Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[NH:22][C:23]([CH2:25][CH:26]([C:31]([F:34])([F:33])[F:32])[CH2:27][C:28]([OH:30])=[O:29])=[O:24].[C:35](=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[NH:22][C:23]([CH2:25][CH:26]([C:31]([F:34])([F:33])[F:32])[CH2:27][C:28]([O:30][CH3:35])=[O:29])=[O:24]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(NC(=O)CC(CC(=O)O)C(F)(F)F)c(Cl)cc2F)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CC(CC(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 214.2 %

Procedure:
To a mixture of 0.20 g of 4-(N-(2-chloro-4-fluoro-5-(1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedion-3-yl)phenyl)carbamoyl)-3-trifluoromethylbutyric acid, 0.06 g of potassium carbonate and 4 ml of N,N-dimethylformamide was added 0.05 g of methyl iodide at room temperature and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate and washed successively with water and a saturated saline solution, and dried over anhydrous sodium carbonate followed by removing ethyl acetate by distillation to obtain 0.44 g of the desired compound as crystal.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:28][CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:10]=12)C1C=CC=CC=1.[H][H].CO>C(O)C.ClCCl.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)[N:11]2[CH2:28][CH2:29][N:30]([CH3:33])[C:31](=[O:32])[C:10]=12
Reactant: CN1CCn2c(CC3(c4ccccn4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: CN1CCn2c(CC3(c4ccccn4)CCCC3)nc(=O)c(O)c2C1=O
Yield: 64.8 %

Procedure:
To a stirred solution of 9-benzyloxy-2-methyl-6-(1-pyridin-2-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (444) (60 mg, 0.135 mmol) in ethanol (5 mL), Pd—C (10%, w/w; 10 mg) was added and the reaction mixture was allowed to stir for 1 h in a hydrogen atmosphere at balloon pressure, while silica thin layer chromatography was performed (10% methanol in dichloromethane, Rf=0.3). After completion of the reaction, the reaction mixture was filtered through a celite bed and concentrated. The resulting crude product was triturated with 70% ethyl acetate in hexane to get 9-hydroxy-2-methyl-6-(1-pyridin-2-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (445) (31 mg, 65%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:4]=1.Cl.Cl.[NH:17]1[CH2:22][CH2:21][CH:20](/[CH:23]=[C:24]2/[C:25]([NH:30][CH2:31][C:32]#[CH:33])=[N:26][C:27](=[O:29])[S:28]/2)[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:17]2[CH2:22][CH2:21][CH:20](/[CH:23]=[C:24]3/[C:25]([NH:30][CH2:31][C:32]#[CH:33])=[N:26][C:27](=[O:29])[S:28]/3)[CH2:19][CH2:18]2)=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:4]=1
Reactant: COc1ccc(CBr)c(C(F)(F)F)c1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(OC)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
To a solution of 4-methoxy-2-(trifluoromethyl)benzyl bromide (516 mg) in DMF (5 mL) were added (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (500 mg) and potassium carbonate (862 mg). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (468 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl.CN(C)[CH2:15][CH2:16]CN=C=N.O.ON1C2C=CC=CC=2N=N1.C(O)C>CN(C)C=O.O>[F:1][C:2]1[CH:10]=[C:6]([C:7]([O:9][CH2:15][CH3:16])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(F)ccc1O
Reactant: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(F)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
5-Fluoro-2-hydroxybenzoic acid (344 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (420 mg), 1-hydroxybenzotriazole hydrate (337 mg), and ethanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give ethyl 5-fluorosalicylate (191 mg, yield 28%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10](=[O:25])[CH2:11][C:12]1[CH:17]=[C:16](Cl)[C:15]([N+:19]([O-])=O)=[CH:14][C:13]=1[N+:22]([O-])=O)[CH3:8].C(O)(=O)C>ClCCl.[Zn]>[CH2:7]([O:9][C:10](=[O:25])[CH2:11][C:12]1[CH:17]=[C:16]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:15]([NH2:19])=[CH:14][C:13]=1[NH2:22])[CH3:8]
