Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:14]([OH:16])=[O:15])[CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)=[O:5].[OH-].[Na+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].Cl>CC(C)=O.O>[CH2:23]([O:22][C:20]([NH:1][CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:14]([OH:16])=[O:15])[CH2:8][C:9]1[N:13]=[CH:12][NH:11][CH:10]=1)=[O:5])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(CCNC(=O)OCc1ccccc1)N[C@@H](Cc1c[nH]cn1)C(=O)O
Temperature: 22.5 °C
Reaction time: 15 h
Yield: 111.1 %

Procedure:
A 0.5 L round-bottom flask is loaded with 22.6 g of 3-aminopropionyl-histidine, 150 ml of water and 30 ml of acetone. The solution is adjusted to pH 13.00 with 30% sodium hydroxide, then cooled to 0-5° C., at which temperature 18.7 g of benzyl chloroformate are dropwise added in about 1 h, keeping pH at 12-13 with sodium hydroxide. Afterwards, the mixture is stirred for 15 h at 20-25° C., acidified to pH 2.0-2.5 with 37% hydrochloric acid, then concentrated under vacuum, at 50° C. maximum, carrying out repeated evaporations with isopropanol to a white solid residue. 40 g of a residue are obtained.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].CN(C)C1C=CC=CC=1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:21]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9])=[O:22])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: O=C(O)c1ccccc1O
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)Oc1ccccc1C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 41.7 %

Procedure:
60 g (434 mmol) of salicylic acid and 111 ml of N,N-dimethylaniline are dissolved in 360 ml of toluene. The medium is cooled to 0° C. and then 41.5 ml (434 mmol) of ethyl chloroformate are added dropwise. After stirring for 2 hours at ambient temperature, the mixture is washed with a 1N aqueous hydrochloric acid solution and then with a saturated sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and concentrated. The residue is taken up in dichloromethane and precipitated from heptane. The solid is filtered off and then dried. 38 g of 2-(ethoxycarbonyloxy)benzoic acid are obtained in the form of a white solid with a yield of 42%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[C:30](Cl)(=[O:33])[CH:31]=[CH2:32]>O1CCCC1>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([CH:18]([CH3:20])[CH3:19])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:30](=[O:33])[CH:31]=[CH2:32])[CH:7]=[CH:6][CH:5]=3)[C:16]=12
Reactant: C=CC(=O)Cl
Reactant: CC(C)n1nc(-c2cccc(N)c2)c2c(N)ncnc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(-c2nn(C(C)C)c3ncnc(N)c23)c1
Reaction time: 1 h
Yield: 26 %

Procedure:
A solution of tetrahydrofuran (20 mL), compound 22 (219 mg, 0.817 mmol) and diisoproylethylamine (156 μL, 0.895 mmol) was cooled to 0° C. Acryloyl chloride (67 μL, 0.828 mmol) was added and the reaction was allowed to proceed for 1 hour and afterwards concentrated in vacuo. The residue was dissolved in dichloromethane (20 mL) and washed with saturated sodium bicarbonate (20 mL). The aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic layers were dried with MgSO4, filtered and concentrated in vacuo. The product was purified by preparative RP-HPLC and lyophilized (70 mg, 26% yield): 1H NMR (400 MHz, DMSO) δ 10.40 (s, 1H), 8.38 (s, 1H), 8.04 (s, 1H), 7.73 (d, J=8.0, 1H), 7.52 (t, J=7.9, 1H), 7.39 (d, J=7.7, 1H), 6.47 (dd, J=17.0, 10.1, 1H), 6.29 (dd, J=17.0, 2.0, 1H), 5.80 (dd, J=10.1, 2.0, 1H), 5.11 (hept, J=6.6, 1H), 1.51 (d, J=6.7, 6H); 13C NMR (100 MHz, DMSO) δ 163.47, 154.87, 151.90, 150.94, 144.73, 139.53, 132.54, 131.68, 129.88, 127.31, 123.42, 119.96, 119.22, 96.91, 48.80, 21.74; [M+H]+ calculated for C17H18N6O 323.1, found 323.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[OH:12]>C(O)(=O)C.[Fe]>[NH2:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([Cl:1])=[C:3]([OH:12])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cc(O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
Iron powder (4.03 g, 72.1 mmol) was added slowly to the solution of 2,4-dichloro-5-nitrophenol (3.00 g, 14.4 mmol) in acetic acid (100 ml). After stirring at room temperature overnight, the reaction mixture became milky with formation of a white precipitate. The precipitate was filtered off and the filtrate was concentrated to ca. 20 mL. The residue was diluted with water (100 mL) and neutralized by slow addition of sodium bicarbonate. The mixture was then extracted with methylene chloride (3×150 mL). The organic layer were combined, dried over sodium sulfate, filtered and concentrated to dryness to afford 5-amino-2,4-dichlorophenol (2.20 g, 86%) as a brown solid. 1H-NMR (DMSO-d6) 89.91 (s, 1H), 7.10 (s, 1H), 6.42 (s, 1H), 5.34 (s, 2H); MS LC-MS (M+H)+=178.2, RT=2.10 min.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:28])[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)=[O:11])=[CH:6][CH:5]=1)([O-])=O>CN(C)C=O.[Pd]>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][C:16]([O:15][CH2:14][CH2:13][O:12][C:10](=[O:11])[CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:30][CH:29]=2)=[O:28])=[CH:20][CH:21]=1
Reactant: O=C(COc1ccc([N+](=O)[O-])cc1)OCCOC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1ccc(OCC(=O)OCCOC(=O)COc2ccc(N)cc2)cc1
Reaction time: 6 h
Yield: 75.8 %

