Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH2:4]1)=O.Cl.[NH:28]1[CH2:33][CH2:32][S:31](=[O:34])[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(N(CC)CC)C>[CH3:26][N:17]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[NH:9][C:8]([C:6]1[S:7][CH:3]([CH2:1][N:28]3[CH2:33][CH2:32][S:31](=[O:34])[CH2:30][CH2:29]3)[CH2:4][N:5]=1)=[CH:16]2)[S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:20]
Reactant: O=S1CCNCC1
Reactant: CN(c1cccc2cc(C3=NCC(C=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(c1cccc2cc(C3=NCC(CN4CCS(=O)CC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 0.17 h
Yield: 33.3 %

Procedure:
To a mixture of N-[2-(5-formyl-4,5-dihydro-1,3-thiazol-2-yl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (550 mg), thiomorpholine 1-oxide hydrochloride (310 mg), triethylamine (200 μL) and tetrahydrofuran (15 mL) was added sodium triacetoxyborohydride (420 mg) at room temperature, and the mixture was stirred for 10 min. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give a colorless oil from a fraction eluted with ethyl acetate:methanol=90:10. The obtained colorless oil was purified by preparative HPLC to give the title compound (230 mg, yield 35%) as white crystals. melting point 204° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:22]([N:24]2[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]2)[CH3:23])[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([CH:22]([N:24]2[CH2:25][CH2:26][CH:27]([NH:30][C:2]3[C:3]4[CH:10]=[C:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[S:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH2:28][CH2:29]2)[CH3:23])[CH:19]=[CH:20][CH:21]=1
Reactant: CC(c1cccc(F)c1)N1CCC(N)CC1
Reactant: CC(C)Cc1cc2c(Cl)ncnc2s1
Product: CC(C)Cc1cc2c(NC3CCN(C(C)c4cccc(F)c4)CC3)ncnc2s1

Procedure:
The title compound was prepared (291 mg, 64%) from 4-chloro-6-isobutylthieno[2,3-d]pyrimidine (250 mg, 1.1 mmol) and 1-(1-(3-fluorophenyl)ethyl)piperidin-4-amine (0.49 mg, 2.2 m. mol) by following the general procedure described for Preparation 6. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.25 (m, 1H), 7.05 (m, 2H), 6.95 (m, 1H), 6.75 (s, 11H), 5.00 (m, 1H), 4.10 (m, 1H), 3.45 (m, 1H), 3.00 (d, 1H), 2.80 (d, 1H), 2.70 (d, 2H), 1.85–2.25 (m, 5H), 1.45–1.65 (m, 2H), 1.35 (d, 3H), 0.95 (d, 6H). MS (ESI) m/z: Calculated: 412.57; Observed: 413.3 (M++1).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2.F[P-](F)(F)(F)(F)F.[N:34]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=N1.C(N(CC)CC)C.C1(N)C=CC=CC=1N>CN(C=O)C.CCOC(C)=O>[NH2:34][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[NH:36][C:21]([C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:26])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[CH:7]=2)=[O:15])=[CH:25][CH:24]=1)=[O:22]
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Nc3ccc(C(=O)O)cc3)ccc21
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccc1N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)CCC(C)(C)c2cc(C(=O)Nc3ccc(C(=O)Nc4ccccc4N)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.2 %

Procedure:
To a solution of 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxamido)benzoic acid 4 (151 mg) in DMF 2 mL was added BOP (0.266 g), triethylamine (0.238 mL, 0.60 mmol) and phenylenediamine (0.093 g, 0.86 mmol). The reaction mixture was stirred 1 h at RT and diluted in EtOAc (25 mL), washed with NaH2PO4 (1M, 2×25 mL), brine (1M, 2×25 mL), NaHCO3 (1M, 2×25 mL), brine (1M, 2×25 mL), dried over Na2SO4, filtered and concentrated to give an oil that was purified using silica gel chromatography with 40% [v/v] EtOAc in cyclohexane to give N-(4-(2-aminophenylcarbamoyl)phenyl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxamide EHT 1800 (8 mg, 4% yield) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:10][CH:11]=1)=[O:16]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NCCc1cccs1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCc1cccs1)c1ccc(-c2ccccc2)cc1
Yield: 54.8 %

