Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[S:5][C:4]=1[NH:12][C:13](=[O:25])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH2:23][CH3:24])#[N:2].C([C:28]1C2CCNCC=2S[C:29]=1[NH:37][C:38](=[O:46])C=CC1OC=CC=1)#N>>[CH2:29]([NH:37][C:38]([N:8]1[CH2:9][CH2:10][C:11]2[C:3]([C:1]#[N:2])=[C:4]([NH:12][C:13](=[O:25])/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH3:24])[S:5][C:6]=2[CH2:7]1)=[O:46])[CH3:28]
Reactant: N#Cc1c(NC(=O)C=Cc2ccco2)sc2c1CCNC2
Reactant: CCOc1ccccc1C=CC(=O)Nc1sc2c(c1C#N)CCNC2
Product: CCNC(=O)N1CCc2c(sc(NC(=O)/C=C/c3ccccc3OCC)c2C#N)C1

Procedure:
The following compounds 246 to 251 may be prepared according to general procedure FF described later herein starting from N-(3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(2-ethoxy-phenyl)-acrylamide or N-(3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(furan-2-yl)-acrylamide respectively.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C@:7]1([CH3:22])[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1>ClCCl>[Cl:3][C@:7]1([CH3:22])[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:6]1
Reactant: COc1ccc(CCN2CCC[C@@]2(C)CO)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CCN2CCC[C@@](C)(Cl)C2)cc1
Yield: 34.7 %

Procedure:
Thionyl chloride (238 mg) was added slowly to a solution of (S)-2-hydroxymethyl-1-(4-methoxyphenethyl)-2-methylpyrrolidine (see Preparation 10) (349 mg) in dichloromethane (15 ml) and the mixture was heated under reflux for 2 hours. The reaction was cooled, diluted with dichloromethane, washed with 10% aqueous sodium carbonate solution, dried over sodium sulphate and evaporated under reduced pressure to give the title compound as a brown gum, (130 mg), which was characterised by NMR and used directly in Example 4 without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:11])([CH3:10])[CH2:8][OH:9].[C:12](OC)(=[O:34])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C[O-].C[N+](C)(C)CC1C=CC=CC=1>[C:12]([CH:8]([OH:9])[C:7]([OH:11])([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH3:10])(=[O:34])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)OC
Reactant: CC(O)(CO)C1CCCCO1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: C[O-]
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)C(O)C(C)(O)C1CCCCO1
Temperature: 70 °C
Yield: 44.1 %

Procedure:
2-Tetrahydropyranyl propylene glycol (16.0 grams, 0.1 mole) is interesterified with 39 grams methyl behenate using 4 ml. of 40% trimethyl benzyl ammonium methoxide as a catalyst. The reactants are stirred in a 250 ml. flask heated at 60-80° C. under a reduced pressure of 200 mm. Hg for 6 hours. The reactants are poured into 600 ml. of hexane and the hexane solution washed with 400 ml. of 1% potassium bicarbonate solution. The washed hexane layer is diluted with 200 ml. ethanol and 75 grams urea are added to the sample, Adduct formation with urea is accomplished by stirring the sample initially at 40° C. and allowing the mixture to cool at 25° C. during a 2 hour interval. The urea adduct is removed by filtration and discarded. The adduction with urea is repeated using 60 grams urea. The filtrate from the second urea adduction is water-washed three times and the hexane layer is evaporated to dryness. The residue is dissolved in 300 ml. hexane and the solution is crystallized at -18° C. Filtration at -18° C yields 21.3 grams of 1-behenoyl-2-tetrahydropyranyl propylene glycol. 1-Behenoyl-2-tetrahydropyranyl propylene glycol (8 grams, 0.0l65 mole) is cleaved by reaction with 11 ml. of 1.6 molar boric acid in trimethyl borate. The reactants are heated in a boiling water bath with application of vacuum. Heating is continued for 15 minutes with a vacuum of 2-5 mm. Hg pressure during the final 10 minutes. The residue is cooled to room temperature and dissolved in 200 ml. ethyl ether and water-washed three times. The ether phase is dried with sodium sulfate, and evaporated to dryness on an evaporator without warming above 30° C. The residue is dissolved in 100 ml. petroleum ether and crystallized at 70° F. The crystals recovered at 70° F. are recrystallized from 200 ml. petroleum ether at 50° F. to yield ca. 5 grams of 1-propylene glycol monobehenate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]([C@H:41]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[N:44]([C:51](=[O:59])[C:52]3[CH:57]=[CH:56][C:55](O)=[CH:54][CH:53]=3)[C@@H:43]([CH3:60])[CH2:42]2)[C:38](=[O:40])[CH3:39])=[CH:33][CH:32]=1.CCOC(/N=N/C(OCC)=O)=O>C1C=CC=CC=1>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([N:37]([C@H:41]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[N:44]([C:51](=[O:59])[C:52]3[CH:57]=[CH:56][C:55]([O:1][CH2:2][CH2:3][CH2:4][N:5]4[CH2:9][CH2:8][CH2:7][C:6]4=[O:10])=[CH:54][CH:53]=3)[C@@H:43]([CH3:60])[CH2:42]2)[C:38](=[O:40])[CH3:39])=[CH:35][CH:36]=1
Reactant: O=C1CCCN1CCCO
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCN3CCCC3=O)cc2)c2ccccc21
Reaction time: 0.08 h
Yield: 45 %

