Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[CH:17][N:16]=[C:15]3[NH:19][N:20]=[C:21]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([O:29]C)=[CH:25][CH:24]=4)[C:14]=23)[CH:9]=[CH:10][CH:11]=1>C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[CH:17][N:16]=[C:15]3[NH:19][N:20]=[C:21]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=4)[C:14]=23)[CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 20 °C
Reaction time: 14 h

Procedure:
Under a nitrogen atmosphere, a solution of 5 ml (51.9 mmol) of boron tribromide in 20 ml of methylene chloride is added dropwise over a period of 30 minutes to a suspension, cooled to 0° C., of 5 g (13.63 mmol) of 4-(3-chloro-phenylamino)-3-(4-methoxy-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 100 ml of methylene chloride. The reaction mixture is stirred at 20° C. for 14 hours and then filtered and the filter residue is digested for 1/2 hour at RT in 85 ml of water. After filtering, the filter residue is partitioned between 50 ml of saturated sodium hydrogen carbonate solution, 50 ml of water and 135 ml of THF. The organic phase is separated off, the aqueous phase is extracted again with 35 ml of THF, the combined THF extracts are washed with brine and the organic phase is dried over sodium sulfate and concentration by evaporation is carried out in vacuo. The crystalline residue is digested in 65 ml of boiling ethyl acetate, cooled to RT and filtered, yielding the crude title compound. Recrystallization of a sample from ethyl acetate yields the pure title compound; m.p. >260° C.; TLC-Rf =0.54 (toluene/isopropanol/conc. ammonia [70:29:1]).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:14][C@@H:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12](=[O:22])[O:11][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([O:30][CH2:31][C@@H:32]([C:34]([OH:36])=[O:35])[NH2:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl.CCOCC>[CH2:15]([C@H:13]([CH2:14][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([OH:11])=[O:10])[C:12]([NH:33][C@H:32]([C:34]([OH:36])=[O:35])[CH2:31][O:30][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)O
Reactant: O=C1OC(=O)[C@H](Cc2ccccc2)C[C@H]1Cc1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](COCc1ccccc1)C(=O)O

Procedure:
A solution of 0.5 g of (S,S)-2,4-dibenzylglutaric anhydride and 0.82 g of O-benzyl-(L)-serine 1,2:5,6-di-O-isopropylidene-D-glucofuranos-3-yl ester in 10 ml of methylene chloride is stirred at room temperature overnight. The solution is diluted with ether, washed with 1N hydrochloric acid, water, dried (Na2S04), filtered and concentrated to give N-[(S,S)-2,4-dibenzyl-4-carboxybutyryl]-O-benzyl-(L)-serine 1,2:5,6-di-O-isopropylidene-D-glucofuranos-3-yl ester melting at 55°-58°; [α]D =+2.2°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][CH:15]([CH3:17])[CH3:16])[N:11]3[C:18](=[O:21])[NH:19][N:20]=[C:10]3[C:9]=2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[CH3:29]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].CI>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][CH:15]([CH3:17])[CH3:16])[N:11]3[C:18](=[O:21])[N:19]([CH3:29])[N:20]=[C:10]3[C:9]=2[C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: CC(C)Nc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2n[nH]c(=O)n12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CC(C)Nc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)c2nn(C)c(=O)n12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of crude 7,8-bis(4-chlorophenyl)-5-(isopropylamino)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one, DMF (0.7 mL), and potassium carbonate (21 mg, 0.15 mmol) was added methyl iodide (213 mg, 1.5 mmol). The resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was then diluted with EtOAc, washed with water and saturated aqueous NaCl, dried (Na2SO4), and concentrated at reduced pressure. The residue was purified by preparative reverse phase HPLC to obtain 14 mg (65% over two steps) of the title compound as a light yellow solid. HPLC/MS: retention time=4.54 min, [M+H]30 =428.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([OH:18])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](Cl)(=[O:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:19]([O:18][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(NC(=O)OC(C)(C)C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 52.2 %

Procedure:
To a solution of 5-tert-butoxycarbonylamino-2-hydroxybenzoic acid (1.02 g, 4.02 mmole) in DMF (20.0 ml) was added with acetyl chloride (39 mg, 4.83 mmole) and potassium carbonate (555 mg, 4.02 mmole). The reaction mixture was stirred for 4 hr at room temperature. After the reaction mixture was concentrated, the residue was dissolved in ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous Na2SO4. After evaporation of the solvent, the residue was recrystallized from ethyl acetate/hexane to give 0.62 g (52% yield) of 2-ethanoyloxy-5-tert-butoxycarbonylaminobenzoic acid as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](Cl)=[O:14])=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[NH:24][C:23]2=[O:31])[CH2:18][CH2:17]1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:16]2[CH2:17][CH2:18][CH:19]([N:22]3[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[NH:24][C:23]3=[O:31])[CH2:20][CH2:21]2)=[O:14])=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: Cc1ccc(-c2oncc2C(=O)Cl)cc1
Solvent: ClCCl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(n3c(=O)[nH]c4ccccc43)CC2)cc1
Reaction time: 1 h

