Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.NN.[OH-].[Na+].[N+:6]([C:9]1[C:22]2[C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:24])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([O-])=O>O>[NH2:6][C:9]1[C:22]2[C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:24])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reaction time: 1 h

Procedure:
500 Parts of water, 20 parts of hydrazine hydrate and 100 parts of 30% sodium hydroxide solution are heated to 70°. 51 Parts of 1-nitro-anthraquinone are entered over the course of 1 hour. The temperature of the reaction mixture is kept at between 70° and 75°. After the addition of the whole amount of 1-nitroanthraquinone, the suspension is heated to 80° and stirred for 1 hour. 70 Parts of 40% sodium hydroxide solution are subsequently added. The reaction mass is then stirred at 90° over the course of 90 minutes and filtered. The precipitate is washed with water until the filtrate is colourless and neutral, and then dried. 43 Parts of 1-amino-anthraquinone are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=3[C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][C:22]=1[C:29]([F:32])([F:31])[F:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:1][C:2]2[CH:10]=[CH:9][C:8]3[NH:7][C:6]4[CH:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH2:13][C:5]=4[C:4]=3[CH:3]=2)=[CH:23][C:22]=1[C:29]([F:30])([F:31])[F:32]
Reactant: FC(F)(F)c1cc(CCl)ccc1Cl
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(Cl)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.7 %

Procedure:
A mixture of ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (222 mg, 0.856 mmol), 1-chloro-4-(chloromethyl)-2-(trifluoromethyl)benzene (240 mg, 1.048 mmol), and cesium carbonate (165 mg, 0.856 mmol) in DMF (5 mL) was stirred at room temperature. After 3 days, more cesium carbonate (165 mg, 0.856 mmol) was added. After stirring for an additional 2 d, the mixture was extracted with water and CH2Cl2. The organics were dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a white solid (258 mg). LCMS m/z=452.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (t, J=7.2 Hz, 3H), 2.06-2.14 (m, 1H), 2.47-2.54 (m, 1H), 2.71-2.86 (m, 4H), 3.51-3.57 (m, 1H), 4.17-4.25 (m, 2H), 5.10 (s, 2H), 6.82 (dd, J=8.8, 2.5, 1H), 6.96 (d, J=2.5 Hz, 1H), 7.21 (dd, J=8.8, 0.32 Hz, 1H), 7.49-7.52 (m, 1H), 7.58 (dd, J=8.2, 2.6 Hz, 1H), 7.80 (d, J=1.92 Hz, 1H), 8.48 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]([F:21])([F:20])[C:15]([NH:17][CH2:18]O)=[O:16].OS(O)(=O)=O>>[F:13][C:14]([F:21])([F:20])[C:15]([NH:17][CH2:18][C:8]1[C:9]([O:11][CH3:12])=[CH:10][C:2]([Cl:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])=[O:16]
Reactant: O=C(NCO)C(F)(F)F
Reactant: COc1ccc(C(=O)O)c(Cl)c1
Agent: O=S(=O)(O)O
Product: COc1cc(Cl)c(C(=O)O)cc1CNC(=O)C(F)(F)F
Yield: 39.9 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-26 by using 2-chloro-4-methoxybenzoic acid (0.060 g), 2,2,2-trifluoro-N-(hydroxymethyl)acetamide (0.050 g) and H2SO4 (2 mL) to afford 0.040 g of the desired product.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:14](O)[C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[C:5]1=[O:24])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:26]>O1CCOCC1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:14]([Cl:26])[C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[C:5]1=[O:24])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)C(=C(O)c2ccc(C#N)cc2)c2ccc(Cl)cc21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CC(=O)N1C(=O)C(=C(Cl)c2ccc(C#N)cc2)c2ccc(Cl)cc21
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A suspension of 7.0 g of 1-acetyl-3-[1-hydroxy-1-(4-cyanophenyl)methylene]-6-chloro-2-indolinone (starting material VI.18) and 6.39 g of phosphorus pentachloride in 150 ml of dioxane is stirred at 100° C. for 6 hours. After addition of a further 1.0 g of phosphorus pentachloride, the mixture is stirred at 110° C. for another 4 hours. The solvent is then distilled off and the residue is washed with ethyl acetate.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.[CH2:22]([N:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](O)=[O:39])=[CH:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[C:41]([O:45][C:46]([C:48]1[C:56]2[CH2:55][CH2:54][N:53]([CH2:57][C:58]3[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=3)[CH:52]([CH2:66][NH2:67])[C:51]=2[S:50][C:49]=1[NH2:68])=[O:47])([CH3:44])([CH3:43])[CH3:42]>O1CCCC1>[C:41]([O:45][C:46]([C:48]1[C:56]2[CH2:55][CH2:54][N:53]([CH2:57][C:58]3[CH:59]=[CH:60][C:61]([O:64][CH3:65])=[CH:62][CH:63]=3)[CH:52]([CH2:66][NH:67][C:38]([C:31]3[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:29]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:30]=3)=[O:39])[C:51]=2[S:50][C:49]=1[NH2:68])=[O:47])([CH3:44])([CH3:42])[CH3:43]
Reactant: O=C(O)c1cn(Cc2ccccc2)c2ccccc12
Reactant: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CNC(=O)c2cn(Cc3ccccc3)c3ccccc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
Diisopropylethylamine (1.8 ml, 10.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (760 mg, 4.0 mmol) were added to a mixture of 1-benzyl-1H-indole-3-carboxylic acid (902 mg, 3.6 mmol) in tetrahydrofuran (50 ml). After stirring for 1 hour, the solution was cooled to 0° C. and a solution of 2-amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (700 mg, 1.7 mmol) in tetrahydrofuran (7 ml) was added dropwise. The reaction was allowed to slowly warm to room temperature. After 8 hours of stirring the solution was concentrated in vacuo and the residue dissolved in ethyl acetate (40 ml), washed with saturated aqueous sodium bicarbonate (2×30 ml), brine (1×30 ml), dried (MgSO4), filtered, and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a mixture of hexane/ethyl acetate/triethylamine, (50:50:1) as eluent, which afforded 560 mg (51%) of 2-amino-7-(((1-benzyl-1H-indole-3-carbonyl)amino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12]C(=O)C)[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=1[F:8]>Cl.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N+:9]([O-:11])=[O:10])=[CH:6][C:7]=1[F:8])[NH2:12]
Reactant: CC(=O)Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 101.3 %

