Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[N:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10](=[O:11])[C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)[C@@H:3]1[CH2:2][NH:1][C:25]1[N:30]=[N:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: N#Cc1ccc(Cl)nn1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C#N)nn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 6-chloropyridazine-3-carbonitrile. ESI-MS (m/z): 417 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[Br:34][C:35]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][C:36]=1[CH2:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>CN(C)C=O>[Br:34][C:35]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][C:36]=1[CH2:37][CH:38]1[CH2:39][CH2:40][N:41]([C:9](=[O:11])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:42][CH2:43]1
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: Oc1ccc(Br)c(CC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1Cl)N1CCC(Cc2cc(O)ccc2Br)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
In N,N-dimethylformamide (10 ml) were dissolved 4-(2-bromo-5-hydroxybenzyl)piperidine (the compound of Example 10) (2010.9 mg, 7.500 mmol), 2-chlorophenylacetic acid (1279.5 mg, 7.500 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1716.3 mg, 9.000 mmol) and 1-hydroxybenzotriazole (1114.8 mg, 7.500 mmol), and the resulting solution was stirred at room temperature for 5 hours. The reaction was terminated by adding water (100 ml), followed by extraction with a toluene-diethyl ether mixture (1:1). The organic layer was washed successively with a 5% aqueous sodium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent, whereby the title compound (2754.4 mg, 6.547 mmol) was obtained in a yield of 87%.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[CH:16]12[C:23](=[O:24])[O:22][C:20](=[O:21])[CH:17]1[CH2:18][CH2:19]2>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([NH:6][C:23]([C@H:16]2[CH2:19][CH2:18][C@H:17]2[C:20]([OH:22])=[O:21])=[O:24])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: O=C1OC(=O)C2CCC12
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1CC[C@H]1C(=O)O

Procedure:
From 2.3 g of 3,5-bistrifluoromethyl aniline and 1.1 g of cyclobutane-1,2-dicarboxylic anhydride used as starting materials, the title compound was obtained in the same manner as in Example 1.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[NH:10][C:11]2[CH2:15][CH2:14][C:13](=[O:16])[CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:24]I>CN(C)C=O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:17]=[CH:18][C:19]=2[O:20][CH3:21])[N:10]([C:11]2[CH2:15][CH2:14][C:13](=[O:16])[CH:12]=2)[CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CI
Reactant: COc1ccc(NC2=CC(=O)CC2)cc1OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)C2=CC(=O)CC2)cc1OC1CCCC1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
0.10 g (0.35 mmole) of 3-(3-cyclopentyloxy-4-methoxyanilino)-2-cyclopenten-1-one produced in Example 1, 0.02 g of sodium hydride (60%), and 0.06 g (0.42 mmole) of methyl iodide were dissolved in 4 ml of N,N-dimethylformamide and the solution was stirred at room temperature for one night. The reaction solution was quenched with water, then was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo to obtain a crude product. The crude product was purified by flash chromatography (SiO2; eluted by 2% methanol/methylene chloride) to obtain the title compound 0.10 g (yield 93.4%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14].C(N(CC)CC)C>O1CCCC1.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.[Cu]I>[N+:9]([C:5]1[CH:6]=[C:7]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[C:2]([NH2:1])=[N:3][CH:4]=1)([O-:11])=[O:10]
Reactant: Nc1ncc([N+](=O)[O-])cc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc([N+](=O)[O-])cnc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
12.0 g 2-Amino-3-bromo-5-nitropyridine, 1.93 g dichlorobis(triphenyl-phosphine)palladium(II) and 0.524 g copper(I) iodide were dispersed under nitrogen in 60 ml dry tetrahydrofuran (THF). 7.03 g trimethylsilylacetylene and 16.71 g triethylamine were added and the mixture was stirred 16 hours (hrs) at room temperature (RT). The mixture was filtered, the filtrate was evaporated and the residue purified by chromatography on silica in ethyl acetate/heptane mixtures.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].OS(O)(=O)=O.[CH3:18][CH2:19]O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:18][CH3:19])=[O:11]
Reactant: CCO
Reactant: Cc1ccc(C)c(CC(=O)O)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(C)ccc1C
Yield: 84 %

