Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C1(CN)CCCCC1.[O:17]=[C:18]1[C:26]2([CH2:30][O:29][C:28]3[CH:31]=[C:32]4[C:36](=[CH:37][C:27]2=3)[CH2:35][CH2:34][O:33]4)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]1[CH2:38][C:39]1[CH:47]=[CH:46][CH:45]=[CH:44][C:40]=1[C:41](O)=[O:42].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:41](=[O:42])[C:40]2[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=2[CH2:38][N:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]3([CH2:30][O:29][C:28]4[CH:31]=[C:32]5[C:36](=[CH:37][C:27]3=4)[CH2:35][CH2:34][O:33]5)[C:18]2=[O:17])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(Nc1cccc(Cl)c1)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 3-chloroaniline to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(3-chlorophenyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (81%) as a colorless solid: mp>230° C.; 1H NMR (300 MHz, DMSO-d6) δ10.71 (s, 1H), 7.96-7.90 (m, 1H), 7.65-7.57 (m, 2H), 7.52-7.31 (m, 3H), 7.26-7.10 (m, 4H), 6.99 (dd, J=7.4, 7.4 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.38 (s, 1H), 5.16-4.99 (m, 2H), 4.82 (d, J=9.4 Hz, 1H), 4.67 (d, J=9.4 Hz, 1H), 4.46 (t, J=8.8 Hz, 2H), 3.01-2.83 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ177.8, 167.8, 161.6, 161.2, 142.8, 140.9, 136.1, 134.5, 133.5, 132.7, 131.1, 130.8, 129.1, 128.5, 127.9, 127.4, 124.1, 123.9, 123.6, 120.9, 120.3, 119.8, 119.6, 118.7, 109.8, 92.9, 80.4, 72.6, 57.4, 41.7, 28.8; MS (ES+) m/z 523.1 (M+1).
Reaction SMILES: [OH:1][C@@H:2]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH3:6])=[O:4].ClC(Cl)(Cl)C(=N)O[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.FC(S(O)(=O)=O)(F)F>C(Cl)Cl>[CH2:15]([O:1][C@@H:2]([CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH3:6])=[O:4])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: COC(=O)[C@@H](O)CC(C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)OCc1ccccc1
Yield: 74.7 %

Procedure:
To a stirred solution of methyl (2S)-2-hydroxy-4-methylpentanoate (0.5 g, 3.4 mmol) in anhydrous CH2Cl2 (10 mL) at R.T. under Ar was added benzyl 2,2,2-trichloroacetimidate (1.4 mL, 6.8 mmol) and trifluoromethylsulfonic acid (25 μl). After 30 min the reaction mixture was taken up in CH2Cl2 (20 mL). The organic layer was washed with sat. NaCl (2×10 mL), 1N HCl (2×10 mL), sat. NaCl (2×10 mL), dried (MgSO4). filtered and concentrated. Purification by flash chromatography on silica gel (EA:H; 1:10) afforded methyl (2S)-2-benzoxy-4-methylpentanoate as an oil (0.6 g, 73.5%): 1H NMR (CDCl3, 300 MHz) δ 0.80-0.98 (m, 6H), 1.40-1.58 (m, 1H), 1.69-1.87 (m, 2H), 3.74 (s, 3H), 3.93-4.06 (m, 1H), 4.42 (d, 1H, J=12.0 Hz), 4.68-4.80 (m, 1H), 7.14-7.32 (m, 5H) ppm.
Reaction SMILES: NCC1(CO[C:10](=[O:30])[NH:11][CH2:12]CCCCCCCCCCCCCCCCC)CCCO1.[CH2:31]([S:47][CH2:48][CH:49]([OH:71])[CH2:50]OC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].[Cl:72][CH2:73][CH2:74][CH2:75][S:76]([NH:79]CC(OC)CSCCCCCCCCCCCCCCCC)(=[O:78])=[O:77]>>[Cl:72][CH2:73][CH2:74][CH2:75][S:76]([NH:79][CH2:50][CH:49]([O:71][C:10](=[O:30])[NH:11][CH3:12])[CH2:48][S:47][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])(=[O:78])=[O:77]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: CCCCCCCCCCCCCCCCSCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC1(CN)CCCO1
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC(=O)NC