Procedure:
N-(3-hydroxypropyl)-2-pyrrolidone was dissolved in benzene at room temperature with PPh3 (0.044 g, 0.16 mmol) added (2S,4R)-N-(4-chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.100 g, 0.22 mmol) and stirred for 5 min. DEAD (0.029 g, 0.16 mmol) was added and the reaction was stirred for 18 h at room temperature. The reaction was concentrated and purified by silica gel chromatography (4% MeOH/96% CH2Cl2 to 5% MeOH/95% CH2Cl2 to 6% MeOH/94% CH2Cl2) to afford the product in 45% yield.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=[N:23][NH2:24])[NH2:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C2C(=CC(CN3C4=NC(C#N)=CN=C4N=N3)=CC=2)C=CC=1.Cl.[NH:48]([C:50](N)=[O:51])N>>[NH2:22]/[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)=[N:23]/[NH:24][C:50]([NH2:48])=[O:51]
Reactant: NN=C(N)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: NNC(N)=O
Agent: Cl
Agent: N#Cc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Product: NC(=O)N/N=C(/N)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1

Procedure:
The title compound was prepared in analogy to the synthesis of compound 64.2 from 1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine-6-carbonitrile and hydrazinecarbox-amide hydrochloride. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.80 (s, 1H), 8.88 (m, 1H), 8.34 (d, 1H), 8.05 (d, 1H), 8.00 (d, 1H), 7.86 (d, 1H), 7.52 (dd, 1H), 6.18 (s, 2H). LCMS (method B): [MH]+=363, tR=1.70 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]#[C:20][CH2:21][CH2:22][CH2:23][N:24]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(OC(C)C)(C)C>O1CCCC1.C(O)C.O.NN>[NH2:24][CH2:23][CH2:22][CH2:21][C:20]#[C:19][C:12]1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[N:14][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[N:10][CH:11]=1
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1C#CCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)OC(C)C
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1C#CCCCN
Reaction time: 0.17 h
Yield: 61.2 %

Procedure:
To a solution of 2-(5-(2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)-4-pentyn-1-yl)isoindoline-1,3-dione (F3, 2.51 g) in tetrahydrofuran (20 mL) and ethanol (10 mL), hydrazine monohydrate (5.1 mL) was added at room temperature, and the mixture was stirred for 10 minutes under reflux by heating. To the reaction mixture, ethanol (10 mL) was added, and the mixture was stirred at room temperature for 3 hours and 20 minutes. To the reaction mixture, diisopropyl ether was added, the insoluble matter was removed by filtration, and then water was added to the filtrate. The organic layer was separated, washed successively with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 5-(5-amino-1-pentyn-1-yl)-N2-(3-fluorophenyl)-N4-propylpyrimidine-2,4-diamine (F4, 1.10 g) as white solid.
Reaction SMILES: [CH2:1]([OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH3:14].[OH-].[Na+].Cl[C:19]1[O:23][C:22]([C:24]([OH:26])=[O:25])=[CH:21][CH:20]=1.CN(C)P(=O)(N(C)C)N(C)C>C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:1]([O:15][C:19]1[O:23][C:22]([C:24]([OH:26])=[O:25])=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH3:14]
Reactant: CC/C=C\CCCCCCCCCCO
Reactant: O=C(O)c1ccc(Cl)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC/C=C\CCCCCCCCCCOc1ccc(C(=O)O)o1
Reaction time: 3 h