Procedure:
To 5-(4-methylphenyl)isoxazole-4-carbonyl chloride (10 mg, 0.054 mmol) in dichloromethane (1 mL) was added 1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one (10 mg, 0.046 mmol, 1 eq.), and the reaction mixture was stirred for 1 h. The solvent was removed, and the residue was purified by preparative reverse-phase HPLC to give the title compound. HRMS (ESI, pos. ion) m/z calcd for C23H22N4O3: 402.1692, found 402.1695.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([NH2:12])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:15][C:16](=O)[CH2:17][C:18](=O)[CH3:19])C>C1(C)C=CC=CC=1>[CH3:19][C:18]1[NH:12][C:9]2[N:10]([N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=2)[C:16](=[O:15])[CH:17]=1
Reactant: Nc1cc(-c2ccccc2)[nH]n1
Reactant: CCOC(=O)CC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(=O)n2nc(-c3ccccc3)cc2[nH]1
Temperature: 120 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
A mixture of 5-phenyl-1H-pyrazol-3-ylamine (501 mg, 3.15 mmol) and 3-oxobutanoic acid ethyl ester (0.433 mL, 3.39 mmol) in anhydrous toluene (2.9 mL) is heated at 120° C. in a sealed vial. After 2 hr, the reaction is cooled to room temperature. The precipitate is collected in a Buchner funnel and washed with hexanes to afford 5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7(4H)-one (577 mg, yield 81%). LCMS: (AA) M+1 226; 1H NMR (400 MHz, DMSO) δ 12.35 (s, 1H), 8.01-7.92 (m, 2H), 7.49-7.43 (m, 2H), 7.42-7.37 (m, 1H), 6.57 (s, 1H), 5.60 (s, 1H), 2.29 (s, 3H).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([N:15]2[CH2:20][CH2:19][CH2:18]/[C:17](=[CH:21]\[C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]4)=[C:24]([O:34][CH3:35])[CH:23]=3)/[C:16]2=[O:36])[C:11]([O:13]C)=[O:12])=[CH:6][CH:5]=1.Cl>CO>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([N:15]2[CH2:20][CH2:19][CH2:18]/[C:17](=[CH:21]\[C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]4)=[C:24]([O:34][CH3:35])[CH:23]=3)/[C:16]2=[O:36])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1
Reactant: COC(=O)C(c1ccc(F)cc1)N1CCC/C(=C\c2ccc(-n3cnc(C)c3)c(OC)c2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(/C=C2\CCCN(C(C(=O)O)c3ccc(F)cc3)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
A 1 N aqueous solution of sodium hydroxide (0.8 mL) was added to a solution of a solution of methyl (E)-(4-fluorophenyl)-(3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)-2-oxopiperidin-1-yl)acetate synthesized by the method described in Example 924 (74 mg) in methanol (3 mL), and the reaction solution was stirred at room temperature for 13 hours. 2 N hydrochloric acid (0.4 mL) was added to the reaction solution, and the reaction solution was concentrated under reduced pressure to obtain 72 mg of crude (E)-(4-fluorophenyl)-(3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)-2-oxopiperidin-1-yl)acetic acid. HOBT (16 mg) and EDC (23 mg) were added to a solution of the resulting crude (E)-(4-fluorophenyl)-(3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)-2-oxopiperidin-1-yl)acetic acid (36 mg) and methylamine (2M THF solution, 0.4 mL) in DMF (3 mL), and the reaction solution was stirred at room temperature for 5 hours. Saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent:ethyl acetate→ethyl acetate:methanol=9:1) to obtain 32 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [CH2:1](OC1C=C(I)C=C(OCC)C=1OCC)C.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:30][CH2:31]C)[C:26]=1OCC)[NH2:23])C>>[CH3:31][O:30][C:25]1[CH:24]=[C:22]([CH:21]=[C:20]([O:19][CH3:17])[C:26]=1[CH3:1])[NH2:23]
Reactant: CCOc1cc(I)cc(OCC)c1OCC
Reactant: CCOc1cc(N)cc(OCC)c1OCC
Product: COc1cc(N)cc(OC)c1C

