Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=O)[CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.B.CO>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cccc(C)c1NC(=O)CCCc1cccnc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc(C)c1NCCCCc1cccnc1

Procedure:
A solution of 13.9 g of N-(2,6-dimethylphenyl)-3-pyridinebutanamide in dry tetrahydrofuran was added dropwise with stirring to an excess of 1 molar borane in tetrahydrofuran and the resulting solution was heated to reflux for two hours. After cooling, excess methanol was added to decompose the remaining borane and the solution was evaporated to dryness. The residue was acidified by the cautious addition of 2N hydrochloric acid and was warmed on the steam bath for 20 minutes. The resulting solution was cooled, made strongly basic with sodium hydroxide solution and was extracted with dichloromethane. The combined layers were dried with potassium carbonate and concentrated to give N-(2,6-dimethylphenyl)-3-pyridinebutanamine as an oil. A solution of the free base in methanol was treated with an excess of fumaric acid in methanol and the resulting solution was diluted with ether. The resulting difumarate was crystallized from 200 ml of 2-propanol to give 20.6 g of N-(2,6-dimethylphenyl)-3-pyridinebutanamine (E)-2-butenedioate(1:2) salt, mp 138°-140° C. (decomposition). Recrystallization from 2-propanol gave the analytical sample, mp 140°-142° C. (decomposition).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:24])[C:4](=[O:23])[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=1[S:14]([NH:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])(=[O:16])=[O:15].[H-].[Na+].Br[CH2:28][CH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1>CN(C=O)C>[CH3:2][N:3]([CH3:24])[C:4](=[O:23])[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=1[S:14]([N:17]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH2:28][CH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)(=[O:15])=[O:16]
Reactant: BrCCOC1CCCCO1
Reactant: CN(C)CCNS(=O)(=O)c1cccc([N+](=O)[O-])c1C(=O)N(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCN(CCOC1CCCCO1)S(=O)(=O)c1cccc([N+](=O)[O-])c1C(=O)N(C)C
Reaction time: 20 h

Procedure:
To a suspension of N,N-dimethyl 2-[N-(2-dimethylaminoethyl)aminosulfonyl]-6-nitrobenzamide hydrochloride (347 mg, 0.91 mmol) in DMF (5 ml) under N2 was added 50% NaH (87 mg, 1.82 mmol). After stirring at 20°-25° for 15 minutes until all of the NaH had reacted, a solution of 2-(2-bromoethoxy)tetrahydro-2H-pyran in DMF (2 ml) was added. The solution was stirred at 20°-25° under N2 for 20 hours and then concentrated under reduced pressure to remove most of the DMF. The residue was partitioned between EtOAc and a saturated aqueous solution of NaCl. After drying (Na2SO4) the EtOAc extract, filtering and concentrating, the residue was chromatographed over silica gel. Elution with 7% MeoH-93% CHCl3 gave 100 mg of product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[N:6][CH:7]=1.[C:18]([N:25]1[CH2:33][CH2:32][CH:28]([C:29](O)=[O:30])[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:29]([CH:28]2[CH2:32][CH2:33][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:26][CH2:27]2)=[O:30])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 15 h
Yield: 17.9 %

Procedure:
To a stirred solution of N-(5-chloropyridin-2-yl)-2-aminobenzamide (0.5 g, 1.79 mmol) and Boc-isonipecotic acid (0.41 g, 1.79 mmol) in N,N-dimethylformamide (30 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.69 g, 3.58 mmol). After stirring for 15 h, the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and water, and the layers separated. The organic phase was washed with saturated aqueous sodium chloride, dried (magnesium sulfate), filtered, and concentrated in vacuo. The solid was suspended in ether, sonicated, and filtered to give 0.147 g (18%) of a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=2[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:4][CH:3]=1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH2:38]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)[CH:39]([CH3:41])[CH3:40]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([N:45]3[CH2:46][CH2:47][N:42]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:43][CH2:44]3)=[O:14])=[CH:10][C:9]=2[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:21][CH:22]=1
Reactant: CC(C)Cc1cc(C(=O)O)ccc1OCc1ccc(F)cc1
Reactant: CC(C)CN1CCNCC1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)Cc1cc(C(=O)N2CCN(CC(C)C)CC2)ccc1OCc1ccc(F)cc1
Reaction time: 0.67 h
Yield: 84.2 %