Procedure:
3-Hexadecylthio-2-methylcarbamoyloxypropylamine IV c1 is allowed to react and worked up by the same procedure as described in (4). m.p. 84.5°-85.5° C. The summary of the experimental condition and the physical data of the product are listed in the Table 7.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.[C:14]([O:18][C:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[CH2:26]Br)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:12]([C:10]1[CH:9]=[CH:8][N:7]=[C:6]([C:4]2[N:3]=[CH:2][N:1]([CH2:26][CH:22]3[CH2:23][CH2:24][CH2:25][N:21]3[C:19]([O:18][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:20])[CH:5]=2)[CH:11]=1)#[N:13]
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Reactant: CC(C)(C)OC(=O)N1CCCC1CBr
Product: CC(C)(C)OC(=O)N1CCCC1Cn1cnc(-c2cc(C#N)ccn2)c1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and tert-butyl-2-(bromomethyl)pyrrolidine-1-carboxylate according to the procedure for the preparation of Example 43, part A (heating to 120°). [M+H] Calc'd for C19H23N5O2, 354. Found, 354.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)[Cl:21].[C:25]([C:27]1[C:31]([CH:32]=O)=[CH:30][N:29]([C:34]2[C:39]([Cl:40])=[CH:38][C:37]([C:41]([F:44])([F:43])[F:42])=[CH:36][C:35]=2[Cl:45])[N:28]=1)#[N:26]>ClCCl>[C:25]([C:27]1[C:31]([CH:32]=[C:20]([Cl:24])[Cl:21])=[CH:30][N:29]([C:34]2[C:39]([Cl:40])=[CH:38][C:37]([C:41]([F:42])([F:44])[F:43])=[CH:36][C:35]=2[Cl:45])[N:28]=1)#[N:26]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C=O
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C=C(Cl)Cl

Procedure:
A solution of triphenylphosphine (0.983 g) and carbon tetrachloride (0.145 ml) in anhydrous dichloromethane (5 ml) at 0° C. was stirred for 5 minutes. 3-Cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-formylpyrazole (0.25 g) was then added and the mixture was heated under reflux for 5 hours and then evaporated. The residue was purified by column chromatography on silica gel eluting with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p. 99-101° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].CCN(C(C)C)C(C)C.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>ClCCl.O>[O:9]=[C:5]1[N:4]([CH2:3][CH2:2][O:1][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:8][CH2:7][O:6]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1OCCN1CCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CS(=O)(=O)OCCN1CCOC1=O
Reaction time: 3 h
Yield: 40.7 %

Procedure:
To a mixture of 3-(2-hydroxy-ethyl)-oxazolidin-2-one (1.00 g, 7.63 mmol) and Hunigs base (2.92 mL, 16.8 mmol) in dichloromethane (19 mL) at 0° C. was added mesyl chloride (0.650 mL, 8.40 mmol) slowly via syringe. The mixture was stir cold for three hours, diluted with 10 mL of water and 25 mL of dichloromethane. The layers were separated and the organic layer was washed with aqueous NaHCO3 (3×30 mL) followed by water (1×15 mL). The organic layer was then dried (Na2SO4), filtered, and concentrate under reduced pressure to provide 650 mg of methanesulfonic acid 2-(2-oxo-oxazolidin-3-yl)-ethyl ester as a light brown oil. In a separate flask 6-nitroindazole (318 mg, 1.95 mmol) was treated with potassium carbonate (538 mg 3.9 mmol) in DMF (10 mL) for 30 minutes, afer which methanesulfonic acid 2-(2-oxo-oxazolidin-3-yl)-ethyl ester (490 mg 2.34 mmol) was added. The reaction mixture was heated to 60° C. for 6 hours, cooled to room temperature, filtered through a plug of silica gel and rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure and purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30) to provide the title compound (210 mg, 39% yield). 1H NMR (300 MHz, DMSO-d6) ppm 3.49 (m, 2H), 3.62 (t, J=5.76, 2H), 4.13 (m, 2H), 4.76 (t, J=5.76, 2H), 7.97–8.03 (m, 2H), 8.33 (m, 1H), 8.83 (m, 1H); MS (DCI/NH3) m/z 277 [M+H]+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:21][C:22]([F:25])([F:24])F)[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2.[CH2:26](C([Sn])=C(CCCC)CCCC)[CH2:27]CC.[NH4+].[F-:42]>C1(C)C=CC=CC=1.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>[F:42][C:22]([F:24])([F:25])[O:21][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([CH:26]=[CH2:27])[CH:3]=1)[O:10][CH:9]([C:12]([F:15])([F:13])[F:14])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: [F-]
Reactant: CCOC(=O)C1=Cc2cc(OC(F)(F)F)cc(I)c2OC1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: C=Cc1cc(OC(F)(F)F)cc2c1OC(C(F)(F)F)C(C(=O)OCC)=C2
Reaction time: 18 h
Yield: 64 %