Procedure:
Following the procedure of the synthesis of 3,4,5-triethoxy-1-iodobenzene from the oil containing 3,4,5-triethoxyaniline in Reference Example 5,1-iodo-3,5-dimethoxy-4-methylbenzene was obtained as a pale yellow amorphous powder (7.59 g, yield: 87%) from 3,5-dimethoxy-4-methylaniline (J. Chem. Soc., 497–506 (1963)) (5.23 g, 31.3 mmol).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][N:3]=1.[C:13]1(/[CH:19]=[CH:20]/B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CN1CCCC1=O>[CH3:11][N:8]1[C:7](=[O:12])[NH:6][C:5]2[C:9]1=[N:10][C:2](/[CH:20]=[CH:19]/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[N:3][CH:4]=2
Reactant: OB(O)/C=C/c1ccccc1
Reactant: Cn1c(=O)[nH]c2cnc(Cl)nc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: Cn1c(=O)[nH]c2cnc(/C=C/c3ccccc3)nc21
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-chloro-9-methyl-7,9-dihydro-8H-purine-8-one <the compound of Reference Example 1> (200 mg), trans-2-phenylvinylboronic acid (192 mg), potassium carbonate (448 mg) and 1-methylpyrrolidin-2-one (3 ml) was added bis(tri-tert-butylphosphine)palladium (28 mg) under nitrogen atmosphere and the mixture was stirred at 150° C. under microwave irradiation for 1 hour. To the reaction mixture was added 1 mol/L hydrochloric acid (50 ml) and the crude solids precipitated were collected by filtration. The obtained crude solids were purified by silica gel column chromatography (eluent: chloroform/methanol=100/0˜90/10) to give the title compound 179 mg.
Reaction SMILES: C1COCC1.I[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1.[C:18]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)#[CH:19]>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.[Cu]I.O>[CH:24]([C:23]1[CH:26]=[CH:27][C:20]([C:18]#[C:19][C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)=[CH:21][CH:22]=1)=[O:25]
Reactant: C#Cc1ccc(C=O)cc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1

Procedure:
TEA (46 mL) was added to a THF (0.40 L) suspension of ethyl 4-iodobenzoate (30 g), 4-ethynylbenzaldehyde (14 g) obtained by the synthesis method described in the literature (Tetrahedron Letters, 2007, Vol. 48(33), pp. 5817-5820), PdCl2(PPh3)2 (3.9 g), and CuI (2.1 g), and the mixture was stirred for 4 hours at 45° C. After the reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The desiccant was filtered out, and the solvent was distilled off under reduced pressure. Hexane/ethyl acetate (1:1 (v/v)) was added to the resulting residue, the mixture was stirred, and then the precipitate was filtered off and dried. The filtrate was concentrated, and then the same procedure was performed. As a result, ethyl 4-[(4-formylphenyl)ethynyl]benzoate (yellow solid) was obtained (27 g, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[S:11])=[CH:5][CH:4]=1.[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][NH2:16]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([NH:16][CH2:15][CH:14]([O:17][CH3:18])[O:13][CH3:12])=[S:11])=[CH:7][CH:8]=1
Reactant: COC(CN)OC
Reactant: COc1ccc(N=C=S)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(NC(=S)NCC(OC)OC)cc1

Procedure:
A solution of 10 g (0.06 mole) of p-methoxyphenyl isothiocyanate in 100 ml of chloroform was treated with 6.3 g (0.06 mole) of aminoacetaldehyde dimethyl acetal. The solvent was evaporated and the residue was recrystallized from ethanol to yield N-(p-methoxyphenyl)-N'-(β,β-dimethoxyethyl)thiourea, 9.2 g (57%). A suspension of this thiourea in a solution of 5 ml of concentrated sulfuric acid and 20 ml of water was refluxed for 3 hours. The mixture was cooled and a solid was filtered, washed with water, and dried. Recrystallization from ethanol gave 1-(4-methoxyphenyl)-2-mercaptoimidazole, 4.9 g (70%), mp 215°-217° C.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]([NH2:12])=[O:11].[F:13][C:14]([F:27])([F:26])[C:15]1[CH:16]=[CH:17][C:18]2[S:22][C:21]([CH2:23]O)=[CH:20][C:19]=2[CH:25]=1>>[F:1][C:2]1[C:7]([O:8][CH2:23][C:21]2[S:22][C:18]3[CH:17]=[CH:16][C:15]([C:14]([F:26])([F:13])[F:27])=[CH:25][C:19]=3[CH:20]=2)=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]([NH2:12])=[O:11]
Reactant: OCc1cc2cc(C(F)(F)F)ccc2s1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Product: NC(=O)c1c(F)ccc(OCc2cc3cc(C(F)(F)F)ccc3s2)c1F
Yield: 3 %

