Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[CH2:11][CH2:12][NH2:13].[C:17]([NH:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][C:25]([CH2:31]Br)=[CH:26][CH:27]=2)[N:22]=1)(=[O:19])[CH3:18]>CN(C=O)C>[C:17]([NH:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][C:25]([CH2:31][NH:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[C:8]([F:7])[CH:9]=3)=[CH:26][CH:27]=2)[N:22]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1ccc2ccc(CBr)cc2n1
Reactant: NCCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc2ccc(CNCCc3cccc(F)c3)cc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
Anhydrous Cs2CO3 (0.295 g, 0.906 mmol) was diluted in anhydrous DMF (10 mL). 3-Fluorophenethylamine (22, 0.126 g, 0.906 mmol) was added, and the mixture was stirred at room temperature for 30 min before a solution of 21 (0.220 g, 0.788 mmol) in DMF (4 mL) was added slowly over 5 min. The cloudy yellow mixture was stirred at room temperature for 16 h and concentrated. The residue was diluted with EtOAc (50 mL) and washed with H2O (2×50 mL) and sat. aq. NaCl (50 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by flash column chromatography (SiO2) eluting with 10% MeOH in EtOAc to yield the product as a clear yellow oil (0.187 g, 70%). 1H-NMR (500 MHz; CDCl3): δ 8.95 (s, 1 H), 8.40 (br d, J=8.2 Hz, 1 H), 8.15 (d, J=8.9 Hz, 1 H), 7.74 (d, J=8.3 Hz, 1 H), 7.72 (s, 1 H), 7.41 (dd, J=8.3, 1.5 Hz, 1 H), 7.26-7.22 (m, 1 H), 6.98 (d, J=7.7 Hz, 1 H), 6.93-6.88 (m, 2 H), 4.00 (s, 2 H), 2.95 (t, J=7.0 Hz, 2 H), 2.85 (t, J=7.0 Hz, 2 H), 2.23 (s, 3 H); 13C NMR (126 MHz; CDCl3): δ 169.3 (1 C), (163.9+162.0, 1 C), 151.3 (1 C), 146.5 (1 C), (142.47+142.41, 1 C), 142.37 (1 C), 138.5 (1C), (129.95+129.88, 1 C), 127.8 (1 C), 125.76 (1 C), 125.71 (1 C), 125.4 (1 C), (124.42+124.40, 1 C), (115.63+115.46, 1 C), 114.0 (1 C), (113.23+113.06, 1 C), 53.7 (1 C), 50.1 (1 C), 36.1 (1 C), 24.9 (1 C); ESIMS m/z (rel. intensity) 338 (MH+, 80).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:8]=2[N:9]=1.[N+:17]([O-])([OH:19])=[O:18]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:16])[NH:4][C:5]1[S:6][C:7]2[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)cccc2s1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2c(OC)ccc([N+](=O)[O-])c2s1
Temperature: 70 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a stirred solution of 13.6 g (57.1 mmol) (4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester in 300 ml acetic acid at room temperature was added 200 ml 65% nitric acid and the mixture heated at 70° C. for 4 h. The mixture was then poured onto stirred ice-water and the resulting slurry was filtered. The filter-cake was dissolved in THF and 5 N sodium hydroxide solution was added until the pH was 8. This mixture was then stirred for 1 h, filtered, and the filter-cake dried in vacuo to afford 7.61 g (47%) (4-methoxy-7-nitro-benzothiazol-2-yl)-carbamic acid methyl ester as a yellow crystalline solid. Meanwhile, the filtrate was separated into its aqueous and organic phases and the organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was resuspended in 200 ml THF and 200 ml methanol and heated at 70° C. overnight. The mixture was then cooled to room temperature and the resulting crystals were collected by filtration, washed with THF, and dried in vacuo to afford a further 1.50 g (9%) of product as a yellow crystalline solid. ES-MS m/e (%): 306 (M+Na+, 28), 2,S4 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:7]([CH3:21])[C:6]=2[C:5]([C:22]#[N:23])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C[Si]([N:35]=[N+:36]=[N-:37])(C)C.C([Sn](=O)CCCC)CCC>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:22]2[NH:37][N:36]=[N:35][N:23]=2)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:7]2[CH3:21]