Procedure:
8.8 g (0.0414 mole) of cis-11-tetradecen-1-ol was combined with 4.0 g (0.0829 mole) of sodium hydroxide (50% in oil) in 200 ml of dry toluene and heated to reflux with stirring for 3 hours. 6.1 g (0.414 mole) of 5-chloro-2-furoic acid was added, followed by 25 ml of hexamethylphosphoric triamide (HMPA), and the reaction mixture refluxed with stirring for 20 hours, cooled, and acidified with acetic acid. The mixture was extracted into ether and the organic layer washed with water and with brine and evaporated to yield cis-5-(11-tetradecenyloxy)furan-2-carboxylic acid, M.P. 89°-90° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[CH:15]1([C:21](O)=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:13][C:5]1([CH3:14])[C:4]2[C:8](=[CH:9][C:10]3[NH:11][C:21]([CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)=[N:1][C:2]=3[CH:3]=2)[NH:7][C:6]1=[O:12]
Reactant: O=C(O)C1CCCCC1
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Product: CC1(C)C(=O)Nc2cc3[nH]c(C4CCCCC4)nc3cc21

Procedure:
Analogously to Example 1, from 960 mg. (5.0 mmole) 5,6-diamino-3,3-dimethylindolin-2-one and 640 mg. (5.0 mmole) cyclohexanecarboxylic acid, after 1.5 hours at 240° C., there is obtained 1.37 g. of crude product. 300 mg. thereof are purified over a silica gel column (elution agent: dichloromethane/methanol 9:1 v/v). After removal of the solvent in a vacuum, there is obtained a greenish oil which is crystallised with diethyl ether. There are obtained 192 mg. (53% of theory) of the title compound in the form of pale brown crystals; m.p. 315°-318° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:20]([OH:22])=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:4][C:3]=1[F:24].FC(F)(F)C([O-])=O.FC(F)(F)C(O)=O.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[C@@H:50]3[CH2:51][NH:52][CH2:53][C@@H:49]3[O:48][N:47]=2)=[CH:42][CH:41]=1.C(N(CC)CC)C>C(#N)C>[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([C:46]2[CH:50]3[CH2:51][N:52]([C:2]4[N:11]=[C:10]5[C:5]([C:6](=[O:23])[C:7]([C:20]([OH:22])=[O:21])=[CH:8][N:9]5[C:12]5[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=5[F:19])=[CH:4][C:3]=4[F:24])[CH2:53][CH:49]3[O:48][N:47]=2)=[CH:44][CH:45]=1
Reactant: Clc1ccc(C2=NO[C@H]3CNC[C@@H]23)cc1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CC4ON=C(c5ccc(Cl)cc5)C4C3)c(F)cc2c1=O

Procedure:
7-Chloro-1-(2,4-difluorophenyl-6-fluoro-4-oxo-1,4-dihydronapthyridine-3-carboxylic acid (50) (120 mg; 0.34 mmol), trifluoroacetate salt 4a (131 mg; 0.39 mmol) and triethylamine (0.3 mL) in acetonitrile (3 mL) were heated at reflux temperature overnight. After cooling, the volatiles were evaporated. The residue was triturated with water, filtered and dried to yield acid 101 as an off-white solid.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][NH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[CH:22][CH:21]=1.Cl>CN(C)C=O>[CH3:31][C:30]1[O:29][C:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[N:27][C:26]=1[CH2:25][O:24][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][N:12]2[CH:13]=[C:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11]2)=[CH:39][CH:38]=1
Reactant: COC(=O)c1c[nH]cc1-c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1-c1ccccc1
Reaction time: 1 h
Yield: 87.5 %

Procedure:
Sodium hydride (60%, oily, 298 mg) was added to a mixture of methyl 4-phenylpyrrole-3-carboxylate (1.50 g), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (2.34 g) and N,N-dimethylformamide (15 ml) at 0° C., and the mixture was stirred for one hour. The reaction mixture was poured into dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and methyl 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-4-phenylpyrrole-3-carboxylate (3.12 g, yield: 88%) was obtained as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 115–116° C.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][Si:17]([CH3:26])([CH3:25])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)[C:6](=O)[CH3:7])[CH3:2].[Cl-].[OH:28][NH3+:29]>N1C=CC=CC=1>[CH2:1]([O:3][N:4]=[C:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][Si:17]([CH3:26])([CH3:25])[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)[C:6](=[N:29][OH:28])[CH3:7])[CH3:2]
Reactant: CCON=C(C(C)=O)c1ccc(OC[Si](C)(C)c2ccc(F)cc2)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: c1ccncc1
Product: CCON=C(C(C)=NO)c1ccc(OC[Si](C)(C)c2ccc(F)cc2)cc1