Procedure:
To a mixture of ethyl 8-iodo-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 21a, Step 2 (1.00 g, 2.07 mmole) and Pd(PPh3)4 (0.239 g, 0.207 mmole) in anhydrous toluene (50 mL) under a dry N2 atmosphere was added tributylvinyltin (0.665 mL, 2.28 mmole). The mixture was refluxed for 3 h and stirred at r.t for 18 h. After refluxing for and additional 21 h, sat. NH4F solution (50 mL) was added, the mixture was stirred for 30 minutes and extracted with EtOAc (200 mL). The extract was washed with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo. Purification by silica chromatography (95:5 hexanes:EtOAc) gave 0.510 g (64% yield) of the product as a crystalline solid: EIHRMS m/z 382.0620 (M+, C16H12F6O4, Calc'd 382.0640).
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[C:13]([C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)[N:18]=1)([CH3:16])([CH3:15])[CH3:14].[NH2:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH2:41][CH2:42][O:43][C:44]2[CH:49]=[CH:48][N:47]=[C:46]([NH2:50])[CH:45]=2)=[CH:33][CH:32]=1.C1COCC1>C(Cl)Cl.CO>[NH2:50][C:46]1[CH:45]=[C:44]([O:43][CH2:42][CH2:41][C:34]2[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:31]([NH:30][C:6]([NH:22][C:20]3[N:19]([C:23]4[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=4)[N:18]=[C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:21]=3)=[O:7])=[CH:32][CH:33]=2)[CH:49]=[CH:48][N:47]=1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: Nc1cc(OCCc2ccc(N)c3ccccc23)ccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(CCOc3ccnc(N)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.4 %

Procedure:
To a suspension of CDI (122 mg, 0.752 mmol) in DCM (2 mL) was added a solution of 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine (172 mg, 0.752 mmol) in DCM (2.0 mL) and the reaction mixture was stirred at RT for 16 hr. An aliquot (1.0 mL) of this reaction mixture was added to a stirred suspension of 4-(2-(4-aminonaphthalen-1-yl)ethoxy)pyridin-2-amine (34) (42 mg, 0.150 mmol) in DCM (2.0 mL). THF (0.5 mL) was added and the reaction mixture was stirred for 1 hr. A second aliquot (1.0 mL) of the CDI reaction mixture was added and the mixture was stirred for a further 20 hr at RT. Methanol was added and stirring continued for 30 min. The solvent was evaporated and the residue was purified by flash column chromatography (SiO2, 0-5% MeOH in DCM, gradient elution). The resulting impure product was dissolved in ethyl acetate, washed with water and brine, dried (MgSO4) and evaporated in vacuo to afford the title compound (Intermediate F) (42 mg, 52%); m/z 535 (M+H)+, (ES+).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:26])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:8][CH:7]=[CH:6][CH:5]=2.C(N(C(C)C)CC)(C)C.[CH2:36]([O:38][CH2:39]Cl)[CH3:37]>ClCCl>[CH2:36]([O:38][CH2:39][O:1][C:2]1[C:3](=[O:26])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:23])[CH3:24])=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH3:37]
Reactant: C[Si](C)(C)CCCCCCCCCC1=C(O)C(=O)c2ccccc2C1=O
Reactant: CCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOCOC1=C(CCCCCCCCC[Si](C)(C)C)C(=O)c2ccccc2C1=O
Reaction time: 0.05 h