Reactant: Cc1nc2c(Cl)ccc(C#N)c2c(C)c1Cc1ccc(Cl)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nc2c(Cl)ccc(-c3nnn[nH]3)c2c(C)c1Cc1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A mixture of 8-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinoline-5-carbonitrile (0.048 g), toluene (1.5 mL), trimethylsilyl azide (0.081 g) and dibutyltin oxide (0.007 g) were sealed in a flask and heated at 100° C. for 66 hours. The mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with saturated aqueous sodium hydrogen carbonate solution and the pH of the aqueous phase was adjusted to 5 by the addition of glacial acetic acid. The resulting precipitate was collected by filtration, washed with diluted aqueous acetic acid solution and dried to afford title compound as a white solid, 0.017 g.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][C:11]([CH3:54])([CH2:52][CH3:53])[CH2:12][C:13]1[N:14]=[C:15]([CH2:37][CH:38]([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)=[CH:42][CH:41]=2)O)[N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:10][C:11]([CH3:54])([CH2:52][CH3:53])[CH2:12][C:13]1[N:14]=[C:15]([CH2:37][CH:38]([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)=[CH:42][CH:41]=2)[F:7])[N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)c2ccc(-c3ccccn3)cc2)n1
Reactant: CCN(CC)S(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(F)c2ccc(-c3ccccn3)cc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Diethylaminosulfur trifluoride (0.1 mL, 0.78 mmol) was added to a 0° C. solution of 2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-(4-pyridin-2-ylphenyl)ethanol (385 mg, 0.65 mmol) in methylene chloride (10 mL). After stirring at 0° C. for 30 min then warming to ambient temperature then letting sit at −20° C. overnight, triethylamine (1 mL) was added. After stirring for a further 5 min, the reaction mixture was concentrated in vacuo. Chromatography over silica eluting with 0-40% ethyl acetate/hexane afforded 2-(4-{2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-fluoroethyl}phenyl)pyridine.
Reaction SMILES: [CH3:1][NH:2]C(C1C(=O)C(C2C=CN=C(C(F)(F)F)C=2)=C(C)N(C(C2C=CC(Br)=CN=2)C)C=1)=O.[CH2:32]([NH:34][C:35]([C:37]1[C:38](=[O:63])[C:39]([C:53]2[CH:58]=[CH:57][N:56]=[C:55]([C:59]([F:62])([F:61])[F:60])[CH:54]=2)=[C:40]([CH3:52])[N:41]([CH:43]([C:45]2[CH:50]=[CH:49][C:48](Br)=[CH:47][N:46]=2)[CH3:44])[CH:42]=1)=[O:36])[CH3:33]>>[CH2:32]([NH:34][C:35]([C:37]1[C:38](=[O:63])[C:39]([C:53]2[CH:58]=[CH:57][N:56]=[C:55]([C:59]([F:62])([F:61])[F:60])[CH:54]=2)=[C:40]([CH3:52])[N:41]([CH:43]([C:45]2[CH:50]=[CH:49][C:48]([C:1]#[N:2])=[CH:47][N:46]=2)[CH3:44])[CH:42]=1)=[O:36])[CH3:33]
Reactant: CNC(=O)c1cn(C(C)c2ccc(Br)cn2)c(C)c(-c2ccnc(C(F)(F)F)c2)c1=O
Reactant: CCNC(=O)c1cn(C(C)c2ccc(Br)cn2)c(C)c(-c2ccnc(C(F)(F)F)c2)c1=O
Product: CCNC(=O)c1cn(C(C)c2ccc(C#N)cn2)c(C)c(-c2ccnc(C(F)(F)F)c2)c1=O