Procedure:
(4-nitro-phenoxy)-acetic acid-2-[2-(4-nitrophenoxy)acetoxy]ethyl ester 42 (100 g, 238 mmol) was dissolved in dry dimethylformamide (500 ml) in a pressure vessel, palladium on carbon (5%, 22 g) added, and the mixture stirred under an atmosphere of hydrogen (4 Kg) for 6 hours. The catalyst was removed by filtration and ice water (2.5 L) was added to the filtrate. Crude 43 was filtered off, dried and recrystallised in a mixture of methanol:chloroform (1:1) to give pure 43 (65 g, 78%) as a light brown shining powder. M.p: 124-125.8° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1.C([BH3-])#N.[Na+]>>[Cl:14][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][CH2:4][NH:3][O:2][CH3:1])[CH:12]=[CH:11][C:10]=1[Cl:13]
Reactant: CON=CCCc1ccc(Cl)c(Cl)c1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCCCc1ccc(Cl)c(Cl)c1
Yield: 48 %

Procedure:
Reduction of 3-(3,4-dichlorophenyl)-propionaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of compound 3-B gave the title hydroxylamine as a clear oil after chromatography on silica gel and distillation in vacuo (48% yield): bp 75-80° C./0.3 torr (bulb to bulb distillation, air bath temperature). 1HNMR 400 MHz (CHCl3) δ (ppm): 1.81 (2H, m, CH2), 2.63 (2H, t, J=7.8 Hz, CH2), 2.90 (2H, t, J=7.1 Hz, CH2), 3.52 (3H, s, OCH3), 5.55 (broad, NH), 7.01 (1H, dd, J=2.0 Hz and J=8.1 Hz, aromatic), 7.27 (1H, broad d, aromatic), 7.32 (1H, d, J=8.1 Hz, aromatic). The hydrochloride salt was obtained as a white solid: mp 81-83° C. Anal. calcd for C10H13Cl2NO—HCl: C, 44.39; H, 5.22; N, 5.18. Found: C, 44.57; H, 5.05; N, 5.18.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:33][C@H:32]([O:34][C:35](=[O:38])[NH:36][CH3:37])[C@@:31]2([CH3:39])[C:12](=[CH:13][CH:14]=[C:15]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:40])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[CH:20]([CH3:26])[CH:21](OC)[O:22]C)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CO.S([O-])([O-])(=O)=O.[Cu+2]>[C:1]([O:9][C@H:10]1[CH2:33][C@H:32]([O:34][C:35](=[O:38])[NH:36][CH3:37])[C@@:31]2([CH3:39])[C:12](=[CH:13][CH:14]=[C:15]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:40])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[CH:20]([CH:21]=[O:22])[CH3:26])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)O[C@H]1C[C@H](OC(=O)c2ccccc2)CC2=CC=C3[C@@H]4CC[C@H](C(C)C(OC)OC)[C@@]4(C)CC[C@@H]3[C@]21C
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CO
Product: CNC(=O)O[C@H]1C[C@H](OC(=O)c2ccccc2)CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@]21C
Temperature: 60 °C
Reaction time: 7 h
Yield: 65.5 %

