Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[S:11][CH:12]=[C:13]([C:15]([NH:17][C:18]3[C:19]4[C:23]([CH:24]=[C:25]([C:27]5[CH:28]=[N:29][C:30]([O:39][CH3:40])=[C:31]([NH:33][S:34]([CH:37]=[CH2:38])(=[O:36])=[O:35])[CH:32]=5)[CH:26]=3)=[N:22][N:21](C3CCCCO3)[CH:20]=4)=[O:16])[N:14]=2)[CH2:3]1.[CH3:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>C(#N)C>[CH3:8][C@H:6]1[O:7][C@@H:2]([CH3:1])[CH2:3][N:4]([CH2:9][C:10]2[S:11][CH:12]=[C:13]([C:15]([NH:17][C:18]3[CH:26]=[C:25]([C:27]4[CH:28]=[N:29][C:30]([O:39][CH3:40])=[C:31]([NH:33][S:34]([CH2:37][CH2:38][N:51]5[CH2:52][CH2:53][N:48]([CH3:47])[CH2:49][CH2:50]5)(=[O:35])=[O:36])[CH:32]=4)[CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][NH:22]4)=[O:16])[N:14]=2)[CH2:5]1
Reactant: C=CS(=O)(=O)Nc1cc(-c2cc(NC(=O)c3csc(CN4C[C@@H](C)O[C@@H](C)C4)n3)c3cn(C4CCCCO4)nc3c2)cnc1OC
Reactant: CN1CCNCC1
Solvent: CC#N
Product: COc1ncc(-c2cc(NC(=O)c3csc(CN4C[C@@H](C)O[C@@H](C)C4)n3)c3cn[nH]c3c2)cc1NS(=O)(=O)CCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Acetonitrile (10 ml) was added to 2-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-N-[6-[5-[(ethenylsulfonyl)amino]-6-(methyloxy)-3-pyridinyl]-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl]-1,3-thiazole-4-carboxamide (250 mg) followed by 1-methylpiperazine (0.33 ml). The reaction was stirred at RT for 3 hours. The reaction was evaporated to dryness and the residue was separated between DCM and water. The DCM was passed through a hydrophobic frit then evaporated to dryness. The residue was dissolved in DMSO:methanol (1:1, v/v, 2 ml) and purified by MDAP (method E). Pure fractions were combined and evaporated to dryness. Analysis showed complete deprotection on dry-down to give title compound (116 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:9][C:10]([CH:12]1[CH2:14][CH2:13]1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH:10]([CH:12]2[CH2:14][CH2:13]2)[CH3:9])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)C1CC1
Reactant: Nc1cccc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(Nc1cccc(Cl)c1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.2 %

Procedure:
To a solution of 3-chloroaniline (1.27 g, 10 mmol) in 1,2-dichloroethane (20 ml) were added molecular sieves (4 g, size 0.4 nM) and cyclopropyl methyl ketone (0.84 g, 10 mmol). After stirring the mixture for 5 min at room temperature sodium triacetoxyborohydride (3.18 g, 15 mmol) and acetic acid (0.6 g, 10 mmol) were added. The reaction mixture was stirred at room temperature overnight. For workup dichloromethane (100 ml) and 1 M sodium bicarbonate solution (40 ml) were added and the mixture was shaken. The organic layer was separated, dried over magnesium sulfate and evaporated. The residue was purified using flash chromatography (heptane/ethyl acetate=9:1) to yield a colourless liquid (0.083 g, 4.5%); MS (ISP): 196.3 (M+H)+.).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>ClCCCl>[C:7]([N:3]1[CH2:4][CH2:5][O:1][C:2]1=[O:6])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1NCCO1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C1OCCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
To a solution of 2-oxazolidinone (4.68 g; 0.05 mol) in 1,2-dichlorethane (60 ml), there is added benzoyl chloride (5.6 ml, 0.05 mol) and triethylamine (7.0 ml; 0.05 mol), with stirring at ambient temperature for 30 mins. The solution is then concentrated at reduced pressure and ethyl acetate is added, thereafter it is filtered to remove the base hydrochloride; the filtrate is partly evaporated and diluted with n-heptane and the precipitated solid is removed by filtration. After washing with water and drying, it gives 3-benzoyl-2-oxazolidinone (5.94 g; 90%). From absolute ethanol it crystallises in nacar scales with m.p. = 166°-170° C. A portion of the substance in ethanol, with a catalytic amount of sodium ethoxide at room temperature immediately gives ethyl benzoate and, with aniline, benzanilide.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:28]1[N:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=1>CN1C(=O)CCC1.C(OCC)(=O)C>[F:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:20][CH2:19][N:18]([C:28]4[N:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=4)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ncc(F)c(N2CCC(C3CCNCC3)CC2)n1
Reactant: Fc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ncc(F)c(N2CCC(C3CCN(c4ncc(F)cn4)CC3)CC2)n1
Temperature: 70 °C