Procedure:
4-(4-fluorobenzyloxy)-3-isobutylbenzoic acid (16.5 g) was dissolved in a mixture of chloroform (150 ml) and triethylamine (15.3 ml). To this mixture was added diphenylphosphinic chloride (11.5 ml) while being cooled with ice. After being stirred for 40 minutes, the mixture, with 1-isobutylpiperazine (7.83 g) added thereto, was stirred for 1.5 hours at room temperature. This reaction mixture was washed with saturated sodium hydrogencarbonate solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. Thus obtained residue was purified by silica gel column chromatography (chloroform: methanol=50:1) and the resulting solid was recrystallized (from n-hexane), thereby yielding 19.6 g of the aimed compound.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[F:14])[CH2:3][C:4]([OH:6])=[O:5].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.O>CN(C=O)C>[F:14][C:8]1[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=1[CH:2]([N:1]1[C:18](=[O:19])[C:17]2[C:16](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]1=[O:20])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NC(CC(=O)O)c1ccc(F)cc1F
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CC(c1ccc(F)cc1F)N1C(=O)c2ccccc2C1=O
Temperature: 135 °C

Procedure:
5.0 g of rac-3-amino-3-(2,4-difluorophenyl)propanoic acid (24.85 mmol) and 3.68 g of phthalic anhydride (24.85 mmol) were dissolved in 20 ml of DMF and the mixture was heated at reflux at 135° C. overnight. The reaction solution was added to about 160 ml of water and extracted twice with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulphate, filtered and concentrated. The crude product was purified by silica gel chromatography (mobile phase: dichloromethane/methanol 80:1, isocratic) and then by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). This gave 3.43 g of the title compound (27% of theory).
Reaction SMILES: [F:1][CH:2]([F:24])[S:3][CH2:4][C@@H:5]1[CH2:9][C@@H:8](O)[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:56]([SH:64])(=[O:63])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>O1CCCC1>[C:56]([S:64][C@@H:8]1[CH2:7][N:6]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:5]([CH2:4][S:3][CH:2]([F:24])[F:1])[CH2:9]1)(=[O:63])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: O=C(S)c1ccccc1
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@H](O)C[C@H]1CSC(F)F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(S[C@H]1C[C@@H](CSC(F)F)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1

Procedure:
To a solution of (2S,4R)-2-(difluoromethyl)thiomethyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.01 g) and triphenylphosphine (1.1 g) in tetrahydrofuran (20 ml) was added dropwise a solution of diethyl azodicarboxylate (0.66 ml) in tetrahydrofuran (3 ml) at -10° C. to -5° C. with stirring. The mixture was stirred at the same temperature for 30 minutes. To the solution was added thiobenzoic S-acid (0.49 ml) at the same temperature and the mixture was stirred under ice-cooling for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (60 ml). The solution was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride successively, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of n-hexane and ethyl acetate (3:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-4-benzoylthio-2-(difluoromethyl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.01 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:28]=[C:27]([CH:34]=O)[CH:26]=2)=[CH:21][CH:20]=1>>[C:30]([N:29]1[C:25]([C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][CH:23]=2)=[CH:26][C:27]([CH2:34][NH:17][CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:14][CH2:13]2)=[N:28]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)n1nc(C=O)cc1-c1ccc(Cl)cc1
Reactant: COc1ccc(N2CCN(CCN)CC2)cc1
Product: COc1ccc(N2CCN(CCNCc3cc(-c4ccc(Cl)cc4)n(C(C)(C)C)n3)CC2)cc1
Yield: 86 %