Procedure:
In 5 ml of methanol was dissolved 100 mg of 3β-benzoyloxy-21,21-dimethoxy-20-methyl-1α-(N-methylcarbamoyl)oxypregna-5,7-diene, followed by addition of 5 ml of water and 100 mg of copper sulfate. The mixture was stirred in an atmosphere of argon gas at a temperature of 60° C. for 7 hours. The reaction mixture was then worked up in the same manner as Example 156 to give 60 mg of 3β-benzoyloxy-1α-(N-methylcarbamoyl)oxypregna-5,7-diene-20-carbaldehyde showing the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[OH:34][C:35]([C:38]1[CH:45]=[CH:44][C:41]([CH2:42][NH2:43])=[CH:40][CH:39]=1)([CH3:37])[CH3:36]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:43][CH2:42][C:41]1[CH:44]=[CH:45][C:38]([C:35]([OH:34])([CH3:36])[CH3:37])=[CH:39][CH:40]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)cnc1Oc1ccc(F)cc1
Reactant: CC(C)(O)c1ccc(CN)cc1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(O)c1ccc(CNC(=O)c2cc(Cl)cnc2Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.8 %

Procedure:
5-Chloro-2-(4-fluoro-phenoxy)-nicotinic acid (1.37 g) was dissolved in anhydrous dichloromethane (15 mL). 4-Methylmorpholine (0.80 mL) was added and the solution cooled in a dry ice/acetone bath. Isobutyl chloroformate (0.85 mL) was added and the solution stirred for 15 minutes. 4-(1-Hydroxy-1-methyl-ethyl)-benzyl amine (0.946 g) was added and the solution warmed to ambient temperature overnight. The solution was then poured into a separatory funnel and water (15 mL) was added. The solution was shaken, and the organics were removed. The remaining aqueous portion was extracted with dichloromethane (6×20 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated to dryness in vacuo to yield the crude product (2.65 g). Purification of the crude material by silica gel chromatography (ethyl acetate:hexanes 1:3) yielded pure title compound (1.61 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:19]([OH:21])=O)[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:11]=1.[CH3:22][C:23]1[N:28]=[CH:27][C:26]([CH2:29][NH2:30])=[CH:25][CH:24]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:19]([NH:30][CH2:29][C:26]2[CH:27]=[N:28][C:23]([CH3:22])=[CH:24][CH:25]=2)=[O:21])[CH:9]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[CH:11]=1
Reactant: Cc1ccc(CN)cn1
Reactant: COCCOc1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc(C(=O)NCc2ccc(C)nc2)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(2-methoxyethoxy)-4′-methylbiphenyl-3-carboxylic acid (50 mg, 0.18 mmol) in N,N-dimethylformamide (1 mL) were added (6-methylpyridin-3-yl)methanamine (45 mg, 0.37 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (150 mg, 0.39 mmol) and N,N-diisopropylethylamine (150 μL, 0.86 mmol). The reaction mixture was stirred for 16 hours at 25° C. LC-MS indicated the reaction was complete. The reaction mixture was purified by preparative HPLC to afford the title product.
Reaction SMILES: [O:1]([CH:8]1[CH2:12][CH2:11][N:10]([C:13](Cl)=[O:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>O1CCCC1>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][C:13]([N:10]1[CH2:11][CH2:12][CH:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)=[O:14]
Reactant: CN(C)CCN
Reactant: O=C(Cl)N1CCC(Oc2ccccc2)C1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)N1CCC(Oc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.8 %

Procedure:
A stirred solution of 0.088 mole of crude 3-phenoxy-1-pyrrolidinecarbonyl chloride in 100 ml of tetrahydrofuran was cooled to 0° C., treated with 7 g (0.088 mole) of pyridine (to remove any benzyl chloride contaminant), warmed to ambient temperature (1 hr.) and treated with 15.5 g (0.176 mole) of N,N-dimethylethylenediamine at a rapid drop rate. The reaction was slightly exothermic and after 2 hours, the mixture was filtered to remove a fine silvery precipitate (hydrochloride of the diamine) and concentrated in vacuo to a dark oil. The oil was partitioned between isopropyl ether and water, the isopropyl ether phase separated and the aqueous portion extracted with 100 ml of isopropyl ether. The isopropyl ether extracts were combined and concentrated in vacuo to give an amber oil, 5 g. The aqueous phase was extracted with 3×50 ml of benzene, the extracts combined, washed with 20 ml of water, dried over magnesium sulfate and concentrated in vacuo to a dark oil, 12 g. This residue partially crystallized overnight and was recrystallized 2 times with charcoal treatment, first from isopropyl ether/ligroin, then from isopropyl ether (cooled in a refrigerator) to give 4.1 g of white crystalline product which after drying at 64° C. under reduced pressure for 18 hours weighed 3.9 g, m.p. 72°-73° C. The residue from the original isopropyl extracts (5 g) was combined with the filtrate from above and upon reworking, gave an additional 4.3 g of product, m.p. 71°-73° C. The fraction with m.p. 72°-73° C. was submitted for elemental analysis and testing.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>[Rh]>[C:9]([O:8][C:6]([NH:5][CH:4]([CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[C:3]([O:2][CH3:1])=[O:20])=[O:7])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Rh]
Product: COC(=O)C(CC1CCCCC1)NC(=O)OC(C)(C)C
Yield: 86316.1 %