Procedure:
Example 19c is prepared as described for Example 15, substituting preparation 15b with preparation 19b. ESI mass spectrum: [M+H]+=456; Retention time HPLC: 0.96 min (Z018_S04).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=O)[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.O.[NH2:14][NH2:15]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[C:6](=[O:7])[NH:15][NH:14][C:9]2=[O:8]
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH][nH]c(=O)c2cc(Cl)ccc12
Yield: 92.6 %

Procedure:
A mixture of 4-chlorophthalic anhydride (1.81 g, 10 mmol) and acetic acid (15 mL) was added to a solution of hydrazine hydrate (0.62 mL, 10 mmol) in acetic acid (2 mL). The resulting mixture was stirred at reflux for 2 h. The precipitate was collected and dried to give the title compound as a white solid (1.82 g, 95%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.S([O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH3:25])=[CH:20][CH:19]=1)(O)(=O)=O>>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:24]([C:21]3[CH:22]=[CH:23][C:18]([OH:17])=[CH:19][CH:20]=3)[CH3:25])=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ncnc2c1
Reactant: CNc1ccc(OS(=O)(=O)O)cc1
Product: CN(c1ccc(O)cc1)c1ncnc2cc(Cl)ccc12

Procedure:
4,7-Dichloroquinazoline (prepared according to the method of Price et al, J. Am. Chem. Soc., 1946, 68, 1305) was reacted with 4-(N-methylamino)phenol sulfate, following essentially the same procedure as that described in Example 3 part a), to give 4-[N-(7-chloro-4-quinazolinyl)-N-methylamino]phenol as a yellow solid, mp 165° C.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH3:8][C:9]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:34])[CH2:17][CH2:18][C:19](=[O:33])[CH:20]([CH3:32])[CH2:21][CH2:22][CH:23]=[C:24]([CH3:31])[CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])=CCO>N1C=CC=CC=1>[C:5]([O:4][CH2:1][CH:2]=[C:9]([CH3:8])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:34])[CH2:17][CH2:18][C:19](=[O:33])[CH:20]([CH3:32])[CH2:21][CH2:22][CH:23]=[C:24]([CH3:31])[CH2:25][CH2:26][CH:27]=[C:28]([CH3:30])[CH3:29])(=[O:7])[CH3:6]
Reactant: CC(C)=CCCC(C)=CCCC(C)C(=O)CCC(C)=CCCC(C)=CCO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCC=C(C)CCC=C(C)CCC(=O)C(C)CCC=C(C)CCC=C(C)C
Temperature: 0 °C
Yield: 89.9 %

Procedure:
To a mixture of acetic anhydride (8.1 g) and pyridine (3.2 g), 3,7,11,15,19-pentamethyl-2,6,14,18-eicosatetraen-10-on-1-ol (15 g) is added, and stirring is continued while cooling with ice for 3 hours. The reaction mixture is poured into ice water and extracted with ether. The ether extract is washed with water, dired and evaporated to give 1-acetoxy-3,7,11,15,19-pentamethyl-2,6,14,18-eicosatetraen-10-one (15 g). IR: 1740, 1710, 1675 cm-1. NMR (carbon tetrachloride): δ 1.01 (d), 1.56 (s), 1.65 (s), 1.90 (s), 1.97 (s), 2.05-2.71 (m), 4.43 (d), 4.70-5.39 (m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1>>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23]([N:16]2[CH:17]=[C:13]([C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:9][O:10][C:11]=3[C:18]([F:21])([F:19])[F:20])[N:14]=[CH:15]2)=[CH:24][CH:25]=1
Reactant: Fc1ccc(-c2noc(C(F)(F)F)c2-c2c[nH]cn2)cc1
Reactant: COC(=O)c1ccc(F)cc1
Product: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Yield: 44 %

Procedure:
As described for Example 24, 3-(4-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (900 mg, 3.0 mmol), using methyl 4-fluorobenzoate instead of 4-fluoroacetophenone, was converted to the title compound (580 mg, 44%) which was obtained as a white solid. MS: m/e=432.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)#[N:23].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:21])[C@@H:4]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:27]2[CH:28]=[CH:29][C:24]([C:22]#[N:23])=[CH:25][CH:26]=2)=[CH:8][CH:7]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)OC(C)(C)C
Yield: 68.2 %

Procedure:
To a solution of (S)-3-(4-Bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester (70.1 mmol) in toluene (250 mL) was added 4-cyanobenzeneboronic acid (105 mmol), Pd(PPh3)4 (3.5 mmol), and 1N Na2CO3 solution (105 mL). The mixture was heated at reflux for 7 h. After completion of the reaction, the aqueous layer was drained. The organic was washed with 10% Na2CO3 and 1 N HCl. The organic was dried over sodium sulfate and concentrated under reduced pressure to afford the crude product. The residue was purified by column chromatography (hexanes-EtOAc) to provide (S)-2-tert-Butoxycarbonylamino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (18.2 g). LC-MS (m/z) 382.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:15](Cl)(=[O:17])[CH3:16]>C(Cl)Cl>[C:15]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: Oc1cccc(F)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc(F)c1
Temperature: 25 °C

Procedure:
A solution of 3-fluorophenol (100 g, 0.890 mol) in methylene chloride is cooled to 0° C. to 5° C., treated with pyridine (75.0 mL, 0.930 mol), stirred for several minutes, treated dropwise with acetyl chloride (66.0 mL, 0.930 mol) while maintaining the reaction mixture temperature below 17° C., stirred at ice-bath temperature for two hours, warmed to room temperature, and poured into an ice-water mixture. The organic phase is separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the title product as a yellow oil which is identified by 1H NMR spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20](O)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.[CH2:25]([O:27][C:28](=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:37])[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([NH:36][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH2:13][CH2:12][N:11]3[S:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:23][CH3:24])(=[O:9])=[O:10])=[CH:15][CH:16]=2)=[O:21])=[CH:34][CH:35]=1)[CH3:26]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2ccc(C(=O)O)cc21
Product: CCOC(=O)Cc1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CC3)cc1

