Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]=[CH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.C[O-].[Na+].Br[C:30]1[CH:31]=[N:32][C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][C:30]2[CH:31]=[N:32][C:33]3[C:38]([CH:39]=2)=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Brc1cnc2ccccc2c1
Reactant: C=CCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: B1C2CCCC1CCC2
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCCc2cnc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
A solution of 260 mg (1.15 mmol) of 1-(t-butoxycarbonyl)-4-(prop-2-enyl)piperidine (from EXAMPLE 33, Step B) in 3 mL of THF under argon was treated with 2.30 mL of 0.5 M 9-BBN solution in THF. The resulting mixture was stirred at rt for 2 h, then treated with 68 mg (1.25 mmol) of NaOMe. The resulting mixture was stirred until it was homogeneous (˜15 min) and then was treated with 0.155 mL (1.15 mmol) of 3-(bromo)quinoline and 41 mg (0.05 mmol) of [1,1′-bis(triphenyl-phosphino)ferrocene]dichloropalladium.CH2Cl2. The resulting mixture was heated at reflux for 30 min, cooled and quenched with 20 mL of 1.0 N NaOH. The quenched reaction was extracted with 2×50 mL of ether; the extracts were dried over MgSO4, combined and concentrated. Flash chromatography on 15 g of silica gel using 4:1 v/v hexanes/EtOAc as the eluant afforded 240 mg (59%) of the title compound: 1H NMR (300 MHz) B 1.00-1.16 (m, 2H), 1.25-1.40 (m, 2H), 1.45 (s, 9H), 1.60-1.80 (5H), 2.62-2.72 (m, 2H), 2.79 (t, J=7.8,22H), 4.06 (br s, 2H), 7.52 (m, 1H), 7.66 (m, 1H), 7.76 (dd, J=8.0, 1.6, 1H), 7.91 (d, J=1.6, 1H), 8.77 (d, J=2.2, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH:14]=1)([O-:3])=[O:2].CC(O)=O.Cl.[CH3:25][NH2:26].[OH-].[Na+]>ClCCCl>[CH3:25][NH:26][CH:16]1[CH2:17][CH2:18][C:13]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=2)=[CH:14][CH2:15]1
Reactant: O=C1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Reactant: CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CNC1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Reaction time: 14 h
Yield: 99.9 %