Procedure:
Reaction of 2-thiopheneethylamine (50 μL, 0.42 mmol) in THF (2.5 mL) with 4-biphenylcarbonyl chloride (120 mg, 0.55 mmol) in presence of triethylamine (78 μL, 0.55 mmol) according to method A gave biphenyl-4-carboxylic acid (2-thiophen-2-yl-ethyl)-amide (70 mg, 0.23 mmol, 55% yield) as a grey powder after crystallisation in hexane/EtOAc.
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1)([O-:3])=[O:2].[C:11]1([S:17]([CH2:20][C:21]#[N:22])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C(O)C>[N+:1]([C:4]1[S:5][C:6](/[CH:9]=[C:20](/[S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:18])=[O:19])\[C:21]#[N:22])=[CH:7][CH:8]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Reactant: N#CCS(=O)(=O)c1ccccc1
Solvent: O
Solvent: CCO
Product: N#C/C(=C\c1ccc([N+](=O)[O-])s1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 50 %

Procedure:
2-Nitrothiophen-5-carboxaldehyde (0.157 g) and phenylsulfonyl acetonitrile (0.199 g) were stirred in 2 mL of ethanol containing 0.01 mL piperidine for four hours at 100 C. The mixture was cooled to room temperature and water was added for crystalization. The crude product was filtered and recrystalized from ethanol and water to give 0.16 g of (E)-3-(2-nitrothien-5-yl)-2-(phenylsulfonyl)acrylonitrile. Alternatively, the crude product was purified on a silica gel column with a mixture of ethylacetate and hexane as eluent.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][CH3:19])[CH:15]=2)[C:10]1=[O:20].[CH2:21]([O:23]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:22]>>[C:21]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][CH3:19])[CH:15]=2)[C:10]1=[O:20])(=[O:23])[CH3:22]
Reactant: COc1ccc2c(c1)CC(Cc1ccncc1Br)C2=O
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Product: COc1ccc2c(c1)CC(Cc1ccncc1C(C)=O)C2=O