Procedure:
A solution of N-(3-chloro-4-fluoro-6-nitrophenyl)acetamide (30 g) in concentrated hydrochloric acid (50 ml) and ethanol (200 ml) was refluxed for 2.5 hours. To the reaction mixture was added ice water (300 ml) and the resulting precipitate was collected by filtration, washed with water and dried to give the title compound (24.9 g) as yellow needles, mp 149.5°-150° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[CH:25]=[CH:24][O:23][CH:22]=1.[Cl:26]N1C(=O)CCC1=O.CCOCC.O>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[CH:25]=[CH:24][O:23][C:22]=1[Cl:26]
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccoc1
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccoc1Cl
Reaction time: 1.5 h

Procedure:
To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(furan-3-yl)pyrazole (0.095 g) in acetonitrile (6 ml) was added N-chlorosuccinimide (0.0345 g). The mixture was left at room temperature for 1.5 hours and then poured into ether (50 ml) and water (50 ml). The layers were separated and the aqueous phase extracted with a second portion of ether (50 ml). The combined organic layers were washed with water (25 ml), then dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (10 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p. 153° C.
Reaction SMILES: [OH:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[CH:8]=[C:9]3[C:14](=[C:15]4[N:20]([CH3:21])[CH2:19][CH:18]=[CH:17][C:16]=24)[N:13]=[CH:12][N:11]([C@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]2[OH:28])[C:10]3=[O:29])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>ClCCl>[CH3:39][N:40]([CH3:44])[C:41](=[O:42])[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:8]=[C:9]3[C:14](=[C:15]4[N:20]([CH3:21])[CH2:19][CH:18]=[CH:17][C:16]=24)[N:13]=[CH:12][N:11]([C@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]2[OH:28])[C:10]3=[O:29])=[CH:30][CH:31]=1
Reactant: CN(C)C(=O)Cl
Reactant: CN1CC=Cc2c(Cc3ccc(O)cc3)cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)Oc1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3c2C=CCN3C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-(4-hydroxybenzyl)-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one (Example 7, 0.025 g, 0.060 mmol) in 2 mL of dichloromethane at 0° C. was added triethylamine (0.012 mL, 0.090 mmol) and dimethyl carbamyl chloride (0.010 g, 0.090 mmol). After 2 h, the mixture was warmed to rt and additional dimethyl carbamyl chloride (0.019 g, 0.18 mmol) was added. After 20 h, the reaction was warmed to 35° C., and after an additional 36 h, diluted with dichloromethane and washed with water and brine. The organic solution was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-3% methanol in dichloromethane, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 489.1 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 3.24 (d, J=8.4 Hz, 1H), 8.03 (s, 1H), 7.41-7.38 (m, 1H), 7.14 (d, J=7.9 Hz, 2H), 7.01-6.98 (m, 2H), 4.77-4.64 (m, 2H), 4.37 (s, 2H), 3.64 (br s, 1H), 3.27 (s, 3H), 3.06 (s, 3H), 2.98 (s, 3H), 2.22-2.19 (m, 1H), 2.12-2.09 (m, 1H), 1.91 (br s, 1H), 1.82 (br s, 1H), 1.64-1.60 (m, 1H), 1.49-1.25 (m, 4H).
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([CH2:18][CH3:19])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:20].[C:21]1([CH:27]([CH2:31][CH3:32])[C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[CH2:18]([C:16]1[C:14](=[O:15])[NH:13][C:11](=[O:12])[N:10]([CH:17]=1)[C@@H:8]1[O:9][C@H:5]([CH2:4][NH:3][C:28](=[O:29])[CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:31][CH3:32])[C@@H:6]([OH:20])[CH2:7]1)[CH3:19]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O
Reactant: CCC(C(=O)Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)C(CC)c3ccccc3)O2)c(=O)[nH]c1=O
Reaction time: 0.17 h
Yield: 69.8 %

