Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[N:7]=[C:8]([Sn](CCCC)(CCCC)CCCC)[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]=2[S:4][C:3]=1[CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]([CH3:42])([CH3:41])[C:38]([NH2:40])=[O:39])[CH2:33][CH2:32]1.C(OC([N:50]1[C:54]2=[N:55][CH:56]=[CH:57][C:58](Br)=[C:53]2[CH:52]=[CH:51]1)=O)(C)(C)C>C1(C)C=CC=CC=1.[Cu]I>[CH3:42][C:37]([N:34]1[CH2:35][CH2:36][N:31]([CH2:30][C:3]2[S:4][C:5]3[C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[N:9][C:8]([C:58]4[CH:57]=[CH:56][N:55]=[C:54]5[NH:50][CH:51]=[CH:52][C:53]=45)=[N:7][C:6]=3[C:2]=2[CH3:1])[CH2:32][CH2:33]1)([CH3:41])[C:38]([NH2:40])=[O:39]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)c(C)c2n1
Reactant: CC(C)(C)OC(=O)n1ccc2c(Br)ccnc21
Agent: [Cu]I
Solvent: Cc1ccccc1
Product: Cc1c(CN2CCN(C(C)(C)C(N)=O)CC2)sc2c(N3CCOCC3)nc(-c3ccnc4[nH]ccc34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
A mixture of 2-[4-(7-methyl-4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (200 mg, 0.28 mmol), 4-bromo-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butylester (100 mg, 0.34 mmol), Pd(Ph3)4 (33 mg, 0.028 mmol) and CuI (65 mg, 0.34 mmol) in toluene (5 mL) was purged with argon, then subjected to microwave irradiation at 140° C. for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The residue was then dissolved in DCM/TFA (8 mL/8 mL) and stirred for 2 h at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH. The residue was purified by column chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 05:95) to give 696 as a white powder (0.036 g, 24%). LCMS (Method F): RT 5.68 min, [M+H]+ 535.2. 1H NMR (CDCl3, 400 MHz) δ 9.42-8.74 (m, 1 H); 8.59-7.95 (m, 1 H); 7.92-7.49 (m, 1 H); 7.46-7.35 (m, 2 H); 7.14-7.06 (m, 1 H); 5.27 (s, 1 H); 4.09 (t, J=4.2 Hz, 4); 3.92 (t, J=4.2 Hz, 4 H); 3.85 (s, 2 H); 2.66-2.61 (m, 4 H); 2.53 (s, 3 H); 1.63-1.58 (m, 4 H); 1.26 (s, 6 H)
Reaction SMILES: C(NC(C)C)(C)C.[Li].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].[Br:17][C:18]1[C:19]([F:29])=[C:20]([F:28])[C:21](F)=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24]>C1COCC1>[Br:17][C:18]1[C:19]([F:29])=[C:20]([F:28])[C:21]([NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[Cl:9])=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24]
Reactant: Nc1ccccc1Cl
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1F
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Reaction time: 0.17 h
Yield: 66.1 %

Procedure:
To a solution of lithium diisopropylamine (49.0 mL, 2 M in THF/heptane) in THF (40 mL) was added 2-chlorophenylamine (6.50 mL, 60.6 mmol) at −78° C. After vigorous stirring for 10 minutes, a solution of 5-bromo-2,3,4-trifluoro-benzoic acid (2) (7.70 g, 30.2 mmol) in THF (60 mL) was added. The dry-ice bath was removed and the reaction mixture stirred for 4 hours at room temperature. The mixture was concentrated, treated with 10% aqueous HCl (75 mL), and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification by trituration with boiling CH2Cl2 gave 7.24 g (66%) of the desired acid (3) as a yellow solid
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2.Cl[CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33].Cl>>[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:16]=[C:17]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33])[CH2:22][CH2:21]4)[S:18][CH:19]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCNCC4)n3)ccc21
Reactant: OCCOCCCl
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(C4CCN(CCOCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 100 mg (0.26 mmol) of 4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidine hydrochloride and 34 μl (0.31 mmol) of 2-(2-chloroethoxy)ethanol. The product is in the form of the hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@@H:4]([CH2:6][C:7]1[N:11]=[CH:10][NH:9][CH:8]=1)[NH2:5].N1C=CC=CC=1.CO.[C:21](=O)=[O:22].Cl>C(Cl)(Cl)Cl.CCOCC.CCCCCC>[CH3:1][O:2][C:3]([C@@H:4]1[NH:5][C:21](=[O:22])[N:11]2[CH:10]=[N:9][CH:8]=[C:7]2[CH2:6]1)=[O:12]
Reactant: COC(=O)[C@H](N)Cc1c[nH]cn1
Reactant: O=C=O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)[C@H]1Cc2cncn2C(=O)N1
Reaction time: 0.25 h