Procedure:
A solution of compound 79 (0.07 g, 0.273 mmol) in 1,2-dichloroethane (3 mL) was treated with AcOH (0.015 mL, 0.273 mmol), methylamine hydrochloride (0.018 g, 0.273 mmol), NaBH(OAC)3 (0.086 g, 0.409 mmol) at room temperature and stirred for over night (14 h). The reaction was basified with 2 N NaOH (25 mL) and product was extracted into ethyl acetate (2×20 mL). The combined ethyl acetate layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 80 (0.074 g, quantitative) as a solid. mp 208-210° C.; 1H NMR (DMSO-d6) δ 1.44-1.53 (m, 1H), 1.97-2.01 (m, 2H), 2.35 (s, 3H), 2.40-2.57 (m, 3H), 2.60-2.70 (m, 1H), 6.13 (brs, 1H), 7.54 (d, 1H, J=9.0 Hz), 7.63 (s, 1H), 8.00 (d, 1H, J=7.5 Hz), 8.67 (s, 1H), 11.85 (brs, 1H); ESI-MS m/z (%): 272 (M+, 100).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([NH2:14])=[CH:11]2)=[N:6]1.[O:16]([C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][N:5]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([NH:14][C:30]([NH:29][C:26]3[CH:27]=[CH:28][C:23]([O:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)=[CH:24][CH:25]=3)=[O:31])=[CH:11]2)=[N:6]1
Reactant: CN(C)CCn1cc2cc(N)ccc2n1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCn1cc2cc(NC(=O)Nc3ccc(Oc4ccccc4)cc3)ccc2n1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
A mixture of 2-(2-dimethylamino-ethyl)-2H-indazol-5-ylamine (42.0 mg, 0.206 mmol), 4-phenoxyphenyl isocyanate (43.4 mg, 0.206 mmol) and 2 mL of THF, was stirred at 50° C. for 6 hours. The solvents were removed under vacuo, the residue was dissolved in 1.5 mL of a 1:1 mixture of dimethylsulfoxide/methanol and purified by preparative reverse-phase HPLC. 1H NMR (300 MHz, DMSO-d6) ppm 2.56 (s, 8H), 4.66 (m, 2H), 6.95–7.38 (m, 10H), 7.56 (m, 1H), 7.93 (m, 1H), 8.3 (s, 1H), 8.75 (m, 2H); MS (DCI/NH3) m/z 416 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:6]2[CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][CH2:9][CH2:10][C:5]=2[N:4]=1)[CH3:2].[C:54]([O:60][CH2:61][CH3:62])(=[O:59])[CH2:55][C:56]([O-])=[O:57].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH2:1]([C:3]1[N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:31][N:32]=[N:33][N:34]=3)=[CH:22][CH:23]=2)[C:6]2[CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]([C:56](=[O:57])[CH2:55][C:54]([O:60][CH2:61][CH3:62])=[O:59])[CH2:9][CH2:10][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: CCOC(=O)C1NCCc2nc(CC)n(Cc3ccc(-c4ccccc4-c4nnnn4C(c4ccccc4)(c4ccccc4)c4ccccc4)cc3)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)N1CCc2nc(CC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c2C1C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
Ethyl 2-ethyl-3-{2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]-pyridine-4-carboxylate (1.94 g), monoethyl malonate (0.74 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.80 g), and triethylamine (1.40 g) are dissolved in dichloromethane (20 ml). The mixture is stirred overnight at room temperature. The reaction mixture is washed with water, dried over sodium sulfate, and then evaporated to remove the solvent. The residue is dissolved in ethanol (30 ml) and thereto is added fumaric acid (2.00 g). The mixture is refluxed for three hours and evaporated to remove the solvent. The resulting residue is treated with a saturated sodium hydrogen carbonate solution and extracted with chloroform. The organic layer is dried and evaporated to remove the solvent. The resulting residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-ethyl-3-{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl-5-ethoxycarbonylacetyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (1.07 g) as foam.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:11]([C:16]2[C:35]([CH:36]3[CH2:38][CH2:37]3)=[CH:34][C:19]3[C:20]([C:30]([NH:32][CH3:33])=[O:31])=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[O:22][C:18]=3[CH:17]=2)[S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:39][S-:40].[Na+]>CC#N.C(O)(C)C>[CH:36]1([C:35]2[C:16]([N:11]([C:4]3[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([S:40][CH3:39])[CH:3]=3)[S:12]([CH3:15])(=[O:14])=[O:13])=[CH:17][C:18]3[O:22][C:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)=[C:20]([C:30]([NH:32][CH3:33])=[O:31])[C:19]=3[CH:34]=2)[CH2:38][CH2:37]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(Cl)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: C[S-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC#N
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])c(SC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(N-(3-chloro-4-nitrophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (2 g, 3.58 mmol), and sodium thiomethoxide (0.685 g, 9.78 mmol) was dissolved in 20 mL of 1:1 CH3CN/Isopropanol and was stirred at room temperature for 3 h. Solvent was evaporated and water (60 mL) was added. The yellowish solid formed was filtered, washed with water to provide light yellowish solid which was used in the next step. (1.6 g, 86%) LCMS (m/z, ES+)=570 (M+H+).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1B(O)O>>[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccco1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(-c2ccco2)c(-c2ccccc2)n1
Yield: 35.3 %