Procedure:
1-(5-fluoro-2-methylpyrimidin-4-yl)-4,4′-bipiperidine (16 mg, 0.058 mmol) and cesium carbonate (57 mg, 0.17 mmol) were stirred in NMP (0.6 ml) and 2-chloro-5-fluoropyrimidine (0.014 mL, 0.116 mmol) was added. The mixture was heated at 70° C. for 1 h. The reaction was cooled down to r.t. and diluted with ethyl acetate (5 mL) and was washed with water 2 mL (×1) and brine 2 mL (×1). The organic phase was dried over magnesium sulfate, filtered, and concentrated on rotavapor. The crude material was purified by preparative TLC with 30% acetone: hexane to yield the titled compound. LC-MS: 375.06 (M+H). Examples reported in Table 14 are prepared in accordance with Procedure 14.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([N+]([O-])=O)[CH:11]=1>C(O)C>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[C:14]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH3:8])[CH:15]=1
Reactant: Cc1ccccc1N
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CCO
Product: Cc1ccccc1Nc1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
81 ml of o-toluidine was added to a solution of 10 g of 1-chloro-3,4-dinitrobenzene in 50 ml of ethanol, and it was refluxed for 72 hours. It was concentrated by evaporation in a vacuum, the residue was taken up in ethyl acetate and 2N aqueous hydrochloric acid. The organic phase was extracted three more times with 2N aqueous hydrochloric acid, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by chromatography on silica gel.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:16])[CH:8]=1)=[O:5])#[N:2].[H-].[Na+].[C:19](N1C=CN=C1)(=[O:21])[CH3:20].Cl>O1CCCC1.C(O)(=O)C>[CH3:16][C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])/[C:3](/[C:1]#[N:2])=[C:19](\[OH:21])/[CH3:20])[CH:12]=[CH:11][C:10]=1[N+:13]([O-:15])=[O:14]
Reactant: Cc1cc(NC(=O)CC#N)ccc1[N+](=O)[O-]
Reactant: CC(=O)n1ccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C/C(O)=C(\C#N)C(=O)Nc1ccc([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Cyano-N-(3-methyl-4-nitrophenyl)acetamide (0.61 g; 2.8 mmol) is dissolved in tetrahydrofuran (30 ml) and sodium hydride (80% strength dispersion in oil; 0.21 g; 7 mmol) is added. The mixture is stirred at 25° C. for 15 minutes and 1-acetylimidazole (0.46 g; 4.2 mmol) is added dropwise over the course of 5 minutes and the mixture is stirred for a further 15 minutes. 2 ml of glacial acetic acid are added and the mixture is stirred at 25° C. for 1 hour and then poured into ice-cold water (100 ml). The pH of the solution is then adjusted to 1 using concentrated hydrochloric acid, and the precipitate is filtered, washed with water and brought to dryness under reduced pressure. N-(3-Methyl-4-nitrophenyl)-2-cyano-3-hydroxycrotonamide is thus obtained.
Reaction SMILES: [CH:1]1([C:11](OC)=[O:12])[CH2:6][CH2:5][CH:4]([C:7](OC)=[O:8])[CH2:3][CH2:2]1.[H][H]>[Cr].[Cu]>[CH:1]1([CH2:11][OH:12])[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1
Reactant: COC(=O)C1CCC(C(=O)OC)CC1
Reactant: [H][H]
Agent: [Cr]
Agent: [Cu]
Product: OCC1CCC(CO)CC1
Temperature: 260 °C