Procedure:
1.7 g (10 mmol) of D-histidine methyl ester and 1.58 g (20 mmol, 1.61 ml) of distilled pyridine are dissolved in 50 ml of absolute chloroform, cooled to -40° to -50° C. with methanol/dry ice, and, at this temperature, a weak stream of HCl-free phosgene is introduced for 15 minutes. The mixture is stirred for 15 minutes in the cold state and poured into 200 ml of cold ether/hexane (2:1). A white, deliquescent precipitate is obtained which is quickly suctioned off and washed with ether. The precipitate is taken up in 100 ml of 1N Na2CO3 solution and extracted six times with chloroform. After drying of the organic phase over sodium sulfate, the solvent is removed by evaporation; any present traces of pyridine are removed under a high vacuum. The compound is crystallized from methanol.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH2:5][CH2:4][O:3]1.[OH-:13].[Na+].Cl.C(Cl)(Cl)Cl>O.C(O)C>[OH:3][CH2:4][CH2:5][CH:6]([N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[C:2]([OH:13])=[O:1]
Reactant: O=C1OCCC1N1CCCC1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(O)C(CCO)N1CCCC1=O
Yield: 30.3 %

Procedure:
67.6 g (0.4 mol) of 1-(tetrahydro-2-oxo-3-furyl)-2-pyrrolidinone and 32 g (0.8 mol) of sodium hydroxide in 210 ml of water are heated for 2 hours under reflux, cooled and then acidified with hydrochloric acid to a pH value of 1. The reaction mixture is evaporated to dryness under reduced pressure and the residue taken up three times in benzene and evaporated in vacuo. The residue obtained is finally treated with a mixture of chloroform and ethanol (4:1 v/v) and the insoluble material filtered off. The filtrate is evaporated and the residue is recrystallized from ethanol. 22.7 g (yield: 30% of theory) of alpha-(2-hydroxyethyl)-2-oxo-1-pyrrolidineacetic acid are obtained. M.P.: 123°-124° C.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:55]([C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([F:63])[C:58]=1[OH:64])[CH3:56]>C(Cl)(Cl)Cl>[Br:1][C:61]1[CH:60]=[C:59]([F:63])[C:58]([OH:64])=[C:57]([CH2:55][CH3:56])[CH:62]=1
Reactant: [Br-]
Reactant: CCc1cccc(F)c1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)cc(F)c1O
Reaction time: 24 h
Yield: 57.8 %

Procedure:
A solution of tetrabutyl ammonium tribromide (4.2 g, 8.6 mmol) in CHCl3 (25 mL) was added to a stirred solution of 2-ethyl-6-fluoro-phenol (1.1 g, 7.9 mmol) dissolved in CHCl3 (25 mL). The reaction mixture was stirred for 24 hrs and then quenched with 5% solution of sodium thiosulfate (30 mL). The biphasic mixture was stirred for 30 mins and then the layers were separated. The organic layer was washed with 1N HCl, saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The crude residue was purified by flash column chromatography (0-10% EtOAc in hexanes) to give the desired product (1 g, 60%). 1H NMR (400 MHz, CDCl3): δ 1.21 (t, J=7.6 Hz, 3H), 2.65 (q, J=7.6 Hz, 2H), 5.09 (d, J=4.8 Hz, 1H), 7.06 (s, 1H), 7.09 (d, J=11.9 Hz, 1H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][NH:30][CH2:29][C@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:32][CH2:31][N:30]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:29][C@H:28]4[OH:33])=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC[C@H]1O
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)[C@H](O)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f16) and commercially methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[CH3:8][O:9][CH:10]([O:26][CH3:27])[CH2:11][CH2:12][CH2:13][NH:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][N:23]=2)[N:18]=[CH:17][C:16]=1[NH2:25].[OH-].[Na+]>ClCCl>[CH3:27][O:26][CH:10]([O:9][CH3:8])[CH2:11][CH2:12][CH2:13][N:14]1[C:15]2[C:24]3[N:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:25]=[C:5]1[CH2:4][O:3][CH2:1][CH3:2]
Reactant: COC(CCCNc1c(N)cnc2cccnc12)OC
Reactant: CCOCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOCc1nc2cnc3cccnc3c2n1CCCC(OC)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
Ethoxyacetyl chloride (4.2 mL, 37.4 mmol, 1.1 eq) was added dropwise over 8 minutes to a solution of N4-(4,4-dimethoxybutyl)[1,5]naphthyridine-3,4-diamine (9.50 g, 34.0 mmol) in dichloromethane (140 mL) and stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethanol (140 mL). Sodium hydroxide (6M) solution (8.5 mL, 51 mmol) was added to the reaction mixture, which was then heated for 60° C. for 3 hours. The mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (150 mL) and water (100 mL). The pH of the mixture was adjusted to 7 and the layers were separated. The aqueous layer was back-extracted with dichloromethane (2×50 mL) and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 10.52 g of 1-(4,4-dimethoxybutyl)-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridine.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[S:15]1[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16]1.[ClH:22].[OH-].[NH4+]>>[ClH:22].[ClH:22].[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]3[NH:13][C:20]([C:17]4[CH:18]=[CH:19][S:15][CH:16]=4)=[N:14][C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Nc1ccc(Cn2ccnc2)cc1N
Reactant: O=Cc1ccsc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: c1cn(Cc2ccc3[nH]c(-c4ccsc4)nc3c2)cn1
Reaction time: 36 h
Yield: 8.5 %

