Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:6][C@@H:5]([C:7](Cl)=[N:8]OS(C)(=O)=O)[C:4]([CH3:16])([CH3:15])[O:3]1.[S-:18][C:19]#[N:20].[Na+].N1C=CC=CC=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34][C:35]1[CH:36]=[C:37]([O:42][C:43]2[C:44]([CH3:50])=[N:45][N:46]([CH3:49])[C:47]=2[CH3:48])[C:38]([NH2:41])=[N:39][CH:40]=1>O.C(#N)C>[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34][C:35]1[CH:36]=[C:37]([O:42][C:43]2[C:44]([CH3:50])=[N:45][N:46]([CH3:49])[C:47]=2[CH3:48])[C:38]([NH:41][C:19]2[S:18][N:8]=[C:7]([C@H:5]3[C:4]([CH3:15])([CH3:16])[O:3][C:2]([CH3:1])([CH3:17])[O:6]3)[N:20]=2)=[N:39][CH:40]=1
Reactant: CC1(C)O[C@@H](C(Cl)=NOS(C)(=O)=O)C(C)(C)O1
Reactant: Cc1nn(C)c(C)c1Oc1cc(Sc2ccccn2)cnc1N
Reactant: N#C[S-]
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Solvent: O
Product: Cc1nn(C)c(C)c1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@@H]2OC(C)(C)OC2(C)C)ns1
Temperature: 40 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
A flask was charged with (R)-2,2,5,5-tetramethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoyl chloride (0.371 g, 1.30 mmol), sodium thiocyanate (0.0929 g, 1.15 mmol), pyridine (0.278 ml, 3.44 mmol), and acetonitrile (25 mL) and the reaction was heated to 40° C. for 30 minutes. 5-(Pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-amine (0.250 g, 0.764 mmol) was added and the reaction was stirred at 70° C. overnight. Water was added and the reaction was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified over silica gel (50 to 100% ethyl acetate in hexanes) to afford (S)-N-(5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-yl)-3-(2,2,5,5-tetramethyl-1,3-dioxolane-4-yl)-1,2,4-thiadiazol-5-amine (0.233 g, 56.5% yield) as yellow solid.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15](=[O:38])[CH2:16][C:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:19]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)(=[O:28])=[O:27])[C:18]=1[CH3:37].CI>C1COCC1>[CH3:13][O:14][C:15](=[O:38])[CH:16]([C:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:19]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)(=[O:27])=[O:28])[C:18]=1[CH3:37])[CH3:1]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(Cl)c(Cl)c2)c2ncccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1c(C)n(S(=O)(=O)c2ccc(Cl)c(Cl)c2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirring solution of diisopropylamine (34 μL, 0.24 mmol) in THF (1 mL), at −78° C., is added a 2.5M solution of n-BuLi in hexanes (105 μL, 0.26 mmol). After 20 minutes, a solution of [1-(3,4-dichloro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (Method B; 100 mg, 0.24 mmol) and MeI (15.2 μL, 0.24 mmol) in THF (1 mL) is added. The reaction is continued for 30 minutes, then allowed to warm to room temperature. The reaction mixture is evaporated to dryness and purified by flash chromatography (4:1 iso-hexane/EtOAc elution), to afford 2-[1-(3,4-dichloro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-propionic acid methyl ester; MH+=427.
