Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:3]1[CH2:5][C@H:4]1[CH2:6][OH:7])#[CH:2].Cl.NO.Br[C:12]#[C:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1>C(N)CCC.[Cu]Cl>[OH:7][CH2:6][C@@H:4]1[CH2:5][C@H:3]1[C:1]#[C:2][C:12]#[C:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccc(C#CBr)cc1
Reactant: C#C[C@@H]1C[C@H]1CO
Agent: Cl[Cu]
Agent: Cl
Agent: NO
Solvent: CCCCN
Product: O=C(O)c1ccc(C#CC#C[C@@H]2C[C@H]2CO)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 16.3 %

Procedure:
A stirring solution of racemic ((trans)-2-ethynylcyclopropyl)methanol (1.7, 11 g, 106 mmol), copper(I) chloride (0.20 g, 2.03 mmol), and hydroxylamine hydrochloride (0.42 g, 6.08 mmol) in 30% aqueous butylamine (156 mL) was poured into a 1 L jacketed reactor and cooled to 0° C. A solution of 4-(bromoethynyl)benzoic acid (INT-1, 22.81 g, 101 mmol) and hydroxylamine hydrochloride (0.42 g, 6.08 mmol) in 30% aqueous butylamine (111 mL) was then added dropwise and the reaction was stirred for 2 hr. The reaction mixture was washed with MTBE (2×230 mL) and the aqueous layer was diluted with methyl THF (460 mL). The solution was cooled to 0° C. and acidified by dropwise addition of 6M HCl (100 ml) to pH 1. The reaction mixture was filtered through Celite, and washed with methyl-THF (230 ml). The two layers were partitioned and the aqueous layer was back-extracted with methyl-THF (230 mL). The organic layers were washed with 2M HCl (2×230 mL), water (230 ml), and brine (230 ml), dried over Na2SO4 and filtered. The organic layer was concentrated under reduced pressure until the solution turned cloudy, then heptane (230 mL) was added. The resulting solution was concentrated under reduced pressure to 5 volumes and then additional heptane (230 mL) was added. The resulting solution was concentrated to 5 volumes to give a slurry. The solids were collected by filtration, washed with heptane (50 mL), and dried under reduced pressure to yield 4-(((trans)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diyn-1-yl)benzoic acid (3.4, 3.96 g). MS: m/z calcd for C15H12O3 240.08. found [M−H]+ 239.1. 1H NMR (DMSO-d6, 400 MHz) δ 13.18 (s, 1H), 7.85 (d, 2H), 7.61 (d, 2H), 4.72 (t, 1H), 3.39-3.52 (m, 1H), 3.21-3.32 (m, 1H), 1.41-1.51 (m, 2H), 0.81-0.99 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3=[CH:19][CH:20]=[CH:21][C:22]([C:23](OC)=[O:24])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.O.[NH2:28][NH2:29]>CN(C=O)C.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[C:12]3=[CH:19][CH:20]=[CH:21][C:22]([C:23]([NH:28][NH2:29])=[O:24])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: COC(=O)c1cccc2c1nc(Nc1cccc(Cl)c1)c1ccncc12
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: NNC(=O)c1cccc2c1nc(Nc1cccc(Cl)c1)c1ccncc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
Methyl 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-7-carboxylate (47 mg) was mixed with Methanol (1 ml) and Hydrazine hydrate (1 ml). 2-3 drops of DMF were added and the mixture was stirred at 60° C. for 2 hours. The volatiles were removed and another amount of reagent Methanol (1 ml) and Hydrazine (1 ml) were added, and the mixture was stirred at 60° C. for an extra 2 hours. The volatiles were removed in vacuo and the material was crashed out using AcOEt/hexanes. Filtration and drying afforded 5-(3-chlorophenylamino)benzo[c][2,6]naphthyridine-7-carbohydrazide as a solid (29 mg, 62% yield). LCMS (ES): >85% pure, m/z 364 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[NH:17][C:16]=2[CH2:25][CH3:26])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[CH3:51][O:52][C:53]([CH:55]1[CH2:58][CH:57](OS(C)(=O)=O)[CH2:56]1)=[O:54]>CN(C)C=O>[CH3:51][O:52][C:53]([C@H:55]1[CH2:58][C@H:57]([N:17]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH2:24])[C:23]=3[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=3)=[C:16]2[CH2:25][CH3:26])[CH2:56]1)=[O:54]
Reactant: CCc1[nH]c2ncnc(N)c2c1-c1cccc(OCc2ccccc2)c1
Reactant: COC(=O)C1CC(OS(C)(=O)=O)C1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@H](C(=O)OC)C1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1.26 g (2.74 mmol) 5-(3-benzyloxy-phenyl)-6-ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, 1.53 g (10.9 mmol) of powdered potassium carbonate and 2.92 g (10.9 mmol) 18-crown-6 ether in 12 ml dry N,N-dimethylformamide is stirred for 15 min at 80° C. 1.7 g (8.2 mmol) of 3-Methanesulfonyloxy-cyclobutanecarboxylic acid methyl ester, dissolved in 9 ml dry N,N-dimethylformamide, is added dropwise in 15 min. After stirring for 42 h at 80° C., work-up is effected by filtering the reaction mixture on hyflo and evaporating the solvent. The residue is partitioned between water and ethyl acetate. The organic layer is dried over sodium sulfate and concentrated in vacuo. The crude product is purified and separated by flash chromatography (hexane-ethyl acetate 1:2). The ratio cis to trans isomer is about 70:30 (by HPLC, Grad25).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:12][O:11]2)[CH:5]=[CH:4][CH:3]=1.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1>CCO>[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]([OH:11])[CH2:12][N:14]2[CH2:15][CH2:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)[CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Brc1cccc(NCC2CO2)n1
Solvent: CCO
Product: OC(CNc1cccc(Br)n1)CN1CCc2ccccc2C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 6.7 %

