Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][Si](C(C)(C)C)(C)C)[CH2:10][C@:9]1([CH2:31][CH2:32][CH3:33])[C:21](=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+](C)(C)C.[F-]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][C@@:9]1([C:21](=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=1)[CH2:31][CH2:32][CH3:33])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC[C@]1(C(=O)c2ccc(Cl)c(Cl)c2)CC(O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: C[N+](C)(C)C
Agent: [F-]
Product: CCC[C@]1(C(=O)c2ccc(Cl)c(Cl)c2)CC(O)CN1C(=O)OC(C)(C)C

Procedure:
(R)-2-(3,4-Dichloro-benzoyl)-4-hydroxy-2-propyl-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared by treating (R)-4-(tert-Butyl-dimethyl-silanyloxy)-2-propyl-2-(3,4-dichloro-benzoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester with TMAF following the procedure of step 3 of Example 11.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([O:21][N:22]1C(=O)C2=CC=CC=C2C1=O)[CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CNN>ClCCl>[CH2:1]([O:8][CH2:9][C@H:10]([O:21][NH2:22])[CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1O[C@H](CCOCc1ccccc1)COCc1ccccc1
Agent: CNN
Solvent: ClCCl
Product: NO[C@H](CCOCc1ccccc1)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
A solution of (R)-N-(1,4-dibenzyloxybut-2-oxy)phthalimide (0.6 g, 1.3 mmol) in dichloromethane (5 ml) was treated with methylhydrazine (86 μl, 1.6 mmol). A deep red colouration developed, disappearing gradually as a white solid precipitated out of solution. After stirring at room temperature for 30 minutes additional methylhydrazine (8 μl, 0.15 mmol) was added. The mixture was stirred at room temperature for an additional 30 minutes, filtered and the filtrate washed with 3% sodium carbonate solution (5 ml). The organic phase was dried (MgSO4), the solvent removed under reduced pressure and the residue chromatographed on silica eluting with ethyl acetate-hexane to give (R)-1,4-dibenzyloxybut-2-oxyamine (0.32 g, 77%), [α]D25 +10.1° (c 0.14 in ethanol); IR: υmax (film) 3310, 3250, 3090, 3060, 3030, 2920, 2860, 1585, 1495, 1450, 1365, 1310, 1200, 1100, 1030, 950, 915, 740, 700 cm-1 ; 1H NMR: δH (CDCl3) 1.85 (2H, m, CH2), 3.55 (4H, m, 2×CH2), 3.90 (1H, m, CH), 4.49 (2H, s, CH2), 4.45 (2H, s, CH2), 5.36 (2H, s, D2O exchangeable NH2) 7.35 (10H, m, 2×C6H5); m/z 302 (MH+), 301 (M+, 3%), 181 (5), 163 (10), 106 (15), 105 (5), 92 (15), 91 (100), 71 (15), 65 (10). M+ observed 301.1670; C18H23NO3 requires M+ 301.1678.
Reaction SMILES: Br[C:2]1[N:18]([C@@H:19]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]2)[C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[C:3]=1[C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:33][CH:32]=1.[Li]CCCC.CN([CH:52]=[O:53])C>C1COCC1>[C:14]([O:13][C:11]([NH:10][C:9]1[C:4]2[C:3]([C:31]3[CH:36]=[CH:35][C:34]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:33][CH:32]=3)=[C:2]([CH:52]=[O:53])[N:18]([C@@H:19]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:20]3)[C:5]=2[N:6]=[CH:7][N:8]=1)=[O:12])([CH3:16])([CH3:15])[CH3:17]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)c(Br)n2[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)c(C=O)n2[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 8.2 %