Procedure:
6-(Furan-2-yl)-5-phenyl-1,2,4-triazin-3-amine (100 mg, 35%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.3 g, 1.19 mmol) and 2-furanboronic acid (0.16 g, 1.428 mmol) according to the general procedure of Example 1.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.S(=O)(=O)(O)O.[CH3:24]O>>[CH3:24][O:15][C:14](=[O:16])[CH2:13][C:5]1[CH:4]=[C:3]([C:2]([F:17])([F:18])[F:1])[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=1
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
To a solution of 3,5-bis-trifluoromethylphenylacetic acid (3.0 g, 11.03 mmol) (Aldrich) in methanol (20 mL) was added concentrated sulfuric acid (1.0 mL) and the reaction mixture was heated at reflux overnight. The reaction mixture was concentrated in vacuo. The residue was then diluted with ethyl acetate (100 mL) and successively washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography to give 3,5-bis-trifluoromethylphenylacetic acid methyl ester as a colorless oil. (Yield 2.27 g, 72.1%).
Reaction SMILES: Cl[C:2]1C(F)=C(C(F)=C[CH:9]=1)C=O.[Cl:12][C:13]1[C:14]([F:23])=[C:15]([C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[CH:16]=[O:17]>>[Cl:12][C:13]1[C:14]([F:23])=[C:15]([C:16](=[O:17])[CH:2]=[CH2:9])[C:18]([O:21][CH3:22])=[CH:19][CH:20]=1
Reactant: COc1ccc(Cl)c(F)c1C=O
Reactant: O=Cc1c(F)ccc(Cl)c1F
Product: C=CC(=O)c1c(OC)ccc(Cl)c1F

Procedure:
1-(3-Chloro-2-fluoro-6-methoxyphenyl)prop-2-en-1-one was prepared using a procedure analogous to intermediate 1 except that 3-chloro-2,6-difluorobenzaldehyde was replaced with 3-chloro-2-fluoro-6-methoxybenzaldehyde. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.43-7.36 (m, 1H), 6.75-6.56 (m, 2H), 6.13-6.03 (m, 2H), 3.80 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]#[C:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[C:8]([F:18])[C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+].CO>O>[CH3:15][C:14]([CH3:17])([CH3:16])[C:13]#[C:12][C:10]1[CH:9]=[C:8]([F:18])[C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[CH:11]=1
Reactant: COC(=O)c1c(F)cc(C#CC(C)(C)C)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)C#Cc1cc(F)c(C(=O)O)c(F)c1
Yield: 82.9 %

Procedure:
Methyl 2,6-difluoro-4-(3,3-dimethylbut-1-ynyl)benzoate (1.0 g, 0.004 mol) and lithium hydroxide (0.57 g, 0.012 mol) were placed in a 3:1 mixture of methanol:water (60 mL) and heated at 60° C. for 3.5 h. The reaction was cooled and concentrated in vacuo to a volume of 20 mL. The mixture was placed in an ice-water bath and acidified to pH 5 with coc. HCl. A white solid crashed out which was filtered and washed thoroughly with water. The solid was dried in the vacuum oven to give the product (0.79 g, 84%) as a solid. m/z=237.1 (M−1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][CH2:14][CH2:15][CH3:16])[C:7]([OH:9])=[O:8])([O-])=O.[H][H]>[C].[Pd].O1CCCC1>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:13][CH2:14][CH2:15][CH3:16])[C:7]([OH:9])=[O:8]
Reactant: [H][H]
Reactant: CCCNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCNc1ccc(C(=O)O)cc1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 80.1 %

Procedure:
To a tetrahydrofuran solution (20 mL) of 3-nitro-4-n-propylaminobenzoic acid (see Working Example 82-1) (1.94 g, 10.8 mmol) was added 10% palladium-carbon (200 mg), a hydrogen atmosphere was substituted in the flask, and this was stirred at room temperature for 6 hours. After the reaction was finished, this was filtered through Celite, and the filtrate was concentrated to yield the title compound (1.68 g, quant.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[CH3:12].C(N(CC)C(C)C)(C)C.[NH2:26][C@@H:27]([CH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[CH2:28][N:29]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]1=[O:39].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:26][C@H:27]([CH2:28][N:29]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]2=[O:39])[CH2:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[O:15])[S:10][C:11]=1[CH3:12]
Reactant: N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1sc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (187 mg, 0.62 mmol), N,N-diisopropylethylamine (0.54 ml, 3.10 mmol) and 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (200 mg, 0.62 mmol)) [Prepared according to the procedure of Preparation 6, except substituting 3-cyclohexyl-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-alanine (5 g, 18.4 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (347 mg, 0.74 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 50% EtOAc in hexanes) yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-5-methyl-2-thiophenecarboxamide (226 mg, 0.40 mmol, 64% yield) as a white foam: LCMS (ES) m/e 569, 571 (M, M+2)+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([OH:17])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[C:34]([NH:38]O)([CH3:37])([CH3:36])[CH3:35].O>CN(C)C=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[C:7]3[C:14]([C:15]([O:17][NH:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:16])=[N:13][NH:12][C:8]=3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)NO
Reactant: O=C(O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NOC(=O)c1n[nH]c2c(=O)[nH]c3cc(Cl)ccc3c(=O)c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 60.4 %