Procedure:
A solution of (2,5-dimethylphenyl)acetic acid (3.0 g; 18.3 mmol) and H2SO4 (conc.; 0.1 mL) in EtOH (40 mL) was refluxed over 6 days. The solution was concentrated, ether (40 mL) was added, and the resultant mixture was washed with Na2CO3 solution (2×25 mL) and water (1×25 mL). The organic phase was dried (MgSO4) and evaporated, yielding 2.94 g (84%) of the sub-title compound a clear colourless liquid. Purity 97%.
Reaction SMILES: [CH3:1][C:2]1([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2>[Pd].C(OCC)(=O)C>[CH3:1][C:2]1([O:12][C:13]2[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=2)[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2
Reactant: CC1(Oc2ccc([N+](=O)[O-])cc2)C2CC3CC(C2)CC1C3
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(Oc2ccc(N)cc2)C2CC3CC(C2)CC1C3

Procedure:
A solution of 15.0 g. (0.0522 mole) of 4-(2-methyl-2-adamantyloxy)-nitrobenzene in 150 ml. of ethyl acetate was hydrogenated over 10% Pd/C. The crude product was recrystallized from CH2Cl2 and Skellysolve B to give 8.6 g. of light tan solid, m.p. 95.6°-97.9° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:17]2[CH:18]=[N+:19]([O-:23])[CH:20]=[CH:21][CH:22]=2)[C:8]2[C:15](=[O:16])[O:14][CH2:13][C:9]=2[NH:10][C:11]=1[CH3:12])=[O:5])[CH3:2].[CH3:24][NH2:25]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:17]2[CH:18]=[N+:19]([O-:23])[CH:20]=[CH:21][CH:22]=2)[C:8]([C:15]([NH:25][CH3:24])=[O:16])=[C:9]([CH2:13][OH:14])[NH:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CN
Reactant: CCOC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccc[n+]([O-])c1
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)NC)C1c1ccc[n+]([O-])c1

Procedure:
A mixture of 10.0 g of 2-methyl-4-(1-oxido-3-pyridyl)-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carboxylic acid ethyl ester and 100 ml of a 33% solution of methylamine in ethanol is heated at 90° in a sealed tube for 16 hours. The reaction mixture is concentrated to dryness by evaporation under reduced pressure and the residue is partitioned between methylene chloride and a 2N aqueous sodium carbonate solution. The organic phase is removed, washed with water, dried and concentrated by evaporation under reduced pressure. The residue is chromatographed over silica gel and eluted with ethyl acetate. The uniform fractions ascertained by means of a thin layer chromatograph are concentrated to dryness by evaporation under reduced pressure and the residue is recrystallised from a mixture of isopropanol and petroleum ether to yield 6-hydroxymethyl-2-methyl-5-methylaminocarbonyl-4-(1-oxido-3-pyridyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester melting at 197°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][C@H:19]([C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=2)[CH3:20])=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([NH2:40])(=[O:39])=[O:38]>>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)=[C:4]([CH:3]=1)[C:16]([NH:18][C@H:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:40][S:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[Cl:30])(=[O:39])=[O:38])=[O:27])=[CH:23][CH:22]=1)[CH3:20])=[O:17]
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)O)cc1
Reactant: NS(=O)(=O)c1ccccc1Cl
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)NS(=O)(=O)c2ccccc2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 103 from 4-[(1S)-1-({[5-chloro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid (step 5 of Example 44) and 2-chlorobenzenesulfonamide: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.6 Hz), 8.23–8.12 (2H, m), 8.04 (1H, d, J=2.6 Hz), 7.87 (1H, d, J=7.3 Hz), 7.47–7.16 (5H, m), 7.15–7.01 (5H, m), 5.45–5.25 (1H, m), 1.48 (3H, d, J=6.4 Hz); MS (ESI) m/z 588 (M+H)+, 586 (M−H)−.
Reaction SMILES: CC1C=CC(S([NH:11][C:12]2[CH:17]=[C:16]([F:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][C:13]=2[F:22])(=O)=O)=CC=1.S(=O)(=O)(O)O>O>[F:22][C:13]1[CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]([F:18])=[CH:17][C:12]=1[NH2:11]
Reactant: Cc1ccc(S(=O)(=O)Nc2cc(F)c([N+](=O)[O-])cc2F)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1cc(F)c([N+](=O)[O-])cc1F
Temperature: 90 °C
Reaction time: 4 h
Yield: 143.6 %

Procedure:
A stirred solution of 25.0 grams (0.076 mole) of N-(4-methylphenylsulfonyl)-2,5-difluoro-4-nitroaniline in 50 mL of water was cooled in an ice-water bath, and 150 mL of concentrated sulfuric acid was carefully added portionwise. Upon completion of the addition, the reaction mixture was heated to about 90° C., where it stirred for about four hours. The reaction mixture was then cooled and poured into wet ice. The resultant solid was collected by filtration and dried, yielding about 19.0 grams of 2,5-difluoro-4-nitroaniline. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(Br)(Br)Br.C(OCC)C>C(Cl)Cl>[C:13]1([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:11]=[CH:12][C:3]=2[OH:2])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc2ccccc2c1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOCC
Product: Oc1ccc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
In methylene chloride (300 mL), dissolved was 2-methoxy-1-phenylnaphthalene (13.0 g, 55.5 mmol), and 670 mL of boron tribromide solution (1 M in methylene chloride) was added dropwise thereto at −78° C. Reaction was carried out for 3 hours while slowly raising the temperature to ambient temperature. When the reaction was completed, mixture of ice (150 g) and diethyl ether (250 mL) was added thereto. After isolating the organic layer, the aqueous layer was extracted with diethyl ether. The combined organic layer was dried over magnesium sulfate, and evaporated to remove the volatiles. The residue was purified via silica gel column chromatography by using mixed solvent of hexane and methylene chloride to obtain 1-phenylnaphthalen-2-ol (10.0 g, yield: 81.8%) as white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]([N:19]1[CH2:22][CH:21]([OH:23])[CH2:20]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.C(O)(=O)/C=C\C(O)=O>C1C=CC=CC=1.C1(C)C=CC=CC=1.C(OCC)C>[CH:6]([N:19]1[CH2:22][CH:21]([O:23][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:20]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: CCOCC
Product: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 0.5 h

Procedure:
Slowly add 1.0 mole of methanesulfonyl chloride to an agitating solution of 1.0 mole 1-benzhydryl-3-hydroxyazetidine and triethylamine in benzene or toluene maintained at 10° to 15° C. Agitate the reaction mixture at 15° to 18° C. for half an hour, then at 20°-23° C. for another half hour. Add diethyl ether and agitate for 10 minutes longer. Remove the triethylamine hydrochloride precipitate by filtration and add the filtrate to a solution of 1.0 mole maleic acid in diethyl ether and stir for about one hour. Isolate the product 1-benzhydryl-3-methanesulfonyloxyazetidine as the hemimaleate salt (1:1) by filtration.
Reaction SMILES: Cl[C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2.[CH3:24][O-:25].[Na+]>CO>[Cl:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:14])[N:3]([C@@H:15]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]1[OH:17])[C:2]([O:25][CH3:24])=[C:10]2[C:11]#[N:12]
Reactant: C[O-]
Reactant: N#Cc1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Agent: [Na+]
Solvent: CO
Product: COc1c(C#N)c2cc(Cl)c(Cl)cc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Yield: 67.5 %