Procedure:
250 Parts of dimethyl 1,4-cyclohexanedicarboxylate and 25 parts of a copper-chromium catalyst were placed in an autoclave having a volume of 2 liters, and the mixture was stirred at 260° C. and reduced with hydrogen under a hydrogen pressure of 15 MPa. Then, the catalyst was removed by filtration, methanol formed as a side product was removed from an obtained filtrate by concentration, and the remaining filtrate was distilled under reduced pressure (160-175° C./1.33-2.00×103 Pa), to give 1,4-cyclohexanedimethanol (to be sometimes referred to as “CHDM” hereinafter). This product was subjected to 1H-NMR (JNM-AL400 supplied by JEOL) to show an isomer structure ratio of 71% of a trans-isomeric compound and 29% of a cis-isomeric compound (CHDM1).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Li]CCCC.C([O:21][C:22](=O)[C:23]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:26]([O:39][CH2:40][CH2:41][OH:42])=[C:25]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:52])([F:51])[F:50])[CH:44]=2)[CH:24]=1)C.Cl>C1COCC1>[CH2:1]([NH:13][C:22](=[O:21])[C:23]1[CH:24]=[C:25]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:49]([F:51])([F:52])[F:50])[CH:44]=2)[C:26]([O:39][CH2:40][CH2:41][OH:42])=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[CH:28]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Reactant: CCCCCCCCCCCCN
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCNC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c(OCCO)c(-c2cccc(C(F)(F)F)c2)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 92.6 %

Procedure:
To a flame-dried flask containing dodecyl amine (0.278 g, 1.5 mmol) in THF (5 mL) cooled to −78° C. was added n-BuLi (titrated to 2.37 M in hexanes) (0.670 mL, 1.59 mmol) dropwise. The solution was stirred at −78° C. for 20 min. and then warmed to room temperature over 20 min. The reaction was then recooled to −40° C. and 3,5-bis-(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)benzoic acid ethyl ester (0.215 g, 0.43 mmol) in THF (5 mL) was added. This mixture was allowed to warm to room temperature over 20 min. The reaction mixture was then poured into 0.1 N HCl solution and extracted with EtOAc. The combined organic layers were washed with 2 N HCl solution (3×), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (30% EtOAc:hexane) to afford N-dodecyl-3,5-bis(m-trifluoromethylphenyl)-4-(2-hydroxyethoxy)benzamide (0.254 g, 93%) as a white solid. 1H NMR (CDCl3) δ 7.90 (m, 2H); 7.82-7.76 (m, 4H); 7.65-7.56 (m, 4H); 6.22 (bt, 1H); 3.45 (dd, 2H); 3.30 (m, 4H); 1.60 (m, 2H); 1.25 (m, 18H); 0.84 (m, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:37])[S:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[C:17]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[N:18][C:19]3[C:24]([N:25]=1)=[CH:23][C:22]([C:26]([O:28]C)=[O:27])=[CH:21][CH:20]=3)[CH2:11][CH2:10][CH2:9]2)(=[O:5])=[O:4].[OH-].[Na+]>CO.O>[CH3:1][N:2]([CH3:37])[S:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[C:17]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[N:18][C:19]3[C:24]([N:25]=1)=[CH:23][C:22]([C:26]([OH:28])=[O:27])=[CH:21][CH:20]=3)[CH2:11][CH2:10][CH2:9]2)(=[O:4])=[O:5]
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(S(=O)(=O)N(C)C)ccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)S(=O)(=O)c1ccc2c(c1)CCCN2c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
To a solution of methyl 3-[6-(dimethylsulfamoyl)-1,2,3,4-tetrahydroquinolin-1-yl]-2-(4-fluorophenyl)quinoxaline-6-carboxylate (120 mg, 0.23 mmol) in methanol (30 mL) and water (2 mL) was added sodium hydroxide (36.9 mg, 0.92 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL) and adjusted to pH 5 with hydrogen chloride (3 N). The solids were collected by filtration to afford 3-[6-(dimethylsulfamoyl)-1,2,3,4-tetrahydroquinolin-1-yl]-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a light yellow solid (43.5 mg, 37%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][CH2:25][CH2:26][CH2:27][C:28](OCC)=[O:29].[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:27]([CH2:26][CH2:25][CH2:24][C:20]3[O:19][CH:23]=[CH:22][CH:21]=3)[C:28]2=[O:29])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CCCCc1ccco1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCCc2ccco2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 5-(2-furyl)pentanoate (1.5 eq., prepared in Synthetic Example 18) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[3-(2-furyl)propyl]-1,8-naphthyridin-2(1H)-one, mp 166 to 167° C./DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:14])[CH:13]=1)=[C:10]([O:15][CH2:16][CH:17]([OH:30])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=1)[CH:9]=[CH:8][CH:7]=2)([OH:3])=[O:2].[CH:31]1C=CC=C[CH:32]=1.C(O)C>S(=O)(=O)(O)O.O>[C:1]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:14])[CH:13]=1)=[C:10]([O:15][CH2:16][CH:17]([OH:30])[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([CH3:27])([CH3:29])[CH3:28])=[CH:24][CH:25]=1)[CH:9]=[CH:8][CH:7]=2)([O:3][CH2:31][CH3:32])=[O:2]
Reactant: c1ccccc1
Reactant: CC(C)(C)c1ccc(OCC(O)COc2cccc3oc(C(=O)O)cc(=O)c23)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(=O)c2c(OCC(O)COc3ccc(C(C)(C)C)cc3)cccc2o1