Procedure:
315.3 g (1.28 mmol) of t-butoxycarbonyl-L-phenylalanine methyl ester are hydrogenated in the presence of 5% rhodium on aluminium oxide at room temperature and 440 kPa according to the method described by J. Boger et al. in J. Med. Chem., 28, 1779 (1985), whereby there are obtained 315.3 g of methyl 2-t-butoxycarbonylamino-3-cyclohexylpropionate as an oil which is used directly in the next step.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:68]=[N:69][C:70]([CH3:73])=[CH:71][CH:72]=2)[C:56]=1[CH3:74].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:68]=[N:69][C:70]([CH3:73])=[CH:71][CH:72]=4)[C:56]=3[CH3:74])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Cc1ccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)cn1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc3cc(F)cc(F)c3c(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)c2C)cn1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.025 g, 0.053 mmol), 2,5-dimorpholinopyridin-3-amine (0.104 g, 0.39 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(6-methylpyridin-3-yl)quinoline (0.1 g, 0.33 mmol), Pd2dba3 (0.012 g, 0.013 mmol) and sodium tert-butoxide (0.079 g, 0.82 mmol) in toluene (2.7 mL) at 120° C. for 7 days. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(6-methylpyridin-3-yl)-quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (1H, d, J=2.0 Hz), 7.90 (1H, dd, J=8.0, 2.3 Hz), 7.75 (1H, d, J=11.2 Hz), 7.66 (1H, J=2.7 Hz), 7.61 (1H, br d, J=9.2 Hz), 7.36 (4H, d, J=8.0 Hz), 6.98-7.06 (1H, ddd, J=13.3, 8.4, 2.4 Hz), 6.36 (1H, d, J=2.5 Hz), 3.91 (4H, t, J=4.8 Hz), 3.81 (4H, app t, J=4.37 Hz), 3.22 (4H, br. s.), 3.03 (3H, app t, J=4.9 Hz), 2.68 (3H, s), 2.18 (3H, s). Mass Spectrum (ESI) m/e=533.2 (M+1).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CC#N>[CH2:20]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:19]=[CH2:18]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCC(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
A 500 mL three necked round bottom flask was charged with diethyl malonate (20 g), dry potassium carbonate (43 g) and dry CH3CN (200 mL) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 10 minutes and allylbromide (23 g) was slowly added to the reaction mixture at room temperature. The reaction mixture was heated to 80° C. for 24 hours. The reaction mixture was cooled to room temperature and filtered through celite bed. The celite bed was washed with acetonitrile (100 mL) and the combined filtrate was concentrated to give diethyl 2-allylmalonate (24 g) as colorless liquid. 1H NMR (CDCl3): δ 1.26 (t, 6H), 2.61-2.67 (m, 2H), 3.42 (t, 1H), 4.20 (q, 4H), 5.03-5.16 (m, 2H), 5.70-5.85 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)C=O.N.CC1C=CC(S(C[N+]#[C-])(=O)=O)=CC=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28]C1>C(O)C>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:4]([C:30]2[NH:29][CH:28]=[N:26][CH:31]=2)[C:3]=1[OH:11]
Reactant: O=Cc1cc(F)cc(Cl)c1O
Reactant: C1CNCCN1
Agent: N
Agent: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Solvent: CCO
Product: Oc1c(Cl)cc(F)cc1-c1cnc[nH]1
Yield: 65 %

