Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O:16]C1C=CC=CC=1)([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CI.P(OC)(OC)O[CH3:27]>>[CH3:27][P:1](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COP(OC)OC
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CI
Product: CP(=O)(Oc1ccccc1)Oc1ccccc1
Temperature: 210 °C

Procedure:
To a three-necked flask equipped with thermometer, magnetic stirrer, distillation head and nitrogen inlet 163 g (0.52 mol) of triphenyl phosphite and 1.0 mL of methyl iodide were charged. Then, 32.7 g (0.26 mol) of trimethyl phosphite was added drop-wise at 100–110° C. over the course of one hour. The reaction temperature was then raised to 210° C. and an exothermic reaction was observed. The reaction temperature was maintained at 230° C. for two hours, and the reaction mixture was analyzed before it underwent transesterification. Diphenyl methylphosphonate was obtained as a liquid. The 31P NMR (CDCl3) indicated 95% diphenyl methylphosphonate. The impurities included triphenyl phosphate (0.8%, δ=−16.4 ppm), trimethyl phosphate (0.6%, δ=−10.3 ppm), and unknown compounds (δ=19.8, 20.4. 28.4 ppm). The acid number of this crude diphenyl methylphosphonate was 5.4 mg KOH/g
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:15]([O:22][C:23](ON1C(=O)CCC1=O)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O.C(OCC)(=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:23]([O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:24])[C@H:10]([CH3:14])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Reaction time: 12 h

Procedure:
A mixture of 2.4 g (R)-4-N-Boc-2-methyl-piperazine, 3.5 g N-(Benzyloxycarbonyl-oxy)succinimide and 2.0 g NaHCO3 in 10 ml dioxane/water 1/1 was stirred for 12 h. The mixture was diluted with ethyl acetate, the phases separated and the organic phase washed with water, saturated aqueous NaHCO3, 0.1 M HCl and brine. The crude product obtained after drying over MgSO4 and evaporation of the solvents was used in the subsequent reaction. Yield: 4.3 g.
Reaction SMILES: C(O)CCCCCCC.C[O-].[Li+].C(OP([O-])OCC)C.C([P:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])([O-:26])([O-:25])[O-:24])C.C(OP([O-])OCCCCCCCC)CCCCCCC.[OH-].[Na+].Cl>CO.O>[CH2:27]([PH:23]([OH:26])([OH:24])[OH:25])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCP([O-])([O-])([O-])CC
Agent: CCCCCCCCOP([O-])OCCCCCCCC
Agent: CCOP([O-])OCC
Agent: C[O-]
Solvent: O
Solvent: CCCCCCCCO
Solvent: CO
Product: CCCCCCCC[PH](O)(O)O