Procedure:
At −78° C. under N2 atmosphere, to a solution of (R)-tert-butyl 3-(6-bromo-4-(tert-butoxycarbonylamino)-5-(4-phen-oxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (119) (1.57 g, 2.41 mmol) in THF (20 mL) was added n-BuLi (3 mL, 7.23 mmol, 2.5M in THF) dropwise. The resulting mixture was stirred at −78° C. for 1 hr before introducing DMF (264 mg, 3.62 mmol). Stirring was continued for another 1 hr at −78° C. The reaction was quenched with sat. NH4Cl before extracted with EA (30 mL×3). Combined organic layers were washed with brine and dried over Na2SO4. Solvents were removed under vacuum and the residue was purified by flash chromatography (silica gel, 0 to 50% EA in PE) to provide (R)-tert-butyl 3-(4-(tert-butoxycarbonylamino)-6-formyl-5-(4-phenoxyphenyl)-7H-pyrr-olo[2,3-d]pyrimidin-7-yl)pyrrolidine-1-carboxylate (120) (118 mg, 8%) as a yellow oil. LC-MS (ESI): m/z (M+1) 600.0.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([Cl:16])[C:8]2[NH:13][C:12](=[O:14])[O:11][CH2:10][C:9]=2[CH:15]=1)(=O)C.[OH-].[Na+].O.C(O)(=O)C>CO>[Cl:16][C:7]1[C:8]2[NH:13][C:12](=[O:14])[O:11][CH2:10][C:9]=2[CH:15]=[C:5]([OH:4])[CH:6]=1
Reactant: CC(=O)Oc1cc(Cl)c2c(c1)COC(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: O=C1Nc2c(Cl)cc(O)cc2CO1

Procedure:
An amount of 7.6 gm (31.4 mol) of 6-acetoxy-8-chloro-4H-3,1-benzoxazin-2-one is suspended in 50 ml of methanol, and 20 ml (40 mmol) of 2N sodium hydroxide solution are added, under stirring. The clear solution which is immediately produced is stirred for a further ten minutes at ambient temperature, water is added, and the mixture is made acidic with acetic acid. The precipitate is subjected to suction filtration and recrystallized from isopropanol.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH:23](=[O:27])[CH:24]([CH3:26])[CH3:25]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:23]([OH:27])[CH:24]([CH3:26])[CH3:25])[C:9]1=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C=O
Reactant: O=C1COCCN1Cc1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)C(O)C1OCCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2 (5.05 g, 26.4 mmol) in tetrahydrofuran (25 ml) at −78° C. under nitrogen was added lithium diisopropylamide (14.5 ml of a 2M solution, 29.0 mmol) dropwise over 40 minutes. The reaction mixture was stirred at the same temperature over 30 minutes after which time a solution of isobutyraldehyde (2.63 ml, 29.0 mmol) in tetrahydrofuran (15 ml) was added dropwise over 30 minutes. After one hour, the reaction mixture was allowed to warm to room temperature and quenched by addition of saturated ammonium chloride solution. Extraction with dichloromethane and drying over magnesium sulphate gave 53 as a mixture of diastereomers. Upon concentration in vacuo one diastereomer precipitated as a white solid (53a: 0.99 g). The remaining mother liquors were purified by column chromatography (30% ethyl acetate in hexane [v/v]) to give 53 (2.06 g). MW 263.34; C15H21NO3; LCMS (6 min method): m/z 286 [M+Na]+; RT=2.748.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[H-].[Na+].Cl[C:18]1[O:19][C:20]2[C:21](=[C:23]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=[CH:25][CH:26]=2)[N:22]=1>C1COCC1>[C:11]([O:10][C:8]([N:3]1[CH2:4][CH2:5][N:6]([C:18]2[O:19][C:20]3[C:21](=[C:23]([C:27]([O:29][CH3:30])=[O:28])[CH:24]=[CH:25][CH:26]=3)[N:22]=2)[CH2:7][CH:2]1[CH3:1])=[O:9])([CH3:13])([CH3:12])[CH3:14]
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Reactant: CC1CNCCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc2oc(N3CCN(C(=O)OC(C)(C)C)C(C)C3)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 63.5 %