Procedure:
A mixture of 5 parts of 4-(1H-imidazol-1-ylmethyl)-1,2-benzenediamine, 3 parts of 3-thiophenecarboxaldehyde and 50 parts of a hydrochloric acid solution 3N was stirred for 36 hours at reflux temperature. After cooling, the mixture was poured into 100 parts of crushed ice and ammonium hydroxide. The product was extracted three times with 75 parts of trichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography (HPLC) over silica gel using a mixture of trichloromethane, methanol and ammonium hydroxide (90:10:0.1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 8 parts of 2-propanone and ethanol at 0° C. The salt was filtered off and crystallized from a mixture of methanol and 2-propanone. The product was filtered off and dried, yielding 0.8 parts (8.5%) of 5-(1H-imidazol-1-ylmethyl)-2-(3-thienyl)-1H-benzimidazole dihydrochloride; mp.>300° C. (dec.) (compound 205).
Reaction SMILES: NCCCNCCCCNCCCN.C([O-])(=[O:27])CCCCCCCCCCC.[Na+].[OH-].[Na+].CC(=CCC/C(=C/CO)/C)C.CCCCCCCCCCCCCCCC([O:60][CH2:61][CH:62]([OH:70])[C@H:63]1[O:67][CH2:66][C@H:65]([OH:68])[C@H:64]1[OH:69])=O>C(O)CCCCCCC>[O:27]=[CH:66][C@@H:65]([C@H:64]([C@@H:63]([C@@H:62]([CH2:61][OH:60])[OH:70])[OH:67])[OH:69])[OH:68]
Reactant: CCCCCCCCCCCC(=O)[O-]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O
Agent: CC(C)=CCC/C(C)=C/CO
Agent: NCCCNCCCCNCCCN
Agent: [Na+]
Solvent: CCCCCCCCO
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
A composition was prepared by dissolving human insulin with spermine and polyvinylpyrrolidone (PVP-40), sodium dodecanoate (SD) and methylcellulose (MC-400) in DDW containing NaOH. The solution was then lyophilized and suspended with octanol and geraniol in a mixture of medium chain triglyceride (MCT) oil and castor oil, further containing sorbitan monopalmitate (Span-40). Components and concentrations are detailed in Table 4.
Reaction SMILES: O1CCOCC1.[F:7][C:8]1[C:13](B(O)O)=[CH:12][C:11]([CH3:17])=[CH:10][N:9]=1.Cl[C:19]1[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH2:26])[N:20]=1.C([O-])(=O)C.[K+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:7][C:8]1[C:13]([C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH2:26])[N:20]=2)=[CH:12][C:11]([CH3:17])=[CH:10][N:9]=1
Reactant: Cc1nc(N)nc(Cl)n1
Reactant: Cc1cnc(F)c(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: C1COCCO1
Product: Cc1cnc(F)c(-c2nc(C)nc(N)n2)c1
Temperature: 120 °C
Yield: 41 %