Procedure:
To a stirred solution of 2-hydroxy-3-(9-trimethylsilylnonyl)-1,4-naphthoquinone, Example 12, (500 mg, 2.06 mmol) in dry dichloromethane (20 ml) at room temperature was added diisopropylethylamine (1.33 g, 10.3 mmol) and, after 3 minutes, ethoxymethyl chloride (831 mg, 10.3 mmol) in dichloromethane (5 ml). The reaction was stirred for 1 h before diluting with dichloromethane (30 ml), washing with water (2×20 ml), dilute hydrochloric acid (20 ml), saturated sodium chloride solution (20 ml) and drying (MgSO4). Filtration and evaporation of the solvent under reduced pressure and chromatography, eluent hexane/ether, gave 2-ethoxymethoxy-3-(9-trimethylsilylnonyl)-1,4-naphthoquinone (567 mg), nD 1.5182. NMR peaks at: 185.3, 181.6, 155.5, 137.1, 133.8, 133.2, 132.0, 131.4, 126.3, 126.2, 33.6, 30.1, 29.5, 29.4, 29.3, 28.9, 24.1, 23.9, 16.7, -1.6; 96.9, 65.8, 15.0 (O--CH2 --O--CH2CH3).
Reaction SMILES: [OH-].[K+].[CH:3]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[S:18]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH2:27][N:26](C(=O)C(F)(F)F)[CH2:25][CH2:24]4)(=[O:20])=[O:19])=[C:13]([F:46])[CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1>C(O)C.O>[CH:3]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=3)[S:18]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH2:27][NH:26][CH2:25][CH2:24]4)(=[O:19])=[O:20])=[C:13]([F:46])[CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COc1ccc(CN(c2ccc(OCCC3CCCC3)cc2F)S(=O)(=O)c2ccc3c(c2)CCN(C(=O)C(F)(F)F)C3)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(CN(c2ccc(OCCC3CCCC3)cc2F)S(=O)(=O)c2ccc3c(c2)CCNC3)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
An aqueous solution (1 mL) of potassium hydroxide (29 mg, 0.51 mmol) was added to a solution of N-[4-(2-cyclopentylethoxy)-2-fluorophenyl]-N-(4-methoxybenzyl)-2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide obtained (163 mg, 0.26 mmol) in ethanol (4 mL), and the mixture was stirred at room temperature for 15 hr. The mixture was diluted with water and extracted with chloroform. The organic layer was concentrated under reduced pressure to afford the title compound as a colorless oil (145 mg).
Reaction SMILES: [C:1]([PH:4](=[O:6])[O-:5])(=O)[CH3:2].[Na+:7].[NH2:8][CH2:9][CH2:10][CH2:11][NH2:12].C1(C)C=CC=CC=1>C(O)C>[CH3:2][C:1]1([P:4]([O-:6])[O-:5])[NH:12][CH2:11][CH2:10][CH2:9][NH:8]1.[Na+:7].[Na+:7]
Reactant: NCCCN
Reactant: CC(=O)[PH](=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(P([O-])[O-])NCCCN1