Procedure:
To a solution of tert-butyl 2-methylpiperazine-1-carboxylate (340 mg, 1.70 mmol) in THF (5 mL) was added sodium hydride (60%, 82 mg, 2.04 mmol). The reaction mixture was stirred at room temperature for 5 min, then methyl 2-chlorobenzoxazole-4-carboxylate (300 mg, 1.41 mmol) in THF (5 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 19 h. The mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography (silica gel, 20% EtOAc in hexane) to afford methyl 2-(4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)benzoxazole-4-carboxylate (336 mg, 63%) as yellow solid. MS consistent.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[C:6]([CH:8]=1)[NH2:7].Cl.Cl[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]Cl.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[C:6]([N:7]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:8]=1
Reactant: Nc1cc(F)ccc1OCC(F)(F)F
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Product: Fc1ccc(OCC(F)(F)F)c(N2CCNCC2)c1
Yield: 14.5 %

Procedure:
A stirred mixture of 0.52 g of Compound 5B, 0.45 g of bis-(2-chloroethyl)amine hydrochloride, 0.5 g of potassium iodide, 0.34 g of anhydrous potassium carbonate and 20 mL of n-butanol was refluxed for 32 hours under nitrogen. The solvent was removed under reduced pressure. The residue was treated with 10 mL of water and 10 mL of 20% aqueous sodium carbonate and extracted with 2×30 mL of ethyl acetate. The organic layer was washed with brine, dried over sodium sulphate and evaporated to dryness in vacuo. The residue was purified by flash chromatography (chloroform:2N ammonia in methanol gradient from 100:3 to 100:5) to afford 0.1 g (14%) of Compound 5C as an oil.
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4]([N:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH:15]=O)=[C:9]1[C:17]([O:19]C)=O)=[CH:5][CH2:6][CH3:7]>C(O)(=O)C.ClCCl>[CH2:4]([N:8]1[C:9]2[C:17](=[O:19])[NH:2][N:3]=[CH:15][C:10]=2[C:11]([CH3:14])=[C:12]1[CH3:13])[CH:5]=[CH:6][CH3:7]
Reactant: NN
Reactant: CCC=Cn1c(C)c(C)c(C=O)c1C(=O)OC
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC=CCn1c(C)c(C)c2cn[nH]c(=O)c21
Temperature: 100 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
1.10 g (0.0220 mole) of hydrazine hydrate was added to a solution of 4.50 g (0.0191 mole) of methyl 1-butenyl-3-formyl-4,5-dimethylpyrrole-2-carboxylate (cis/trans=24/76) in 47 ml of acetic acid and the resulting mixture was stirred at 100° C. for 2 hours. The reaction mixture cooled to room temperature was poured into ice-water. Precipitated crystals were collected by filtration and washed with water. The crystals thus obtained were dissolved in 300 ml of dichloromethane and the solution was dried over anhydrous sodium sulfate. Distilling off the solvent gave 3.53 g (0.0163 mole) of 1-(2-butenyl)-2,3-dimethyl-6,7-dihydropyrrolo[2,3-d]-pyridazine-7-one (cis/trans=21/79) as pale brown crystals.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:12]C1C=C2C(C(=O)CCN2)=CC=1>>[Cl:12][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=C1CCNc2cc(Cl)ccc21
Reactant: Oc1ccnc2ccccc12
Product: Clc1ccnc2ccccc12

Procedure:
a yield of 4-hydroxyquinoline of 15% relative to the 7-chloro-1,2,3,4-tetrahydroquinolin-4-one converted.
Reaction SMILES: [NH2:1][CH:2]1[C:23](=[O:24])[N:4]2[CH:5]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[O:11])[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.C(OCC)(=O)C>COC(OC)N(C)C>[CH3:3][N:4]([CH:23]=[N:1][C@@H:2]1[C:23](=[O:24])[N:4]2[CH:5]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[O:11])[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12)[CH3:5]
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: COC(OC)N(C)C
Solvent: CCOC(C)=O
Product: CN(C)C=N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(C)(C)S[C@H]12
Temperature: 0 °C
Yield: 159.2 %