Procedure:
The title compound 113 is prepared according to the procedure reported in Example 36.5 with compound 106 (235 mg, 0.71 mmol) and (1-ethoxyvinyl)tri(n-butyl)stannane (0.34 mL, 0.99 mmol) as reactants. White solid. (Yield 135 mg, 64%).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13](N)[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]([C:25]([O:27][CH3:28])=[O:26])=[N:17]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(O)=O.N([O-])=O.[Na+].[NH4+].[OH-].[ClH:39]>O>[C:1]([C:9]1[CH:14]=[C:13]([Cl:39])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]([C:25]([O:27][CH3:28])=[O:26])=[N:17]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C(=O)OC)n(-c2ccc(N)cc2C(=O)c2ccccc2)n1
Reactant: Cl
Agent: O=N[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(C(=O)OC)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 13.1 g. (34.5 mmol) of the final product of Example 2 in 50 ml. HOAc and 75 ml. of 3N HCl, stirred at 3°, was added dropwise so as to maintain a temperature of 3°-6°, a solution of 2.50 g. (36.3 mmol) of sodium nitrite in 25 ml. H2O. When the addition was complete, the reaction was stirred at 3° for 20 minutes. A fresh solution of cuprous chloride in concentrated hydrochloric acid (prepared from 27 g. cupric sulfate pentahydrate*) was mixed with an equal volume of water and cooled to 3°. The diazotized solution, which had to be kept cold (<5°) at all times, was slowly poured into the vigorously stirred 5° cuprous chloride solution in several portions, in order to control foaming. When addition was complete, the reaction was stirred for one hour while slowly warming to room temperature, then heated on a steam bath to an internal temperature of 95°. After cooling to room temperature, the reaction was made basic with NH4OH and extracted well with CH2Cl2. The combined extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to a brown oil. This crude product was chromatographed on silica gel using a 2% EtOAc in benzene solution as eluent to give the final product. An analytical sample was prepared by recrystallization from ether/hexane and was obtained as colorless crystals: mp 118°-120°.
Reaction SMILES: [Li+].[BH4-].[Cl:3][C:4]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([O:17][CH3:18])=[CH:10][C:5]=1[C:6](OC)=[O:7].CCOC(C)=O.[NH4+].[Cl-]>C1COCC1>[Cl:3][C:4]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([O:17][CH3:18])=[CH:10][C:5]=1[CH2:6][OH:7]
Reactant: COC(=O)c1cc(OC)c([N+](=O)[O-])cc1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(CO)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
A 2M solution of LiBH4 in THF (2 mmol) was added drop-wise to a stirred solution of methyl 2-chloro-5-methoxy-4-nitrobenzoate (1 mmol) in dry THF (10 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 5 hours. EtOAc (10 mL) was added to the mixture followed by saturated NH4Cl solution (2 mL) and stirring continued for 15 minutes. The mixture was partitioned between EtOAc (10 mL) and water (10 mL) and the separated aqueous phase was extracted with EtOAc (10 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to afford the title compound (89%) which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH:2]1[CH2:7][C:8]([O:10][CH3:11])=[O:9].Br[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH3:11][O:10][C:8](=[O:9])[CH2:7][CH:2]1[CH2:3][N:4]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH2:5][CH2:6][N:1]1[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: COC(=O)CC1CNCCN1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CC1CN(CCc2ccc([N+](=O)[O-])cc2)CCN1CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of methyl piperazin-2-ylacetate (0.40 g, 1.73 mmol) in DMF (2.5 mL) was added 1-(2-bromoethyl)-4-nitrobenzene (1.0 g, 4.3 mmol), tetrabutyl ammonium iodide (cat.) and potassium carbonate (1.20 g, 8.7 mmol). The mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organics were washed with water (2×) and brine, then dried (Na2SO4), filtered and concentrated. The desired methyl {1,4-bis[2-(4-nitrophenyl)ethyl]piperazin-2-yl}acetate was purified by mass-directed HPLC. LC-MS (IE, m/z): 456.2 [M+1]+. (0.39 μM)
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O=[C:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]#[N:22])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1.C1[CH2:27][O:26][CH2:25]C1>>[CH3:25][O:26][CH:27]=[C:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]#[N:22])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: C1CCOC1
Reactant: N#Cc1ccc2c(c1)CCC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: COC=C1CCc2cc(C#N)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of CH3OCH2PPh3I (8.9 g, 26 mmol) in THF (80 mL) was added a solution of NaHMDS in THF (2.0M, 13 mL, 26 mmol)) at 0° C. The mixture was stirred 1 hour at 0° C. Then a solution of 1-Oxoindane-5-carbonitrile (2.0 g, 13 mmol) in THF (10 mL) was added. The mixture was stirred for 2 hours at 0° C. The reaction was quenched with water and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatograph to give the title compound. MS m/z: 186 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=[C:2]([NH:29][C@H:27]([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)[CH3:28])[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ccc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(F)cc1
Temperature: 165 °C
Yield: 100.2 %

