Na]>CO>[Cl:1][C:9]1[CH:14]=[CH:13][C:12]([C:27]([O:25][C:22]2[CH:23]=[CH:24][C:15]([CH:3]([OH:2])[CH:4]([NH:7][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:5][CH3:6])=[C:16]3[C:21]=2[NH:20][C:19](=[O:26])[CH:18]=[CH:17]3)=[O:28])=[CH:11][CH:10]=1
Reactant: CCC(NCc1ccccc1)C(O)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: C[O-]
Reactant: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCC(NCc1ccccc1)C(O)c1ccc(OC(=O)c2ccc(Cl)cc2)c2[nH]c(=O)ccc12
Reaction time: 1 h

Procedure:
1 g of 5-(1-hydroxy-2-benzylaminobutyl)-8-hydroxycarbostyril hydrochloride was suspended in 20 ml of methanol, and sodium methylate prepared from 135 mg of sodium metal and 2.8 ml of absolute methanol was added to the suspension. The mixture was then concentrated to dryness, and the resulting residue was dissolved in 10 ml of dimethylformamide. 490 mg of p-chlorobenzoyl chloride was then added dropwise to the mixture while cooling with ice-water. The mixture was then stirred for 1 hour, and water was added to the mixture. The mixture was then extracted with chloroform, and chloroform was removed by distillation. Diethyl ether was added to the residue to crystallize the product, and the crystals were separated by filtration, washed with diethyl ether and recrystallized from a mixture of chloroform and diethyl ether to obtain 110 mg of 8-(p-chlorobenzoyloxy)-5-(1-hydroxy-2-benzylaminobutyl)carbostyril having a melting point of 125°-126° C.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=O.[CH2:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>CO>[CH2:19]([NH:27][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCc1ccccc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.9 %

Procedure:
Combine 4-(4-Formyl-phenoxy)-benzamide (from Example 247, step 2)(0.39 g, 1.6 mmol), phenethylamine (0.15 g, 1.2 mmol), 20 mL of methanol and 2 g of 3 {acute over (Å)} molecular sieves, and stir at ambient temperature under nitrogen for 5 h. Add sodium borohydride (0.18 g, 4.8 mmol), and stir at ambient temperature for 18 h at ambient temperature. Filter the reaction mixture through Celite, and adsorb on silica gel. Purify by Biotage Flash 40S, eluting with 95:5:0.5 chloroform/ethanol/ammonium hydroxide to afford 0.27 g (93%) of the title compound: mass spectrum (ion spray): m/z=347.28 (M+1); HPLC retention time: 6.01 min (HPLC method in this experiment and subsequent experiments: 5:95-95:5 ACN/0.1% TFA in water over 10 minutes using a 15 cm Zorbax column, running at 1 mL/minute, ultraviolet detector set at 254 nM).
Reaction SMILES: [CH2:1]1CCC(N=C=NC2CCCCC2)C[CH2:2]1.[C:16]1([CH2:22][CH2:23][CH:24]=[CH:25][C:26]([OH:28])=[O:27])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCCCCC>CN(C1C=CN=CC=1)C.CCO.C1COCC1>[CH2:1]([O:27][C:26](=[O:28])[CH:25]=[CH:24][CH2:23][CH2:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:2]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)C=CCCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C=CCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
The reagents DCC (33 mM) and DMAP (30 mM) were added to a solution of 5-phenylpent-2-enoic acid (5.3 g, 30 mM) in EtOH (50 mL) and THF (20 mL), which was cooled to 0° C. The resulting mixture was stirred for 30 min at 0° C., then allowed to react for 15 h at room temperature. The suspension was filtered, and the filtrate was concentrated. The residue was dissolved in EtOAc and washed with 1 M HCl (3×30 mL), H2O (10 mL), saturated NaHCO3 (3×30 mL), H2O (10 mL), saturated NaCl (20 mL), dried over MgSO4, and concentrated. Chromatography on a silica gel column using 1:2 EtOAc:hexane as the eluent afforded 5-phenyl-pent-2-enoic acid ethyl ester (3.75 g, yield=61%).
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:9]=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:18]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25](O)=[O:26])[CH:19]([CH3:21])[CH3:20].C(OCC)(=O)C>C(#N)C>[CH2:18]([O:22][C:23]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][C:24]=1[C:25]([N:5]1[CH2:4][CH2:3][N:2]([C:8]2[CH:9]=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][CH2:6]1)=[O:26])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: c1ccc2ncc(N3CCNCC3)cc2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)COc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2cnc3ccccc3c2)CC1

Procedure:
Prepared in analogy to example 1.1 (b) from 3-piperazin-1-yl-quinoline hydrochloride and 2-isobutoxy-5-methanesulfonyl-benzoic acid (example 2.4) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.BrC[CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: COC(=O)CCCBr
Product: COC(=O)CCCSc1c(Cl)ccc2c1CCNCC2
Product: Cl

Procedure:
Use a method similar to the Example 347, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and methyl 4-bromobutyrate to give, after deprotection by the General Procedure 1-4, the title compound as a white solid. MS (ES+) m/z: 314 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]([CH3:24])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]([CH3:24])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][N:21]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:22][CH2:23]2)[C:12](=[O:15])[C:13]=1[OH:14])=[O:8]
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCNCC2)C1
Reactant: CS(=O)(=O)Cl
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCN(S(C)(=O)=O)CC2)C1

Procedure:
Compound 764 was prepared from 4-hydroxy-5-oxo-1-(2-piperazin-1-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide and methanesulfonyl chloride using the method described for compound 759. The title compound was purified by preparative HPLC (C18, ODS-A, S-75 μm, 10%–20%–30% acetonitrile/water/0.5% HCl) and isolated as a brown solid (0.0140 g, 12% yield). HRMS (M+H) calcd for C20H27N4Cl2O5S: 505.10793. found: 505.1095.