Procedure:
A solution of 34 mmoles of p-nitrobenzyl 6-amino-2,2-dimethylpenam-3-carboxylate (6APA p-nitrobenzyl ester) in 100 ml of dimethylformamide dimethylacetal was stirred at room temperature for three hours. The reaction mixture was then poured into a stirred mixture of ice water and ethyl acetate and the organic phase separated. The organic phase was layered over water and the pH adjusted to 1.8 with hydrochloric acid. The acidified aqueous layer was separated, slurried with ethyl acetate, and the pH adjusted to 7.5 with 1 N sodium hydroxide. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated to dryness. The product was obtained as a residual oil and was crystallized in trituration with diethyl ether. There were obtained 11 g (80% yield) of the title compound.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:39])=[C:34](B(O)O)[CH:35]=1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:32]3[CH:31]=[C:30]([F:29])[CH:35]=[CH:34][C:33]=3[CH3:39])[C:3]([N:22]3[CH2:26][C@H:25]([OH:27])[C@@H:24]([OH:28])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(F)cc1B(O)O
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Product: Cc1ccc(F)cc1-c1cc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cnc1N1C[C@H](O)[C@@H](O)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 290 using 5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)nicotinamide (Stage 248.1) and 5-fluoro-2-methylphenylboronic acid to afford a white solid. HPLC (Condition 10) tR=6.25 min, UPLC-MS (Condition 11) tR=1.08 min, m/z=508.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.59-1.90 (s, 2H) 1.95/2.06 (s, 3H) 2.76-3.00 (m, 1H) 3.04-3.25 (m, 2H) 4.09-4.21 (m, 1H) 4.76-4.90 (m, 2H) 7.08-7.17 (m, 1H) 7.25-7.35 (m, 4H) 7.81-7.97 (m, 3H) 8.74 (s, 1H) 10.07-10.17 (m, 1H).
Reaction SMILES: Cl[O-].[Na+].[OH-].[K+].[NH2:6][C:7]1[CH:12]=[C:11]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:10]=[CH:9][C:8]=1[N+:21]([O-:23])=[O:22]>C(O)C>[CH3:20][C:17]1[CH:16]=[CH:15][C:14]([S:13][C:11]2[CH:10]=[CH:9][C:8]3[C:7]([CH:12]=2)=[N:6][O:22][N+:21]=3[O-:23])=[CH:19][CH:18]=1
Reactant: Cc1ccc(Sc2ccc([N+](=O)[O-])c(N)c2)cc1
Agent: [K+]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCO
Product: Cc1ccc(Sc2ccc3c(c2)no[n+]3[O-])cc1
Yield: 83.5 %

Procedure:
60 ml of sodium hypochlorite solution (13%) is added dropwise at ca. 30° C internal temperature, with continuous stirring, to a solution of 3 g of potassium hydroxide in 150 ml of ethanol and 7 g of 2-amino-4-(4'-methylphenylthio)-nitrobenzene. After completion of the addition, stirring is continued for half an hour at room temperature; the precipitated product is filtered off with suction and then washed with 200 ml of water. Recrystallisation from ethanol yields 5.8 g (= 83.5% of theory) of 5-(4'-methylphenylthio)-benzofurazan-N-oxide, M.P. 86°-88° C.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([O:18]CC)=[O:17])=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.[OH-].[Na+].Cl>C1COCC1.CO.O>[O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)CCCNC3=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cc3n(c2c1)CCCNC3=O
Temperature: 70 °C
Yield: 67 %