Procedure:
50 g (0.38 mol) of n-octanol was premixed with 3.5 mL of a 2.2M solution of lithium methoxide in methanol. The mixture was rapidly added at room temperature to 53 g (0.38 mol) diethylphosphite. The colour of the solution changed from colourless to yellow. The resultant mixture was then distilled under vacuum of 1.00 mBar. At 23° C. ethanol was removed. At 43-48° C., unreacted diethyl phosphite was distilled, with the remaining 65 g comprising a 1.6:1 mole mixture of ethyloctylphosphite and dioctylphosphite. The mixture of ethyloctylphosphite and dioctyl phosphite was added slowly at room temperature to 26 g of a 50% sodium hydroxide solution in water. The reaction was exothermic but did not require cooling, however, the rate of addition was adjusted such that the temperature did not exceed 50° C. Afterwards the mixture was treated dropwise with concentrated hydrochloric acid until a pH of 2 was measured. Two phases formed and the upper organic phase was separated. The n-octanol formed as a by-product of the reaction was removed under vacuum leaving behind 49.8 g of n-octyl phosphorous acid as a colourless liquid containing small amounts of sodium chloride.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])=[C:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+].[C:23]([O:29][CH2:30]I)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25].C(OCC)(=O)C>CN(C)C=O>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])=[C:8]2[C:12]([O:14][CH2:30][O:29][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:13])[CH3:3]
Reactant: CC(C)(C)C(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3ccccc3O)C[C@H]12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(c3ccccc3O)C[C@H]12
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
A solution of sodium (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(hydroxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (106 mg) in dry dimethylformamide (4.5 ml) was cooled with ice, and thereto pivaloyloxymethyl iodide (123 mg) was added. The mixture was stirred for 1 hour at the same temperature. Ethyl acetate and ice water were added to the reaction solution, and the mixture was separated with a separating funnel. After the organic layer was washed with a cold saturated aqueous sodium chloride solution (4 times), it was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and then the residue was purified by silica gel column chromatography (chloroform/methanol) to give [(2,2-dimethylpropanoyl)oxy]methyl(5R,6S)-6-[(1R)-1-hydroxyethyl]-3-(hydroxyphenyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (36 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][N:7]([C:17]1[C:18]([N+:22]([O-:24])=[O:23])=[CH:19][N:20]=[C:15]([Cl:14])[N:16]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: CCOC(=O)CCNC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A solution of 1.85 g (0.01 mole) of 3-cyclopentylamino-propanoic acid ethyl ester in 30 mL of water was added dropwise to a solution of 1.94 g (0.01 mole) of 2,4-dichloro-5-nitro-pyrimidine in 30 mL of ethyl ether. At 0 degrees, 2.0 g (0.020 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-80:20) gave 3.05 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-propanoic acid ethyl ester (IV-10)
Reaction SMILES: Cl[C:2]1C=C(C2C3N=CC=CC=3C(=O)NN=2)C=C[CH:7]=1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[C:27]3[CH:36]=[CH:35][CH:34]=[N:33][C:28]=3[C:29](=[O:32])[NH:30][N:31]=2)[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[C:27]3[CH:36]=[CH:35][CH:34]=[N:33][C:28]=3[C:29](=[O:32])[N:30]([CH2:2][CH3:7])[N:31]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: O=c1[nH]nc(-c2cccc(Cl)c2)c2ncccc12
Reactant: O=c1[nH]nc(-c2cccc(Cl)c2)c2cccnc12
Product: CCn1nc(-c2cccc(Cl)c2)c2cccnc2c1=O

Procedure:
Following the procedures of Example 17A and substituting for 8-(3-chlorophenyl)pyrido[2,3-d]pyridazin-5-one with 5-(3-chlorophenyl)pyrido[2,3-d]pyridazin-8-one there is obtained 5-(3-chlorophenyl)-7-ethylpyrido[2,3-d]pyridazin-8-one.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].[CH3:30][NH:31][CH3:32].C1COCC1>>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][CH2:2][N:31]([CH3:32])[CH3:30])=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: CNC
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Solvent: C1CCOC1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN(C)C)c1OCCC(C)c1ccc(F)cc1
Yield: 56 %

Procedure:
Example 8a (50 mg, 0.10 mmol) was reacted with 1.0 M solution of dimethylamine in THF (1 mL, 1 mmol) at 55° C. at for 24 h. The solvent was removed under vacuum and the crude mixture was suspended in Et2O (910 mL) and 2N HCl (10 mL). The ethereal layer was separated, dried over MgSO4 and evaporated to dryness. The isolated white solid was again suspended in mixture of Et2O and hexane (1/9) sonicated for 1 minute and solid was filtered and dried. The isolated solid was suspended in DCM and washed with NaHCO3 (aq) solution. The organic layer was dried over MgSO4 and evaporated to dryness to afford the title compound as a pale yellow oil (26 mg, 56%). 1H NMR (300 MHz, CDCl3) δ 7.20-7.15 (m, 2H), 7.00-6.95 (m, 2H), 4.05 (t, J=6.0 Hz, 2H), 3.96 (t, J=6.6 Hz, 2H), 3.82 (s, 3H), 3.03-2.96 (m, 1H), 2.57 (t, J=6.0 Hz, 2H), 2.49 (s, 3H), 2.27 (s, 6H), 2.18 (s, 3H), 2.03-1.98 (m, 2H), 1.29 (d, J=6.9 Hz, 3H). MS (ES+) m/z 452.2.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:13]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:11]#[C:2][CH2:3][CH2:4][CH3:5])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:13]
Reactant: Oc1ccc2cc(Br)ccc2c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CCCC#Cc1ccc2c(Cl)c(O)ccc2c1
Temperature: 25 °C
Yield: 177.5 %

