Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:9]([NH:11][CH2:12][CH2:13][N:14]([CH2:34]COC)[CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=O)C1C=CC=CC=1>[Pd].CO>[CH3:34][N:14]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:13][CH2:12][NH:11][CH3:9]
Reactant: COCCN(CCNC(=O)OCc1ccccc1)CCOCCOCCOCCNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CNCCN(C)CCOCCOCCOCCNC(=O)OC(C)(C)C
Yield: 105.8 %

Procedure:
tert-Butyl N-[2-[2-[2-[2-[2-(benzyloxycarbonylamino)ethyl-(2-methoxyethyl)amino]-ethoxy]ethoxy]ethoxy]ethyl]carbamate (2.99 g,) and palladium on carbon (10%, wet, 0.6 g) in methanol (30 mL) were stirred under a hydrogen atmosphere (balloon) for 2 hours. The mixture was filtered through celite and evaporated to give product as an oil (2.18 g, quantitative).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].C(=O)([O-])O.[Na+]>CC(C)=O>[CH3:2][C:3]1([CH3:5])[O:4][C@@H:3]([C@H:5]2[O:6][C@@H:11]3[O:12][C:9]([CH3:11])([CH3:7])[O:10][C@@H:9]3[C@H:7]2[OH:8])[CH2:2][O:1]1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)[C@H](O)[C@H]2O1
Reaction time: 9 h
Yield: 171.7 %

Procedure:
To 250 ml of acetone were added 10.0 g of D-glucose and 125 mg of anhydrous cupric chloride, and the mixture was stirred for 9 hours under reflux in a warm-water bath at 57° to 58° C. The refluxing solvent was continuously dried with 20 g of molecular sieves 3A which was placed between the reaction vessel and the cooling tube. After the conclusion of the reaction, a small amount of aqueous sodium hydrogencarbonate was added to the reaction mixture, and the acetone was distilled off under reduced pressure. The residue was dissolved in benzene, and the benzene solution was washed with aqueous sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. When the benzene was distilled off under reduced pressure, there was obtained 12.4 g (86%) of 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose (purity of not less than 97%). The compound, when recrystallized from a solvent mixture of chloroform-hexane (1:2), showed a melting point of 107° to 109° C.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:26][CH2:25][C:8]2([C:12](=[O:13])[N:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[Li]CCCC.Br[CH2:33][CH2:34][CH2:35][C:36](Cl)=[O:37]>C1COCC1>[O:37]1[CH2:36][CH2:35][CH2:34]/[C:33]/1=[CH:1]/[S:2]([N:5]1[CH2:6][CH2:7][C:8]2([C:12](=[O:13])[N:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)[CH2:25][CH2:26]1)(=[O:4])=[O:3]
Reactant: O=C(Cl)CCCBr
Reactant: CS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)/C=C1/CCCO1)CC2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 25.1 %

Procedure:
To a solution of 8-methanesulfonyl-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 208, step A) (50 mg, 13 mmol) in THF (3 mL) at −78° C. was added nBuLi (1.6M solution in heptane, 80 uL, 13 mmol), and the reaction mixture was stirred at −78° C. for 10 mins. Then a solution of 4-bromo-butyryl chloride (15 uL 0.13 mmol) in THF (1 mL) was added and the reaction mixture was stirred for a further 30 mins at −78° C. and then another 2 equivalents of nBuLi were added and the reaction mixture was warmed to room temperature. The reaction was quenched with water and extracted with ethyl acetate. The organic phases were combined, dried (Na2SO4), filtered and concentrated in vacuo to give a crude residue was purified by flash column chromatography (4:1 AcOEt/heptane) to yield 8-[dihydro-furan-(2Z)-ylidenemethanesulfonyl]-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (15 mg, 26%) as a white solid. MS (ESI): 461.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[CH3:19])=[CH:16]/[CH2:17][OH:18])=[CH:11][CH:10]=1.[CH2:20]([O:22][C@@H:23]([CH2:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:21]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12](/[C:15](/[CH3:19])=[CH:16]/[CH2:17][O:18][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][C@H:23]([O:22][CH2:20][CH3:21])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:35][CH:34]=2)=[CH:11][CH:10]=1
Reactant: C/C(=C\CO)c1ccc(-c2cccc(Cl)c2Cl)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cccc(Cl)c3Cl)cc2)cc1)OCC
Yield: 79.9 %