Procedure:
To a suspension of ethyl 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylate (900 mg, 3.3 mmol) in THF:methanol (1:1, 20 mL) is added 1N NaOH (9.0 mL, 9.0 mmol). The reaction mixture is heated at 70° C. for 2 h. The reaction mixture is cooled to room temperature, diluted with water (80 mL) and is acidified with 3N HCl to pH 2-3. The resulting yellow precipitate is filtered, washed with water and dried in vacuo oven at 60° C. to afford the title compound (540 mg, 67%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:19])[CH:11]=[C:12]([C:16]([OH:18])=O)[N:13]([CH3:15])[CH:14]=2)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[N:55]1([CH2:60][CH2:61][NH2:62])[CH2:59][CH2:58][CH2:57][CH2:56]1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:19])[CH:11]=[C:12]([C:16]([NH:62][CH2:61][CH2:60][N:55]3[CH2:59][CH2:58][CH2:57][CH2:56]3)=[O:18])[N:13]([CH3:15])[CH:14]=2)=[CH:20][CH:21]=1
Reactant: NCCN1CCCC1
Reactant: COc1ccc(COc2cn(C)c(C(=O)O)cc2=O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(COc2cn(C)c(C(=O)NCCN3CCCC3)cc2=O)cc1
Reaction time: 3 h
Yield: 81.8 %

Procedure:
A mixture of 5-((4-methoxybenzyl)oxy)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid (1.21 g, 4.18 mmol), HATU (1.908 g, 5.02 mmol), diisopropylethyl amine (1.5 ml, 8.59 mmol) in N,N-dimethylformamide (15.0 ml) was stirred at room temperature for 30 min. at which time 2-(pyrrolidin-1-yl)ethanamine (0.58 ml, 4.61 mmol) was added and the reaction was allowed to stir for 3 h. The reaction was concentrated under vacuum, the residue was triturated with dichloromethane. The solid material was filtered and further washed with dichloromethane. The supernatant was collected, concentrated under reduced pressure and the residue was purified on silica gel eluting with methanol/dichloromethane/ammonium hydroxide. The fractions containing the desired product were concentrated, the residue was dissolved in dichloromethane, and washed with water. The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to give 5-((4-methoxybenzyl)oxy)-1-methyl-4-oxo-N-(2-(pyrrolidin-1-yl)ethyl)-1,4-dihydropyridine-2-carboxamide (1.32 g, 3.42 mmol, 82% yield) as nearly white solid. LCMS: (M+H)+: 386.2
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:35]([CH3:37])[CH3:36])[N:11](/[CH:20]=[CH:21]/[C@@H:22]([OH:34])[CH2:23][C@@H:24]([OH:33])[CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[OH-].[Na+:39]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:35]([CH3:37])[CH3:36])[N:11](/[CH:20]=[CH:21]/[C@@H:22]([OH:34])[CH2:23][C@@H:24]([OH:33])[CH2:25][C:26]([O-:28])=[O:27])[C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1.[Na+:39]
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@@H](O)C[C@@H](O)CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@@H](O)C[C@@H](O)CC(=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 1,1-dimethyleth-1-yl (3R,5S,E)-7-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-3,5-dihydroxy-6-heptenoate (51 mg) in ethanol (5 ml) was treated with aqueous sodium hydroxide solution (0.1M, 1 ml) and the clear solution was stirred at room temperature. After 18 h the solution was concentrated to ca 1 ml and then diluted with water (20 ml) and the solution washed with ether (2×7 ml). The solution was briefly evaporated and then freeze dried to give the title compound (52 mg), as a white fluffy solid, [α]D20 +19.5° (c 0.41, H2O); δ(D2O) 1.20-1.55, 1.55-1.82 (m, 2H, CH(OH)CH2CH(OH)), 1.34 (d, J 7 Hz, 6H, CH(CH3)2), 2.26 (d, J 7 Hz, 2H, CH2CO2Na), 3.28 (septet, J 7 Hz, 1H, --CH(CH3)2), 3.67 (m, 1H, =CHCH(OH)CH2CH(OH)), 4.35 (m, 1H, CH=CHCH(OH)), 5.61 (dd, J 14 and 7 Hz, 1H, NCH=CH), 6.75 (d, J 14 Hz, 1H, NCH=CH), 7.01 (t, J 9 Hz, 2H, C-3 and C-5 protons of 4-fluorophenyl), 6.91-7.41 (m, 6H, aromatics).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27](O)=[O:28])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37](=[N:39]O)[NH2:38]>>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]1[N:39]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]3)=[O:10])[CH2:12]2)[O:28][N:38]=1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Reactant: NC(=NO)c1ccccc1F
Product: N#CC1CCN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(-c4ccccc4F)no3)C2)CC1