Procedure:
To a stirred mixture of 6-bromo-N-(oxiran-2-ylmethyl)pyridin-2-amine (1.33 g, 5.81 mmol) in EtOH (10 mL) was added 1,2,3,4-tetrahydroisoquinoline (773 mg, 5.81 mmol). The mixture was stirred at 80° C. for 16 hours. The reaction mixture was concentrated and the residue was purified column to afford the desired compound (140 mg). LCMS (m/z): 362.1/363.1 [M+H]+/[M+2H]+
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[BH4-].[Na+].O[N:9]=[CH:10][C:11]1[S:15][C:14]([C:16]2[S:17][C:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)=[CH:19][CH:20]=2)=[CH:13][CH:12]=1.[OH-].[Na+]>O.COCCOC>[NH2:9][CH2:10][C:11]1[S:15][C:14]([C:16]2[S:17][C:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)=[CH:19][CH:20]=2)=[CH:13][CH:12]=1
Reactant: ON=Cc1ccc(-c2ccc(-c3cccs3)s2)s1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: NCc1ccc(-c2ccc(-c3cccs3)s2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A volume of 1.65 ml tin(IV)chloride and 0.76 g of sodium borohydride are added at 0° C. to 30 ml of 1,2-dimethoxyethane. The above-obtained oxime in a quantity of 1.5 g is added portion-wise to the above mixture, after which the reaction mixture is stirred overnight at room temperature. Then a mixture of water and a 2N NaOH solution is added while cooling on ice, after which the product is extracted with ethyl acetate. The ethyl acetate layer is treated with 2N hydrochloric acid and the product is filtered. The desired 5-aminomethyl-2,2':5',2''-terthiophene (1) is obtained, after drying, in a yield of 0.6 g; UV-abs. spectrum: λmax =355 nm, γ=20,000.
Reaction SMILES: ClC1C=CC(C(OO)=[O:9])=CC=1.[CH3:12][S:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH2:27][N:28]3[CH2:32][CH:31]([CH2:33][CH2:34][CH3:35])[CH2:30][C:29]3=[O:36])=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=2)[N:19]=1>C(Cl)(Cl)Cl>[CH3:12][S:13]([C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH2:27][N:28]3[CH2:32][CH:31]([CH2:33][CH2:34][CH3:35])[CH2:30][C:29]3=[O:36])=[C:21]([C:23]([F:25])([F:24])[F:26])[N:22]=2)[N:19]=1)=[O:9]
Reactant: CCCC1CC(=O)N(Cc2c(C(F)(F)F)nc3ccc(SC)nn23)C1
Reactant: O=C(OO)c1ccc(Cl)cc1
Solvent: ClC(Cl)Cl
Product: CCCC1CC(=O)N(Cc2c(C(F)(F)F)nc3ccc(S(C)=O)nn23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
4-chloroperbenzoic acid (36 mg, 0.134 mmol, 1 eq) is added to a solution of 1-{[6-(methylthio)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propyl pyrrolidin-2-one 33 (50 mg, 0.134 mmol) in chloroform (2 ml) at −30° C. After 30 minutes, the mixture is warmed to room temperature then stirred for additional 16 hours. After hydrolysis with a saturated aqueous NaHCO3 solution (2 ml) and extraction with CHCl3 (2 ml), the cumulated organic layers are dried over MgSO4 and condensed under reduced pressure. The resulting crude product is purified by reverse phase liquid chromatography (gradient acetonitrile/water/TFA) to yield 1-{[6-(methylsulfinyl)-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-propylpyrrolidin-2-one 82.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCc1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
To a solution of 4-phenylbutanol (1 g) in dichloromethane (35 mL) at 0° C. was added PDC (7.5 g). The resulting suspension was stirred for 2 h at room temperature. The reaction solution was then filtered through a pad of silica gel. Concentration of the filtrate and flash chromatography of the residue (20% ethyl acetate/hexanes) provided 4-phenylbutanal (237 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[CH:11]1(OS(C)(=O)=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CS(=O)(=O)OC1CCCCC1
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1OC1CCCCC1