Procedure:
1-(2-carboxychromon-5-yloxy)-2-hydroxy-3-p-t-butylphenoxypropane (10.7 g), benzene (100 ml), ethanol (5 ml) and sulphuric acid (10 drops) were heated under reflux in a Dean and Stark separator until no more water passed over (about 6 hours). After cooling, the solution was washed with saturated sodium bicarbonate solution, and then water. The solvent was removed under reduced pressure to give a very viscous brown oil, from which solid material separated on standing. This solid was filtered off and washed several times with ether to give 1-(2-carbethoxy-chromon-5-yloxy)-2-hydroxy-3-p-t-butylphenoxypropane, 6.1 g, as a cream solid. A portion recrystallized from aqueous ethanol afforded almost colorless flakes m.p. 99°-101.5°.
Reaction SMILES: [C:1]([Si:5]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[O:6][CH2:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14])([CH3:4])([CH3:3])[CH3:2].Br.Br[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([Si:5]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[O:6][CH2:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccn1
Reactant: Cc1oc(-c2ccc(O)cc2)nc1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1oc(-c2ccc(OCc3ccccn3)cc2)nc1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 78.6 %

Procedure:
A mixture of 4-{4-[2-(tert-Butyl-diphenyl-silanyloxy)-ethyl]-5-methyl-oxazol-2-yl}-phenol (1.0 g, 2.25 mmol), 2-bromomethylpyridine hydrobromide (0.85 g, 3.4 mmol), and K2CO3 (1.1 g, 7.9 mmol) in acetone (20 mL) is heated at reflux for 12 h. The mixture is filtered, and the solvent is removed in vacuo. The residue is partitioned between EtOAc and water. The organic phase is washed with water and brine, dried (Na2SO4), and concentrated. The residue is purified by flash chromatography (90 g SiO2, elute 10% to 50% EtOAc/hexane) to yield 0.97 g of the title compound. MS (ES+) 549.3
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8](C(O)=O)=[N:9][CH:10]=1.C1(P([N:28]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C(O)(C)(C)C>[NH2:28][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH2:2][CH3:1])=[CH:10][N:9]=1
Reactant: CCCCc1ccc(C(=O)O)nc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CCCCc1ccc(N)nc1

Procedure:
Fusaric acid (2 g), diphenylphosphoryl azide (2.4 mL) and triethylamine (1.6 mL) in t-butanol (70 mL) were refluxed overnight. The contents were concentrated in vacuo and treated with 25% aqueous HBr (20 mL) for 24 hours. After neutralizing with 50% NaOH, contents were extracted with CH2Cl2, dried (MgSO4) and concentrated in vacuo to give 2-amino-5-(n-butyl)pyridine as an oil (1.1 g).
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([O:13]C(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[N:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=1)=C=O.[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([NH:21][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=2)=[O:13])[C@H:8]([C:18]([NH:35][CH2:34][CH2:33][O:32][CH3:31])=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: COCCN
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Cc1cccc(N=C=O)c1
Product: C=CCON=C1C[C@@H](C(=O)NCCOC)N(C(=O)Nc2cccc(C)c2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 1-isocyanato-3-methylben-zene, and 2-methoxyethylamine the title compound was obtained in 85% purity by LC/MS. MS(ESI+): m/z=375.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:26][O:27][C:28]1[CH:43]=[CH:42][C:31]([CH2:32][O:33][CH2:34][C@@H:35]2[C@@H:40]3[C@H:36]2[CH2:37][O:38][C:39]3=[O:41])=[CH:30][CH:29]=1.Cl>C1COCC1.CCOC(C)=O>[F:15][C:3]1[CH:4]=[C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:6]=[CH:7][C:2]=1[NH:1][C:37]([C@@H:36]1[C@@H:35]([CH2:34][O:33][CH2:32][C:31]2[CH:42]=[CH:43][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[C@@H:40]1[CH2:39][OH:41])=[O:38]
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Reactant: COc1ccc(COC[C@H]2[C@@H]3COC(=O)[C@H]23)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(COC[C@H]2[C@H](CO)[C@@H]2C(=O)Nc2ccc(-n3ccccc3=O)cc2F)cc1
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of 850 mg (3.4 mmol) of 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (prepared according to C. F. Bigge et al., patent application WO 2003045912) in 80 ml of THF was cooled to −78° C., treated dropwise with 4.8 ml of a 1M lithium bis(trimethylsilyl)amide-solution in THF and stirred for 30 min at 78° C. To this solution were added 839 mg (4.8 mmol) of (1R,5S,6S) 6-(4-methoxy-benzyloxymethyl)-3-oxa-bicyclo[3.1.0]hexan-2-one dissolved in 5 ml of THF. Stirring was continued at −78° C. for 1 hr and then for 3 hrs at RT. Pouring of the mixture into a 2M aqueous solution of HCl, extraction with AcOEt, drying of the combined organic phases over Na2SO4, filtration and evaporation of the solvent gave 1.2 g (77%) of (1S,2S,3S) 2-hydroxymethyl-3-(4-methoxy-benzyloxymethyl)-cyclopropanecarboxylic acid [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. Yellow semisolid. 453 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19](O)=[O:20])=[CH:15][CH:14]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:6]=2[N:7]=1.S(Cl)([Cl:27])=O>C(Cl)(Cl)Cl>[CH3:1][N:2]([C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([Cl:27])=[O:20])=[CH:15][CH:14]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:6]=2[N:7]=1
Reactant: CC(Oc1ccc(N(C)c2nc3cc(Cl)ccc3o2)cc1)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(Oc1ccc(N(C)c2nc3cc(Cl)ccc3o2)cc1)C(=O)Cl