Procedure:
2,5,6-Trichloro-3-cyano-1-(β-D-ribofuranosyl)indole (4.4, 100 mg, 0.27 mmol) was dissolved in dry MeOH (10 mL) to which was added sodium methoxide (100 mg, 1.9 mmol). The resulting solution heated at reflux for 2 h, then cooled to room temperature and the solvent evaporated. The residual solid was recrystallized from MeOH/H2O to yield 68 mg (63%) of 4.26 as a white powder: mp 245-246° C.; Rf 0.2 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 8.36 (s, 1H), 7.65 (s, 1H), 5.80 (d, 1H), 5.37 (d, 1H, D2O exch.), 5.28 (t, 1H, D2O exch.), 5.20 (d, 1H, D2O exch.), 4.39-4.37 (m, 4H), 4.10 (m, 1H), 3.93 (d, 1H), 3.66 (m, 2H). 13C-NMR (125 MHz, DMSO-d6): δ 158.44, 128.52, 126.05, 125.01, 124.81, 118.21, 115.02, 114.47, 86.89, 85.86, 71.06, 69.67, 65.16, 61.10, 60.81. HRMS (EI) m/z calcd. for C15H14Cl2N2O5 372.0280, found 372.0265. Anal calcd for C15H14Cl2N2O5: C, 48.28; H, 3.78; N, 7.51. Found: C, 47.97; H, 3.75; N, 7.34.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:31]1[C:36]([C:37]2[N:42]=[C:41]([CH3:43])[N:40]=[C:39]([N:44]([CH2:54][C:55]3[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=3)[CH2:45][C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=3)[N:38]=2)=[CH:35][CH:34]=[CH:33][N:32]=1>C1COCC1>[CH3:62][O:61][C:58]1[CH:57]=[CH:56][C:55]([CH2:54][N:44]([CH2:45][C:46]2[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[CH:50][CH:51]=2)[C:39]2[N:40]=[C:41]([CH3:43])[N:42]=[C:37]([C:36]3[C:31]([NH:1][C:2]4[CH:3]=[C:4]([NH:9][S:10]([C:13]5[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=5)(=[O:11])=[O:12])[C:5]([Cl:8])=[N:6][CH:7]=4)=[N:32][CH:33]=[CH:34][CH:35]=3)[N:38]=2)=[CH:60][CH:59]=1
Reactant: Nc1cnc(Cl)c(NS(=O)(=O)c2ccc(F)cc2)c1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3cnc(Cl)c(NS(=O)(=O)c4ccc(F)cc4)c3)n2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.7 %

Procedure:
A mixture of N-(5-amino-2-chloropyridin-3-yl)-4-fluorobenzenesulfonamide (0.08 g, 0.265 mmol) in THF (5 mL) was cooled to 0° C. under N2. Lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydrofuran (Aldrich) (0.795 mL, 0.795 mmol) was added dropwise and the mixture was stirred at 0° C. for 30 min before 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.142 g, 0.318 mmol) was added. The resulting mixture was stirred at 0° C. for 10 min then removed from the ice bath and stirred for 3 h. The reaction mixture was quenched with water. The resulting mixture was partitioned between EtOAc and sat. NH4Cl. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with water, brine, dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, 20% to 30% acetone in hexanes) to give the product as a yellow solid (0.090 g). m/z (ESI, +ve ion) 727.1 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 12.48 (s, 1H); 8.78-8.95 (m, 2H); 8.41 (d, J=3.51Hz, 1H); 8.27 (s, 1H); 7.93 (dd, J=8.62, 4.97 Hz, 2H); 7.22 (d, J=6.58 Hz, 4H); 7.14 (t, J=8.48 Hz, 2H); 6.77-6.97 (m, 6H); 4.85 (d, J=3.36 Hz, 4H); 3.81 (d, J=5.12 Hz, 6H); 2.61 (s, 3H).
Reaction SMILES: [F:1][CH:2]([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:12](OCC)(OCC)[O:13][CH2:14][CH3:15].C(OC(=O)C)(=O)C>>[CH2:14]([O:13]/[CH:12]=[C:4](/[C:3](=[O:10])[CH:2]([F:11])[F:1])\[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:15]
Reactant: CCOC(=O)CC(=O)C(F)F
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCO/C=C(\C(=O)OCC)C(=O)C(F)F
Temperature: 100 °C
Yield: 74.8 %

Procedure:
To a freshly prepared solution of sodium ethoxide (prepared by addition of 1.11 g, 48.35 mmol Na metal in 8 mL EtOH) in EtOH was added a solution of ethyl difluoroacetate (5.0 g, 40.29 mmol) in EtOAc (9 mL) at rt and the reaction mixture was heated at 65° C. for 2 h. Then the reaction mixture was quenched with 1N HCl at rt and the pH was adjusted to 6-7. Then the reaction mixture was extracted with EtOAc and the organic layer was washed with water and brine, separated, dried, filtered and concentrated to afford 5.5 g of ethyl 4,4-difluoro-3-oxobutanoate which was taken to the next step without further purification. To a mixture of ethyl 4,4-difluoro-3-oxobutanoate (5.5 g, 33.11 mmol) and triethyl orthoformate (12 mL, 66.26 mmol) was added acetic anhydride (27.0 g, 265.0 mmol) and the reaction mixture was heated at 100° C. for 12 h. Then the reaction mixture was concentrated to afford 5.5 g of the title product which was taken to the next step without further purification.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1.[NH2:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([OH:21])=[C:16]([Cl:22])[CH:15]=1>>[Cl:20][C:18]1[CH:19]=[C:14]([NH2:13])[CH:15]=[C:16]([Cl:22])[C:17]=1[O:21][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:5]=2[N:6]=1
Reactant: COc1cccc2sc(Cl)nc12
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Product: COc1cccc2sc(Oc3c(Cl)cc(N)cc3Cl)nc12