Procedure:
In a manner similar to the method described in Example 4a, 5-chloro salicylaldehyde (Aldrich) reacted with methanesulfonic acid cyclohexyl ester prepared in Example 132a and potassium carbonate in dimethylformamide to give a solid. MS (H+), 239.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:12]([O-])=O)[CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)#[N:2].NN>CO.[Pd]>[C:1]([C:3]1[CH:4]=[C:5]([NH2:12])[CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)#[N:2]
Reactant: N#Cc1cc([N+](=O)[O-])cc2cc[nH]c12
Agent: [Pd]
Agent: NN
Solvent: CO
Product: N#Cc1cc(N)cc2cc[nH]c12
Yield: 100.9 %

Procedure:
A solution of 7-cyano-5-nitroindole (1.5 g, 8.2 mmol), hydrazine (1.0 mL, 31.2 mmol) and 10% Pd/C (20 mg) in 30 mL of MeOH was stirred at reflux for 2 h. The reaction mixture was filtered and concentrated in vacuo to provide 1.3 g (>95%) of the amine.
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[S:3][CH:2]=1.Br[C:11]1[C:18]([Cl:19])=[CH:17][C:16]([F:20])=[CH:15][C:12]=1[C:13]#[N:14].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O.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.[Cu]I>[Cl:19][C:18]1[C:11]([C:2]2[S:3][C:4]3[CH:5]=[N:6][CH:7]=[CH:8][C:9]=3[N:1]=2)=[C:12]([CH:15]=[C:16]([F:20])[CH:17]=1)[C:13]#[N:14]
Reactant: c1cc2ncsc2cn1
Reactant: N#Cc1cc(F)cc(Cl)c1Br
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(F)cc(Cl)c1-c1nc2ccncc2s1
Temperature: 150 °C
Yield: 20.7 %

Procedure:
A mixture of thiazolo[5,4-c]pyridine (0.5 g, 3.67 mmol), 2-bromo-3-chloro-5-fluorobenzonitrile (1.3 g, 5.5 mmol), Pd(PPh3)4 (0.42 g, 0.36 mmol), copper(I) iodide (70 mg, 0.37 mmol) and cesium carbonate (3.9 g, 12 mmol) in dimethylformamide (15 mL) was heated at 150° C. in a microwave reactor for 5 minutes. The cooled mixture was poured into water and extracted twice with ethyl acetate. The combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica (10% diethylether in DCM) to yield a pale solid (0.22 g). The reaction was repeated on the same scale, and the combined product from both reactions was purified by chromatography on silica (5% diethylether in DCM) to give the title compound as an off-white solid (0.30 g, 14%). 1H NMR (300 MHz, CDCl3): δ 9.35 (s, 1H), 8.78 (d, J=6.2 Hz, 1H), 8.10 (d, J=6.2 Hz, 1H), 7.58 (dd, J=7.8, 2.5 Hz, 1H), 7.53 (dd, J=7.4, 2.5 Hz, 1H). LCMS (Method E): RT=2.78, m/z: 290 [M+H+].
Reaction SMILES: [CH3:1][C@@:2]12[C:10]3[NH:11][C:12]4[CH:13]=[CH:14][CH:15]=[C:16]([C:18]([O:20]C)=O)[C:17]=4[C:9]=3[C:8](=O)[CH2:7][N:6]1[CH2:5][CH2:4][CH2:3]2.C(O)(=O)C.O.[NH2:28][NH2:29].O>CO>[CH3:1][C@:2]12[CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][C:8]1[C:9]3[C:17]4[C:16]([C:18](=[O:20])[NH:28][N:29]=1)=[CH:15][CH:14]=[CH:13][C:12]=4[NH:11][C:10]=32
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CN1CCC[C@]31C
Reactant: NN
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: C[C@]12CCCN1CC1=NNC(=O)c3cccc4[nH]c2c1c34
Reaction time: 7 h