Procedure:
100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 41.4 mg (0.269 mmol) of 2-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 72.8 mg (55% of theory).
Reaction SMILES: ClN1C(=O)CCC1=O.CSC.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[S:20][C:19]([CH2:21][OH:22])=[CH:18][C:17]=2[CH:23]=1.C(N(CC)CC)C>CCOCC.C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]2[S:20][C:19]([CH:21]=[O:22])=[CH:18][C:17]=2[CH:23]=1
Reactant: OCc1cc2cc(Cl)ccc2s1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=Cc1cc2cc(Cl)ccc2s1
Temperature: 25 °C

Procedure:
To a mixture of N-chlorosuccinimide (13.1 mmol) and 50 ml toluene, at 0°, is slowly added dimethylsulfide (18.1 mmol). The mixture is stirred briefly, cooled to -25° and 5-chlorobenzothiophene-2-methanol (10. 1 mmol) added followed by stirring for 2 hours. Triethylamine (13.1 mmol) is added and the mixture allowed to warm to RT. The mixture is taken up in ether, washed with 10% HCl, water and brine, dried over sodium sulfate and solvent removed to give 5-chlorobenzothiophene-2-carboxaldehyde.
Reaction SMILES: [OH:1][CH:2]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].I[CH3:14]>CN(C=O)C>[CH3:14][O:1][CH:2]([CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: CI
Reactant: COC(=O)CC(O)CC(=O)OC
Solvent: CN(C)C=O
Product: COC(=O)CC(CC(=O)OC)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of dimethyl 3-hydroxypentanedioate (9 g, 51.1 mmol) in DMF (70 mL) was added Ag2O (35.5 g, 154.3 mmol) and iodomethane (48.2 g, 339.2 mmol) under ice-cooling. The mixture was stirred at room temperature overnight. The mixture was filtrated and the filtrate was washed with water. Ether was added and the organic layer was dried and concentrated to give the crude product, which was purified by column chromatography to give dimethyl 3-methoxypentanedioate (8 g, 82%). 1H-NMR (CDCl3): 2.48 (m, 4H), 3.21 (m, 3H), 3.50 (m, 6H), 3.85 (s, 1H).
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[CH:8]=[C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:6]=[C:5]2[CH2:17][C:18]([O:20]CC)=O)[CH2:3][CH2:2]1.C[Al](C)C.[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH2:30][CH2:31][NH:32]2.CO>C1(C)C=CC=CC=1.O1CCCC1>[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH2:30][CH2:31][N:32]2[C:18](=[O:20])[CH2:17][C:5]1[N:4]([CH:1]2[CH2:3][CH2:2]2)[C:9](=[O:10])[CH:8]=[C:7]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:6]=1
Reactant: Clc1cccc2c1CCN2
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)n1C1CC1
Agent: C[Al](C)C
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)n1C1CC1)N1CCc2c(Cl)cccc21
Temperature: 90 °C
Yield: 32.1 %

Procedure:
2 ml of toluene, 90 mg of ethyl (1-cyclopropyl-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate and, finally, dropwise, 0.55 ml of a 2M solution of trimethylaluminum in toluene are successively added to a solution of 113 mg of 4-chloroindoline in 4 ml of tetrahydrofuran. The reaction mixture is heated at 90° C. for 4 hours, and then cooled to ambient temperature, and 5 ml of methanol are added. After the addition of 10 g of silica, the reaction mixture is concentrated under reduced pressure. After purification by silica column chromatography (solid deposit), elution being carried out with a mixture of dichloromethane and methanol (100/0 then 98/02 V/V), 39 mg of 2-[2-(4-chloro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-cyclopropyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white solid, the characteristics of which are the following: