Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:9]1CCC[CH2:10]1.[H-].[Na+].[CH2:16]([Sn:20]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:21]I)[CH2:17][CH2:18][CH3:19]>C(OCC)(=O)C.O.CN(C)C=O>[CH2:16]([Sn:20]([CH2:21][O:9][CH2:10][CH2:7][N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Reactant: OCN1CCCCC1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)COCCN1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a mixture of 1-piperidinemethanol (1.3 g, 10 mmol) and tetrahydrofuran (30 ml) was added sodium hydride (60%, 418 mg, 10 mmol) at 0° C. (external temperature), followed by stirring at room temperature for 30 minutes. Then, to the reaction mixture was added dropwise a mixture of tributyl-iodomethyl-tin (3.0 g, 7.0 mmol), tetrahydrofuran (5 ml), and N,N-dimethylformamide (30 ml) at 0° C. Then, the reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated. The organic layer was sequentially washed with water and an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=20:1, NH silica gel) to obtain the title compound (2.1 g, 4.9 mmol, 70%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.[OH2:19].O.O.C([O-])(=O)C.[Na+].Cl.[NH2:28]O>C(O)C.O>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][C:15](=[N:28][OH:19])[CH2:14][CH2:13]1
Reactant: NO
Reactant: CS(=O)(=O)c1ccc(N2CCC(=O)CC2)c(F)c1
Reactant: O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(N2CCC(=NO)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
Compound 1b (341 mg, 1.3 mmol) and sodium acetate trihydrate (513 mg, 3.8 mmol) were combined in ethanol (5 mL) and heated to reflux for 15 minutes. Hydroxylamine hydrochloride (131 mg, 1.9 mmol) was added and heating was continued for 3 h. The mixture was cooled to room temperature and diluted with water (30 mL). The mixture was chilled in an ice-bath and the resulting white precipitate was isolated by filtration, washed with water, and dried under vacuum to afford 266 mg (74%) of 1c: 1H NMR (300 MHz, CDCl3) δ 7.98 (br s, 1 H), 7.65-7.56 (m, 2 H), 7.02 (t, J=8.4 Hz, 1 H), 3.42-3.33 (m, 4 H), 3.04 (s, 3 H), 2.82 (t, J=5.9 Hz, 2 H), 2.54 (t, J=5.7 Hz, 2 H); LC-MS 287.1 (MH+).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][SH:6].[H-].[Na+].[H][H].[Cl:12][C:13]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>CN(C)C=O>[ClH:12].[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][S:6][C:13]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: [H][H]
Reactant: CN(C)CCS
Reactant: CC(C)c1cc2ccccc2nc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1cc2ccccc2nc1SCCN(C)C
Temperature: 0 °C

Procedure:
2-Dimethylaminoethanethiol hydrochloride (3.4 g.) was added to a suspension of sodium hydride (2.32 g. of a 50% w/w dispersion in mineral oil) in dimethylformamide (25 ml.) at 0° to 5°. When all the hydrogen had evolved, 2-chloro-3-isopropylquinoline (4.0 g.) was added and the mixture heated at 80° for 5 hr. The reaction mixture was then poured into ice water (500 ml.) and extracted with ethyl acetate (3×120 ml.). The ethyl acetate extract was washed successively with water (100 ml.) and saturated brine (100 ml.) and then dried (MgSO4). The ethyl acetate solution was evaporated and the residual oil was chromatographed on basic alumina (70 g.; Brockmann Grade III), eluted with increasing concentrations of chloroform in petroleum ether. The eluate obtained with 20% v/v chloroform in petroleum ether was evaporated, the residual oil was dissolved in diethyl ether, and ethereal hydrogen chloride was added until precipitation was complete. The solid residue was collected by filtration and crystallised from ethanol-diethyl ether to give 2-(2-dimethylaminoethylthio)-3-isopropylquinoline hydrochloride, m.p. 164°-7°.
Reaction SMILES: C([Li])CCC.[CH2:6]([C:13]1[C:18]([CH3:19])=[C:17]([O:20][CH3:21])[C:16]([CH3:22])=[C:15]([CH3:23])[C:14]=1[O:24][CH3:25])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CC(C)(N)C(C)(C)N.[CH2:34](Br)[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].P(=O)(O)(O)O>O1CCCC1.CCCCCC>[CH3:25][O:24][C:14]1[C:15]([CH3:23])=[C:16]([CH3:22])[C:17]([O:20][CH3:21])=[C:18]([CH3:19])[C:13]=1[CH:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCBr
Reactant: COc1c(C)c(C)c(OC)c(Cc2ccccc2)c1C
Agent: CC(C)(N)C(C)(C)N
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCC(c1ccccc1)c1c(C)c(OC)c(C)c(C)c1OC
Reaction time: 0.42 h
Yield: 77 %

Procedure:
A 3.1 ml (5.0 mmole) portion of n-butyllithium.hexane solution was added dropwise to 1.35 g (5.0 mmole) of 1-benzyl-2,5-dimethoxy-3,4,6-trimethylbenzene and 0.83 ml (5×1.1 mmole) of 1,1,2,2-tetramethylethylenediamine dissolved in anhydrous tetrahydrofuran (15 ml), under an atmosphere of argon at 50° C. over the period of 5 minutes, followed by stirring at 50° to 55° C. for 25 minutes. Then, a solution of 0.83 (5.0 mmole) of n-hexyl bromide in tetrahydrofuran (5 ml) was added dropwise to the mixed solution over the period of 5 minutes, followed by stirring at 50° C. for further 10 minutes. The reaction solution was cooled with ice and made acid by adding a 10% aqueous phosphoric acid solution, and the product was extracted with isopropyl ether. The organic layer was separated out, washed with aqueous sodium chloride solution, dried (magnesium sulfate) and evaporated. The residual solution was chromatographed on a silica gel column to effect purification (elution with hexane/isopropyl ether) to thereby give 1.37 g (77%) of 7-(2,5-dimethoxy-3,4,6-trimethylphenyl)-7-phenylheptane. Its typical physical properties and nuclear magnetic resonance specrum data are shown in Table 14.
Reaction SMILES: [F:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([C:8](=[CH2:21])[CH2:9][C:10]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1.[H][H]>CO.C(O)(=O)C.[Pd]>[F:1][C:2]1[C:3]([O:22][CH3:23])=[C:4]([CH:8]([CH3:21])[CH2:9][C:10]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: C=C(CC(O)(C(=O)OCC)C(F)(F)F)c1cccc(F)c1OC
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C(O)(CC(C)c1cccc(F)c1OC)C(F)(F)F
Yield: 95.9 %

Procedure:
1.56 g (5.7 mmol) of 1,1′-bi-2-naphthol are admixed with 5.7 ml (2.85 mmol) of a 0.5 M titanium tetraisopropoxide solution in toluene and the red solution is stirred for 2 hours at room temperature. 9.5 g (57.2 mmol) of 2-fluoro-6-(1-methyleneethyl)anisole and 12.5 ml (95 mmol) of ethyl trifluoropyruvate are added and the mixture is heated at 140° C. for 18 hours. After cooling it is immediately purified by column chromatography on silica gel (hexane/ethyl acetate 0-5%) to give 8.9 g of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate. 8.9 g (26.5 mmol) of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate are dissolved in 200 ml of methanol and 2 ml of acetic acid, and 890 mg of palladium on carbon (10%) are added. The suspension is shaken for 1.5 hours under a hydrogen atmosphere under atmospheric pressure until the hydrogen uptake is 560 ml. The mixture is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. Removal of the solvent gives 8.6 g of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanoate. 8.6 g (25.4 mmol) of ethyl 4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pentanoate in 350 ml of diethyl ether are cooled to −30° C. and over 15 minutes 1.7 g (44.7 mmol) of lithium aluminum hydride in solid form are added in portions. The mixture is stirred for 1.5 hours, in the course of which the temperature climbs to −15° C., followed by dropwise addition in succession of ethyl acetate and water and by a further hour of stirring until a readily filterable precipitate has formed. The suspension is filtered through Celite, the filter bed being thoroughly rinsed with ethyl acetate. The phases of the filtrate are separated and extraction is carried out again with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo. Separation by column chromatography on silica gel (hexane/diisopropyl ether 0-15%) yields 3.1 g of (2R*,4R*)-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal
Reaction SMILES: C([CH:3]([O:7][C:8]1[CH:12]=[C:11]([C:13](O)=O)[N:10]([CH3:16])[N:9]=1)[C:4]([OH:6])=[O:5])C.CCN=C=NCCCN(C)C.Cl.[CH2:29]([N:32]1[C:39]([NH2:40])=[C:38]([NH2:41])[C:36](=[O:37])[N:35]([CH2:42][CH:43]=[CH2:44])[C:33]1=[O:34])[CH:30]=[CH2:31]>CO>[CH2:42]([N:35]1[C:36](=[O:37])[C:38]2[NH:41][C:13]([C:11]3[N:10]([CH3:16])[N:9]=[C:8]([O:7][CH2:3][C:4]([OH:6])=[O:5])[CH:12]=3)=[N:40][C:39]=2[N:32]([CH2:29][CH:30]=[CH2:31])[C:33]1=[O:34])[CH:43]=[CH2:44]
Reactant: CCC(Oc1cc(C(=O)O)n(C)n1)C(=O)O
Reactant: C=CCn1c(N)c(N)c(=O)n(CC=C)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Product: C=CCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CC=C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (5-carboxy-1-methylpyrazol-3-yl)oxyacetic acid (0.5 mmol) and EDCl (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-diallyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[5-(1,3-diallyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4].[CH:8]1[C:20]2[CH:19]([CH2:21][O:22][C:23](ON3C(=O)CCC3=O)=[O:24])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1>O.C1COCC1>[C:23]([N:1]1[CH2:7][CH2:6][CH2:5][C@H:2]1[CH2:3][OH:4])([O:22][CH2:21][CH:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[C:20]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:24]
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCC[C@H]1CO
Reaction time: 1 h
Yield: 74 %

Procedure:
L-prolinol (Compound 1) (0.61 g, 6.0 mmol) was dissolved in 70 ml of pure water, thus preparing an L-prolinol aqueous solution. N-(9-Fluorenylmethoxycarbonyloxy)succinimide (Fmoc-OSu) (2.0 g, 6.0 mmol) was dissolved in 10 ml of THF. This THF solution was added to the L-prolinol aqueous solution, and this was stirred for 1 hour so as to react the L-prolinol and the Fmoc-OSu. The reaction solution was separated into a liquid fraction and a precipitate fraction. These fractions respectively were subjected to extraction with ethyl acetate, and organic layers respectively were collected therefrom. The thus-obtained organic layers were mixed together, and anhydrous sodium sulfate was added thereto to absorb moisture (hereinafter, this process is referred to as a “drying” process). The organic layers were filtered, and the filtrate obtained was vacuum concentrated. The residual substance obtained was purified by silica gel column chromatography (the eluent hexane:ethyl acetate=1:1). Thus, Compound 2 was obtained (1.4 g, yield: 74%). The result of NMR analysis with respect to this compound is shown below.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12]([O:14][C:15]([C:17]1[N:18]([CH3:40])[C:19]([CH2:38][CH3:39])=[C:20]([C:36]#[N:37])[C:21]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[NH2:35])=[CH:24][CH:23]=1)=[O:16])[CH3:13].[CH:41]([S:44](Cl)(=[O:46])=[O:45])([CH3:43])[CH3:42].O>C(Cl)Cl>[CH2:12]([O:14][C:15]([C:17]1[N:18]([CH3:40])[C:19]([CH2:38][CH3:39])=[C:20]([C:36]#[N:37])[C:21]=1[C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[NH:35][S:44]([CH:41]([CH3:43])[CH3:42])(=[O:46])=[O:45])=[CH:26][CH:27]=1)=[O:16])[CH3:13]
Reactant: CCOC(=O)c1c(-c2ccc(Oc3ccccc3N)cc2)c(C#N)c(CC)n1C
Reactant: CC(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(Oc3ccccc3NS(=O)(=O)C(C)C)cc2)c(C#N)c(CC)n1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Add DBU (0.29 mL, 1.92 mmol) to 3-[4-(2-amino-phenoxy)-phenyl]-4-cyano-5-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (0.25 g, 0.64 mmol, prepared in example E-95) in methylene chloride at room temperature with stirring. After 10 minutes, cool to 0° C. and add isopropyl-sulfonylchloride (0.11 mL, 0.96 mmol). Stir the reaction mixture at 0° C. for 30 minutes and then at room temperature for 2-6 hours. Then pour the reaction mixture into water and extract with methylene chloride. Combine the organic extracts, wash with 1N HCl, water and brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with acetonitrile:methylene chloride to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(#N)C.C(=O)([O-])O.[Na+]>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.C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH2:19][OH:18])=[CH:7][N:6]3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: OCc1ccccc1B(O)O
Reactant: Clc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: OCc1ccccc1-c1ccc2nc(-c3ccc(Cl)cc3)cn2c1
Yield: 58.3 %

Procedure:
Under a stream of nitrogen, 200 mg of 6-bromo-2-(4-chlorophenyl)imidazo[1,2-a]pyridine (prepared as described in 5.1), 148 mg of 2-(hydroxymethyl)phenyl boronic acid and 22.5 mg of tetrakis(triphenylphosphine)palladium are placed in a microwave tube containing a mixture of 3 ml of acetonitrile, 3 ml of toluene and 3 ml of a 2M solution of sodium hydrogen carbonate. The tube is placed in a microwave apparatus and irradiated at 150° C. for 15 min. The organic phase is separated, dried and concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a 98/2 dichloromethane/methanol mixture. The solid obtained is triturated in diisopropyl ether and recovered by filtration and then dried in a dessicator under reduced pressure. 127 mg of compound are obtained. Mp=164-166° C. 1H NMR (DMSO-d6, δ in ppm): 4.44 (d, J=5.6 Hz, 2H); 5.19 (t, J=5.4 Hz, 1H); from 7.25 to 7.64 (m, 8H); 7.98 (m, J=8.3 Hz, 2H); 8.41 (s, 1H); 8.54 (m, 1H). M+H=335.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](OCC)=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([Cl:14])[CH:3]=1.O.[NH2:16][NH2:17]>C(O)C.O>[Cl:14][C:4]1[N:5]=[C:6]([CH3:13])[C:7]2[C:8](=[O:9])[NH:16][NH:17][C:2]=2[CH:3]=1
Reactant: CCOC(=O)c1c(Cl)cc(Cl)nc1C
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1nc(Cl)cc2[nH][nH]c(=O)c12
Temperature: 80 °C
Reaction time: 17.5 h

Procedure:
A mixture of ethyl 4,6-dichloro-2-methylnicotinate (5.00 g, 21.36 mmol) and hydrazine monohydrate (2.1 mL, 43.3 mmol) in ethanol (22 mL) was heated to 80° C. and stirred for 17.5 h. The reaction was cooled to room temperature, diluted with water, filtered, rinsed with water, and dried under vacuum to provide 6-chloro-4-methyl-1H-pyrazolo[4,3-c]pyridin-3(2H)-one, which was carried onto the next step without further purification. MS ESI calc'd. for C7H6ClN3O [M+1]+ 184. found 184.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][O:10]COC.C([Li])CCC.[B:19](OC(C)C)(OC(C)C)[O:20]C(C)C.Cl>C1COCC1.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[B:19]([OH:20])[O:10][CH2:9][C:3]=2[CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COCOCc1cc(F)ccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OB1OCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 60.4 %

Procedure:
To a solution of 5b (73.2 g, 293 mmol) in dry THF (400 mL) was added n-butyllithium (1.6 M in hexanes; 200 mL) over 45 min at −78° C. under nitrogen atmosphere. Anion precipitated. After 5 min, (i-PrO)3B (76.0 mL, 330 mmol) was added over 10 min, and the mixture was allowed to warm to room temperature over 1.5 h. Water and 6 N HCl (55 mL) were added, and the solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. To a solution of the residue in tetrahydrofuran (360 mL) was added 6 N HCl (90 mL), and the mixture was stirred at 30° C. overnight. The solvent was removed under reduced pressure to about a half volume. The mixture was poured into ethyl acetate and water. The organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the residue was treated with i-Pr2O/hexane to give 19b (26.9 g, 60%) as a white powder: mp 118-120° C.; 1H NMR (300 MHz, DMSO-d6) δ (ppm) 4.95 (s, 2H), 7.15 (m, 1H), 7.24 (dd, J=9.7, 1.8 Hz, 1H), 7.74 (dd, J=8.2, 6.2 Hz, 1H), 9.22 (s, 1H); ESI-MS m/z 151 (M−H)−; HPLC purity 97.8%; Anal (C7H6BFO2) C, H.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]([NH2:14])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:16][CH:17]([CH3:25])[C:18](=O)[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(O)(=O)C.O>C1C=CC=CC=1>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([CH:6]([NH:14][C:18]([CH:17]([CH3:25])[CH3:16])=[CH:19][C:20]([O:22][CH3:23])=[O:21])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])=[CH:12][CH:11]=1
Reactant: COC(=O)CC(=O)C(C)C
Reactant: CCOC(=O)CC(N)c1ccc(Cl)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)CC(NC(=CC(=O)OC)C(C)C)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
5.70 g (25.0 mmol) of ethyl-3-amino-3-(4-chlorophenyl)propanoate [V. Wehner et al., Synthesis 14, 2023-2036 (2002)], 3.993 ml (27.5 mmol) of methyl 4-methyl-3-oxopentanoate and 2.87 ml (50.1 mmol) of acetic acid were taken up in 70 ml of benzene and reacted at reflux on a water separator overnight. After cooling, the mixture was washed with saturated aqueous sodium bicarbonate solution, the organic phase was dried with magnesium sulfate and the solvent was destilled off under reduced pressure. This gave 8.57 g (68% of theory) of the target compound in a purity of 70%. The fraction was used without further work-up for the subsequent steps.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(OC([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccc2nccc(Cl)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc2nccc(N3CCNCC3)c2c1
Yield: 59.4 %