Procedure:
A solution of compound (R)-methyl 11b-methyl-6-oxo-2,3,5,6,11,11b-hexahydro-1H-indolizino[8,7-b]indole-7-carboxylate (58 mg, 0.19 mmol), acetic acid (0.4 mL), and hydrazine hydrate (0.2 mL) in methanol (10 mL) was heated at reflux. After 7 h, the reaction was cooled and water (5 mL) was added. The mixture was extracted with EtOAc (3×5 mL) and the combined organic layers were washed with brine (10 mL) and dried over MgSO4. The mixture was filtered, evaporated to dryness, and the residue was purified by Pre-TLC using CH2Cl2 as eluent to give 40 mg of (R)-10a-methyl-7,8,9,10,10a, 11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one. 1H NMR (DMSO-d6) δ 12.9 (s, 1H), 10.6 (s, 1H), 7.50-7.52 (m, 2H), 7.12 (t, 1H, J=7.8 Hz), 3.24-3.26 (m, 1H), 2.91 (d, 1H, J=18.4 Hz), 2.37-2.38 (m, 1H), 2.30-2.32 (m, 1H), 2.20-2.21 (m, 1H), 1.95-1.96 (m, 1H), 1.41-1.43 (m, 1H), 1.34 (s, 3H), and 1.18-1.19 (m 1H). MS (ESI) m/e [M+1]+ 281.0.
Reaction SMILES: ClC(CC)CC(C1C=CC=CC=1N)C.[CH2:15]1[CH2:17][CH:16]1[C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27]C(=O)C(C)(C)C)([CH3:20])[CH3:19].Cl>>[CH2:15]1[CH2:17][CH:16]1[C:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C(=O)Nc1ccccc1C(C)(C)C1CC1
Agent: CCC(Cl)CC(C)c1ccccc1N
Agent: Cl
Product: CC(C)(c1ccccc1N)C1CC1

Procedure:
2-(3-Chloro-1-methylpentyl)phenylamine (III-3) is obtained by initially preparing N-[2-(2-cyclopropylisopropyl)phenyl]-2,2-dimethylpropanamide analogously to Examples (III-1a) and (III-1b). In the third step, the material is reacted with hydrochloric acid which gives, in addition to 2-(2-cyclopropylisopropyl)phenylamine, also the compound (III-3).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([CH2:16][CH:17]=[CH2:18])(C(OCC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[Cl-].[Li+].CN(C=O)C.O>CS(C)=O>[CH3:1][O:2][CH2:3][CH2:4][CH:5]([CH2:16][CH:17]=[CH2:18])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: C=CCC(CCOC)(C(=O)OCC)C(=O)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: C=CCC(CCOC)C(=O)OCC
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A mixture of diester 2 (40 g, 155 mmol), prepared according to Example 1, and lithium chloride (13 g, 300 mmol) in DMSO (100 mL). DMF (20 mL), and water (2 mL) was heated to 170° C. for 6 h and cooled to room temperature. The mixture was poured into water (250 mL), extracted with CH2Cl2 (3×100 mL), and dried over MgSO4. The solvent was removed under reduced pressure to afford the monoester ether 3 (25.2 g, 87%); IR (KBr) υmax 3079, 2974, 2921, 2869, 1732, 1640, 1461, 1443, 1470, 1374, 1177, 1121, 1029, 990, 916, 855 cm−1; 1HNMR (CDCl3) δ1.25 (t, J=7.05 Hz, 3H), 1.65-1.75 (m, 1H), 1.85-1.95 (m, 1H), 2.20-2.40 (m, 2H), 2.50-2.60 (m, 1H), 3.30 (s, 3H), 3.35-3.45 (m, 2H), 4.13 (q, J=7.05, 2H), 5.00-5.07 (dd, J=10.2, 25 Hz, 2H), 5.71-5.74 (m, 1H); 13CNMR (CDCl3) δ14.21, 31.44, 36.45, 42.12, 58.48, 60.12, 70.37, 70.38, 116.79, 135.19, 175.19; mass spectrum (EI), m/Z (rel intensity) 223 (11), 200 (19), 185 (M-1, 4.5), 154 (19), 153 (46), 143 (33), 128 (33), 121 (37), 120 (34), 112 (22), 108 (88), 95 (28), 82 (41), 81 (98), 79 (94), 59 (38), 57 (71), 55 (100), 54 (38), 53 (59),
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][NH:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH2:12](Br)[C:13]#[CH:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:14]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][NH:7][C:8]2=[O:11])=[CH:4][CH:3]=1)[C:13]#[CH:12]
Reactant: O=C1NCc2ccc(O)cc21
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1ccc2c(c1)C(=O)NC2
Yield: 68.7 %