Reaction SMILES: Br[C:2]([F:9])([F:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[O:10]1C[CH2:13][CH2:12][CH2:11]1.BrC(F)(F)C(OCC)=O.C(=O)CC.O1CCCC1.C(=O)CC>[Zn].O1CCCC1>[CH2:6]([O:5][C:3](=[O:4])[C:2]([F:9])([F:8])[CH:11]([OH:10])[CH2:12][CH3:13])[CH3:7]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: C1CCOC1
Agent: [Zn]
Solvent: CCC=O
Product: CCOC(=O)C(F)(F)C(O)CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.3 %

Procedure:
Into a 2-L glass flask with a dropping funnel and a condenser, 70.6 g (1.08 mol/1.1 eq) of activated zinc metal and 300 mL of tetrahydrofuran (THF, dehydrated) were added. An ethyl bromodifluoroacetate/THF solution (prepared by dissolving 200 g (0.985 mol) of ethyl bromodifluoroacetate into 80 mL of THF (dehydrated)) and a propionaldehyde/THF solution (prepared by dissolving 58.7 g (1.01 mol/1.0 eq) of propionaldehyde in 80 mL of THF (dehydrated)) were simultaneously dropped into the glass flask. The resulting solution was stirred for 2 hours at room temperature. The completion of the reaction was confirmed by gas chromatography. After that, the solution was separated into an organic layer and an aqueous layer with the addition of water and diisopropyl ether. The thus-obtained organic layer was washed with diluted hydrochloric acid and with water, dried, concentrated under a reduced pressure, and then, distillated under a reduced pressure. With this, 110 g of 2,2-difluoro-3-hydroxy-pentanoic acid ethyl ester was obtained as a light-brown oily substance (yield: 60%, purity: 98%).
Reaction SMILES: [C:1]([O:5][CH3:6])(=O)[CH2:2][OH:3].[C:7]([O:11][CH3:12])(=[O:10])[CH:8]=C.Cl.C(OCC)(=O)C.CCCCCC>CCOCC>[CH3:12][O:11][C:7]([CH:8]1[C:2](=[O:3])[CH2:1][O:5][CH2:6]1)=[O:10]
Reactant: COC(=O)CO
Reactant: C=CC(=O)OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCCCCC
Product: COC(=O)C1COCC1=O
Yield: 53.6 %

Procedure:
To a suspension of Nail (6.66 g, 166.5 mmol) in ether (500 mL) add methyl glycolate (15.0 g, 166.5 mmol) drop wise. Stir the reaction until evolution of H2 gas ceases. Concentrate and dissolve the solid in DMSO (300 mL). Cool the reaction to 0° C. and add methyl acrylate (16.6 mL, 183.17 mmol) drop wise. Warm the reaction to room temperature and stir overnight. Acidify the reaction with 10% HCl and extract with ether (3×). Combine organic extracts and wash with brine. Dry the organic solution (Na2SO4), filter, and concentrate in vacuo. Purify by flash chromatography (250 g SiO2, 40 mL/min, 0-50% ethyl acetate/hexane for 20 minutes and then 50% ethyl acetate/hexane for 13 minutes) to yield 4-oxo-tetrahydro-furan-3-carboxylic acid methyl ester 4a (12.9 g, 89.2 mmol, 54%) as a colorless oil. 1H NMR (δ, 400 MHz, CDCl3): 4.50 (dd. 1H, J=8.4, 9.6 Hz), 4.46 (dd, 1H, J=8.4, 9.6 Hz), 4.05 (d, 1H, J =16.8 Hz), 3.79, (s, 3H), 3.97 (d, 1H, J=16.8, Hz), 3.54 (t, 1H, J=8.4 Hz). MS calcd. 144; found (EI) 144.