Procedure:
Compound 46 was prepared using the same method as that of Example 1 except that 4-(4-methoxyphenyl)piperazin-1-ylethylamine and 5-(4-chlorophenyl)-1-t-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Cl:10][S:11](O)(=[O:13])=[O:12]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([S:11]([Cl:10])(=[O:13])=[O:12])[CH:3]=1
Reactant: COc1ccc(F)cc1
Reactant: O=S(=O)(O)Cl
Product: COc1ccc(F)cc1S(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Fluoroanisole (10.0 g) was carefully added to chlorosulphonic acid (45.81 g) at 0° C. The mixture was stirred at RT for 2 h, then quenched with ice-water (500 ml) and the solid filtered and dried, yield 16.50 g.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:29]([O:36][C:37]1[CH:38]=[C:39]([C:44](Br)=[CH:45][N:46]=1)[C:40]([O:42][CH3:43])=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C([O-])(=O)C.C([O-])(=O)C.[Pd+2].CN1C(=O)CCC1>[CH2:29]([O:36][C:37]1[CH:38]=[C:39]([C:44]([CH:3]=[CH:2][C:1]([O:5][CH3:6])=[O:4])=[CH:45][N:46]=1)[C:40]([O:42][CH3:43])=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C=CC(=O)OC
Reactant: COC(=O)c1cc(OCc2ccccc2)ncc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN1CCCC1=O
Product: COC(=O)C=Cc1cnc(OCc2ccccc2)cc1C(=O)OC
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To NMP (1 mL) was added methyl acrylate (commercially available from Sigma-Aldrich, St. Louis, Mo., USA), tri-o-tolylphosphine (8.5 mg, 28 μmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) and palladium diacetate (2.5 mg, 11 μmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA). The solution was degassed three time with nitrogen. To this solution was then added a 1 mL NMP solution of methyl 2-(benzyloxy)-5-bromoisonicotinate (120 mg, 372 μmol). The reaction was stirred at 90° C. overnight and then purified by column chromatography (silica gel, 10% EtOAc/hexane) to give desired product H6.2 (50.2 mg, 41.4%). MS ESI (pos.) m/e: 328.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3]
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1cc(OCc2ccccc2)ccc1O
Temperature: 25 °C
Yield: 41.1 %

Procedure:
2,5-dihydroxyacetophenone (5.00 g, 0.0329 mol), benzyl bromide (3.72 ml, 0.031 mol), potassium carbonate (4.31 g, 0.031 mol) and acetone (150 ml) were added to a 500 ml round bottom flask. The reaction mixture was heated overnight at reflux and then was cooled to ambient temperature. When cool, deionized water (150 ml) was added to the reaction mixture and the reaction mixture was extracted three times with 100 ml portions of diethyl ether. The combined ether layers were dried with sodium sulfate and concentrated in vacuo yielding a dark solid. This dark solid was recrystallized from 50:50 (ethanol:water) yielding 3.09 g of 2-hydroxy-5-benzyloxyacetophenone as yellow needles.
Reaction SMILES: C([Mg]Cl)(C)C.[Li+].[Cl-].[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1Br.O1CCN([C:23](=[O:50])[CH2:24][O:25][CH:26]([CH:48]=[CH2:49])[CH2:27][O:28][C:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)CC1>C1COCC1>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C:23](=[O:50])[CH2:24][O:25][CH:26]([CH:48]=[CH2:49])[CH2:27][O:28][C:29]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C=CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCC(=O)N1CCOCC1
Reactant: Fc1cccc(Br)c1F
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCC(=O)c1cccc(F)c1F
Reaction time: 1 h