Procedure:
A mixture of 6-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Method 77; 0.30 g, 1.07 mmol), (S)-1-(4-fluoro-phenyl)ethylamine (0.23 g, 1.61 mmol), and DIEA (0.23 ml, 1.34 mmol) in n-BuOH (5 ml) was heated in a sealed tube at 165° C. for 18 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=1:1) to give the title compound as a yellow solid (0.41 g, 99%). NMR (400 MHz) 12.22 (s, 1H), 10.98 (s, 1H), 8.70 (d, J=7.2 Hz, 1H), 8.10 (d, J=9.2 Hz, 1H), 7.39 (m, 2H), 7.18 (m, 2H), 6.22 (d, J=9.2 Hz, 1H), 6.17 (s, 1H), 5.27 (m, 1H), 1.89 (m, 1H), 1.52 (d, J=6.4 Hz, 3H), 0.95 (m, 2H), 0.64 (m 2H). MS: Calcd.: 382; Found: [M+H]+ 383.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([O:13][C:14]([CH3:17])(C)C)=[O:12].Cl.O1CCOCC1.ClC1C=C(C#N)C=CC=1CC(OCC)=O.C(O[CH:43](OCC)[N:44]([CH3:46])[CH3:45])C>C(O)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[C:10](=[CH:43][N:44]([CH3:46])[CH3:45])[C:11]([O:13][CH2:14][CH3:17])=[O:12]
Reactant: CCOC(OCC)N(C)C
Reactant: CC(C)(C)OC(=O)Cc1ccc(C#N)cc1Cl
Agent: CCOC(=O)Cc1ccc(C#N)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1Cl
Temperature: 60 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
Combined tert-butyl 2-(2-chloro-4-cyanophenyl)acetate (274 mg, 1.089 mmol) and 4N HCl in dioxane (0.136 mL, 0.544 mmol) in ethanol (2.51 mL). The mixture was stirred for 16 hours at 60° C., then concentrated by rotary evaporation and combined with ethyl 2-(2-chloro-4-cyanophenyl)acetate (0.243 g, 1.086 mmol) and 1,1-diethoxy-N,N-dimethylmethanamine (0.931 mL, 5.43 mmol) in DMF (2.173 mL) and stirred for 16 hours at 100° C. The reaction was concentrated in rotary evaporation and purified on a NH silica gel column eluting with hexanes and EtOAc to give the title compound (164 mg, 54%) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 1.04-1.29 (m, 1 H) 3.96-4.31 (m, 1H) 7.38 (d, J=7.8 Hz, 1 H) 7.49 (dd, J=7.8, 1.8 Hz, 1 H) 7.63-7.71 (m, 1 H).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[C:5]([C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])=[N:4][CH:3]=1.[CH3:25][N:26]1CCCC1=O>O.C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:25]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[C:5]([C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])=[N:4][CH:3]=1)#[N:26]
Reactant: CN1CCCC1=O
Reactant: COC(=O)c1ccc2c(Br)cnc(-c3c(F)cc(F)cc3F)c2c1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C#N)cnc(-c3c(F)cc(F)cc3F)c2c1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 4-bromo-1-(2,4,6-trifluorophenyl)isoquinoline-7-carboxylate (66 mg), zinc cyanide (content 60%, 21 mg), tris(dibenzylideneacetone)dipalladium (0) (14 mg), 1,1′-bis(diphenylphosphino)ferrocene (17 mg), and N-methyl-2-pyrrolidone (3 mL) was heated under stirring in an oil bath at 150° C. for 3 hours. The reaction mixture was returned to room temperature, diluted with water and ethyl acetate, and then the insoluble materials were separated by filtration. The filtrate was subjected to liquid separation, and the organic layer was concentrated under reduced pressure. Then, the resulting residue was purified under silica gel column chromatography (hexane/ethyl acetate) to obtain methyl 4-cyano-1-(2,4,6-trifluorophenyl)isoquinoline-7-carboxylate (44 mg).
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[CH2:13][Mg]Br.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Br:9][C:10]1[CH:11]=[C:12]([CH2:13][CH:1]([NH2:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: N#Cc1ccccc1
Reactant: Br[Mg]Cc1cccc(Br)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NC(Cc1cccc(Br)c1)c1ccccc1
Yield: 31.4 %

Procedure:
Benzonitrile (500 mg, 4.849 mmol) was added dropwise to a solution of 3-bromobenzylmagnesium bromide (0.275 M solution in diethyl ether, 21.1 ml, 5.818 mmol) under an atmosphere of nitrogen at room temperature. The reaction mixture was then heated to reflux for a period of 2 hours then allowed to cool. Lithium aluminium hydride (1.0 M in THF, 4.85 ml, 4.849 mmol) was then added cautiously and the reaction mixture was allowed to heat at reflux for a further 16 hours. Upon cooling, the reaction was quenched by cautious and dropwise addition of water (5 ml) and then partitioned between water (20 ml) and ethyl acetate (100 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated. Purification by ion exchange chromatography afforded the desired compound (420 mg, 31%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1)=O.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH3:24][C:21]([O:20][C:18]([N:12]1[CH2:17][CH2:16][N:15]([CH2:1][C:3]2[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=2)[CH2:14][CH2:13]1)=[O:19])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1cccc(B(O)O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(B(O)O)c2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 120.6 %