Procedure:
A solution of 7-chloro-3-(carboxy)pyrazolo[3,4-c][1]-benzazepine-4,10(1H,9H)-dione (400 mg, 1.37 mmol) (compound of Example 9) and 1,1′-carbonyldiimidazole (334 mg, 2.06 mmol) in N,N-dimethylformamide (16 mL) was stirred for 1 hour. In one portion, N-tert-butylhydroxylamine hydrochloride (516 mg, 4.11 mmol) was added and the solution was stirred for 17 hours at room temperature. To the resulting solution was added water (20 mL). The insoluble material was filtered and washed with hot methanol (3×20 mL) to give the title compound (300 mg, 61% yield, m.p. 258° C.).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:21](/B(O)O)=[CH:22]\[CH2:23][CH2:24][CH2:25][CH3:26]>>[CH:21](/[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[CH:22]\[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Brc1cnc2ccc(NCCCN3CCOCC3)nn12
Reactant: CCCC/C=C/B(O)O
Product: CCCC/C=C/c1cnc2ccc(NCCCN3CCOCC3)nn12

Procedure:
Prepared from the product of step A (example 16) and (E)-1-hexeneboronic acid according to general procedure 2 providing the alkene (100 mg, 90%) as a brown oil; 1H NMR (500 MHz, CD3OD) δ 7.51 (d, J=9.6 Hz, 1H), 7.41 (s, 1H), 6.75 (dt, J=7.0, 16.1 Hz, 1H), 6.62-6.58 (m, 2H), 3.70 (t, J=4.8 Hz, 4H), 3.41 (t, J=6.9 Hz, 2H), 2.52 (m, 6H), 2.30-2.26 (m, 2H), 1.94-1.88 (m, 2H), 1.52-1.41 (m, 4H), 0.96 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH:12]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][CH2:25][C:24]=4[CH:28]=3)[CH2:13][C@@H:14]3[NH:18][C:17](=[O:19])[CH2:16][CH2:15]3)=[N:8][C:9]=2[O:10]C)[CH2:3][CH2:2]1.CCCCCC>C(O)C>[CH:1]1([C:4]2[C:9](=[O:10])[NH:8][C:7]([CH:12]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][CH2:25][C:24]=4[CH:28]=3)[CH2:13][C@H:14]3[CH2:15][CH2:16][C:17](=[O:19])[NH:18]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: COc1nc(C(C[C@H]2CCC(=O)N2)c2ccc3c(c2)CCO3)ccc1C1CC1
Solvent: CCCCCC
Solvent: CCO
Product: O=C1CC[C@H](CC(c2ccc3c(c2)CCO3)c2ccc(C3CC3)c(=O)[nH]2)N1