Procedure:
3,5-Dichloro-4-(4-methoxy-benzothiazol-2-yloxy)-phenylamine was synthesized (21%) from 2-chloro-4-methoxybenzotiazole (257) and 4-amino-2,6-dichlorophenol (Aldrich) in a similar manner as described in Example 417. 1H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J=8.0 Hz, 1H), 7.28 (t, J=8.1 Hz, 1H), 7.01 (d, J=8.1 Hz, 1H), 6.73 (s, 2H), 5.86 (s, 2H), 3.85 (s, 3H). MS (EI): m/z 341 (M+H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@@H:33]6[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:50]([O:52][CH:53]([CH3:55])[CH3:54])=[O:51]>>[Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@@H:33]6[CH2:38][CH2:37][C@H:36]([NH:39][C:50](=[O:51])[O:52][CH:53]([CH3:55])[CH3:54])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](N)CC4)cc3)nc2n1COCC[Si](C)(C)C
Product: CC(C)OC(=O)N[C@H]1CC[C@@H](c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O[Si](C)(C)C(C)(C)C)n4COCC[Si](C)(C)C)cc2)CC1

Procedure:
The title compound is prepared from (cis)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanamine and isopropyl chloroformate following a procedure analogous to that described for Intermediate 8.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])/[CH:25]=[CH:26]\[C:27]([OH:29])=O)([OH:3])=[O:2].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>>[C:24]1(=[O:30])[N:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:27](=[O:29])[CH:26]=[CH:25]1
Reactant: O=C(O)/C=C\C(=O)NCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: O=C(O)CCCCCCCCCCCCCCCCCCCN1C(=O)C=CC1=O
Yield: 46.3 %

Procedure:
A mixture of N-(19-carboxynonadecyl)maleamic acid (500 mg, 1.22 mmoles), 3.44 ml of acetic anhydride and anhydrous sodium acetate (50.1 mg, 0.61 mmole) was reacted for 1 hour at 100° C. After the completion of reaction, the reaction mixture was treated in the same manner as in Example 1, to give 20-maleimidoeicosanoic acid (230 mg, 46%) having the following properties.
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][O:4][C:5]1[C:14]([C:15]([CH3:17])=[CH2:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]=1>CO.[Pd]>[F:18][CH:2]([F:1])[CH2:3][O:4][C:5]1[C:14]([CH:15]([CH3:16])[CH3:17])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]=1
Reactant: C=C(C)c1cc(C(=O)OC)cnc1OCC(F)F
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cnc(OCC(F)F)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Palladium 10% on carbon (50 mg) is added to a solution of methyl 6-(2,2-difluoroethoxy)-5-(prop-1-en-2-yl)nicotinate (491 mg, 1.91 mmol, Step-1) in methanol (20 mL) and stirred at room temperature under hydrogen atomosphare (1 atm) for 2 hours. The reaction mixture is filtrated through a pad of Celite and filtrate is concentrated in vacuo to give 490 mg (99% yield) of the title compound as colorless oil. This material is used for the next reaction (Step-3) without further purification.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.F[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Sc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Sc1ccncc1
Yield: 57.4 %

Procedure:
A mixture of 4-mercaptopyridine (2.00 g, 18.0 mmol), 1-fluoro-2-nitrobenzene (2.54 g, 18.0 mmol) and potassium carbonate (2.49 g, 18.0 mmol) in DMF (15 mL) was stirred under reflux for 2 h. After removal of DMF, the residue was dissolved in DCM and washed with NaOH (5%, 3×20 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated. Flash Master chromatography of the crude product using DCM to DCM/MeOH 98:2 gradient as eluent gave 4-(2-nitrophenylsulfanyl)-pyridine (2.4 g, 57%) as a yellow solid, mp 119-122° C.