Procedure:
To a solution of (3-formylphenyl)boronic acid (3.0 g, 20.0 mmol) in DCM (100 mL) was added 1,1-dimethylethyl 1-piperazinecarboxylate (3.91 g, 21.0 mmol), NaBH(OAc)3 (6.36 g, 30.0 mmol) and this mixture was stirred at room temperature for 17 h. The organic layer was diluted with EtOAc (100 mL), which was washed with H2O (30 mL), then dried over Na2SO4, filtered and concentrated to afford the title compound 7.72 g (quantitative). LC-MS m/z 321 (M+H)+, 1.49 min (ret time).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=O)[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22]CC2C=CC=CC=2)=[C:18]([CH3:30])[CH:17]=1)=O.[NH2:32][C:33]([NH2:35])=[O:34].[ClH:36].O1CCOCC1>C(O)C>[ClH:36].[OH:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[CH:13]=[C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[O:5][CH2:4][CH2:3][O:2][CH3:1])[NH:35][C:33](=[O:34])[N:32]=2)=[CH:17][C:18]=1[CH3:30]
Reactant: NC(N)=O
Reactant: COCCOc1ccccc1C(=O)CC(=O)c1ccc(OCc2ccccc2)c(C)c1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: COCCOc1ccccc1-c1cc(-c2ccc(O)c(C)c2)nc(=O)[nH]1
Temperature: 25 °C
Yield: 19 %

Procedure:
A solution of 1-(2-{[2-(methyloxy)ethyl]oxy}phenyl)-3-{3-methyl-4-[(phenylmethyl)oxy]phenyl}propane-1,3-dione (0.24 g, 0.56 mmol), urea (0.34 g, 5.6 mmol), 4.0M hydrochloric acid in dioxane (1.4 mL, 5.6 mmol) in ethanol (2 mL) was heated in a 110° C. oil bath for 12 h. The solution was allowed to cool to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate (10% methanol) and aqueous saturated sodium bicarbonate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. This crude mixture was taken up in 2.0 mL trifluoroacetic acid and heated in an 80° C. oil bath for 1 hour then concentrated. Purification of the residue by HPLC (reverse-phase, acetonitrile/water with 0.1% trifluoroacetic acid), followed by concentration in vacuo, treatment with methanol and 4.0 M hydrochloric acid in dioxane, and lyophilization gave the title compound 4-(4-hydroxy-3-methylphenyl)-6-(2-{[2-(methyloxy)ethyl]oxy}phenyl)pyrimidin-2(1H)-one hydrochloride (0.037 g, 19%). 1H NMR (400 MHz, d6-DMSO): 11.07 (s, 1H), 8.01 (d, 1H), 7.92 (dd, 1H), 7.74 (dd, 1H), 7.63 (dt, 1H), 7.47 (s, 1H), 7.29 (d, 1H), 7.19 (dt, 1H), 7.10 (d, 1H), 4.29 (m, 2H), 3.71 (m, 2H), 3.27 (s, 3H), 2.20 (s, 3H). MS (EI) for C20H20N2O4: 352 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[NH:37]1[CH2:42][CH2:41][CH:40]([C:43]2[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=2)[CH2:39][CH2:38]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][CH:12]([NH:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:21][CH2:20]1)=[O:18])[C:13](=[O:14])[N:46]1[CH2:45][CH2:44][CH:43]([C:40]2[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=2)[CH2:48][CH2:47]1)[CH3:2]
Reactant: c1cc(C2CCNCC2)ccn1
Reactant: CCc1ccc(CC(NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Product: CCc1ccc(CC(NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(c3ccncc3)CC2)cc1CC

Procedure:
Prepared analogously to Example 3f) from 3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 1,2,3,4,5,6-hexahydro-[4,4′]bipyridinyl.
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH:7]=[O:8])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[C:13]([Mg]Br)#[CH:14]>C1COCC1>[S:1]1[C:5]([CH2:6][CH:7]([OH:8])[C:13]#[CH:14])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: O=CCc1cc2ccccc2s1
Reactant: C#C[Mg]Br
Solvent: C1CCOC1
Product: C#CC(O)Cc1cc2ccccc2s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of crude 9-3 (8.77 g) in THF (100 mL) was added to a solution of ethynylmagnesium bromide (450 mL, 225 mmol, 0.5 M/THF) at 0° C. by cannula. The mixture was stirred for 1 h at 0° C. and for 1 h at room temperature. The reaction was then quenched by addition of 200 mL saturated NH4Cl solution. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×200 mL). The combined organic solution was washed with brine and then was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (10% 20% ethyl acetate/hexanes) gave 8-4 (7.67 g, 37.9 mmol, 84% from 9-2).