Procedure:
1,4-Dioxane (3.00 mL, 8.5 mmol) was added to a mixture of bis(di-tert-butyl (4-dimethylaminophenyl)phosphine)dichloropalladium(II) (Aldrich, St. Louis, Mo.) (0.27 g, 0.43 mmol), 2-fluoro-5-methylpyridin-3-ylboronic acid (1.6 g, 10 mmol), 4-chloro-6-methyl-1,3,5-triazin-2-amine (1.24 g, 8.5 mmol) and potassium acetate (2.5 g, 26 mmol) and the mixture was sealed and heated at 120° C. for 30 min under microwave irradiation. After cooling, the mixture was passed through a short plug of Celite® (diatomaceous earth). The filter cake was washed with DCM (3×20 mL). The combined organic phases were concentrated. Flash column chromatographic purification (short column, SiO2, pure DCM to 5% MeOH in DCM) provided 4-(2-fluoro-5-methylpyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.76, 41%) as a white solid which was used for the next step. LCMS (API-ES) m/z 220 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([CH3:13])([C:7]1[O:8][C:9]([CH3:12])=[CH:10][CH:11]=1)[CH3:6].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH3:13][C:5]([C:7]1[O:8][C:9]([CH3:12])=[CH:10][CH:11]=1)([CH3:6])[CH2:4][CH2:3][OH:2]
Reactant: COC(=O)CC(C)(C)c1ccc(C)o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(C)CCO)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
Step D To a solution of 3-methyl-3-(5-methyl-furan-2-yl)-butyric acid methyl ester (1.5 g, 7.8 mmol) in anhydrous tetrahydrofuran (50 mL) at 0° C. was added a tetrahydrofuran solution (1 M) of LiAlH4 (10 mL, 10 mmol) under nitrogen. The reaction mixture was stirred at 0° C. for 1 h, then poured into a ice-water. The mixture was extracted with ethyl acetate. The organic layer were separated, washed with water, aqueous HCl solution, brine, dried over MgSO4, and concentrated to give 3-methyl-3-(5-methyl-furan-2-yl)-butan-1-ol as a yellow oil (1.2 g, 77%).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:13][CH:14]([CH3:35])[CH2:15][C:16]1([CH2:31][C:32](O)=[O:33])[CH2:20][C:19](=[O:21])[N:18]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:17]1=[O:30].Cl.[CH2:37]([O:44][NH2:45])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CN1CCOCC1>C(Cl)Cl>[CH2:37]([O:44][NH:45][C:32](=[O:33])[CH2:31][C:16]1([CH2:15][CH:14]([CH3:13])[CH3:35])[CH2:20][C:19](=[O:21])[N:18]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:17]1=[O:30])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)CC1(CC(=O)O)CC(=O)N(CCc2ccccc2)C1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)CC1(CC(=O)NOCc2ccccc2)CC(=O)N(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.5 %

Procedure:
CDI (153 mg, 0.945 mmol) is added to a mixture of 3-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-3-pyrrolidineacetic acid (300 mg, 0.945 mmol) and CH2Cl2 (7.5 mL) at room temperature. Afar stirring at room temperature for 1 hour, O-benzylhydroxylamine hydrochloride (181 mg, 1.13 mmol) and 4-methylmorpholine (124 μL, 1.13 mmol) are added to the solution. The mixture is allowed to stir overnight at room temperature. Basic workup (CH2Cl2, NaHCO3, MgSO4) and purification by column chromatography (1.5% MeOH/CHCl3) affordes 70 mg (18%) of the title compound as a white solid (mp 115°-117° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=2[CH3:16])[N:5]=[C:4]([S:17][CH2:18][C:19]([OH:21])=O)[N:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:35]([CH2:37][NH2:38])[OH:36]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=2[CH3:16])[N:5]=[C:4]([S:17][CH2:18][C:19]([NH:38][CH2:37][CH2:35][OH:36])=[O:21])[N:3]=1
Reactant: NCCO
Reactant: Cc1cccc(Nc2cc(Cl)nc(SCC(=O)O)n2)c1C
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc(Nc2cc(Cl)nc(SCC(=O)NCCO)n2)c1C

Procedure:
To the solution of [4-chloro-6-(2,3-xylidino)-2-pyrimidinyl-thio]-acetic acid (85 g.), triethylamine (45 ml.), in anhydrous chloroform (750 ml.), cooled to -5° C., 35 ml. of ethyl chlorocarbonate and then 22 ml. of ethanolamine were added with stirring while the temperature was kept below +10° C. The reaction mixture was washed with water (350 ml.), and dried over sodium sulphate and the solvent was removed under reduced pressure. The residue was washed with benzene (500 ml.) and crystallised several times from acetone. 55 g. of [4-chloro-6-(2,3-xylidino)-2-pyrimidinyl-thio]-(N-β-hydroxyethyl)-acetamide were obtained, identical with the compound prepared as in Example 1.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]([C:12](=[O:16])[CH2:13][CH:14]=[CH2:15])[C:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][C:8]=1[CH3:9])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([C:3]1[CH:4]([C:12](=[O:16])/[CH:13]=[CH:14]/[CH3:15])[C:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][C:8]=1[CH3:9])[CH3:2]
Reactant: C=CCC(=O)C1C(CC)=C(C)CCC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C/C=C/C(=O)C1C(CC)=C(C)CCC1(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.3 %