Procedure:
Isopropylmagnesiumchloride-LiCl complex (1.30 M in THF, 155.0 mL, 0.0715 mol) under nitrogen was cooled to 0-5° C., and 2,3-difluorobromobenzene (13.8 g, 0.0715 mol, 1.50 equiv.) was added while T<10° C. After 1 h at 0-5° C., a solution of 1-morpholino-2-(1-(trityloxy)but-3-en-2-yloxy)ethanone 14 (21.8 g, 0.048 mol, 1.0 equiv.) in THF (2.0 vols) was added while T<10° C. The reaction mixture was stirred for 2.5 hours and monitored for consumption of 1-morpholino-2-(1-(trityloxy)but-3-en-2-yloxy)ethanone (target >97%). The reaction mixture was quenched by charging into cold sat. aq. NH4Cl (110 mL) and water (33 mL) while T<20° C. 2-Methoxy-2-methylpropane (218 mL) was added and the layers were separated. The organics were washed with sat. aq. NH4Cl (65 mL) and 18% aq. NaCl (44 mL). The organics were concentrated under vacuum T<25° C. to a light yellow oil of ketone 15 (21.6 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][C@@:18]([CH3:33])([S:29]([CH3:32])(=[O:31])=[O:30])[C:19]([NH:21][O:22]C3CCCCO3)=[O:20])[CH:15]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl>CCO>[C:1]([C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH2:17][C@@:18]([CH3:33])([S:29]([CH3:32])(=[O:30])=[O:31])[C:19]([NH:21][OH:22])=[O:20])[CH:15]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: C[C@@](CCn1cc(C#Cc2cccc(C#N)c2)cn1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CCO
Product: C[C@@](CCn1cc(C#Cc2cccc(C#N)c2)cn1)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a solution of (2R)-4-{4-[(3-cyanophenyl)ethynyl]-1H-pyrazol-1-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (0.209 g, 0.444 mmol) in EtOH (40 mL) was added 1M HCl (20 mL). The reaction was allowed to stir at room temperature overnight. The reaction mixture was concentrated, taken back up in MeOH, and concentrated again to give (2R)-4-{4-[(3-cyanophenyl)ethynyl]-1H-pyrazol-1-yl}-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide (160 mg, 93% yield) as a white solid.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:8][C:9](=[O:17])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:3]1.Br[CH2:19][CH2:20][OH:21]>>[OH:21][CH2:20][CH2:19][N:2]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:8][C:9](=[O:17])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:3]1
Reactant: O=c1[nH]c(C2CCNC2)cc2ccccc12
Reactant: OCCBr
Agent: Cl
Product: O=c1[nH]c(C2CCN(CCO)C2)cc2ccccc12

Procedure:
By the reaction in the same manner as in Example 2a, using 3-(pyrrolidin-3-yl)-2H-isoquinolin-1-one hydrochloride (201 mg) and 2-bromoethanol (285 μl), 3-[1-(2-hydroxyethyl)pyrrolidin-3-yl]-2H-isoquinolin-1-one (58 mg) was obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][C:14]([CH2:18][C:19]([OH:21])=O)=[C:15]([CH3:17])[N:16]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:13][C:14]([CH2:18][C:19]([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:21])=[C:15]([CH3:17])[N:16]=2)=[CH:10][CH:11]=1
Reactant: Cc1nc(-c2ccc(OCCCCl)cc2)sc1CC(=O)O
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc(OCCCCl)cc2)sc1CC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
A solution of {2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazol-5-yl}acetic acid i103 (0.5 g, 1.41 mmol, 1 eq), triethylamine (0.2 ml, 1.41 mmol, 1 eq), and piperidine (0.15 ml, 1.45 mmol, 1.03 eq) in dichloromethane (30 ml) is cooled (ice bath) and treated with 1-hydroxybenzotriazole (38 mg, 0.28 mmol, 0.2 eq) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.271 g, 1.41 mmol, 1 eq). The mixture is stirred at room temperature overnight, then diluted with 70 ml of dichloromethane. The organic layer is washed with water (2×50 ml), brine, dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure to obtain an orange solid. The solid is triturated in acetonitrile, filtered and rinsed with cold diethyl ether to give 0.18 g of 1-({2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazol-5-yl}acetyl)piperidine i104 as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].I[CH3:24]>>[CH3:24][N:15]([C@@H:12]1[CH2:13][CH2:14][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11]1)[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
tert-Butyl (R)-[1-(4-nitrophenyl)pyrrolidin-3-yl]carbamate was alkylated with iodomethane by method F. This resulted in the product with the molecular weight of 321.38 (C16H23N3O4); MS (ESI): 322 (M+H+).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH2:7])[C:4]([Cl:8])=[CH:3][CH:2]=1.[O-:9][C:10]#[N:11].[K+]>O.C(O)(=O)C>[Cl:8][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[NH:7][C:10]([NH2:11])=[O:9]
Reactant: N#C[O-]
Reactant: Nc1ccccc1Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccccc1Cl
Temperature: 15 °C
Yield: 70.4 %