Procedure:
The title compound (0.41 g, 80% yield) was prepared from (E)-3-(2′,3′-dichloro-biphenyl-4-yl)-but-2-en-1-ol (0.293 g, 1.0 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.25 g, 1.05 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH2:22]([NH:24][C:25]([C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[CH:30]2)=[O:26])[CH3:23]>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:32]3[C:33]4[C:29](=[CH:28][C:27]([C:25](=[O:26])[NH:24][CH2:22][CH3:23])=[CH:35][CH:34]=4)[CH:30]=[CH:31]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCNC(=O)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: CCNC(=O)c1ccc2c(ccn2-c2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-6) and N-ethyl-1H-indole-5-carboxamide (intermediate-15).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([CH3:3])[CH3:2].[OH-].[K+].[I:15]I.[O-]S([O-])=O.[Na+].[Na+]>CS(C)=O>[I:15][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=2)[NH:9][N:8]=1
Reactant: CC(C)c1ccc2[nH]ncc2c1
Reactant: II
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)c1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.4 %

Procedure:
To a stirred solution containing mainly 5-isopropyl-1H-indazole (0.85 g, crude) in 70 mL of DMSO was added KOH (0.52 g, 8 mmol) at room temperature. Then I2 (1.35 g, 5.3 mmol) was added slowly, after the addition, the mixture was stirred at room temperature for 2 hours. The mixture was poured into 200 mL of saturated Na2SO3 solution, then extracted with ethyl acetate (2×100 mL). The combined organic layers was washed with water (100 mL) and brine (100 mL) dried over Na2SO4 and concentrated under reduced pressure to give crude 3-iodo-5-isopropyl-1H-indazole (0.78 g). LCMS: (M+H)+=287.
Reaction SMILES: [N:1]1([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]3[CH:18]=[N:19][C:20]([C:21]([OH:23])=O)=[C:10]3[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClCCl.C(P(=O)([O-])OCC)#N.Br.Br[CH2:37][CH2:38][NH2:39]>C(N(CC)CC)C>[O:23]1[CH2:37][CH2:38][N:39]=[C:21]1[C:20]1[N:19]=[CH:18][N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([C:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[O:7])[CH2:9][C:10]=12
Reactant: O=C(O)c1ncn2c1CN(C(=O)N1CCCC1)c1ccccc1-2
Reactant: NCCBr
Agent: Br
Agent: CCOP(=O)([O-])C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N1CCCC1)N1Cc2c(C3=NCCO3)ncn2-c2ccccc21
Reaction time: 0.67 h

