Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C@H:2]([Br:21])[CH2:3][CH2:4][CH2:5][CH2:6][B:7]([O:9][C:10]12[CH2:18][CH:14]([C:15]1([CH3:17])[CH3:16])[CH2:13][CH2:12][C:11]2([OH:20])[CH3:19])[OH:8].[CH3:22][Mg]Br.[Cl-].[NH4+]>C1COCC1>[C:10]12([OH:9])[CH2:18][CH:14]([C:15]1([CH3:17])[CH3:16])[CH2:13][CH2:12][C:11]2([OH:20])[CH3:19].[Br:21][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([B:7]([O-:8])[O-:9])[CH3:22]
Reactant: C[Mg]Br
Reactant: CC1(O)CCC2CC1(OB(O)CCCC[C@H](Cl)Br)C2(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CCC2CC1(O)C2(C)C
Product: C[C@H](CCCCBr)B([O-])[O-]
Temperature: -78 °C

Procedure:
In a 500 ml round bottomed flask, 300 ml of anhydrous THF and the crude pinanediol (R)-1-chloro-5-bromopentylboronate from the previous reaction (assuming 89 g; 0.247 moles) were mixed and cooled to -78° C. with stirring under argon. To the solution was added methylmagnesium bromide (3.26N, 79.6 ml). The solution was warmed to room temperature overnight. Petroleum ether (500 ml) and saturated ammonium chloride (250 ml) were added, forming an emulsion. The aqueous phases were separated. The organic phase was washed with saturated ammonium chloride (2×250 ml), causing the emulsion to disappear. The combined aqueous phases were washed with petroleum ether (2×250 ml). The combined organic phases were dried over sodium sulfate, filtered and evaporated under vacuum to yield 85.85 g of crude pinanediol (R)-5-bromo-1-methylpentylboronate.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:3]=1[C:4]([NH:6][C:7]([NH:9][C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:11]=1[O:17][CH3:18])=[O:8])=[O:5].CN1CC[CH2:28][C:27]1=[O:31].C(OC(=O)C)(=O)C>O>[Cl:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:3]=1[C:4]([NH:6][C:7](=[O:8])[NH:9][C:10]1[CH:15]=[C:14]([NH:16][C:27](=[O:31])[CH3:28])[CH:13]=[CH:12][C:11]=1[O:17][CH3:18])=[O:5]
Reactant: COc1ccc(N)cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Reactant: CN1CCCC1=O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc(NC(C)=O)cc1NC(=O)NC(=O)c1cc(F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.10 g (0.3 mmol) of 1-(2-chloro-4,5-difluorobenzoyl)-3-(5-amino-2-methoxyphenyl)urea was admixed with 1 ml of N-methylpyrrolidone, 0.11 g (0.3 mmol) of acetic anhydride and stirred at room temperature for 2 hours. The mixture was diluted with 20 ml of H2O and extracted three times with 20 ml of ethyl acetate each time. The combined organic phase was washed with H2O, concentrated and dried. The crude product was purified by preparative HPLC (column: Waters Xterra™ MS C18, 5 μm, 30×100 mm, eluent: A: H2O+0.2% trifluoroacetic acid, B: acetonitrile, gradient: 2.5 minutes 90% A/10% B to 17.5 minutes 10% A/90% B). 0.03 g of the desired product was obtained.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([S:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][N:11]=2)=[N:2]1.[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C1COCC1>[C:19]1([C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:1]2[CH:5]=[N:4][C:3]([S:6][CH2:7][CH2:8][O:9][C:10]3[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][N:11]=3)=[N:2]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N#Cc1ccnc(OCCSc2nc[nH]n2)c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccnc(OCCSc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
A solution of 2-{[2-(1H-1,2,4-triazol-3-ylthio)ethyl]oxy}pyridine-4-carbonitrile obtained in Reference Example 17 (3.40 g, 13.7 mmol), trityl chloride (5.73 g, 20.6 mmol) and triethylamine (2.87 mL, 20.6 mmol) in THF (30 mL) was stirred at room temperature for 15 hr. The mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate and water. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The obtained oil was purified by silica gel column chromatography (20%-40% ethyl acetate/hexane) to give the title compound as a white powder (5.37 g, 80%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:8][C:9]([C:14]#[C:15][Si](C)(C)C)=[C:10]([Cl:13])[C:11]=2[Cl:12])=[N:5][C:4]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])=[N:3]1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O.CCCCC.Cl>CO.CCCCC>[CH3:1][N:2]1[C:6]([C:7]2[S:8][C:9]([C:14]#[CH:15])=[C:10]([Cl:13])[C:11]=2[Cl:12])=[N:5][C:4]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])=[N:3]1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1sc(C#C[Si](C)(C)C)c(Cl)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1sc(-c2nc(-c3c(F)cccc3Cl)nn2C)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 96.3 %