Reactant: CCOC(=O)Cc1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: C1CCNCC1
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)Cc1cc(N2CCCCC2)c(N)cc1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Piperidine (120 mg) was added to a solution of (5-chloro-2,4-dinitro-phenyl)-acetic acid ethyl ester (150 mg) in dichloromethane (5 mL) and the resulting mixture was stirred at room temperature for 10 minutes. Glacial acetic acid (0.3 mL) and zinc dust (1 scoop) were added and the reaction mixture was stirred at room temperature for 20 minutes. The resulting mixture was filtered through a CELITE™ pad, the filter cake was washed with dichloromethane and the filtrate was evaporated under reduced pressure. The residue was then diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give (2,4-diamino-5-piperidin-1-yl-phenyl)-acetic acid ethyl ester. This material was dissolved in toluene (2.5 mL) and heated at 150° C. in a microwave reactor for 10 minutes. The reaction mixture was then cooled, evaporated under reduced pressure and the residue was purified by flash chromatography (DCM/MeOH, 95/5) to give 30 mg of 6-amino-5-piperidin-1-yl-1,3-dihydro-indol-2-one. MS=232 [M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[C@H:3]1[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C(N(CC)CC)C.[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[C:25]1[C:33](O)=[O:34].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][C@H:3]2[C@H:2]([NH:1][C:33]([C:25]3[O:24][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[CH:26]=3)=[O:34])[CH:7]3[CH2:6][CH2:5][N:4]2[CH2:9][CH2:8]3)[CH:12]=1
Reactant: N[C@@H]1C2CCN(CC2)[C@H]1Cc1cccnc1
Reactant: O=C(O)c1cc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1C2CCN(CC2)[C@H]1Cc1cccnc1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
The (2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane was transferred to a 50 L glass reaction flask equipped with a mechanical stirrer under an inert atmosphere. Dichloromethane (16.5 L), triethylamine (847 mL, 6.08 mol), benzofuran-2-carboxylic acid (948 g, 5.85 mol) and O-(benzotriazol-1-yl)-N,N,N,1-tetramethyluronium hexafluorophosphate (HBTU) (2.17 kg, 5.85 mol) were added to the reaction mixture. The mixture was stirred for a minimum of 4 h at ambient temperature, and the reaction was monitored by HPLC. Upon completion of the reaction, 10% aqueous potassium carbonate (12.7 L, 17.1 mol) was added to the reaction mixture and the mixture was stirred for a minimum of 5 min. The layers were separated and the organic phase was washed with 10% brine (12.7 L). The layers were separated and the organic phase was cooled to 15° C.±10° C. 3 M Hydrochloric acid (8.0 L) was slowly added to the reaction mixture to adjust the pH of the mixture to pH 1. The mixture was then stirred for a minimum of 5 min, and the layers were allowed to partition for a minimum of 5 min. The solids were filtered using a table top filter. The layers of the filtrate were separated, and the aqueous phase and the solids from the funnel were transferred to the reaction flask. 3 M Sodium hydroxide (9.0 L) was slowly added to the flask in portions to adjust the pH of the mixture to pH 14. The aqueous phase was extracted with dichloromethane (2×16.5 L). The combined organic phases were dried over anhydrous sodium sulfate (1.71 kg). The mixture was filtered, and the filtrate was concentrated to give (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octan-3-yl)benzofuran-2-carboxamide (1.63 kg, 77.0% yield) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O.C([O:23][CH2:24][CH3:25])(=O)C>O1CCOCC1.C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:4][C:25]=1[CH2:24][OH:23]
Reactant: CCOC(C)=O
Reactant: OB(O)c1cccnc1F
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: OCc1cc(-c2cccnc2F)ccc1F
Temperature: 90 °C
Yield: 47 %

Procedure:
The crude oil was dissolved in dioxane (100 mL) and treated with 2-fluoropyridin-3-ylboronic acid (3.47 g, 24.63 mmol), potassium phosphate (5.23 g, 24.63 mmol), and 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (0.25 g, 0.35 mmol). Water (10 mL) was added and the reaction heated to 90° C. for 10 min. Water (300 mL) and ethyl acetate (200 mL) were added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification of the crude material using silica chromatography (hexane to ethyl acetate gradient) gave (2-fluoro-5-(2-fluoropyridin-3-yl)phenyl)methanol (2.54 g, 47%). MS m/z=222.1 [M+H]+. Calculated for C12H9F2NO: 221.05.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].[CH3:31][O-:32].[Na+]>CO.CS(C)=O>[CH3:31][O:32][CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:28]([NH2:30])=[O:29])[CH:19]=[C:20]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6]
Reactant: C[O-]
Reactant: NC(=O)c1cc(-c2cccs2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)c[nH]c12
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: COCCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccs4)cc23)CC1

Procedure:
3-{1-[(3-chloropropyl)sulfonyl]-4-piperidinyl}-5-(2-thienyl)-1H-indole-7-carboxamide (35 mg, 0.075 mmol) was reacted with sodium methoxide (0.5 M in methanol, 1.0 mL, 0.488 mmol) in a mixture of methanol (4 ml) and DMSO (0.5 mL) at reflux for 16 h to form the desired product which was purified by reverse phase HPLC eluting with 10% B to 70% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) to give the title compound (15 mg, 43%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[C:11]3[CH:18]=[CH:17][NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[O:9])[CH2:4][CH2:3]1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>C(#N)C.O>[N:13]1[C:12]2[NH:16][CH:17]=[CH:18][C:11]=2[C:10]([C:8]([CH:5]2[CH2:6][CH2:7][N:2]([CH2:25][C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=3)[CH2:3][CH2:4]2)=[O:9])=[N:15][CH:14]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: O=C(c1ncnc2[nH]ccc12)C1CCNCC1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ncnc2[nH]ccc12)C1CCN(Cc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
Piperidin-4-yl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanone hydrochloride (60.0 mg, 0.224 mmol) in acetonitrile (3 mL) was stirred with 4-(trifluoromethyl)benzyl bromide (70.0 mg, 0.292 mmol) and N,N-diisopropylethylamine (144 μL, 0.784 mmol) at 60° C. for 2 hours and allowed to cool to room temperature. After addition of water and saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the title compound as a pale yellow solid (65.0 mg, yield 75%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O)[CH3:2].[C:14]([O-:17])(=[O:16])[CH3:15].[NH4+:18].C(O)(=O)CC(O)=O>C(O)C>[NH2:18][CH:7]([C:6]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[CH2:15][C:14]([OH:17])=[O:16]
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: CC(=O)[O-]
Reactant: [NH4+]
Agent: O=C(O)CC(=O)O
Solvent: CCO
Product: CCOc1cc(C(N)CC(=O)O)ccc1OC
Temperature: 45 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A stirred mixture of 3-ethoxy-4-methoxybenzaldehyde (119.5 grams, 664 mmol) and ammonium acetate (148.3 grams, 1.92 mol) in ethanol (300 mL, 95%) was heated at 45° C. To the mixture was added malonic acid (69 grams, 664 mmol), followed by ethanol (100 mL, 95%). The mixture was refluxed for 18 hours. The mixture was cooled to room temperature and was stirred for 2 hours. The suspension was filtered and the solid was washed with cold ethanol (5×50 mL) to give 3-amino-3-(3'-ethoxy-4'-methoxyphenyl)propionic acid as a white solid, which was dried in a vacuum oven overnight, (94.75 grams, 60% yield): mp, 224.0°-225.5° C.; 1H NMR (D2O/NaOD)δ1.41 (t, J=7 Hz, 3H, CH3), 2.52-2.56 (m, 2H, CH2), 3.83 (s, 3H, CH2), 4.14 (q, J=7 Hz, 2H, CH2), 4.19 (t, J=7 Hz, 1H, NCH), 6.98-7.04 (m, 3H, Ar); 13C NMR (D2O/NaOD)δ16.75, 49.81, 55.45, 58.46, 67.63, 114.17, 114.71, 121.76, 140.69, 149.91, 150.09, 182.97; Anal. Calcd for C12H17NO4 : C, 60.24; H, 7.16; N, 5.85. Found: C, 60.21; H, 7.12;N, 5.88.