Procedure:
14.3 g of 1-(4-[{dimethyl-(4-fluorophenyl)-silyl}methoxy]phenyl)-propane-1,2-dione-1-ethyl-oxime in 50 ml of pyridine are stirred with 3.5 g of hydroxylammonium chloride for 2 hours at 70° C. The reaction mixture is concentrated in vacuo and ethyl acetate is added to the residue; the organic phase is washed with water and saturated sodium chloride solution and dried over sodium sulfate; the solvent is evaporated off. Recrystallisation from hexane yields the title product having a melting point of 100-102° C.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[O:17]([CH2:24][CH2:25]Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[O:17]([CH2:24][CH2:25][O:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Oc1ccccc1)c1ccc(O)cc1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(Oc1ccccc1)c1ccc(OCCOc2ccccc2)cc1

Procedure:
A mixture of phenyl 4-hydroxybenzoate (2.14 g, 10 mmol), 2-phenoxyethyl bromide (12.1 g, 60 mmol) and potassium carbonate (4.1 g, 30 mmol) in 1,4-dioxane (60 mL) was heated to reflux for about 2 days. The mixture was cooled, filtered and concentrated under vacuum. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (3:1) as eluent to provide the desired product. 1H NMR (500 MHz, CDCl3) δ 4.39 (m, 2H), 4.42 (m, 2H), 6.97 (d, J=8 Hz, 2H), 6.99 (t, J=8 Hz, 1H), 7.03 (d, J=8 Hz, 2H), 7.21 (d, J=8 Hz, 2H), 7.25 (m, 1H), 7.35 (t, J=8 Hz, 2H), 7.42 (t, J=8 Hz, 2H), 8.17 (d, J=8 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([NH2:17])=O)[CH:12]=[CH:11][CH:10]=2)[CH:7]=1>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]#[N:17])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: NC(=O)c1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cccc(Cc2cc(Cl)ccc2OCc2ccc(Cl)cc2F)n1
Yield: 84.6 %

Procedure:
A solution of 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)-methyl]-2-pyridinecarboxamide (115 mg) in phosphoryl chloride (1.25 ml) was stirred at 60° C. for 5 hours. Excess phosphoryl chloride was removed in vacuo and ethyl acetate (5 ml) added. The solution was washed with saturated sodium bicarbonate solution (5 ml), and the aqueous layer extracted with ethyl acetate (5 ml). The combined extracts were washed with brine (5 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by mass-directed autopreparation to afford the title compound (93 mg, 85%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]3[NH:24][C:23](=[O:25])[O:22][CH:21]([CH:26]([CH3:28])[CH3:27])[C:20]=3[CH:29]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH:30]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]3[NH:24][C:23](=[O:25])[O:22][CH:21]([CH:26]([CH3:27])[CH3:28])[C:20]=3[CH:29]=2)=[O:30])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(SCCCOc2ccc3c(c2)C(C(C)C)OC(=O)N3)cc1OC
Reactant: OO
Product: COc1ccc(S(=O)CCCOc2ccc3c(c2)C(C(C)C)OC(=O)N3)cc1OC

Procedure:
Prepared analogously to Example 2 from 6-[3-(3,4-dimethoxy-phenylmercapto)-propoxy]-4-isopropyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24])[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.P([O-])([O-])(O)=[O:26].[Na+].[Na+].P([O-])(O)(O)=O.[K+].[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O.O.CC(=O)OCC>[Cl:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24])[C:4]2[C:9]([C:10]=1[C:11]([OH:26])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COCCCOc1ccccc1-n1c(Cl)c(C=O)c2ccccc21
Reactant: O=P([O-])([O-])O
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COCCCOc1ccccc1-n1c(Cl)c(C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To the compound of step 4 (100 mg, 2914 μmol) in a mixture of acetone (2.8 ml), water (1.36 ml) and a disodium hydrogenphosphate/potassium dihydrogenphosphate buffer solution (2.0 ml; pH 7.0) was added with stirring at room temperature potassium permanganate (90.0 mg, 570 μmol) in small portions. After stirring at room temperature for 3 days, the mixture was diluted with water and EA was added. The organic layer was separated, dried over sodium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography (EA/HEP 4:1). 50 mg of the title compound were obtained.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[N+:11]([O-])([O-:13])=[O:12].[K+].C([O-])(O)=O.[Na+]>OS(O)(=O)=O>[N+:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][CH2:2][NH:1]2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: c1ccc2c(c1)CCCN2
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1ccc2c(c1)NCCC2
Temperature: 25 °C
Yield: 24.7 %