Procedure:
To a mixture of 1-methyl-3-(2-chloro-6-fluorophenyl)-5-(3,4-dichloro-5-(2-trimethylsilyl-ethynyl)-thien-2-yl) [1,2,4]triazole (5.0g, 10.9 mmol) in methanol (20 mL) was added potassium carbonate (1.66 g, 12 mmol) at 0° C., and the resulting off-white suspension was stirred at 0° C. for 3.5 hours. TLC analysis (10% EtOAc/Pentane) indicates complete conversion to product. The reaction was acidified with 2 N hydrochloric acid and extracted with ether (2×100 mL). The organics were combined, washed with brine, dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure to give a tan solid. Trituration with pentane affords 4.06 g (96%) of product as a tan powder: mp 145-165 (slow decomposition) 1H NMR (CDCl3) δ3.77 (s, 1H,), 4.04 (s, 3H), 7.08-7.14 (m, 1H), 7.29-7.40 (Ar-m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][N:12]2[N:21]=[C:20]([C:22]3[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=3)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:29])=[O:10])=[CH:4][CH:3]=1>CO.CN(C=O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][N:12]2[N:21]=[C:20]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:29])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)Nn1nc(-c2ccc(Cl)nc2)c2ccccc2c1=O
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(-c2cccnc2)c2ccccc2c1=O
Yield: 51.2 %

Procedure:
A mixture of the product of Example 5 (38 mg, 0.089 mmol) and a catalytic amount of 10% Pd/C in MeOH (1 mL) and DMF (0.5 mL) was stirred at room temperature under H2 (1 atm) for 3 hours, filtered through celite, and chromatographed (30-60% EtOAc/DCM) to give 17.8 mg of the title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 11.75 (s, 1H), 8.78 (dd, J=2.2, 0.7 Hz, 1H), 8.76 (dd, J=4.8, 1.6 Hz, 1H), 8.40-8.43 (m, 1H), 8.06 (ddd, J=7.9, 2.2, 1.7 Hz, 1H), 7.94-8.02 (m, 2H), 7.67-7.75 (m, 1H), 7.61 (ddd, J=7.9, 4.8, 0.8 Hz, 1H), 7.40 (s, 4H), 3.71 (s, 2H); MS (ESI+) M/Z 391 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][C@H:12]([C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][N:9]1[C:22]([O:24][CH3:25])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[NH2:29]O.Cl>CO.CO.O.O>[CH3:25][O:24][C:22]([N:9]1[CH2:10][CH2:11][C@@H:12]([C:14]2[O:21][NH:29][C:16](=[O:17])[CH:15]=2)[CH2:13][C@@H:8]1[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:23]
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccccc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccccc1
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
A solution of trans-methyl 2-benzyl-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (6.35 g, 18.3 mmol) in MeOH (2 mL) was added to a solution of NaOH (0.77 g, 19.4 mmol) in MeOH/H2O (15 mL/0.9 mL) at −30° C. After 10 minutes was added a solution of hydroxylamine hydrochloride (2.54 g, 36.6 mmol) and NaOH (1.46 g, 36.6 mmol) in MeOH (18 mL) and H2O (18 mL). Stirring was continued at −30° C. for 30 minutes. The reaction mixture was then poured into concentrated HCl (20 mL) held at 80° C. The solution was stirred for 30 minutes. The organic solvent was evaporated and the aqueous phase extracted with DEE (×3). The organic phase was dried over Na2SO4 and evaporated to give a solid, 3.68 g, which was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 20-70% acetonitrile in H2O/MeCN/FA 95/5/0.2 buffer, over 18 minutes with a flow of 19 mL/minutes. Trans-methyl-2-benzyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (2.54 g, 54.6%) was isolated as a solid. 1H NMR (600 MHz, cdcl3) δ 1.50-2.21 (m, 4H), 2.91 (m, 2H), 3.10 (m, 2H), 3.58 (d, 3H), 4.04-4.41 (m, 1H), 4.43-4.82 (m, 1H), 5.55-5.84 (m, 1H), 7.15-7.30 (m, 5H); MS m/z 317 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.C(N(CC)CC)C.[CH3:14][N:15]([CH3:19])[C:16](Cl)=[O:17].O>C(#N)C>[CH3:14][N:15]([CH3:19])[C:16](=[O:17])[NH:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1
Reactant: CN(C)C(=O)Cl
Reactant: Nc1nnn[nH]1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)C(=O)Nc1nnn[nH]1