Procedure:
1.25 ml of 1M sodium hydroxide solution were added to 0.255 g of 5'-amino-2',5'-dideoxy-5-ethyluridine in 5 ml of water and then 0.2 g of 2-phenylbutyryl chloride was added to the mixture. The resulting mixture was shaken for 10 minutes, whereby a white solid was deposited. This solid was collected by filtration, washed three times with 5 ml of water each time, dried at 50° C. in vacuo over phosphorus pentoxide and recrystallized from ethanol to give 0.28 g of 2',5'-dideoxy-5-ethyl-5'-(2-phenylbutyramido)uridine of melting point 235°-236° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH3:30])[CH:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[C:18]3[C:19]4[CH2:20][NH:21][CH2:22][CH2:23][C:24]=4[S:25][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:12][CH2:11]1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH3:31][S:32]([N:21]1[CH2:20][C:19]2[C:18]3[C:17]([O:16][CH:13]4[CH2:12][CH2:11][CH:10]([N:9]([CH3:30])[CH3:8])[CH2:15][CH2:14]4)=[N:29][CH:28]=[N:27][C:26]=3[S:25][C:24]=2[CH2:23][CH2:22]1)(=[O:34])=[O:33]
Reactant: CN(C)C1CCC(Oc2ncnc3sc4c(c23)CNCC4)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C1CCC(Oc2ncnc3sc4c(c23)CN(S(C)(=O)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N,N-dimethyl-4-[8-thia-4,6,12-triazatricyclo[7.4.0.0-[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yloxy]cyclohexan-1-amine trifluoroacetate (30 mg, 0.09 mmol, 1.00 equiv) in 5 mL of anhydrous dichloromethane was added TEA (40 mg, 0.40 mmol, 4.38 equiv) and MsCl (14 mg, 0.12 mmol, 1.36 equiv) at 0° C. under nitrogen. The resulting solution was stirred for 2 h at room temperature. The reaction mixture was concentrated under vacuum and the residue was purified by preparative HPLC under the following conditions (Waters): Column: XBridge Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase: water with 0.05% NH4HCO3 and CH3CN (16% CH3CN increasing to 23% in 10 min, up to 100% in 2 min, down to 16% in 2 min); flow rate: 20 mL/min; UV Detection at 254/220 nm. This resulted in 8.0 mg (22%) of 4-([12-methanesulfonyl-8-thia-4,6,12-triazatricyclo[7.4.0.0-[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy)-N,N-dimethylcyclohexan-1-amine as a white solid. MS (ES): m/z 411 (M+H)+; 1H NMR (300 MHz, CD3OD): δ 1.59-1.71 (m, 4H), 2.05-2.10 (d, 2H, J=15 Hz), 2.34-2.50 (m, 9H), 2.98 (s, 3H), 3.08 (t, 2H, J=5.7 Hz), 3.06 (t, 2H, J=5.7 Hz), 4.67 (t, 2H, J=1.8 Hz), 5.26 (m, 1H), 8.53 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([C:11]1[CH:16]=[C:15]([O: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][CH2:33][CH2:34][CH3:35])[CH:14]=[C:13]([OH:36])[CH:12]=1)[CH2:6][C:7]([O:9][CH3:10])=[O:8].Cl.Cl[CH2:40][C:41]1[CH:50]=[CH:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[N:42]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:37])[CH2:4][N:5]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:11]1[CH:12]=[C:13]([O:36][CH2:40][C:41]2[CH:50]=[CH:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:42]=2)[CH:14]=[C:15]([O: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][CH2:33][CH2:34][CH3:35])[CH:16]=1
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(O)cc(N(CC(=O)OC)CC(=O)OC)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(OCc2ccc3ccccc3n2)cc(N(CC(=O)OC)CC(=O)OC)c1
Yield: 78 %