Procedure:
Paraformaldehyde (0.35 g) was added in portions to a mixture of phenol (487.8 mg, 3.33 mmol), triethylamine (1.3 mL, 9.33 mmol), and anhydrous MgCl2 (0.98 g, 10.3 mmol) in acetonitrile (30 mL). The mixture was refluxed for 48 h, cooled to room temperature, acidified with aqueous 3 N HCl solution, and extracted with ether. The ether layer was washed with water, and brine, and dried (MgSO4). Removal of solvent yielded a crude material which was purified by column chromatography (SiO2) to yield 3-chloro-5-fluoro-2-hydroxybenzaldehyde. To this aldehyde (0.25 mmol) in at room temperature was added 3 mL of NH3 (2.0 M solution in EtOH) solution and the solution was stirred overnite (upon addition of NH3 in ethanol, the solution changed to yellow). TosMIC (0.30 mmol equiv) and piperazine (0.38 mmol) were then added directly to the solution at room temperature in solid form. The solution were stirred at room temperature for 3 h until completion confirmed by TLC monitor. The solvent was evaporated mostly under reduced pressure and the crude was purified by column chromatography using 1:1 Hexanes and Ethyl acetate mixtures to afford the desired product as a light yellow solid. Yield=65%. 1H NMR (MeOH-d4): 6.95-6.99 (m, 1H), 7.29-7.33 (m 1H), 7.61 (s, 1H), 7.84 (s, 1H).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([CH3:6])[CH3:5].Cl[CH2:8][C@H:9]([OH:16])[CH2:10][C:11]([O:13]CC)=[O:12]>O>[OH:16][C@H:9]([CH2:10][C:11](=[O:12])[O-:13])[CH2:8][N+:4]([CH3:6])([CH3:5])[CH3:3]
Reactant: CN(C)C
Reactant: CCOC(=O)C[C@@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[N+](C)(C)C[C@H](O)CC(=O)[O-]
Temperature: 0 °C

Procedure:
Sodium hydroxide (17.6 g, 0.44 mol, ca. 2 eq.) was dissolved in water (240 g). Aqueous tri-methylamine (25%, 61.3 g, ca. 1.2 eq.) was added with cooling. The resulting mixture was cooled to 0° C. and ethyl (R)-4-chloro-3-hydroxybutyrate (content 100%, 36 g, 0.216 mol) was added dropwise within 3 h to the stirred reaction mixture. After one additional hour at 0° C. the reaction mixture was warmed to +20° C. and analyzed by HPLC
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH3:15])=[C:9]([N+:16]([O-])=O)[CH:8]=1)=[O:5].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:31]([N:38]1[C:42](=[O:43])[C:41](=[C:44]2[N:48]([CH3:49])[C:47]3[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=3[S:45]2)[S:40][CH2+:39]1SC)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([N:38]1[C:42](=[O:43])[C:41](=[C:44]2[N:48]([CH3:49])[C:47]3[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=3[S:45]2)[S:40][C:39]1=[N:16][C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][N:2]([CH3:19])[CH3:1])[CH:12]=[CH:11][C:10]=1[NH:13][CH2:14][CH3:15])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCNc1ccc(NC(=O)CN(C)C)cc1[N+](=O)[O-]
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 30, intermediate 2-dimethylamino-4′-ethylamino-3′-nitroacetanilide was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. 1H-NMR (CDCl3): δ 8.85 (1H, s), 7.43 (3H, t), 7.18-7.28 (5H, m), 7.10 (2H, t), 6.95 (1H, d), 6.48 (1H, d), 5.10 (2H, s), 3.71 (3H, s), 3.03 (2H, s), 2.93 (2H, q), 2.33 (6H, s), 0.97 (3H, t); MS(ESI): 584(MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH2:9])=[CH:3][CH:2]=1.Cl[C:11]1[C:16]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:11]2[C:16]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:3][CH:2]=1
Reactant: NCCc1ccncc1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1cccnc1Cl
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccnc1NCCc1ccncc1
Temperature: 100 °C

Procedure:
4-Pyridineethanamine (Maybridge Chemical Co, Cornwall, England; 0.31 g, 2.5 mmol) is added to a stirred mixture of 2-chloro-N-[3(trifluoromethyl)phenyl]-3-pyridinecarboxamide (intermediate 1a; 0.90 g, 3 mmol), powdered potassium carbonate (0.35 g, 2.5 mmol) and copper(1)iodide; 0.48 g, 2.5 mmol) in dimethylformamide (10 mL). The resulting mixture is then purged with argon and subsequently heated at 100° C. under an argon atmosphere for 2 hours. The mixture is cooled, treated with water (100 mL) and extracted with ethyl acetate (3×80 mL). The combined extracts are washed with an aqueous solution of ammonia (2×50 mL of 10%), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent ethyl acetate and recrystalised from ethyl acetate—hexane to give the title compound as a colourless crystalline solid, m.p. 128-138° C.