Procedure:
Sodium acetylphosphinate (2.6 g, 0.02 mol) and 1,3-diaminopropane (1.7 ml, 1.5 g, 0.02 mol) were stirred together in ethanol (60 ml) for 21/2 days, giving a cloudy pale yellow solution. This was evaporated inder reduced pressure, giving a sticky hydroscopic yellow solid, which contains ethanol by nmr. The solid was dissolved in ethanol, toluene added and re-evaporated to dryness, giving a yellow foam, mp 144°-6°, decomp (3.2 g, 86%). NMR was consistent with the desired structure.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[F:8][C:9]1[CH:33]=[C:32]([Br:34])[CH:31]=[CH:30][C:10]=1[CH2:11][N:12]1[N:21]=[C:20]([CH2:22][C:23]([O:25]CC)=[O:24])[C:19]2[C:14](=[C:15]([F:28])[CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:29]>O1CCOCC1>[F:8][C:9]1[CH:33]=[C:32]([Br:34])[CH:31]=[CH:30][C:10]=1[CH2:11][N:12]1[N:21]=[C:20]([CH2:22][C:23]([OH:25])=[O:24])[C:19]2[C:14](=[C:15]([F:28])[CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:29]
Reactant: CCOC(=O)Cc1nn(Cc2ccc(Br)cc2F)c(=O)c2c(F)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)Cc1nn(Cc2ccc(Br)cc2F)c(=O)c2c(F)cccc12
Yield: 53.4 %

Procedure:
A mixture of potassium carbonate (1.5 g.), water (16 ml.), dioxan (50 ml.) and ethyl 2-(2-fluoro-4-bromobenzyl)-8-fluoro-1,2-dihydro-1-oxophthalazin-4-ylacetate (1.0 g.) was heated under reflux for 24 hours, and then evaporated. The residue was dissolved in water (100 ml.) and the solution washed with ether (2×100 ml.). The aqueous phase was acidified to pH 2 by addition of concentrated hydrochloric acid. The solid which formed was collected by filtration, washed with water, and recrystallised from a 7:1:5 v/v/v mixture of toluene/isopropanol/petrol (60-80) to give 2-(2-fluoro-4-bromobenzyl)-8-fluoro-1,2-dihydro-1-oxophthalazin-4-ylacetic acid (Example 36) (0.5 g.), m.p. 173°-175° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH:7]([CH3:12])[C:8]([F:11])([F:10])[F:9])[C:3]([OH:5])=[O:4].Cl.C(O)C.C(N([CH2:22][CH3:23])CC)C.[C:24](=O)([O:30]C(C)(C)C)[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>ClCCl.O>[C:26]([O:25][C:24]([NH:1][CH:2]([CH2:6][CH:7]([CH3:12])[C:8]([F:9])([F:10])[F:11])[C:3]([O:5][CH2:22][CH3:23])=[O:4])=[O:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CC(CC(N)C(=O)O)C(F)(F)F
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(CC(C)C(F)(F)F)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 12 h
Yield: 65.2 %

Procedure:
To 2-amino-5,5,5-trifluoro-4-methylpentanoic acid (50 mg, 0.270 mmol) in a flask was added hydrochloric acid 2N in ethanol (1350 μl, 5.40 mmol). The solution was refluxed at 80° C. for 5 h. After cooling, the ethanol was removed under reduced pressure. The residue was triturated with diethyl ether (2×). The solid so obtained (60 mg, 0.240 mmol) was taken up in dichloromethane (5 mL). To this suspension cooled to 0° C. was added triethylamine (0.167 mL, 1.202 mmol) and di-tert-butyl carbonate (0.054 mL, 0.312 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford ethyl 2-((tert-butoxycarbonyl)amino)-5,5,5-trifluoro-4-methylpentanoate (55 mg, 0.176 mmol, 73% crude yield) as a white solid. The material was carried on without further purification. GCMS (ESI) m/e 212 [(M)−, calcd for C8H13F3NO2 212] GC/MS (Method: Agilent GCMS Module-7890 (GC) 5975 C (MSD) HP-5MS, 30 m×0.25 mm ID×0.25 u Film thickness 0.9 mL/min at constant flow of Helium) retention time tR=6.38 min.
Reaction SMILES: OC[C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].[OH2:10].[C:11]1([CH3:21])C=CC(S(O)(=O)=O)=C[CH:12]=1>>[CH3:12][C:11]1([CH3:21])[O:9][CH2:8][C:3]([CH3:7])([C:4]([OH:6])=[O:5])[O:10]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(CO)(CO)C(=O)O
Reactant: O
Product: CC1(C)OCC(C)(C(=O)O)O1
Reaction time: 6 h
Yield: 416.3 %