Procedure:
Synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide and [5-(trifluoromethyl)-1-benzothiophen-2-yl]methanol according to Method C, scheme 3. Yield 3%, mp 150-152° C., HPLC-MS (method 1): m/z 386 [M−H]−, Rt=4.39 min.
Reaction SMILES: Br[C:2]1[C:3]([CH3:14])=[CH:4][C:5]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])=[N:6][CH:7]=1.B([C:18]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:19]=1[O:20][C@@H:21]([CH3:25])[C:22]([OH:24])=[O:23])(O)O>>[Cl:30][C:28]1[CH:27]=[CH:26][C:19]([O:20][C@@H:21]([CH3:25])[C:22]([OH:24])=[O:23])=[C:18]([C:2]2[CH:7]=[N:6][C:5]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=2[CH3:14])[CH:29]=1
Reactant: C[C@H](Oc1ccc(Cl)cc1B(O)O)C(=O)O
Reactant: Cc1cc(N(C)S(C)(=O)=O)ncc1Br
Product: Cc1cc(N(C)S(C)(=O)=O)ncc1-c1cc(Cl)ccc1O[C@@H](C)C(=O)O

Procedure:
The title compound was prepared by the method of example 155 using the product from step (ii) and the product from example 151 step (iv). Yield 0.125 g.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:14])[N:3]=1.CO.[ClH:17]>O1CCCC1.CCOCC>[ClH:17].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][NH2:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:14])[N:3]=1
Reactant: Cc1cc2cc(C#N)ccc2c(N)n1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc2cc(CN)ccc2c(N)n1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1-amino-6-cyano-3-methylisoquinoline (0.68 g) in 15 mL of tetrahydrofuran at room temperature under a nitrogen atmosphere was added 8.4 mL of 2M borane-methylsulfide complex in tetrahydrofuran and thereafter heated at 60° C. for 50 minutes. The reaction mixture was cooled in an ice bath and 7.5 mL of methanol was added slowly. After 15 minutes 18.8 mL of 1M hydrogen chloride in ether was added. The reaction mixture was allowed to warm to room temperature and stirred for an additional 16 hours. The solid was isolated to afford 0.34 g of 1-amino-6-(aminomethyl)-3-methylisoquinoline hydrogenchloride. The filtrate was purified using column chromatography (silica gel; methanol/ammonia=98/2) to yield an additional 0.15 g of 1-amino-6-(aminomethyl)-3-methylisoquinoline. ESI-MS: 188 (MH+).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C[Al](C)C.[CH2:10]([O:12][C:13]1[C:14]([C:25]([O:27]CC)=O)=[N:15][N:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:17]=1)[CH3:11]>>[CH2:10]([O:12][C:13]1[C:14]([C:25]([N:3]([O:4][CH3:5])[CH3:2])=[O:27])=[N:15][N:16]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[N:17]=1)[CH3:11]
Reactant: CCOC(=O)c1nn(-c2ccc(F)cc2)nc1OCC
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Product: CCOc1nn(-c2ccc(F)cc2)nc1C(=O)N(C)OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an oven-dried flask under a nitrogen atmosphere was added N,O-dimethylhydroxylamine hydrochloride (2.8 g, 28.6 mmol) to which a solution of trimethylaluminum (2.0 M in toluene, 14.3 mL, 28.6 mmol) was added at 0° C. and stirred for 30 min. Ethyl 5-ethoxy-2-(4-fluorophenyl)-2H-1,2,3-triazole-4-carboxylate (i.e. the product of Step A, 4.0 g, 14.3 mmol) was added and the resulting solution was stirred at 23° C. for 4 h. The reaction mixture was cooled to 0° C. and carefully quenched by the dropwise addition of water (2 mL). Dichloromethane, (50 mL), sodium sulfate and water (3 mL) were added sequentially to the mixture which was then stirred for 20 min. at 23° C. The mixture was dried (Na2SO4 and MgSO4) and concentrated under reduced pressure to obtain the title compound (3.7 g) as an orange solid.
Reaction SMILES: C1COCC1.[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[C:17]([F:25])[C:16]=2[F:26])=[C:11]([F:27])[C:10]=1[F:28])[CH3:7].C([Li])CCC.[CH2:34]([C@H:37]1[CH2:42][CH2:41][C@H:40]([CH:43]2[CH2:46][CH2:45]O2)[CH2:39][CH2:38]1)[CH2:35][CH3:36]>C(O)=O>[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:36][CH2:35][CH:34]([CH:37]4[CH2:38][CH2:39][CH:40]([CH2:43][CH2:46][CH3:45])[CH2:41][CH2:42]4)[O:23][C:22]3=[O:24])=[C:17]([F:25])[C:16]=2[F:26])=[C:11]([F:27])[C:10]=1[F:28])[CH3:7]
Reactant: CCC[C@H]1CC[C@H](C2CCO2)CC1
Reactant: CCOc1ccc(-c2ccc(CC(=O)O)c(F)c2F)c(F)c1F
Agent: [Li]CCCC
Solvent: O=CO
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCC(c3ccc(-c4ccc(OCC)c(F)c4F)c(F)c3F)C(=O)O2)CC1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
THF (50 ml) was added to 2-(4′-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)acetic acid (10) (2.0 g) prepared in the eighth step. The solution was cooled to −5° C., and n-butyllithium (1.59 M in n-hexane; 7.66 ml) was added dropwise. After the addition had been completed, the reaction mixture was returned to room temperature, and the stirring was continued for 30 minutes. The solution was then cooled to −65° C., and 2-(trans-4-propyl-cyclohexyl)-oxetane (5) (1.0 g) in a THF (5 ml) solution and a boron trifluoride-diethyl ether complex (0.86 g) were added dropwise. After the addition had been completed, the reaction mixture was returned to room temperature, and a 10% aqueous solution of formic acid (100 ml) was added to give two layers. The water layer was extracted with toluene (20 ml) three times and the combined organic layer was washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (silica gel: 200 g, eluent: heptane/ethyl acetate=90/10 by volume) to give 3-(4′-ethoxy-2,2′,3,3′-tetrafluorobiphenyl-4-yl)-6-(4-propylcyclohexyl)tetrahydropyran-2-one (11) (2.35 g) in 86.1% yield.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[N:13]([C:17]3[CH:18]=[C:19]([C:23]4[O:27][C:26](=[O:28])[N:25]([CH3:29])[N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:12][C@H:11]3[N:7]([CH2:8][CH2:9][CH2:10]3)[C:6]=2[N:5]=[C:4]([S:30][CH3:31])[N:3]=1.[CH3:32][NH:33][CH3:34].C1COCC1>C1COCC1>[CH3:32][N:33]([CH3:34])[C:2]1[C:15]2[C:14](=[O:16])[N:13]([C:17]3[CH:18]=[C:19]([C:23]4[O:27][C:26](=[O:28])[N:25]([CH3:29])[N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:12][C@H:11]3[N:7]([CH2:8][CH2:9][CH2:10]3)[C:6]=2[N:5]=[C:4]([S:30][CH3:31])[N:3]=1
Reactant: CSc1nc(Cl)c2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(C)c(=O)o3)c1)C2=O
Reactant: CNC
Solvent: C1CCOC1
Product: CSc1nc(N(C)C)c2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(C)c(=O)o3)c1)C2=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 87.6 %