Procedure:
An (R,S) mixture of the title compound was obtained as a yellow amorphous (78 mg) by performing substantially the same reaction as in Examples 4-207 and 4-208(3) except for using (5R)-5-[2-(5-cyclopropyl-6-methoxypyridin-2-yl)-2-(2,3-dihydro-1-benzofuran-5-yl)ethyl]pyrrolidin-2-one. This was preparatively isolated by a chiral HPLC column (CHIRALPAK IB, hexane:ethanol=30:70 v/v, 40° C., 10 mL/min, 210 nm) to give one diastereomer (A) of the title compound as a colorless amorphous (50 mg) and the other diastereomer (B) of the title compound as a colorless amorphous (45 mg).
Reaction SMILES: [C:1]1([CH:7]2[NH:11][CH:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:31])[NH:26][CH2:27][C:28](O)=[O:29])[CH:21]=[CH:22][CH:23]=1>ClCCCl.S(Cl)(Cl)=O>[CH3:17][C:18]1[CH:19]=[C:20]([NH:24][C:25](=[O:31])[NH:26][CH2:27][C:28]([N:11]2[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][CH:10]2[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:29])[CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)C1CCC(c2ccccc2)N1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)C1CCC(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(C)c1
Yield: 29.2 %

Procedure:
By proceeding in a fashion similar to that described in Example 1 but starting from 2.2 g of ethyl (2RS,5SR)-5-phenylprolinate, 2.1 g of 2-[3-(3-methylphenyl)ureido]acetic acid in suspension in 50 cm3 of anhydrous 1,2-dichloroethane and 0.72 cm3 of sulphinyl chloride, 1.2 g of ethyl (2RS,5SR)-1-{2-[3-(3-methylphenyl)ureido]acetyl}-5-phenylprolinate, melting at 115° C., are obtained after recrystallization in acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28])[CH:11]=[C:12](Br)[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].[CH2:34]([Sn](CCCC)(CCCC)CC=C)[CH2:35][CH2:36]C>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][NH:6][C:7]([C:9]1[N:10]([CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28])[CH:11]=[C:12]([C:35]([CH3:36])=[CH2:34])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COC(Cn1cc(Br)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=C(C)c1cn(CC(OC)OC)c(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 69.5 %

Procedure:
To a solution of 3-benzyloxy-5-bromo-1-(2,2-dimethoxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (138 mg) obtained in Example 161, Step 2 in dioxane (2.5 ml) were added tributyl-2-propenyltin (245 mg) and tetrakis(triphenylphosphine)palladium(0) (60 mg), and the mixture was stirred at 100° C. for 4 hr. The solvent was evaporated, toluene was added, and the mixture was concentrated again. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to give 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-isopropenyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (89 mg).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:22]([C:24]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)#[N:23]>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:27]4[CH2:26][CH2:25][C:24]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)([C:22]#[N:23])[CH2:29][CH2:28]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: N#CC1(c2ccccc2)CCNCC1
Solvent: CN(C)C=O
Solvent: CCO
Product: N#CC1(c2ccccc2)CCN(C[C@@H](O)COc2ccc(-c3noc4cc(F)ccc34)cc2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-cyano-4-phenylpiperidine in ethanol, essentially as described above in Example 70. Purity by LC/MS=<100%, [M+H]+=472.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=C[N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=2[CH3:26])=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=N[NH:39]C(=O)C=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:14]=[N:39][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=2[CH3:26])=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Reactant: O=c1cc(OCc2ccccc2)cn[nH]1
Product: Cc1cc(CO)ccc1C(=O)Cn1ncc(OCc2ccccc2)cc1=O
Yield: 81 %

Procedure:
5-Benzyloxy-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one is prepared following preparation 1c employing 5-benzyloxy-2H-pyridazin-3-one (described in WO 09/103,478) instead of 4-benzyloxy-1H-pyridin-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH2:9][C:10]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[O:11])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([C:10]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[O:11])[CH2:22][C:23]([O:25][CH3:26])=[O:24])=[O:7])=[CH:17][CH:18]=1
Reactant: O=C(CNC(=O)c1ccc(Cl)cc1)c1ccsc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: COC(=O)CC(NC(=O)c1ccc(Cl)cc1)C(=O)c1ccsc1
Yield: 64.3 %

Procedure:
23 g of N-(4-chlorobenzoyl)-N-[(3-thienylcarbonyl)methyl]amine, 6.1 g of 50% sodium hydride and 21.8 g of methyl bromoacetate are treated in the same manner as described in Preparation 1-(4). 18.6 g of methyl 3-(4-chlorobenzoylamino)-3-(3-thienylcarbonyl)propionate are thereby obtained.