Procedure:
A suspension of 3.5 g (15.9 mmol) of 2-ethyl-3,6,6-trimethyl-1-[but-3-enoyl]-2-cyclohexene and 2.0 g of potassium carbonate in 40 ml of acetone is stirred at room temperature under nitrogen for 24 hours. The salt is removed by filtration and the filtrate concentrated. After fractional distillation, the residue yields 3.2 g (91.5%) of 2-ethyl-3,6,6-trimethyl-1-crotonoyl-2-cyclohexene; boiling point 59°-60° C/0.04 mm Hg; nD20 = 1.4952.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)(C)(C)C.C(N(CC)CC)C.ClCC(Cl)=O.[H-].[Na+].[C:32]([OH:38])([C:34](F)(F)F)=O>C(Cl)Cl.C1COCC1>[O:14]1[CH2:15][CH2:16][CH:11]([N:10]2[CH2:9][CH2:8][NH:7][CH2:34][C:32]2=[O:38])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NCCNC1CCOCC1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(Cl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CNCCN1C1CCOCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
To a solution of [2-(tetrahydro-pyran-4-ylamino)-ethyl]-carbamic acid tert-butyl ester (6.60 g, 27.0 mmol) in DCM (100 mL) was added triethylamine (11.3 mL, 81.1 mmol) followed by chloroacetyl chloride (3.64 g, 32.4 mmol) dropwise. The reaction mixture was stirred at RT for 24 h, then partitioned between DCM and saturated NaHCO3 aqueous solution. The organic layer was isolated, dried (Na2SO4) and concentrated in vacuo. To a solution of the resulting residue in THF (50 mL) was added sodium hydride (60% in mineral oil) (1.62 g, 40.6 mmol). The reaction mixture was stirred at RT for 20 h, then partitioned between DCM and water. The organic layer was dried (Na2SO4) and concentrated in vacuo to yield an orange residue. The residue (7.66 g, 27.0 mmol) was dissolved in dichloromethane (15 mL) and TFA (15 mL) was added. The resulting solution was stirred at RT for 4 h before being concentrated in vacuo. The resultant residue was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give the title compound as yellow oil (4.26 g, 86%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:7])[NH:5][CH:6]=1.[Al+3].[Cl-].[Cl-].[Cl-].C([CH:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19])C.CO.C(OCC)(=O)C>S1(CCCC1)(=O)=O.C(Cl)(Cl)Cl.OP(O)=O.O[Mo](O)(=O)=O>[CH3:1][C:2]1[NH:3][C:4](=[O:7])[NH:5][C:6]=1[C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C(CC)CCCC(=O)Cl
Reactant: Cc1c[nH]c(=O)[nH]1
Agent: O=[Mo](=O)(O)O
Agent: O=[PH](O)O
Agent: [Al+3]
Solvent: ClC(Cl)Cl
Solvent: O=S1(=O)CCCC1
Solvent: CO
Product: CCOC(=O)CCCCC(=O)c1[nH]c(=O)[nH]c1C
Temperature: 75 °C
Yield: 109.2 %

Procedure:
A slurry of this crude intermediate [containing 10.6 g (0.108 mol) of 4-methyl-4-imidazolin-2-one by assay] in 51.8 g of sulfolane and 100 ml of chloroform was cooled to ice bath temperature in a 3-necked round bottom flask equipped with reflux condenser, nitrogen inlet, nitrogen outlet, mechanical stirrer and addition funnel and 71.8 g (0.540 mol) of AlCl3 added portionwise. After the addition was complete, the temperature of the bath was raised to 75° C. and 29.0 g (0.151 mol) of ethyl 5-ethoxycarbonylpentanoyl chloride added dropwise over a 60 minute period. On heating an additional 1.5 hours, tlc (silica gel, methanol/ethyl acetate 1:4, UV followed by phosphomolybdic acid visualization) suggested the complete consumption of starting material and the formation of the desired ketoester. The reaction mixture was then poured onto 500 ml of ice containing 16 g of sodium carbonate dissolved in 50 ml of water. The aqueous hydrolysis mixture was stirred rapidly while 400 ml of ethyl ether was added. After 15 minutes the precipitated solid was removed by filtration, washed with ether and dried overnight under vacuum to afford 30.0 g of tan solid shown to be 76% pure by hplc analysis (83% yield corrected for purity). The solid was recrystallized from 1:1 ethanol:water to yield 16.7 g of purified title product, homogeneous by hplc and tlc, m.p. 170°-172° C., identical in physical properties to the product of the preceding Example.