Procedure:
A mixture of 2-{4-[N-methyl-N-(5-chloro-2-benzoxazolyl)amino]phenoxy}propionic acid (3.0 g, 0.0087 mole; see Example 9), thionyl chloride (0.76 ml, 0.01 mole) and chloroform (25 ml) was heated under reflux for a period of 3 hours. The reaction mixture was cooled and the solvent and excess thionyl chloride was removed by distillation under reduced pressure to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].[CH3:33][S:34]([OH:37])(=[O:36])=[O:35]>O>[CH3:33][S:34]([O-:37])(=[O:36])=[O:35].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S+:11]([C:30]2[CH:31]=[CH:32][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=2)[C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)O
Reactant: CC(C)(C)c1ccccc1
Reactant: CC(C)(C)c1ccc(S(=O)c2ccc(C(C)(C)C)cc2)cc1
Solvent: O
Product: CC(C)(C)c1ccc([S+](c2ccc(C(C)(C)C)cc2)c2ccc(C(C)(C)C)cc2)cc1
Product: CS(=O)(=O)[O-]
Temperature: 100 °C
Yield: 20.6 %

Procedure:
A mixture of 3 g of bis-(4-t-butylphenyl)sulfoxide, 30 ml of t-butylbenzene and 9.17 g of methane sulfonic acid was heated at 100° C. for 24 hours. The mixture was poured into 100 ml of water and extracted with four 50-ml portions of ether followed by five 50-ml portions of chloroform. The chloroform extracts were dried and the chloroform removed on a rotary evaporator to give 1.03 g of tris-(4-t-butylphenyl)sulfonium methane sulfonate (20.6 percent yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[NH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([CH2:19][NH:20][C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([O:28][CH3:29])[N:22]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([CH2:19][NH:20][C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[C:23]([O:28][CH3:29])[N:22]=2)[CH2:15][CH2:14]1)=[O:8]
Reactant: Cc1ncc(Cl)cc1C(=O)Cl
Reactant: COc1ccc(Cl)c(NC[C@H]2CC[C@H](N)CC2)n1
Product: COc1ccc(Cl)c(NC[C@H]2CC[C@H](NC(=O)c3cc(Cl)cnc3C)CC2)n1

Procedure:
The title compound is prepared from 5-chloro-2-methylnicotinoyl chloride (Intermediate C) and trans-(4-Amino-cyclohexylmethyl)-(3-chloro-6-methoxy-pyridin-2-yl)-amine (Intermediate BB) analogously to Example 2.0; 1H NMR (d6-DMSO, 400 MHz) δ 8.52 (1H, d), 8.39 (1H, d), 7.80 (1H, d), 7.42 (1H, d), 6.45 (1H, t), 5.90 (1H, d), 3.79 (3H, s), 3.69 (1H, my 3.22 (2H, t), 2.48 (3H, a), 1.91 (2H, m), 1.80 (2H, m), 1.60 (1H, m), 1.21 (2H, m), 1.07 (2H, m); LC-MS Rt 2.70 mins, [M+H]+ 423.55; Method LowpH_v002.