Procedure:
A mixture of 1.5 g (2.9 mmol) of N-[3-hydroxy-5-(octadecyloxy)phenyl]-N-(2-methoxy-2-oxoethyl)glycine methyl ester, 0.935 g (4.35 mmol) of 2-(chloromethyl)quinoline hydrochloride (Lancaster Organic Research Chemicals), 2.0 g (14.5 mmol) of potassium carbonate and 0.435 g (2.9 mmol) of sodium iodide in 100 ml of acetone and 20 ml of DMF was stirred at reflux under argon for 24 hours. The solvents were removed at reduced pressure and the residue was treated with water and the product was extracted with ethyl acetate. The dried extract was concentrated to a solid which was purified by HPLC using 30% ethyl acetate-hexane followed by recrystallization from hexane to give 1.5 g (78% yield, mp 76°-79°) of N-(2-methoxy-2-oxoethyl)-N-[3-(octadecyloxy)-5-[(2-quinolinyl)methoxy]phenyl]glycine methyl ester.
Reaction SMILES: [N:1]1([CH2:5][C:6]2[N:10]([CH3:11])[N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.Br[C:14]1[C:15](=[O:22])[N:16](C)[N:17]=[C:18]([Cl:20])[CH:19]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Cl>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1COCC1.O1CCOCC1>[N:1]1([CH2:5][C:6]2[N:10]([CH3:11])[N:9]=[C:8]([NH:12][C:14]3[C:15](=[O:22])[NH:16][N:17]=[C:18]([Cl:20])[CH:19]=3)[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: Cn1nc(N)cc1CN1CCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(Nc2cc(Cl)n[nH]c2=O)cc1CN1CCC1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 1,4-dioxane (20 mL), 22 (500 mg, 3.00 mmol), 25 (630 mg, 3.01 mmol) and 1 M THF solution of lithium hexamethyldisilazide (15 mL, 5.00 mmol). After bubbling nitrogen through the resulting solution for 30 min, Xantphos (148 mg, 0.255 mmol) and tris(dibenzylidene acetone)dipalladium(0) (138 mg, 0.150 mmol) were added, and the reaction mixture was heated at reflux for 3 h. After this time, the reaction was cooled to room temperature, and water (20 mL) was added. The pH was adjusted to 7 with 1 N hydrochloric acid. The resulting precipitate was collected by vacuum filtration, washed with water (2×25 mL), absorbed on silica gel and purified by flash chromatography to afford an 66% yield (590 mg) of 26 as a light brown solid: mp 140-141° C. 1H NMR (500 MHz, CDCl3) δ 10.63 (s, 1H), 7.78 (s, 1H), 7.46 (s, 1H), 5.84 (s, 1H), 3.81 (s, 3H), 3.52 (s, 2H), 3.23 (t, 4H, J=7.0 Hz), 2.09 (m, 2H); MS (APCI+) m/z 295.8 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[F:18][C:14]1[CH:13]=[C:12]([C:7]2[C:6]([CH2:4][OH:3])=[C:10]([CH3:11])[O:9][N:8]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1c(-c2cccc(F)c2)noc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2cccc(F)c2)c1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.3 %

Procedure:
To a solution of 3-(3-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (6.18 g, 25 mmol) in THF (320 mL) was added portionwise lithiumaluminiumhydride (528 mg, 14 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 3 h. The mixture was then cooled to 0° C. and water (518 ␣L) added followed by sodium hydroxide (15% solution, 518 μL) and then again water (1.5 mL) and the mixture then stirred overnight at room temperature. The precipitate was then filtered off and washed with THF. The combined washings and filtrate were then evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (3.9 g, 75%) which was obtained as a yellow solid. MS: m/e=208.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11](=O)([O-])OCC.C[O-].[Na+].[OH-].[K+]>O.CC(O)C.CC1C=CC=CC=1C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)[O-]
Reactant: N#CCc1ccc(F)cc1
Agent: C[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CC(C)O
Product: CC(C#N)c1ccc(F)cc1
Reaction time: 20 h