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].Cl.[OH-].[Na+].CC(O)C>O>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3]
Reactant: CN(C)C(=N)N=C(N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CN(C)C(=N)NC(=N)N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
Metformin hydrochloride (49.68 g: 0.3 mol) was dissolved in pure water, and neutralized with 2N sodium hydroxide aqueous solution (150 mL). The mixture was condensed in vacuo until it contained about 30 mL of water. To the mixture was added 2-propanol (300 mL) and stirred at room temperature for 30 minutes. The mixture was filtered and the residue was washed with acetone. The filtrate and the acetone were gathered and the solvent was evaporated in vacuo. Acetone (500 mL) and magnesium sulfate were added to the residue, stirred and filtered. The filtrate was concentrated in vacuo to give free metformin (32.9 g: yield 85%) as white prisms.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH2:11][CH2:12][CH:13]([CH3:41])[CH:14]([OH:40])[CH:15]([CH3:39])[C:16](=[O:38])[CH:17]([CH2:36][CH3:37])[CH:18]2[CH:22]([CH3:23])[CH2:21][C:20]([CH2:34][CH3:35])([CH:24]3[CH2:29][CH2:28][C:27]([CH2:31][CH3:32])([OH:30])[CH:26]([CH3:33])[O:25]3)[O:19]2)=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:42])=[C:4]([CH3:43])[CH:3]=1.[C:44](OC(=O)C)(=[O:46])[CH3:45].C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[C:44]([NH:1][C:2]1[C:10]([CH2:11][CH2:12][CH:13]([CH3:41])[CH:14]([OH:40])[CH:15]([CH3:39])[C:16](=[O:38])[CH:17]([CH2:36][CH3:37])[CH:18]2[CH:22]([CH3:23])[CH2:21][C:20]([CH2:34][CH3:35])([CH:24]3[CH2:29][CH2:28][C:27]([CH2:31][CH3:32])([OH:30])[CH:26]([CH3:33])[O:25]3)[O:19]2)=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:42])=[C:4]([CH3:43])[CH:3]=1)(=[O:46])[CH3:45]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(C(=O)C(C)C(O)C(C)CCc1c(N)cc(C)c(O)c1C(=O)O)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC(C(=O)C(C)C(O)C(C)CCc1c(NC(C)=O)cc(C)c(O)c1C(=O)O)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C

Procedure:
To a suspension of 1.21 g. (2 mmole) of 5-amino-3-methyl-6-{7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-[5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2-tetrahydrofuryl]-heptyl}salicylic acid in 50 ml. glacial acetic acid was added 1 ml. acetic anhydride (~10 mmoles). On warming the mixture to 70° on a steam bath, the amine dissolved and after a further half an hour at room temperature, the solution was poured on to crushed ice. The mixture was carefully made alkaline with sodium carbonate solution and extracted twice with 400 ml. ether. After drying (NaSO4) the ethereal solution was evaporated to approximately 100 ml. The resulting microcrystalline product had m.p. 189-190°, [α]D -17.45° (1 percent, MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O)[CH3:10].C(COC)OC.C([O-])(O)=O.[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1
Reactant: CCOc1ccccc1B(O)O
Reactant: Clc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOc1ccccc1-c1cc(Cl)ncn1

Procedure:
To a solution of 4,6-dichloropyrimidine (6.0 g, 0.04 mol) and 2-ethoxyphenylboronic acid (4.81 g, 0.029 mol) in mixture of dimethoxyethane (120 mL) and water (18 mL) were added NaHCO3 (6.72 g, 0.08 mol) and (PPh3)2PdCl2 (0.84 g) and the reaction mixture was allowed to reflux for 8 h, then it was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (100 mL), the resulting solution was washed with water (20 mL), dried over anhydrous K2CO3, filtered and the solvent removed under reduced pressure. The crude product was purified by flash chromatography on silica (eluent CH2Cl2) and recrystallized from hexanes. Yield of 4-chloro-6-(2-ethoxyphenyl)-pyrimidine 4.97 g (73%).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])=[O:14])[CH:12]=1)[C:7]([OH:9])=O)=[O:3].FC(F)(F)C(O)=O.N[C@@H:30]([CH2:44][C:45]1[CH:50]=[C:49](F)[CH:48]=[C:47](F)[CH:46]=1)[C@H:31]([OH:43])[CH2:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=1>>[CH2:44]([C@H:30]([NH:1][C:2](=[O:3])[C:4]1[CH:5]=[C:6]([CH2:7][OH:9])[CH:10]=[C:11]([C:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])=[O:14])[CH:12]=1)[C@H:31]([OH:43])[CH2:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: COc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCN(CCC)C(=O)c1cc(C(N)=O)cc(C(=O)O)c1