Procedure:
To a mixture of 4,5-dihydro-5-[(pyrrolidino)carbonyl]imidazo[1,5-a]quinoxaline-3-carboxylic acid (I, EXAMPLE 322, 1.03 g) and 25 ml of dichloromethane cooled at 0° in an ice bath are added 1.15 ml of triethylamine and 0.650 ml) of ethyl cyanophosphonate, followed immediately by 0.811 g of 2-bromoethylamine hydrobromide. The ice bath is then removed and the reaction is stirred for 40 min. Aqueous sodium bicarbonate is then added. The mixture is stirred for 10 min and then partitioned with dichloromethane. The organic layers are dried over sodium sulfate and concentrated. The resulting mixture is stirred in 20 ml of THF and 3.3 ml of 1M potassium tert-butoxide is added dropwise over 2-3 min and the reaction is stirred an additional 10 min, at which time the reaction mixture is partitioned between ethyl acetate, water, and saline. The organic layers are dried over magnesium sulfate and concentrated. The crude product is chromatographed on silica gel (300 ml) eluting with methanol/methylene chloride (4/96), the appropriate fractions are pooled and concentrated to give the title compound, mp 217°-220°; MS (m/z) at 337; IR (mineral oil) 1651, 1512, 1416, 1357, 1396 cm-1 ; NMR (CDCl3) 1.81, 3.27, 4.05, 4.42, 4.99, 7.11-7.18, 7.26, 7.51, 8.03 δ.
Reaction SMILES: C([Si](C)(C)[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[CH:8]=[CH:7]1)(C)(C)C.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)[N:21]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:33][C:31]1([CH3:34])[CH2:32][CH:27]([NH:26][C:22]2[N:21]=[C:20]([C:8]3[C:9]4[C:14](=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=4)[NH:6][CH:7]=3)[CH:25]=[CH:24][N:23]=2)[CH2:28][C:29]([CH3:36])([CH3:35])[NH:30]1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2ccc(C#N)cc21
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4cc(C#N)ccc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared as described in Example 215, starting from 1-(tert-butyl-dimethyl-silanyl)-1H-indole-6-carbonitrile (prepared by TBDMS protection of 1H-indole-6-carbonitrile) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by in situ cleavage of the TBDMS protecting group with catalytic amounts of TBAF.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH:9]=[O:10].[BH4-].[Na+].Cl>C(O)C>[CH3:1][N:2]([CH3:11])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][OH:10]
Reactant: CN(C)c1ccncc1C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccncc1CO
Reaction time: 4 h
Yield: 72.4 %

Procedure:
A solution of 4-dimethylaminopyridine-3-carboxaldehyde (J. Het. Chem, 25, 81) (1.5 g) in ethanol (25 ml) was treated with sodium borohydride (200 mg) and the mixture was stirred for 4 hours. Concentrated hydrochloric acid (1 ml) was added and the mixture was concentrated. The residue was treated with saturated aqueous sodium chloride (40 m) and concentrated aqueous sodium hydroxide (2 ml) and the mixture was extracted with dichloromethane (4×20 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (40 ml), dried (PS paper) and concentrated. The residue was dissolved in methanol, treated with decolourising charcoal, filtered and concentrated to give 4-dimethylaminopyridine-3-methanol (1.1 g) as a pale yellow oil. NMR: (d6DMSO): δ 2.9 (6H,s); 4.5(2H,s); 4.0-4.8(1H,br.s); 6.7(1H,d); 8.15(1H,d); 8.3(1H,s); m/e 153 (M+H)+ ; 135(M+H-H2 O)+.
Reaction SMILES: [Li:1]CCCC.[C:6](=[NH:13])([N:10]([CH3:12])[CH3:11])[N:7]([CH3:9])[CH3:8]>C1(C)C=CC=CC=1>[C:6](=[N:13][Li:1])([N:10]([CH3:12])[CH3:11])[N:7]([CH3:9])[CH3:8]
Reactant: [Li]CCCC
Reactant: CN(C)C(=N)N(C)C
Solvent: Cc1ccccc1
Product: [Li]N=C(N(C)C)N(C)C
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
BuLi (1.6 M in hexane, 6.25 mL, 10 mmol) was added to a toluene solution (˜15 mL) of (Me2N)2C═NH (1.151 g, 10 mmol) at −78° C. The solution was warmed to 23° C. in 10 minutes and was further stirred for 30 minutes to give a toluene solution of (Me2N)2C═NLi (10 mmol).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=O)C.[CH3:26][C:27]([Si:30]([CH3:48])([CH3:47])[O:31][CH:32]1[CH:36]([CH2:37][O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:35]([OH:46])[CH:34]=[CH:33]1)([CH3:29])[CH3:28].C(OCC)(=O)C>C(Cl)Cl.C(#N)C>[CH3:29][C:27]([Si:30]([CH3:48])([CH3:47])[O:31][C@@H:32]1[C@@H:36]([CH2:37][O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:35](=[O:46])[CH:34]=[CH:33]1)([CH3:26])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OC1C=CC(O)C1COCc1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CC#N
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1C=CC(=O)[C@@H]1COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a 250-mL 3-necked flask, oven dried and equipped with a mechanical stirrer was charged with pyridinium dichromate (20.24 g, 53.80 mmol), molecular sieves (oven dried) and DCM (40 mL). The resulting slurry was cooled to 0° C. and to this slurry, acetic acid (which had been dried over molecular sieves, 1.61 g, 26.90 mmol) was charged. The resulting mixture was stirred for 30 minutes at 0° C. 9 (10 g, 29.89 mmol) in DCM (10 mL) was added to the reaction mixture over a period of 10 minutes. The resulting reddish colored reaction mixture was stirred for 2 hours at 0° C. After the reaction was completed, ethyl acetate (100 mL), acetonitrile (5 mL), and diatomaceous earth (Celite®, 5 g) were added sequentially, and the resulting mixture was stirred for 10 minutes. The slurry was filtered on a bed of diatomaceous earth (Celite®) to give a dark colored filtrate. The filtrate was washed with 5% aqueous NaHSO3 (2×250 mL) followed by water (100 mL). The organic layer was dried over magnesium sulfate and the solvent was concentrated in vacuo to give 9.5 g of the title compound as a dark transparent, brown oil.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([O:24][CH2:25][CH2:26]Cl)[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:28][C:29]1[CH:30]=[C:31]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH:32]=[CH:33][C:34]=1[NH:35][CH2:36][CH3:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=[O:47])C.[Na+].[OH-].[Na+].Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CO.CN(C=O)C>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([O:24][CH2:25][CH2:26][OH:47])[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:28][C:29]1[CH:30]=[C:31]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH:32]=[CH:33][C:34]=1[NH:35][CH2:36][CH3:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCCl)cc3N2C)C(=O)N1Cc1ccccc1
Reactant: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCO)cc3N2C)C(=O)N1Cc1ccccc1
Temperature: 75 °C
Yield: 5.3 %