Procedure:
The title compound was prepared as for example 8, steps 1 to 4. Step 1 was performed using 5-chloro-2-methoxybenzensulfonyl chloride and yielded 1-(5-chloro-2-methoxybenzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester, which was hydrolyzed to 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid in step 2 and coupled to (4-amino-phenyl)-acetic acid ethyl ester and yielded (4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-phenyl)-acetic acid ethyl ester, which was hydrolyzed to (4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-phenyl)-acetic acid in step 4, MS (ISP): m/e=499.1 (M−H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:12])[C:10]=2[N:11]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][C:16]=1[CH3:24].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][C:16]1[CH:17]=[C:18]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[CH:7][NH:8][C:9](=[O:12])[C:10]=3[N:11]=2)[CH:19]=[CH:20][C:15]=1[O:14][CH3:13]
Reactant: O=c1[nH]cnc2ccc(Cl)nc12
Reactant: COc1ccc(B(O)O)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2ccc3nc[nH]c(=O)c3n2)cc1C
Temperature: 25 °C
Yield: 76.8 %

Procedure:
To a solution of 6-chloro-pyrido[3,2-d]pyrimidin-4(3H)one (1.94 mmole) in 1,4-dioxane (40 ml) and water (20 ml) was added 4-methoxy-3-methylphenyl boronic acid (2.33 mmole), potassium carbonate (4.85 mmole) and tetrakis(triphenylphosphine)palladium(0) (0.097 mmole). The reaction mixture was refluxed for two hours, cooled to room temperature and the solvents were evaporated in vacuo. The residue was adsorbed on silica and purified by silica gel column chromatography (the mobile phase being a methanol/dichloromethane mixture in a ratio of 3:97), affording the title compound as a pure white powder (398 mg, yield 77%) which was characterized by its mass spectrum as follows: MS (m/z): 268 ([M+H]+, 100).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][NH:5][CH3:6].[C:7]([O:11][C:12](=O)[O:13]C(C)(C)C)([CH3:10])([CH3:9])[CH3:8]>C(Cl)Cl>[CH3:1][N:2]([CH2:3][CH2:4][NH:5][CH3:6])[C:12](=[O:13])[O:11][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CNCCNC
Solvent: ClCCl
Product: CNCCN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl methyl(2-(methylamino)ethyl)carbamate was prepared as follows: N1,N2-dimethylethane-1,2-diamine (40 mmol) was dissolved in 100 mL of CH2Cl2 and cooled to 0° C. A solution of di-tert-butylcarbonate (4.0 mmol) in CH2Cl2 (10 mL) was then added dropwise at 0° C. over a period of 15 min. The resulting reaction mixture was stirred at 0° C. for 30 min and then warmed to room temperature. After stirring at room temperature for 2 h. the reaction mixture was diluted with CH2Cl2 (100 mL). The organic layer was washed with brine (3×25 mL), dried (Na2SO4) and concentrated under reduced pressure to afford tert-butyl methyl(2-(methylamino)ethyl)carbamate. This amine was subjected to the same reaction conditions outlined earlier in the preparation of (E)-methyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethylamino)-4-oxobut-2-enoate. The desired product, namely (E)-methyl 4-(2-(4Z,7Z,10Z,13Z,16Z,19Z) -N-methyldocosa-4,7,10,13,16,19-hexaenamido)ethyl)amino)-4-oxobut-2-enoate, was obtained after purification by silica gel chromatography. MS (EI) calcd for C31H46N2O4: 510.35; found 511 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CS(O[CH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]2[O:34][N:33]=[C:32]([CH:35]([CH3:37])[CH3:36])[N:31]=2)[CH2:26][CH2:25]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:37][CH:35]([C:32]1[N:31]=[C:30]([N:27]2[CH2:26][CH2:25][CH:24]([CH2:23][O:17][C:14]3[CH:13]=[N:12][C:11]([C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=4)=[CH:16][N:15]=3)[CH2:29][CH2:28]2)[O:34][N:33]=1)[CH3:36]
Reactant: CC(C)c1noc(N2CCC(COS(C)(=O)=O)CC2)n1
Reactant: CS(=O)(=O)c1ccc(-c2cnc(O)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1noc(N2CCC(COc3cnc(-c4ccc(S(C)(=O)=O)cc4)cn3)CC2)n1
Temperature: 100 °C
Yield: 51 %