Procedure:
Anhydrous 5-aminotetrazole (8.5 g, 0.1 mole) was slurried in 150 ml of acetonitrile. On the addition of triethylamine (10 g, 0.1 mole), the solids dissolved. Dimethylcarbamoyl chloride (13 g, 0.12 mole) was added at once with no exotherm. The mixture was refluxed two hours with the formation of white solids. After cooling, the material was added to cold water to remove by-product triethylamine hydrochloride. The water insoluble material was collected.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:11][CH2:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:5])[CH3:2].[CH3:18][S:19]([NH:22][C:23]1[CH:38]=[CH:37][C:26]2[NH:27][C:28]([CH2:33][C:34](O)=[O:35])=[N:29][S:30](=[O:32])(=[O:31])[C:25]=2[CH:24]=1)(=[O:21])=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.ClCCl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[N:11]([CH2:12][CH2:13][C:14]([CH3:16])([CH3:15])[CH3:17])[C:34](=[O:35])[CH2:33][C:28]1[NH:27][C:26]2[CH:37]=[CH:38][C:23]([NH:22][S:19]([CH3:18])(=[O:21])=[O:20])=[CH:24][C:25]=2[S:30](=[O:31])(=[O:32])[N:29]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NCCC(C)(C)C
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CCC[C@@H]1N(CCC(C)(C)C)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of cis-2-(3,3-dimethylbutylamino)-cyclopentanecarboxylic acid ethyl ester (54.5 mg, 0.226 mmol) in N,N-dimethylformamide (5.0 mL) was added (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 150.6 mg, 0.452 mmol) and a 1.0 M solution of N,N′-dicyclohexylcarbodiimide in dichloromethane (0.23 mL, 0.23 mmol). After stirring at 25° C. for 12 h, the mixture was diluted with dichloromethane and the precipitated N,N′-dicyclohexylurea byproduct was removed by filtration. The filtrate was concentrated and dried in vacuo to afford the crude product, cis-2-{(3,3-dimethylbutyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)acetyl]amino}-cyclopentanecarboxylic acid ethyl ester as a yellowish oil. The crude product was used in the next step without further purification. LC-MS (ESI) calcd for C24H36N4O7S2 556.20, found 557.3 [M+H+].
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:19]=[CH:18][C:9]([O:10][CH2:11][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[CH:8][CH:7]=1)(=[O:5])[CH3:4]>C1C=CC=CC=1>[Br:1][CH2:4][C:3]([C:6]1[CH:19]=[CH:18][C:9]([O:10][CH2:11][C:12]([O:14][CH:15]([CH3:16])[CH3:17])=[O:13])=[CH:8][CH:7]=1)=[O:5]
Reactant: BrBr
Reactant: CC(=O)c1ccc(OCC(=O)OC(C)C)cc1
Solvent: c1ccccc1
Product: CC(C)OC(=O)COc1ccc(C(=O)CBr)cc1
Reaction time: 0.25 h