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCC)C(=O)c1cc(CO)cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNCc2cccc(OC)c2)c1

Procedure:
Following the procedure of CHART P and EXAMPLE 739 and making non-critical variations but using 3-[(dipropylamino)carbonyl]-5-(hydroxymethyl)benzoic acid (IX) and (2R,3S)-3-amino-1-[(3-methoxybenzyl)amino]-4-phenyl-2-butanol (VIII), the title compound is obtained, HRMS (FAB)=615.3571.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[Cl:12].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(Cl)Cl>[Cl:12][C:3]1[CH:4]=[C:5]([S:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(F)c(Cl)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-fluoro-3-chlorobenzenesulphonyl chloride (0.9 g) was stirred in dry DCM (10 ml) and morpholine (0.69 ml) added. The mixture was allowed to stir at RT for 1 h and then quenched with water, extracted with DCM, dried (MgSO4) and evaporated under reduced pressure to give a white solid (1.10 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.CS[C:14](SC)=[CH:15][N+:16]([O-:18])=[O:17].C(O)C>CO.ClCCl>[N+:16]([CH:15]=[C:14]1[NH:11][CH2:10][CH2:9][N:8]1[C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([O-:18])=[O:17]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCNc1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: O=[N+]([O-])C=C1NCCN1c1ccc(Cl)nc1
Yield: 22.8 %

Procedure:
A mixture of N-(6-chloro-3-pyridyl)-1,2-diaminoethane (0.7 g, 0.0041 mol)(ex Example 4), 1,1-bis(methylthio)-2-nitroethene (0.7 g, 0.0042 mol) and ethanol (25 ml) was heated under reflux for 24 hours. The resulting mixture was evaporated to leave a dark brown oil which was subjected to flash chromatography on a silica column using silica gel, 230 to 400 US mesh (0.062 mm to 0.037 mm), and with 2% w methanol in dichloromethane as eluent. The resulting product was recrystallized from ethanol to give 2-nitromethylene-1-(6-chloro-3-pyridyl)imidazolidine as a pale yellow solid (0.225 g, 25%), m.p. 201° C.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][CH:36]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:37]([OH:39])=[O:38])[CH3:28].[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48](O)[CH2:47]2>C1COCC1>[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48]([O:38][C:37](=[O:39])[CH:36]([NH:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:27][CH3:28])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:47]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CCc1ccccc1NC(C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCc1ccccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
PS-DCC (962 mg, 1.37 mmol, loading: 1.33 mmol/g) is suspended in THF (10 mL). HOBT (210 mg, 1.37 mmol), (2-ethyl-phenylamino)-phenyl-acetic acid hydrochloride (160) (200 mg, 0.68 mmol), and (R)-quinuclidin-3-ol (262 mg, 2.06 mmol) are added and the mixture is shaken at RT overnight. PS-DCC is filtered off and washed with THF and the filtrate is evaporated under reduced pressure. The resulting residue is dissolved in EtOAc and washed with sat. NaHCO3, water and brine. The organic layer is separated, dried over Na2SO4, filtered and evaporated. The residue is first purified by flash chromatography (DCM/MeOH=9/1) and then by preparative HPLC. The fractions containing the product are pooled, concentrated under vacuum, basified with sat. NaHCO3 and extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and evaporated to afford the title compound as a colorless oil (52 mg, 21% yield, mixture of diastereoisomers).