Procedure:
The compound (S7-3) was synthesized according to the method disclosed in Synthesis, No. 9, 1439 (2004). 38.3 g of 1-chloro-6-bromo-2-naphthol (S1-2), 5.2 g of PdCl2(PPh3)2, 0.71 g of copper iodide and 400 mL of triethylamine were added to a reactor under a nitrogen atmosphere and stirred at room temperature, to which 35.8 g of 1-heptine (S7-2) was added, followed by refluxing for 6 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the resulting residue, and the mixture was filtered with Celite. The resulting solution was washed with 1N hydrochloric acid and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography with a mixed solvent of heptane and ethyl acetate (3/1) as a developing solvent and dried under reduced pressure to provide 32.3 g of 1-chloro-6-(1-pentynyl)-2-naphthol (S7-3).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:15][C:16]1[CH:21]=[C:20]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:19]([NH:33][C@@H:34]([CH3:37])[CH2:35]O)=[CH:18][N:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:15][C:16]1[N:17]=[CH:18][C:19]2[NH:33][C@@H:34]([CH3:37])[CH2:35][N:22]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:20]=2[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(Br)ncc2N[C@@H](C)CO)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2C[C@H](C)Nc3cnc(Br)cc32)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 61.8 %

Procedure:
Diisopropyl azodicarboxylate (0.013 ml, 0.066 mmol) was added dropwise to a 60° C. solution of (S)-N-(2-bromo-5-(1-hydroxypropan-2-ylamino)pyridin-4-yl)-4-methylbenzene sulfonamide (0.022 g, 0.055 mmol) and triphenylphosphine (0.017 g, 0.066 mmol) in THF (1.0 mL). The reaction mixture stirred at 60° C. for 10 min. The mixture was concentrated and the residue was purified via column chromatography on silica gel (Biotage 10 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford (S)-7-bromo-3-methyl-1-tosyl-1,2,3,4-tetrahydropyrido[4,3-b]pyrazine (0.013 g, 62%) as a light purple solid. MS (ESI, pos. ion) m/z 382, 384.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:15][C:14](=O)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.P(Cl)(Cl)([Cl:19])=O.CN(C)C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O.C(Cl)(Cl)Cl>[Cl:19][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:15]=1
Reactant: O=c1[nH]c(-c2ccco2)nc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)c1ccccc1
Product: Clc1nc(-c2ccco2)nc2ccccc12
Reaction time: 0.25 h

Procedure:
A 2.12 g portion of 2-(2-furyl)quinazolin-4(3H)-one was stirred into 25 ml of phosphorus oxychloride and to this mixture was slowly added 1.21 g of dimethylaniline. This mixture was stirred for 15 minutes. The entire mixture was added slowly to 1 liter of cold water containing 25 ml of chloroform. Solid sodium bicarbonate was added as required to keep the water solution basic. The chloroform extract was separated and the water extracted with an additional 25 ml of chloroform. The chloroform extracts were combined and concentrated to give a yellow solid. The solid was recrystallized from cyclohexane to give 1.4 g of 4-chloro-2-(2-furyl)quinazoline, m.p. 116°-118°; ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][NH2:13])=[CH:3]1.CS(C)=[O:16].[ClH:18]>>[ClH:18].[NH2:13][CH2:12][CH2:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]1=[O:16]
Reactant: CS(C)=O
Reactant: Cn1cc(CCN)c2ccccc21
Agent: Cl
Product: CN1C(=O)C(CCN)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-3-yl)ethanamine (2.5 g cude) in DMSO (1.33 g, 17.0 mmol) was added concentrated hydrochloric acid (1.2 mL) slowly. The resulting reaction mixture was stirred at room temperature in a sealed reactor for 16 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC to afford the title compound (1.5 g, 6.59 mmol, 45% yield over two steps) as a yellow solid. MS (ESI) m/z 191.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[CH2:23]([N:11]1[CH2:12][CH2:13][C:9]([C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)([OH:14])[CH2:10]1)[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: C=CCN1CCC(O)(c2cc(F)cc(F)c2)C1
Temperature: 60 °C
Yield: 23.1 %

Procedure:
In a sealed tube a mixture of enantiomer E2 of 3-(3,5-difluorophenyl)pyrrolidin-3-ol (0.29 g, 1.45 mmol), acetonitrile (15 mL), potassium carbonate (0.4 g, 2.9 mmol) and allylbromide (0.13 mL, 1.59 mmol) was heated at 60° C. for 2 h. Aqueous sodium carbonate (10%, 5 mL) was added and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic phase was dried (Na2SO4) and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 7:1) gave the title compound (0.08 g). [α]D=−20.3° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diisopropyl ether: M.p. 102-103° C.; MS m/z (relative intensity, 70 eV) 239 (M+, 22), 83 (bp), 198 (52), 82 (33), 84 (29), 113 (27).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Si]([O:44][CH2:45][C:46]1[N:51]=[CH:50][C:49]([C:52](=[N:54]O)[NH2:53])=[CH:48][CH:47]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:54]=[C:52]([C:49]3[CH:48]=[CH:47][C:46]([CH2:45][OH:44])=[N:51][CH:50]=3)[N:53]=2)[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Cc1ccc(C(=O)O)cc1F
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(N)=NO)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(CO)nc3)no2)cc1F

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 12 (12a) using 3-fluoro-4-isobutylbenzoic acid (0.12 g, 0.63 mmol) that was obtained in Example 23 (23e), 1-hydroxybenzotriazole (89 mg, 0.66 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.13 g, 0.66 mmol), 6-({[t-butyl(dimethyl)silyl]oxy}methyl)-N′-hydroxypyridine-3-carboximidamide (0.17 g, 0.60 mmol) that was obtained in Example 23 (23c), and 1.0 M solution of tetrabutylammoniumfluoride in tetrahydrofuran (1.2 mL, 1.2 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (2:3 to 1:1) as the eluent to afford the title compound (0.16 g) in a yield of 80% as a white crystalline solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:15])[CH2:7][N:8]([CH:10]=[C:11]([C:13]#[N:14])[CH3:12])[CH3:9])[CH3:4]>CN(C)C=O>[NH2:14][C:13]1[C:11]([CH3:12])=[CH:10][N:8]([CH3:9])[C:7]=1[C:6]([O:5][CH2:3][CH3:4])=[O:15]
Reactant: CCOC(=O)CN(C)C=C(C)C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(N)c(C)cn1C
Temperature: 30 °C

Procedure:
300 mg of 80% sodium hydride are added with stirring at 20° C. to a solution of 9.1 g of N-(2-cyano-1-propenyl)sarcosine ethyl ester (obtained by reacting methacrylonitrile with bromine and subsequent reaction with sarcosine ethyl ester) in 50 ml of anhydrous dimethyl formamide. After warming the reaction mixture to 30° C., an exothermic reaction starts (the temperature rises to 45° C.); this reaction is terminated after 30 minutes. The resulting solution of the title compound (b.p. 70° C., 1.3 Pa) is subsequently processed without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1C)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[CH:9]=1)=[O:6].Cl[C:22]1[C:27]([C:28]2[CH:33]=[CH:32][N:31]=[CH:30][N:29]=2)=[CH:26][CH:25]=[CH:24][N:23]=1.N(CC)(CC)CC.FC(C(O)=O)(F)F>CS(C)=O>[CH3:16][CH:14]([C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:17]=[CH:18][CH:19]=[C:2]([NH:1][C:22]3[C:27]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][N:29]=4)=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:3]=2)[CH:13]=[CH:12][CH:11]=1)[CH3:15]
Reactant: Cc1ccc(C(=O)Nc2cccc(C(C)C)c2)cc1N
Reactant: Clc1ncccc1-c1ccncn1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)c1cccc(NC(=O)c2cccc(Nc3ncccc3-c3ccncn3)c2)c1
Temperature: 90 °C
Reaction time: 22 h