Procedure:
The mixture of 6-hydroxyisoindolin-1-one ((73), 5.1 g, 34.2 mmol), propargyl bromide (80% solution in toluene, 5.70 ml, 51.3 mmol) K2CO3 (9.44 g, 68.4 mmol), KI (1.14 g, 6.8 mmol) in acetone was refluxed for overnight. The reaction mixture was filtered under vacuum and concentrated in vacuo to give the title compound (4.4 g, 68%) as a solid. MS (ES) m/z 188.1.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1)[CH3:7].[Cl:15][C:16]1[C:23]([Cl:24])=[C:22]([OH:25])[CH:21]=[CH:20][C:17]=1[CH:18]=[O:19].[Cl-].[NH4+]>CCCCCC.O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[CH2:6]([O:8][CH2:9][N:10]1[C:14]([CH:18]([OH:19])[C:17]2[CH:20]=[CH:21][C:22]([OH:25])=[C:23]([Cl:24])[C:16]=2[Cl:15])=[CH:13][CH:12]=[N:11]1)[CH3:7]
Reactant: CCOCn1cccn1
Reactant: O=Cc1ccc(O)c(Cl)c1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOCn1nccc1C(O)c1ccc(O)c(Cl)c1Cl
Reaction time: 1 h
Yield: 66.1 %

Procedure:
18.1 ml of 1.6M n-butyl lithium in hexane are added to a tetrahydrofuran solution of 3.56 g of 1-ethoxymethylpyrazole at -55° to -53° C. under argon gas atmosphere and the mixture is stirred at the same temperature for 1 hour. A solution of 2.45 g of 2,3-dichloro-4-hydroxybenzaldehyde in tetrahydrofuran is added to the above mixture, and the reaction mixture is stirred at -55° to -60° C. for 3 hours. 4.9 ml of hexamethylphosphoric triamide are then added and the whole mixture is stirred at room temperature for 16 hours. An aqueous saturated ammonium chloride solution is added and the mixture is extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography and crystallized with a mixture of ethyl acetate and isopropyl ether to give 2.69 g of α-(1-ethoxymethyl-5-pyrazolyl)-2,3-dichloro-4-hydroxybenzylalcohol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[CH:4][CH:3]=1.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1>C1(C)C=CC=CC=1.[Cl-].[Na+].O.CCOC(C)=O.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>[C:25]([O:24][C:22]([NH:21][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:29])[CH:35]=2)=[CH:3][CH:4]=1)[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)Cc1ccc(Br)cc1
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)Cc1ccc(-c2cccc(Cl)c2)cc1
Temperature: 95 °C
Reaction time: 19 h
Yield: 48.1 %