Procedure:
A mixture of 5-[4-(methylsulfonyl)phenyl]-2-pyrazinol (and tautomers thereof) (0.15 g, 0.60 mmol), {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl methanesulfonate (prepared as in Example 100, Step 4, except that on small scale no heptane wash was performed, 0.25 g, 0.81 mmol) and K2CO3 (0.17 g, 1.20 mmol) in DMF (6 mL) was stirred at ambient temperature overnight, then heated at 100° C. for 5 h. The mixture was cooled to ambient temperature, water was added, and the mixture was extracted with EtOAc (60 mL×2). The combined organic extracts were washed with water, brine and dried over Na2SO4, filtered, and the filtrate was concentrated to a brown solid. The crude material was purified by chromatography on a silica gel column eluted with 1:20 acetone/CH2Cl2 to 1:15 acetone/CH2Cl2 to give 0.14 g (51%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.55 (d, 1H, J=0.9 Hz), 8.31 (s, 1H), 8.11 (d, 2H, J=8.6 Hz), 8.02 (d, 2H, J=8.6 Hz), 4.30-4.20 (m, 4H), 3.10-3.05 (m, 5H), 2.91 (septet, 1H, J=7.0 Hz), 2.10-2.00 (m, 1H), 2.00-1.90 (m, 2H), 1.55-1.40 (m, 2H), 1.27 (d, 6H, J=6.6 Hz); LRMS (ESI), m/z 458 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][C:9]([CH2:11][OH:12])=[N:10][C:5]2=[CH:4][CH:3]=1.[H-].[Na+].[CH3:15]I>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:15])[C:9]([CH2:11][OH:12])=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: OCc1nc2ccc(Cl)nc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CO)nc2ccc(Cl)nc21

Procedure:
A procedure similar to that described in Preparation 15 was repeated, except that 3.00 g of 5-chloro-2-hydroxymethyl-3H-imidazo[5,4-b]pyridine (prepared as described in Preparation 43), 0.71 g of sodium hydride (as a 55 by weight dispersion in mineral oil), 1.1 ml of methyl iodide and 70 ml of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 10:1 by volume as the eluent, to give 1.60 g of the title compound, melting at 204-210° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([SH:9])[N:3]=1.[OH-].[Na+].[CH3:12]I>C(O)C.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([S:9][CH3:12])[N:3]=1
Reactant: CI
Reactant: Cc1cc(C)nc(S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1nc(C)cc(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4,6-Dimethyl-pyrimidine-2-thiol (20 g, 142 mmol) is added slowly to a solution of sodium hydroxide (6.3 g, 156 mmol) in ethanol (120 ml) and water (60 ml). Methyl iodide (9.8 ml, 156 mmol) is added dropwise and the mixture is stirred at room temperature for 1 hour. The solvents are removed in vacuo and the residue is partitioned between diethyl ether (200 ml) and water (200 ml). The organic extract is dried (MgSO4) and the solvent is removed to give the titled compound.
Reaction SMILES: O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N([CH2:18][CH3:19])CC)C.[CH:20]1([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30][CH:31]([C:35]([OH:37])=O)[C:32]([OH:34])=[O:33])[CH2:22][CH2:21]1>C(Cl)Cl>[CH:20]1([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30][C:31]2[C:32](=[O:33])[O:34][C:25]([C:24]3[CH:23]=[C:20]([CH3:22])[CH:21]=[C:18]([CH3:19])[CH:29]=3)=[CH:26][C:35]=2[OH:37])[CH2:21][CH2:22]1
Reactant: O=C(O)C(Sc1ccccc1CC1CC1)C(=O)O
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2cc(O)c(Sc3ccccc3CC3CC3)c(=O)o2)c1

Procedure:
The title compound was prepared by Method A using 3,3'-dimethyl acetophenone (2 g, 13.51 mmol), trimethylsilyl triflate (3 g, 13.1 mmol), triethylamine (2.73 g, 27.02 mmol), methylene chloride (20 mL), and diethyl ester of [[2-(cyclopropylmethyl)phenyl]thio]propandioic acid (2.18 g, 6.76 mmol). m.p. 168° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.28 (d, 2H), 0.39 (dd, 2H), 1.13 (m, 1H), 2.26 (s, 6H), 2.67 (d, 2H), 6.85 (s, 1H), 6.92 (m, 1H), 7.11 (m, 2H), 7.22 (s, 1H), 7.33 (m, 1H), 7.47 (s, 2H).