Procedure:
(S)-5-[3-(7-Chloro-9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-3-(2-methyl)-1,3,4-oxadiazol-2(3H)-one (30.0 mg, 0.0654 mmol) obtained in Step 8 of Example 156 was dissolved in THF (3 mL), and the mixture was stirred at room temperature for 2.5 hours after adding a 2.0 mol/L N,N-dimethylamine/THF solution (1.0 mL, 2.00 mmol). The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give (S)-5-[3-(7-dimethylamino-9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-3-methyl-1,3,4-oxadiazol-2(3H)-one (26.8 mg, 88%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:5][CH:4]=1)#[N:2].[C:30]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:30]([C:34]1[CH:35]=[CH:36][C:37]([CH2:38][O:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2/[CH:22]=[CH:21]/[CH:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:40][CH:41]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CCOC(=O)CCCCC(/C=C/c1ccccc1O)CCc1ccc(C#N)cc1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CCCCC(/C=C/c1ccccc1OCc1ccc(C(C)(C)C)cc1)CCc1ccc(C#N)cc1
Yield: 88.8 %

Procedure:
A solution of 2300 mg (5.87 mmol) of ethyl E-6-[2-(4-cyanophenyl)ethyl]-8-(2-hydroxyphenyl)oct-7-enoate from Example 87A in 160 ml of dry acetonitrile is mixed with 1600 mg (7.05 mmol) of 4-(tert-butyl)benzyl bromide and 1220 mg (8.81 mmol) of anhydrous potassium carbonate and heated to reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The resulting crude product is purified by flash chromatography an silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). 2800 mg (5.21 mmol, 88% yield) of a solid are obtained.