Procedure:
To 1.34 g of 3-hydroxyl-2-hydroxymethyl-2-methylpropionic acid and 13 ml of acetonedimethylacetal was added 95 mg of p-toluenesulfonic acid monohydrate at room temperature, and the mixture was stirred for 6 hours. Further added thereto was 95 mg of p-toluenesulfonic acid monohydrate, and the mixture was stirred overnight. The solution was concentrated and poured into water and extracted. The aqueous layer was extracted with chloroform. The combined organic layers were washed with saturated brine, dried, and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=19:1), to give 333 mg of 2,2,5-trimethyl-[1,3]dioxolane-5-carboxylic acid as shown in Table 132 below.
Reaction SMILES: [O:1]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:22](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O[C:46](=[O:48])[CH3:47])(=O)C>N1C=CC=CC=1>[C:2]([O:4][C@@H:3]1[C@@H:5]([O:6][C:5](=[O:6])[CH3:7])[C@H:7]([O:8][C:46](=[O:48])[CH3:47])[C@@H:9]([CH2:11][O:12][C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:10][C@H:2]1[O:1][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)(=[O:1])[CH3:3]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Oc2ccc([N+](=O)[O-])cc2)O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1OC(C)=O
Temperature: 40 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
In a 100-ml round-bottomed flask, 1.42 g of p-nitrophenyl β-D-glucopyranoside and 1.5 g of anhydrous trityl chloride are introduced into 10 ml of anhydrous pyridine, and the flask is left in the dark with stirring at 40° C. The reaction is followed by TLC, adding trityl chloride if necessary. After 24 hours, the flask is brought to room temperature and 6 ml of acetic anhydride are added. The reaction medium is left for 48 hours with stirring, the reaction being followed by TLC (silica gel, ether/petroleum ether, 7:3); it is taken up in 500 ml of ice-cold water and stirred for 2 hours. The mixture is then filtered through celite and the celite is rinsed with dichloromethane. The organic phase is washed successively with ice-cold water, 10% strength hydrochloric acid, saturated aqueous sodium bicarbonate solution and then ice-cold water. It is dried over sodium sulphate and concentrated under vacuum at 35° C. The residue is chromatographed on a column of silica, eluting with a 7:3 ether/petroleum ether mixture. The fractions containing the heteroside are combined and concentrated under vacuum at 35° C. 2.6 g of an oil are obtained (yield=83%), the product being pure in TLC: silica gel, ether/petroleum ether (7:3), Rf=0.33.
Reaction SMILES: N1[C:6]([C:7](OCC)=O)=[N:5][C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:3][C:2]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[Cl-].[NH2:23]C(=[NH2+])C>CN(C=O)C>[CH2:15]([O:14][C:12]([C:4]1[N:3]=[C:2]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7]([NH2:23])=[CH:6][N:5]=1)=[O:13])[CH3:16]
Reactant: CC(N)=[NH2+]
Reactant: CCOC(=O)c1nc(C(=O)OCC)nc(C(=O)OCC)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncc(N)c(C(=O)OCC)n1
Temperature: 100 °C

Procedure:
To a stirred solution of triethyl 1,3,5-triazine-2,4,6-tricarboxylate (J. Org. Chem. 59, 4950, 1994) (2.02 g, 6.80 mmol.) in DMF (15 mL) is added 1-aminoethaniminium chloride (1.29 g, 13.60 mmol). After the addition, the mixture is heated at 100° C. for 18 hours then the mixture is extracted three times with ethyl acetate. The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (heptane/ethyl acetate=3:1) to give diethyl-aminopyrimidine-2,4-dicarboxylate; HPLC Retention time 0.89 minutes (condition C); MS 240.3 (M+1).