Procedure:
To an 8 mL vial was added the product of Example 145 (100 mg, 0.15 mmol), anhydrous DMF (5 mL), and tetra-n-butylammonium iodide (570 mg, 1.54 mmol). The solution was heated at 75° C. for 4 h prior to the addition of sodium acetate (250 mg, 3.08 mmol). The reaction solution was then heated 16 h at 75° C. To the solution was added MeOH (2 mL), 5M aqueous NaOH (1 mL) and H2O (1 mL). After heating at 50° C. for 5 h, the reaction mixture was cooled, neutralized with conc HCl and concentrated under reduced pressure. The residue was taken up into DCM (50 mL), and the organic phase was washed with water (2×25 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was chromatographed (SiO2, 0–10% MeOH/DCM) to provide the title compound (5 mg, 5%). 1H NMR (MeOH-d4): δ 8.92 (1H, s), 7.11–7.26 (7H, m), 6.97 (1H, dd), 6.66 (1H, dd), 6.60 (1H, d), 6.44 (1H, d), 5.01 (2H, s), 3.96 (2H, t), 3.77 (2H, t), 3.62 (3H, s), 3.00 (2H, s), 2.82 (2H, q), 2.28 (6H, s), 0.89 (3H, t); MS(ESI) 633(MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:12]=[CH:11][O:10][C:9]=2[CH3:13])[CH:5]=[CH:4][N:3]=1.[CH3:14][C@H:15]1[O:20][C@@H:19]([CH3:21])[CH2:18][NH:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:21][C@H:19]1[O:20][C@@H:15]([CH3:14])[CH2:16][N:17]([C:2]2[N:7]=[C:6]([C:8]3[CH:12]=[CH:11][O:10][C:9]=3[CH3:13])[CH:5]=[CH:4][N:3]=2)[CH2:18]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: Cc1occc1-c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1occc1-c1ccnc(N2C[C@@H](C)O[C@@H](C)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.7 %