Procedure:
To 3-amino-N-(3-isopropyl-phenyl)-4-methyl-benzamide (300 mg, 1.2 mmol), 4-(2-chloropyridin-3-yl)pyrimidine (100 mg, 0.52 mmol) and DMSO (0.15 mL) was added NEt3-TFA (0.11 mL). The resulting slurry was stirred for 22 hours at 90° C. The crude material was purified by silica gel chromatography (40-60% EtOAc/hexanes) to yield the title compound as a yellow solid. MS m/z=410 [M+1]+. Calc'd for C25H23N5O: 409.49.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:17]=[C:16]([OH:18])[NH:15][N:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[NH:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:17]=[C:16]([OH:18])[NH:15][N:14]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2cc(O)[nH]n2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Oc1cc([C@@H]2CCNC2)n[nH]1
Reaction time: 48 h

Procedure:
To a solution of (R)-3-(5-hydroxy-1H-pyrazol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (44 mg, 0.17 mmol) in CH2Cl2 (1 mL) was added HCl in dioxane (0.2 mL, 4.0 M). The reaction mixture was stirred for 48 h. Solvent was removed at reduced pressure to afford crude (R)-5-pyrrolidin-3-yl-2H-pyrazol-3-ol as a white solid. The material was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=O)[CH2:7][O:8][C:4]=2[CH:3]=1.C1(P(=[CH:31][C:32]([O:34][CH3:35])=[O:33])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:35][O:34][C:32](=[O:33])[CH2:31][C:6]1[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=2[O:8][CH:7]=1
Reactant: O=C1COc2cc(O)ccc21
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)Cc1coc2cc(O)ccc12

Procedure:
A mixture of 6-hydroxy-(2H)-benzofuran-3-one (5.0 g, 33.3 mmol), methyl (triphenylphosphoranylidene)acetate (25.0 g, 73 mmol), and xylenes (100 mL) is refluxed 6 hr. The reaction is concentrated and diluted with enough 1M aqueous hydrochloric acid to adjust pH to 2-3. The product is extracted into ethyl acetate (3×100 mL). The combined extracts are dried over anhydrous magnesium sulfate, filtered and concentrated. The residue is purified via silica chromatography eluting with 7:3 hexanes:ethyl acetate to afford the product as a orange oil, 1.3 g, 20%. MS M++1 207. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[Cl:19][C:20]1[CH:21]=[C:22]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31][CH:32](P(=O)(OCC)OCC)[C:33]3=[O:35])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.C(O)C>O1CCCC1>[Cl:19][C:20]1[CH:21]=[C:22]([C@H:26]2[N:34]3[C@@H:29]([CH2:30][CH2:31]/[C:32](=[CH:8]\[C:7]4[CH:10]=[CH:11][C:12]([N:13]5[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]5)=[C:5]([O:4][CH3:3])[CH:6]=4)/[C:33]3=[O:35])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: CCOP(=O)(OCC)C1CC[C@H]2CC[C@@H](c3cccc(Cl)c3)N2C1=O
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(/C=C2\CC[C@H]3CC[C@@H](c4cccc(Cl)c4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
Lithium hydroxide (0.142 g) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (0.28 g) and diethyl [(3S,8aR)-3-(3-chlorophenyl)-5-oxooctahydroindolizin-6-yl]phosphonate (0.52 g) in tetrahydrofuran (1 mL)-ethanol (4 mL), and the reaction solution was stirred under shading at room temperature for three hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 0.438 g of the title compound as a colorless oil. The property values of the compound are as follows.