Procedure:
A suspension of give (R)-benzyl 4-(4-bromophenyl)-3-(tert-butoxycarbonylamino)butanoate (2.00 g, 4.46 mmol), 3-chlorophenylboronic acid (1.046 g, 6.69 mmol), Pd(PPh3)4 (0.515 g, 0.446 mmol) and Na2CO3aq (4.46 ml, 8.92 mmol) in Toluene (30 ml) is allowed to stir under nitrogen at 95° C. for 19 hr. The reaction mixture is cooled to ambient temperature, and diluted with brine and EtOAc. The products are extracted twice with EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated. The residue is purified by flash column chromatography on 90 g silica gel (eluent: heptane/EtOAc=100:0 to 65:35) to give (R)-benzyl 3-(tert-butoxycarbonylamino)-4-(3′-chlorobiphenyl-4-yl)butanoate (1.03 g); HPLC retention time=1.74 minutes (condition B); MS (ES+)=380.2 (m-BOC+2; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.40 (s, 9H) 2.52 (A of ABX, Jab=15.9 Hz, Jax=5.8 Hz, 1H) 2.58 (B of ABX, Jab=15.9 Hz, Jbx=5.6 Hz, 1H) 2.81-2.98 (m, 2H) 4.19 (br s, 1H) 5.07 (br d, 1H) 5.12 (A of AB, J=12.3 Hz, 1H) 5.17 (A of AB, J=12.3 Hz, 1H) 7.20-7.22 (m, 2H) 7.28-7.39 (m, 7H) 7.42-7.47 (m, 3H) 7.53-7.54 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C@@H:17]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:18][OH:19]>>[OH:19][CH2:18][C@@H:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)C[C@H](N)CO
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Product: CC(C)C[C@@H](CO)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and (2S)-2-amino-4-methyl-1-pentanol (CAN 7533-40-6) as starting materials and isolated (19.4 mg, 59%) as white solid; MS (ESI, m/z): 327.1 (MH+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1/[CH:6]=[CH:7]/[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=1.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][C:27](=[O:50])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:37])=[CH:31][CH:30]=1>CN(C=O)C.CCOC(C)=O>[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][C:27](=[O:50])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([N:1]2[CH2:5][CH2:4][CH2:3][CH:2]2/[CH:6]=[CH:7]/[C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)=[O:37])=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1ccc(/C=C/C2CCCN2)cc1
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(/C=C/C2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)cc1
Reaction time: 15 h
Yield: 100 %

Procedure:
A mixture of ethyl (E)-4-[2-(2-pyrrolidinyl)ethenyl]benzoate (434 mg, 1.77 mmol), pentafluorophenyl 4-[N′-(2-methylphenyl)ureido]phenylacetate (797 mg, 1.77 mmol), Et3 N (0.37 mL, 2.66 mmol) in DMF (15 mL) was stirred for 15 hr. The mixture was diluted with EtOAc (300 mL). The solution was washed with brine (2×200 mL), dried over MgSO4, and evaporated off in vacuo. The residue was chromatographed on silica-gel with CHCl3-EtOAc (4:1) as eluent to give 906 mg (q.y.) ethyl (E)-4-[2-[1-[4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]ethenyl]benzoate as a brown oil. 1H-NMR (CDCl3) δ 1.39 (3 H, t, J=7.3 Hz), 1.83–2.20 (4 H, series of m), 2.24 (3 H, d, J=4.9 Hz), 3.63 (4 H, m), 4.36 (2 H, q, J=7.3 Hz), 4.62 and 4.84 (total 1 H, m), 6.18–6.47 (2 H, m), 7.03–8.02 (14 H, series of m).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][C:10]2[NH:9][C:8](=[S:12])[C:7]([C:13]#[N:14])=[CH:6][C:5]=2[C:4](=[O:15])[CH2:3]1.Br[CH:18]([CH3:20])[CH3:19]>>[CH:18]([S:12][C:8]1[C:7]([C:13]#[N:14])=[CH:6][C:5]2[C:4](=[O:15])[CH2:3][C:2]([CH3:16])([CH3:1])[CH2:11][C:10]=2[N:9]=1)([CH3:20])[CH3:19]
Reactant: CC1(C)CC(=O)c2cc(C#N)c(=S)[nH]c2C1
Reactant: CC(C)Br
Product: CC(C)Sc1nc2c(cc1C#N)C(=O)CC(C)(C)C2
Yield: 21 %

Procedure:
In analogy to the procedure described in Example 1, 7,7-dimethyl-5-oxo-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitrile was treated with 2-bromopropane to give the title compound in 21% yield.