Procedure:
A mixture of 68 parts of 4-fluorobenzeneacetonitrile, 180 parts of ethyl carbonate, 100 parts of a sodium methoxide solution 30% and 200 parts of dimethylbenzene was distilled till an internal temperature of 110° C. was reached. The distillate was cooled and 80 parts of 2-propanol were added, followed by the dropwise addition of 63 parts of methyl sulfate at room temperature (exothermic reaction: temperature rose to 80° C.). The remaining 120 parts of 2-propanol were added while stirring vigorously. Upon completion, stirring was continued for 20 hours. Then there were added 56 parts of potassium hydroxide (exothermic reaction: temperature rose to 75° C.). The whole was stirred and refluxed for 30 minutes. The reaction mixture was cooled and poured into 750 parts of water. The aqueous phase was separated and extracted with methylbenzene. The extract was dried, filtered and evaporated. The oily residue was distilled, yielding 54 parts of 4-fluoro-α-methylbenzeneacetonitrile; bp. 110°- 115° C. at 11 mm. pressure (intermediate 1).
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].[Cl:10][C:11]1[C:20]([CH:21]=[CH:22][C:23](=O)[CH3:24])=[C:19]([Cl:26])[CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]>C(O)C.O>[Cl:10][C:11]1[C:20]([CH:21]=[CH:22][C:23](=[N:2][OH:3])[CH3:24])=[C:19]([Cl:26])[CH:18]=[CH:17][C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1ccc(Cl)c(C=CC(C)=O)c1Cl
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(Cl)c(C=CC(C)=NO)c1Cl

Procedure:
1.8 g (25.9 mmol) of hydroxylamine hydrochloride and 1.5 g (11.0 mmol) of potassium carbonate were added to 5.0 g (18.3 mmol) of methyl 2,4-dichloro-3-(2-oxobut-3-en-4-yl)benzoate in 160 ml of ethanol, and the reaction mixture was admixed with water until a clear solution was obtained. The mixture was heated under reflux for 3 hours and then cooled and the reaction mixture was taken up in 400 ml of water and extracted with ethyl acetate. The combined organic phases were dried and the solvent was removed. Methyl 2,4-dichloro-(2-hydroxyiminobut-3-en-4-yl)benzoate was obtained in quantitative yield.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH2:7][C:8]([OH:10])=[O:9])[C:4]([OH:6])=O.C(Cl)(=O)C>>[CH3:1][O:2][C@@H:3]1[CH2:7][C:8](=[O:9])[O:10][C:4]1=[O:6]
Reactant: CO[C@H](CC(=O)O)C(=O)O
Solvent: CC(=O)Cl
Product: CO[C@@H]1CC(=O)OC1=O

Procedure:
260 mg (1.76 mmol) (R)-methoxy-succinic acid are stirred together with 5 ml acetyl chloride for 2 days at RT, then the acetyl chloride is eliminated by rotary evaporation in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[C:4]([OH:7])([CH3:6])[CH3:5].O([Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])S(C(F)(F)F)(=O)=O.N1C(C)=CC=CC=1C.O>C(Cl)Cl>[Si:17]([O:7][C:4]([CH3:6])([CH3:5])[C:3]([O:2][CH3:1])=[O:8])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: COC(=O)C(C)(C)O
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)C(C)(C)O[Si](C)(C)C(C)(C)C
Yield: 78.5 %

Procedure:
To a stirred, chilled (0° C.) solution of methyl-2-hydroxyisobutyrate (20.0 g) in dry CH2Cl2 was added TBDMS triflate (45 g) dropwise, followed by anhydrous 2,6-lutidine (19.3 g). The mixture was stirred at 0° C. for 1 hour before 150 ml water was added. Stirring was continued for a further hour, the organic layer separated, dried (Na2SO4), and concentrated to dryness at reduced pressure. The crude product was purified by dry flash silica gel chromatography eluting with CH2Cl2 to yield the title compound as a colorless oil (30.9 g). δH (360 MHz, CDCl3) 0.07 (6H, s, Si(CH3)2), 0.87 (9H, s, C(CH3)3), 1.41 (6H, s, C(CH3)2), 3.69 (3H, s, CH3O). m/z 233 (M+1)+, 100%, CI+) 217 (30), 174 (40), 164 (45), 106 (30).