Procedure:
2-Chloro-4-(2-methyl-3-furanyl)pyrimidine (686 mg, 3.52 mmol), cis-2,6-dimethylmorpholine (447 mg, 3.88 mmol) and potassium carbonate (536 mg, 3.88 mmol) were added together in ethanol (16 mL) and the resulting mixture was heated under reflux for 4 hours. A further quantity of cis-2,6-dimethylmorpholine (122 mg, 1.057 mmol) and potassium carbonate (146 mg, 1.057 mmol) were added and the resulting mixture was heated under reflux for 4 hours. The reaction mixture was allowed to cool to room temperature and left to stand overnight. The reaction mixture was filtered, the filtrate evaporated under reduced pressure and the residue purified by SP4 Biotage column chromatography eluting with a gradient of 0-30% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound (737 mg, 2.70 mmol, 76% yield) as a colourless oil. LC/MS [M+H]+=274.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:6][NH:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH2:3]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:39][C:40](O)=[O:41])[CH:25]=[CH:26][C:27]=1[NH:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH3:38])=[O:30].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[F:19][C:2]1([F:1])[CH2:6][N:5]([C:40](=[O:41])[CH2:39][C:24]2[CH:25]=[CH:26][C:27]([NH:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])=[O:30])=[C:22]([O:21][CH3:20])[CH:23]=2)[CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH2:3]1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)c1ccc(OCC2CC(F)(F)CN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC2CC(F)(F)CN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A mixture of methyl 4-(4,4-difluoro-2-pyrrolidinylmethoxy)benzoate (540 mg, 1.99 mmol), 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (626 mg, 1.99 mmol), EDC.HCl (572 mg, 2.99 mmol), HOBt (cat.), and DMAP (cat.) in DMF (10 ml) was stirred overnight. The mixture was diluted with EtOAc (300 ml), washed with brine (2×100 ml), dried over MgSO4, and concntrated in vacuo. The residue was chromatographed on silica gel with CHCl3—MeOH (20:1) as eluent to give methyl 4-[4,4-difluoro-1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]benzoate (1.00 g, 89%) as a colorless foam. 1H-NMR (CDCl3) δ2.31 (s, 3 H), 2.47-2.63 (m, 2 H), 3.52-3.97 (series of s and m, total 10 H), 4.07-4.30 (m, 2 H), 4.67-4.69 (m, 1 H), 6.45 (s, 1 H), 6.65 (d, J=1.7 Hz, 1 H), 6.74-6.76 (m, 1 H), 6.84 (d, J=8.8 Hz, 2 H), 7.14 (m, 2 H), 7.24 (m, 2 H), 7.52-7.54 (m, 1 H), 7.94 9d, J=8.8 Hz, 2 H), 8.09 (d, J=8.1 Hz, 1 H).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C@@H:3]([C:13]([OH:15])=[O:14])[NH:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[O:6].C(O)CCC#C>>[CH3:1][C:2]([CH3:17])([CH3:16])[C@@H:3]([C:13]([OH:15])=[O:14])[NH:4][C:5]([O:7][CH2:8][CH2:9][CH2:10][C:11]#[CH:12])=[O:6]
Reactant: C=CCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: C#CCCCO
Product: C#CCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C

Procedure:
3-Methyl-N-[(pent-4-yn-1-yloxy)carbonyl]-L-valine was prepared according to the procedure for 3-methyl-N-[(pent-4-enyloxy)carbonyl]-L-valine by using pent-4-yn-1-ol instead of 4-pentenol. LRMS (ESI) m/z 242.2 [(M+H)+; calcd for C12H20NO4: 242.1].
Reaction SMILES: [C:1]([C@H:4]([C@@H:16]([CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:17]([N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18])[CH2:5][N:6]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[N:8]([CH3:14])[C:7]1=[O:15])([OH:3])=O.[OH:31][N:32]1C=CC=CC1=O.O1CCN(CC[N+]#[C-])CC1.C([O-])(=O)C.O[NH3+]>C(Cl)Cl.C(N(CC)CC)C>[CH:26]1([CH2:25][C@H:16]([C@@H:4]([C:1](=[O:3])[NH:32][OH:31])[CH2:5][N:6]2[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[N:8]([CH3:14])[C:7]2=[O:15])[C:17]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CN1C(=O)N(C[C@H](C(=O)O)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Reactant: O=c1ccccn1O
Agent: CC(=O)[O-]
Agent: [C-]#[N+]CCN1CCOCC1
Agent: [NH3+]O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)N(C[C@H](C(=O)NO)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Reaction time: 0.25 h
Yield: 82.4 %