Procedure:
Bromine (12g.) was added dropwise to a stirred solution of isopropyl 4-acetylphenoxyacetate (17.6g.) in benzene (200ml.) over 30 minutes. The solution was stirred for a further 15 minutes and then evaporated. The residue was crystallised from ether/hexane to give isopropyl 4-(bromoacetyl)phenoxyacetate, m.p. 60°-61° C.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]([NH:21][C@H:22]([C:27](OC2C=CC([N+]([O-])=O)=CC=2)=[O:28])[CH2:23][C:24]([NH2:26])=[O:25])=[O:20])=[CH:13][CH:12]=1.O>CN(C)C=O>[NH:21]([C:19]([O:18][CH2:17][C:14]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1)=[O:20])[C@H:22]([C:27]([NH:1][C@H:2]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:28])[CH2:23][C:24](=[O:25])[NH2:26]
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Reaction time: 19 h

Procedure:
16.7 g of H-Leu-OMe and 46.0 g of Z-Asn-ONP are dissolved in 100 ml of freshly distilled dimethylformamide. The solution is allowed to stand for 19 hours at 25°C. Thereafter 1.2 liters of water are added and the crystalline precipitate is filtered off. The dipeptide derivative is dried at 40°C in vacuo and is then twice recrystallised from methanol-water. Melting point 180° - 181°C; [α]D20 = +9° (c = 2.05 in chloroform).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C:10](=O)[CH2:9][CH2:8]2.C([BH3-])#[N:15].[Na+].[C:18]([O-:21])(=O)[CH3:19].[NH4+].O>CO>[C:18]([NH:15][CH:10]1[CH2:9][CH2:8][C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[CH2:11]1)(=[O:21])[CH3:19]
Reactant: COc1cccc2c1CC(=O)CC2
Reactant: CC(=O)[O-]
Reactant: [BH3-]C#N
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cccc2c1CC(NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 89 h
Yield: 126.4 %

Procedure:
To a solution of 5.18 gm of 8-methoxy-2-tetralone [described in J. Chem. Soc. 2636 (1965)] dissolved in 100 ml of methanol, were added 560 mg of sodium cyanoborohydride and 4.86 gm of ammonium acetate, and the mixture was stirred for 89 hours at room temperature. The reaction mixture was ice-cooled and adjusted to below pH 1, followed by the addition of 500 ml of water. After washing with ether, the water layer was adjusted to greater than pH 10 with potassium hydroxide and extracted with ether. The extract was dried over anhydrous magnesium sulfate, and the residue obtained by removing the solvent was dissolved in 50 ml of methylene chloride. 2 ml of pyridine and 2.4 ml of acetic anhydride were added to the solution, followed by stirring at room temperature for 1 hour. The reaction mixture was washed with 10% aqueous solution of hydrochloric acid, saturated aqueous solution of sodium bicarbonate, and saturated brine in, this order, and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was crystallized in ethyl acetate and hexane to produce 2.47 gm of the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.I[C:21]1[S:22][CH:23]=[CH:24][CH:25]=1.[O:26]=[C:27]([C:44]1[C:53]2[C:48](=[CH:49][CH:50]=[C:51]([O:54][CH3:55])[CH:52]=2)[N:47]=[CH:46][CH:45]=1)[CH2:28][CH2:29][C@@H:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]#[CH:38])[CH2:32][C@@H:31]1[CH2:39][C:40]([O:42][CH3:43])=[O:41].C(N(CC)CC)C>C(#N)C.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>[O:26]=[C:27]([C:44]1[C:53]2[C:48](=[CH:49][CH:50]=[C:51]([O:54][CH3:55])[CH:52]=2)[N:47]=[CH:46][CH:45]=1)[CH2:28][CH2:29][C@@H:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]#[C:38][C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[CH2:32][C@@H:31]1[CH2:39][C:40]([O:42][CH3:43])=[O:41]
Reactant: C#CCN1CC[C@@H](CCC(=O)c2ccnc3ccc(OC)cc23)[C@@H](CC(=O)OC)C1
Reactant: Ic1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C[C@H]1CN(CC#Cc2cccs2)CC[C@H]1CCC(=O)c1ccnc2ccc(OC)cc12
Reaction time: 0.17 h