Procedure:
To a mixture of 1,2,3,4-tetrahydro-quinoline (20.0 g, 0.15 mol) dissolved in H2SO4 (98%, 150 mL), KNO3 (18.2 g, 0.18 mol) was slowly added at 0° C. The reaction was allowed to warm to room temperature and stirred over night. The mixture was then poured into ice-water and basified with sat. NaHCO3 solution to pH 8. After extraction with CH2Cl2, the combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (petroleum ether—EtOAc, 10:1) to give 7-nitro-1,2,3,4-tetrahydro-quinoline (6.6 g, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:19])=[O:7])=[CH:4][CH:3]=1.[CH2:22]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1Cl)[C:27](N)=O)[CH3:23].COC1C=C2C(=CC=1)[NH:41][C:40](C)=C2CCN.C1(CC(O)=O)C=CC=CC=1>>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH3:19])=[O:7])=[CH:4][CH:3]=1.[CH2:22]([C:24]1[CH:25]=[C:26]([CH2:27][CH2:40][NH-:41])[CH:30]=[CH:31][CH:32]=1)[CH3:23]
Reactant: COc1ccc2[nH]c(C)c(CCN)c2c1
Reactant: CCc1cc(C(N)=O)ccc1Cl
Agent: COc1ccc2c(c1)cc(C)n2C(=O)c1ccc(Cl)cc1
Agent: O=C(O)Cc1ccccc1
Product: CCc1cccc(CC[NH-])c1

Procedure:
The procedure employed for preparation of Compound 9e was repeated except as follows. In the treatment of Compound 7, phenylacetic acid was used instead of 4-chlorobenzoic acid, so the resultant was 8i instead of 8e.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][C:13]2[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=2)=[CH:4][CH:3]=1.Cl.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](Cl)=[O:31].C(=O)([O-])[O-].[K+].[K+].CCC(C)=O>O>[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([NH:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][C:13]2[N:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[N:14]=2)=[CH:4][CH:3]=1)=[O:31]
Reactant: COC(=O)c1nc(N)ccc1Oc1nc(OC)cc(OC)n1
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: COC(=O)c1nc(NC(=O)c2ccccn2)ccc1Oc1nc(OC)cc(OC)n1
Yield: 40.7 %

Procedure:
2.0 g (6.5 mmol) of methyl 6-amino-3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinate, 1.2 g (6.5 mmol) of picolinoyl chloride hydrochloride and 2.0 g (14.8 mmol) of potassium carbonate were added to 30 ml of MEK, and the mixture was refluxed for 6 hours under stirring. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was distilled off to obtain crude crystals. The crude crystals were washed with diisopropyl ether-ethyl acetate to obtain the desired product as colorless needle-like crystals.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:38])([CH3:37])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]1=[O:31])([CH3:4])[CH3:3].[CH:39]1[C:52]2[C:51](=[O:53])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[O:44][C:43]=2[CH:42]=[CH:41][CH:40]=1>>[OH:53][C:51]1([C:35]2[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:29]([CH:36]=2)[C@@H:8]2[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[C@H:7]2[O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:38])[CH3:37])[C:50]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[O:44][C:43]2[C:52]1=[CH:39][CH:40]=[CH:41][CH:42]=2
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=c1c2ccccc2oc2ccccc12
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C3(O)c4ccccc4Oc4ccccc43)c(=O)[nH]c2=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
5-(9-Hydroxyxanthen-9-yl)-2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine was prepared from 2',3',5'-tris-O-((1,1-dimethylethyl)dimethylsilyl)uridine according to the method of Example 1 step (i) (using xanthone instead of benzophenone) as a pale yellow solid.