Procedure:
O-chloroaniline (50 g) was added in water (400 g) and acetic acid (200 g), followed by cooling to 15° C. Then, a solution of potassium cyanate (63.6 g) and water (300 g) was added dropwise at not more than 15° C. over 40 minutes. The mixture was heated to 30° C., filtered and then washed with cold water to obtain a white crystal. This crystal was recrystallized from a solution of ethanol (350 g) and water (100 g) to obtain 47.1 g of o-chlorophenylurea as a white needle crystal.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:16])[CH2:7][CH2:8][NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)C.C1COCC1>O>[CH:10]1([NH:9][CH2:8][CH2:7][C:6]([OH:16])=[O:5])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)CCNC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCNC1CCCCC1
Reaction time: 1 h
Yield: 59.1 %

Procedure:
22 g of cyclohexylamine were added to 40 mL of ethanol, 10 g of ethyl 3-bromopropionate were added, and the mixture was heated and refluxed for two hours. The reaction system was concentrated under reduced pressure, the resulting residue was extracted with 200 mL of ethyl acetate, the organic layer was desiccated over anhydrous magnesium sulfate, and the product was then filtered and concentrated. The residue was purified by distillation under reduced pressure, and 6.3 g of N-cyclohexylmethyl β-alanine ethyl ester (yield of 57%) were obtained. 1.26 g of sodium hydroxide were dissolved in 200 mL of water, 6.3 g of N-cyclohexyl-β-alanine ethyl ester were added, and THF was added for dissolution. After stirring for one hour, the product was neutralized using Dowex 50WX4-[H+] and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was recrystallized and 3.2 g of the desired product were obtained (yield of 64%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[C:9]([Cl:13])[C:8]([F:14])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:15][N:16]([CH3:24])[CH:17]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(C(C)C)C(C)C)C>ClCCl>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[C:9]([Cl:13])[C:8]([F:14])=[CH:7][C:3]=1[C:4]([C:18](=[CH:17][N:16]([CH3:24])[CH3:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:5]
Reactant: N#Cc1c(Cl)c(F)cc(C(=O)Cl)c1Cl
Reactant: CCOC(=O)C=CN(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(Cl)c(C#N)c1Cl
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Starting at room temperature, a solution of 1075 g of 2,4-dichloro-3-cyano-5-fluorobenzoyl chloride (about 94% strength, corresponding to 1010.5 g=4.00 mol) in 850 ml of dichloromethane is added dropwise to a solution of 626 g (4.372 mol) of ethyl 3-dimethylamino-acrylate and 591 g (4.572 mol) of ethyl diisopropyl-amine (Hünig's base) in 1060 ml of dichloromethane. In the course of this, the temperature rises to about 50-55° C. (dropwise addition time about 90 minutes). The reaction mixture is subsequently stirred at 50° C. for 2 hours and then employed in the next stage without further working up.
Reaction SMILES: [N:1]1([CH2:5][C@H:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[CH:9]=2)[NH2:7])[CH2:4][CH2:3][CH2:2]1.O[C:18]1[C:19]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([NH2:30])=[O:29])[C:20]=2[N:21]=[N:22][N:23]=1>>[N:1]1([CH2:5][C@@H:6]([NH:7][C:18]2[C:19]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([NH2:30])=[O:29])[C:20]=3[N:21]=[N:22][N:23]=2)[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Reactant: COc1cc([C@H](N)CN2CCC2)ccc1Cl
Product: COc1cc([C@@H](CN2CCC2)Nc2nnnc3c(C(N)=O)cccc23)ccc1Cl

Procedure:
Compound 10 was prepared following general synthetic scheme 7 wherein (S)-2-(azetidin-1-yl)-1-(4-chloro-3-methoxyphenyl)ethanamine was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [413 (M+1)], 1H NMR (400 MHz, DMSO-d6): δ 10.01 (s, 1H), 9.29 (s, 1H), 9.08 (d, 1H), 8.58 (d, 2H), 8.08 (t, 2H), 7.44 (d, 2H), 7.15 (dd, 1H), 6.05-6.00 (m, 1H), 4.44-4.41 (m, 1H), 4.26-4.22 (m, 1H), 4.21-4.05 (m, 2H), 3.89 (s, 3H), 3.80-3.74 (m, 3H), 2.49-2.40 (m, 2H).