Procedure:
0.263 g of triphenylphosphine and then 0.85 g of tetrakis(triphenylphosphine)palladium, 0.4 g of cuprous iodide, and 1.75 cm3 of 2-iodothiophene were added with stirring, at a temperature in the region of 20° C. and under an inert atmosphere, to a solution of 4.3 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[prop-2-ynyl]piperidine-3-acetate in 100 cm3 of acetonitrile. The mixture was stirred for 10 minutes and then 2.95 cm3 of triethylamine were added. After stirring for 48 hours at a temperature in the region of 20° C., the mixture was filtered through celite and the insoluble material was washed with 2 times 50 cm3 of acetonitrile. The filtrate was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The evaporation residue was purified by chromatography at atmospheric pressure on a column of silica gel (particle size 20-45 μm; diameter 4.5 cm; silica volume 500 cm3), elution was carried out with pure ethyl acetate, and approximately 60-cm3 fractions were collected. The fractions corresponding to the expected product were combined. These fractions were concentrated under the above conditions. 4 g of methyl (3R,4R)-4-[3-oxo-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]piperidine-3-acetate were obtained in the form of an oil with a yellow color.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13]Br.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:1]1([C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1cccc(O)c1
Reactant: BrCCCCBr
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Oc1cccc(N2CCCC2)c1
Temperature: 25 °C
Yield: 32.2 %

Procedure:
A solution of m-aminophenol (12.6 gm, 0.115 moles) and 1,4-dibromobutane (50 gm, 0.23 moles) was heated to 130° C. for 12 hr. The mixture was cooled to room temperature and triturated with diethylether and then ethyl acetate. The residue was dissolved in ethyl acetate and extracted with 1 M NaOH, water, and sat. NaCl. After drying the organic layer with MgSO4, filtering, and evaporating solvent under vacuum, the crude product was purified by silica gel chromatography to give a pale yellow solid. The solid was refluxed with 500 ml toluene and 17 ml triethylamine (0.12 moles) for one hr, cooled to room temperature and washed with water and sat. NaCl. The solution was dried again over MgSO4, filtered, and evaporated under vacuum to give 3-pyrrolidinylphenol as a white solid (6.0 gm, 0.037 moles, 32%).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])N.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Cl:19][C:20]1[CH:21]=[C:22]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: Nc1ccc(F)c(Cl)c1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(F)c(Cl)c4)c3c2s1
Yield: 64 %

Procedure:
Prepared from VII and 3-chloro-4-fluoroaniline. Flash chromatography eluent (DCM-EtOAc, 8:2). Yield: 64%; yellow solid; mp 252° C.; IR (KBr) νmax/cm−1 3456, 3015, 2970, 2946, 2229, 1642, 1441, 1153, 1129, 1051, 968, 903, 817, 774, 695; 19F NMR (282 MHz, DMSO-d6) δ −123.8; 1H NMR (300 MHz, DMSO-d6) δ 8.43 (d, 1H, J=9.0 Hz), 8.30 (s, 1H), 7.62 (m, 2H), 7.34 (m, 2H); HRMS calcd for C16H7N5SClF (M+H+): 356.0156, found 356.0167.
Reaction SMILES: N[C@H:2]([C:10]([OH:12])=[O:11])CC1C=CC=CC=1.[NH2:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15]>>[NH2:13][C@H:14]([C:16]([OH:18])=[O:17])[CH2:15][CH2:2][C:10](=[O:11])[OH:12]
Reactant: C[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
1.09 His: 1.00 Phe: 0.98 Ala: 0.99
Reaction SMILES: [N+:1](=[CH2:3])=[N-].[CH:4](=[C:11]1[NH:15][C:14](=[O:16])[C:13]([N+:17]([O-:19])=[O:18])=[C:12]1O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CN>CCOCC.CO>[CH:4](=[C:11]1[NH:15][C:14](=[O:16])[C:13]([N+:17]([O-:19])=[O:18])=[C:12]1[NH:1][CH3:3])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C1NC(=Cc2ccccc2)C(O)=C1[N+](=O)[O-]
Reactant: C=[N+]=[N-]
Agent: CN
Solvent: CCOCC
Solvent: CO
Product: CNC1=C([N+](=O)[O-])C(=O)NC1=Cc1ccccc1
Yield: 45 %