Procedure:
4,6-Dichloroquinoline (De, D., Byers L. D., Krogstad, D. J. J. Heterocyclic Chem. 1997, 34, 315) (0.34 g, 1.7 mmol) and 1-tert-butoxycarbonylpiperazine (1.58 g, 8.5 mmol) are reacted according to method A. The Boc group is cleaved with trifluoroacetic acid (5 mL) in CH2Cl2 (5 mL) giving 0.25 g of the product.
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][CH2:13][C:14]#[C:15][Si](C)(C)C)[N:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([C:26]2[CH:27]=[CH:28][N:29]([CH2:31][CH2:32][C:33]#[C:34][Si](C)(C)C)[N:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:31]([N:29]1[CH:28]=[CH:27][C:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:30]1)[CH2:32][C:33]#[CH:34].[CH2:12]([N:11]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][CH:9]=[N:10]1)[CH2:13][C:14]#[CH:15]
Reactant: C[Si](C)(C)C#CCCn1nccc1-c1ccccc1
Reactant: C[Si](C)(C)C#CCCn1ccc(-c2ccccc2)n1
Product: C#CCCn1ccc(-c2ccccc2)n1
Product: C#CCCn1nccc1-c1ccccc1
Yield: 13 %
Yield: 6 %

Procedure:
The title compounds were prepared in accordance with the general method of Example 108(B), from 5-phenyl-1-(4-trimethylsilanyl-but-3-ynyl)-1H-pyrazole and 5-phenyl-2-(4-trimethylsilanyl-but-3-ynyl)-2H-pyrazole (300 mg, 1.12 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1) to yield 29 mg (0.15 mmol, 13%) of 2-but-3-ynyl-5-phenyl-2H-pyrazole and 13 mg (66 μmol, 6%) of 1-but-3-ynyl-5-phenyl-1H-pyrazole.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:31]1(C)C=CC=CC=1>>[Br-:1].[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:31][P+:18]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([OH:11])=[O:10]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)CCCCCCCBr
Reactant: Cc1ccccc1
Product: O=C(O)CCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]

Procedure:
Dissolve 8-bromooctanoic acid (1.0g) in anhydrous toluene (3 mL) and add triphenylphosphine (1.21g). Heat to reflux overnight. Separate the lower phase crystallize (ethanol/ethyl ether) to give (8-carboxyoctyl)triphenylphosphonium bromide (1.0g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:27][C:28](=[O:50])[CH2:29][NH:30][C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:4]=[N:3]1.[H-].[Na+].[CH3:53]I.O>CN(C)C=O>[CH3:53][N:27]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[NH:7][C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:28](=[O:50])[CH2:29][NH:30][C:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: Cn1ncc(NC(=O)CNC(c2ccccc2)(c2ccccc2)c2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)CNC(c1ccccc1)(c1ccccc1)c1ccccc1)c1cnn(C)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
To a stirred solution of N-[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]-2-(tritylamino)acetamide (2 g) in N,N-dimethylformamide (20 ml) was added sodium hydride (245 mg, 60% oil suspension) at 0° C., and the mixture was stirred for 30 minutes with warming to room temperature. The mixture was cooled to 0° C., and methyl iodide (1.3 g) was added. The whole mixture was stirred at room temperature overnight. Water (5 ml) was added, and the whole mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave N-methyl-N-[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]-2-(tritylamino)acetamide (2.05 g).