Procedure:
30 g 1-[2(R)-[1(R)-carboxy-2-(3,4,4,-trimethyl-2,5-dioxo-1-imidazolidinyl)-ethyl]-3-cyclopentylpropionyl]piperidine and 8.71 g N-hydroxy-pyridone were dissolved in 120 ml CH2Cl2 in a 250 ml round bottom flask. The mixture was treated at r.t. with 10.73 g morpholinoethylisocyanide. After 10-20 min the mixture turned clear and stirring was continued at r.t. overnight. The solution was slowly added to a stirred suspension of 9.94 g hydroxylammonium acetate and 7.2 g triethylamine in 180 ml CH2Cl2 and the mixture was stirred for an additional 4 h. The reaction mixture contains about 97% product and about 3% starting material. This mixture was extracted with 95 ml water. The aqueous layer was extracted with 60 ml CH2Cl2 and the combined organic layers extracted twice with 95 ml (total 190 ml) 5% NaHCO3 solution and once with 95 ml 2% H2SO4 solution. The organic layer was evaporated at 35-40°. The oily residue was treated with 300 ml wet tert butyl methyl ether and evaporated to a volume of 200 ml and stirred for 10 hrs. The solid was filtered off, washed twice with 20 ml tert butyl methyl ether and dried under reduced pressure at r.t. yielding 25.6 g (82%) of pure 1-[3-cyclopentyl-2(R)-[1(R)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine MS (EI): 436, m.p. 120° dec.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[NH2:5].[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][OH:16].[OH-].[K+]>C1(C)C=CC=CC=1.O>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][O:16][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:4]([NH2:5])[CH:3]=1
Reactant: CN(C)CCO
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)CCOc1ccc([N+](=O)[O-])c(N)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 65.9 %

Procedure:
3-Fluoro-6-nitroaniline (0.7 g, 4.48 mmol) and N,N-dimethylethanolamine (1.34 mL, 13.45 mmol) were dissolved in toluene (5 mL). This solution was cooled at 0° C. and finely ground KOH (1.258 g, 22.4 mmol) was added to the stirring mixture. The reaction mixture was stirred for 16 hours at room temperature, diluted with H2O (30 mL) and then extracted with CHCl3 (3×25 mL). The combined organics were dried (Na2SO4), filtered and the solvent was removed in vacuo. Purification by SiO2 chromatography (0% to 10% 2.0M NH3 in MeOH/dichloromethane) gave 5-(2-dimethylamino-ethoxy)-2-nitro-phenylamine as a dark oil (0.665 g, 90%). MS(ESI) m/z 226.0 (M+H)+
Reaction SMILES: [I-:1].Cl[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[CH3:9].[NH:10]1[CH:14]=[CH:13][CH:12]=[N:11]1.C(N(C(C)C)CC)(C)C>C(#N)C>[I-:1].[CH3:9][N+:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1
Reactant: C[n+]1ccccc1Cl
Reactant: c1cn[nH]c1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[n+]1ccccc1-n1cccn1
Reaction time: 8 h

Procedure:
2-Chloro-1-methylpyridinium iodide (5.0 g), pyrazole (1.3 g) and diisopropylethylamine (2.5 g) were added to acetonitrile (50 ml) and the mixture refluxed for 3.5 hours. The acetonitrile was removed and the residue dissolved in hot ethanol. The solution was left in the refrigerator overnight. The product was collected by filtration Yield, 1.73 g; mp 129°-130° C.