Procedure:
An excess of diazomethane in ether is added to a suspension of 0.46 g (2 mmol) benzylidene-4-hydroxy-3-nitro-3-pyrrolin-2-one (prepared by the method of H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, vol. 331, pp. 389-394) and Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 20 ml methanol. When the evolution of nitrogen has subsided, the solvent is stripped off, the residue is dissolved in methanol and the solution is heated under reflux with an excess of methylamine solution for five minutes, whereupon yellow crystals precipitate out, which are filtered off with suction and washed with methanol. 5-Benzylidene-4-methylamino-3-nitro-1,5-dihydropyrrol-2-one was obtained with a melting point of 238° C. in a yield of 45%.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].[CH3:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][N:34]1[CH2:39][CH2:40][CH2:41][NH2:42]>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:42][CH2:41][CH2:40][CH2:39][N:34]4[CH2:35][CH2:36][CH2:37][CH2:38][CH:33]4[CH3:32])=[O:27])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9]
Reactant: CC1CCCCN1CCCN
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCCCN3CCCCC3C)cn2)c1O

Procedure:
The title compound, as a TFA salt, was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-(2-methylpiperidin-1-yl)propan-1-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.32 (m, 3H) 1.38-1.55 (m, 2H) 1.56-1.74 (m, 2H) 1.74-2.06 (m, 4H) 2.40-2.47 (m, 3H) 2.91-3.16 (m, 2H) 3.16-3.34 (m, 2H) 3.35-3.69 (m, 3H) 7.63-7.70 (m, 1H) 7.72-7.86 (m, 2H) 8.20 (br. s., 1H) 8.42 (d, J=7.33 Hz, 2H) 8.85-9.00 (m, 2H) 9.03-9.38 (m, 1H) 12.63-13.81 (m, 1H). MS m/z [M+H]+ 459.2.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:5])#[N:2].[C:14]([CH2:16][C:17]([O:19]CCOCC)=[O:18])#[N:15]>>[C:1]([C:3](=[CH2:14])[C:4]([O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:5])#[N:2].[C:14]([C:16](=[CH2:1])[C:17]([O-:19])=[O:18])#[N:15]
Reactant: CCCCOCCOC(=O)CC#N
Reactant: CCOCCOC(=O)CC#N
Product: C=C(C#N)C(=O)OCCOCCCC
Product: C=C(C#N)C(=O)[O-]

Procedure:
2-Butyloxyethyl 2-cyanoacrylate was prepared in the same manner as in Example 1, except that butyloxyethyl 2-cyanoacetate was substituted for the 2-ethoxyethyl cyanoacetate. The 2-cyanoacrylate obtained contained 400 ppm. of moisture, 0.05% of 2-butyloxyethyanol and 0.3% of 2-butyloxyethyl cyanoacetate. To the above 2-cyanoacrylate was added 20 ppm. of SO2. Adhesive compositions were prepared by adding an antioxidant as shown in Table 2 to the 2-cyanoacrylate.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:7]([C:8]([OH:10])=O)[C:6]([OH:12])=[CH:5][CH:4]=1)#[N:2].[F:13][C:14]([F:27])([F:26])[C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[NH2:18]>>[F:13][C:14]([F:26])([F:27])[C:15]1[CH:16]=[C:17]([NH:18][C:8](=[O:10])[C:7]2[CH:11]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[OH:12])[CH:19]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:21]=1
Reactant: N#Cc1ccc(O)c(C(=O)O)c1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: N#Cc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 16.6 %

Procedure:
Using 5-cyanosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 16 gave the title compound.