Reaction SMILES: [C:1]([OH:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.C(=O)(O)[O-].[K+].[CH2:19](Br)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CS(C)=O>[CH2:19]([O:12][C:1](=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCCc1ccccc1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(/C=C/c1ccc(O)c(O)c1)OCCc1ccccc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
10.0 g of caffeic acid and 6.1 g potassium bicarbonate were mixed in 50 mL of dimethylsulfoxide. 7.6 mL of phenethyl bromide were added and the reaction mixture was heated to 70° C. under agitation. The mixture was stirred for 3 hrs, and then cooled to <25° C. The reaction mixture was slowly added to 500 mL of water under agitation to precipitate the product, which was recovered by filtration. The crude product was washed with dilute potassium bicarbonate and toluene and was then recrystallized via cooling from 200 mL boiling toluene to obtain caffeic acid phenethyl ester The yield was 9.0 g and the assay was 100%.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH3:11])([CH3:10])[C:7](O)=[O:8])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:15])=O>C1(C)C=CC=CC=1>[C:1]([O:4][CH2:5][C:6]([CH3:11])([CH3:10])[C:7]([Cl:15])=[O:8])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)OCC(C)(C)C(=O)O
Solvent: Cc1ccccc1
Product: CC(=O)OCC(C)(C)C(=O)Cl
Yield: 91 %

Procedure:
Under an argon atmosphere a stirred solution of 1.2 grams (0.008 mole) of 3-acetoxy-2,2-dimethylpropionic acid in 30 ml of toluene was heated to 80° and a solution of 1.9 grams (0.015 mole) of oxalyl chloride in 20 ml of toluene was added dropwise. Upon completion of addition the reaction mixture was heated at 80° for 18 hours. The reaction mixture was concentrated under reduced pressure to give 1.3 grams of 3-acetoxy-2,2-dimethylpropionyl chloride as an oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#N)=[C:6]([F:13])[CH:5]=1.I[CH3:15].C[N:17]([CH:19]=O)C>C1COCC1.CCOC(C)=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:15])([CH3:11])[C:19]#[N:17])=[C:6]([F:13])[CH:5]=1
Reactant: N#CCc1ccc(Br)cc1F
Reactant: CN(C)C=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc(Br)cc1F

Procedure:
To a slurry of sodium hydride (60% dispersion in mineral oil, 0.82 g, 20.6 mmol) in DMF (20 mL) cooled to 0° C. was added a solution of (4-bromo-2-fluoro-phenyl)-acetonitrile (2.0 g, 9.35 mmol) from Step 1 above, dissolved in THF (10 mL). The reaction was stirred till gas evolution ceased, and then iodomethane (1.3 mL, 20.6 mmol) was added slowly. The reaction was stirred for 30 minutes, and then diluted with 100 mL EtOAc. The solids were removed by filtration, and the organic layer was washed with 100 mL water. The organic layer was dried over MgSO4, and then filtered. The mother liquor was concentrated by rotary evaporation, and the product was distilled under high vacuum (0.3 torr, 45° C.). Yield: 2.25 g, 99%. %. 1H NMR (CDCl3) δ: 2.81 (s, 3H), 2.88 (s, 3H), 7.20–7.25 (m, 3H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.COB(OC)OC.C(#N)C>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: C1COCCN1
Agent: COB(OC)OC
Solvent: CC#N
Solvent: O
Product: COc1c(N2CCOCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A mixture of 1.48 g of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (5 mmol), 0.85 g of morpholine (10 mmol), 1.04 g of trimethoxyborane (10 mmol) and 7.5 ml of acetonitrile was refluxed with heating for 4 hours. The reaction solution was cooled to room temperature, 20 ml of water was added therein, a pH was adjusted to 8 with 6N--HCl, and separated crystals were filtered and dried to obtain 1.30 g of the objective compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.Cl.[CH3:11][NH:12][CH3:13].[CH2:14]=O.Cl>C(OC)(C)(C)C.O.C(O)CCC>[CH3:11][N:12]([CH3:14])[CH2:13][C:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: CNC
Reactant: C=O
Reactant: c1cnc2[nH]ccc2c1
Agent: Cl
Solvent: O
Solvent: COC(C)(C)C
Solvent: CCCCO
Product: CN(C)Cc1c[nH]c2ncccc12
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 80.5 %

Procedure:
To a mixture of 7-azaindole (150 g), dimethylamine hydrochloride (114 g) and 1-butanol (1.275 L) was added a 37% aqueous formaldehyde solution (103 g), and the mixture was stirred on a 120° C. oil bath for 2.5 hours. The reaction solution was cooled to around 40° C., and placed into water (1.35 L), concentrated hydrochloric acid (54 mL) and methyl tert-butyl ether (MTBE) (630 mL) were added, the mixture was stirred, the layers were separated, and the aqueous layer was taken. This aqueous layer was further washed with MTBE, and a 48% aqueous sodium hydroxide solution was added. This was extracted with chloroform, and a small amount of methanol was added to the extraction solution, followed by drying with anhydrous sodium sulfate. A desiccant was distilled off, followed by concentration under reduced pressure, to obtain the title compound (179 g) having the following physical property values.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+:15]([O-])([OH:17])=[O:16]>CCOCC.C(O)(=O)C>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([CH2:11][C:12]([OH:14])=[O:13])=[C:6]([N+:15]([O-:17])=[O:16])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(CC(=O)O)cc1OC
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1cc(CC(=O)O)c([N+](=O)[O-])cc1OC
Temperature: 25 °C

Procedure:
3,4-Dimethoxyphenylacetic acid (7.84 g) was solubilised in ether (100 ml) and acetic acid (20 ml). Fuming nitric acid (1.68 ml) was added dropwise to the solution. Stirring was maintained at room temperature for 16 hours. The precipitate was collected by filtration, washed with ether and dried to give 4,5-dimethoxy-2-nitrophenylacetic acid (4.19 g); NMR (DMSO-d6) 3.88(s,3H); 3.80(s,3H); 3.97(s,2H); 7.15(s,1H); 7.70(s,1H).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:30][C:31]1[C:36]([F:37])=[C:35]([O:38][CH2:39][CH3:40])[CH:34]=[CH:33][C:32]=1[CH:41]1[CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]1.O>C1COCC1>[CH2:39]([O:38][C:35]1[CH:34]=[CH:33][C:32]([CH:41]2[CH2:46][CH2:45][C:44](=[CH:2][O:3][CH3:4])[CH2:43][CH2:42]2)=[C:31]([F:30])[C:36]=1[F:37])[CH3:40]
Reactant: CCOc1ccc(C2CCC(=O)CC2)c(F)c1F
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(C2CCC(=COC)CC2)c(F)c1F
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
Well-dried methoxymethyltriphenylphosphonium chloride (166.1 g) was mixed with THF (500 ml) under an atmosphere of nitrogen, and the solution was cooled to −30° C. Potassium t-butoxide (t-BuOK; 54.4 g) was added in two portions in the temperature range of −30° C. to −20° C. After 30 minutes of stirring at −20° C., the compound (s9) (102.7 g) dissolved in THF (100 ml) was added dropwise in the temperature range of −30 to −20° C. After 30 minutes of stirring at −10° C., the reaction mixture was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure. The residue was purified by column chromatography with a mixed solvent of heptane and toluene (heptane:toluene=1:1 by volume) as an eluent and silica gel as a stationary phase powder to give 1-(4-ethoxy-2,3-difluorophenyl)-4-methoxymethylenecyclohexane. The compound was mixed with formic acid (87%; 55.8 g) and toluene (300 ml), and the mixture was heated to reflux for 2 hours. After the reaction mixture had been cooled to 30° C., it was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder, and then by recrystallization from a mixed solvent of heptane and toluene (heptane:toluene=2:1 by volume) to give trans-4-(4-ethoxy-2,3-difluorophenyl)-cyclohexanecarboxaldehyde (s10) (54.6 g). The yield based on the compound (s9) was 50.4%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH:12]([S:27][CH2:28][CH:29]([CH3:35])[C:30]([O:32]CC)=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:14]=1)(=[O:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][CH:12]([S:27][CH2:28][CH:29]([CH3:35])[C:30]([OH:32])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:14]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(C)CSC(CCc1ccccc1C(C)=O)c1cccc(COC2CCCCO2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)c1ccccc1CCC(SCC(C)C(=O)O)c1cccc(COC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the ester of Step 7 (6.67 mmol) and 1.0N NaOH (13 mL) in 55 mL of MeOH:THF 3:2 was stirred at r.t. for 24 hours. 25% Aq NH4OAc was then added and the mixture was acidified with HOAC. The title acid was extracted with EtOAc, dried over Na2SO4 and purified by flash chromatography on silica with acetone:toluene:HOAc.
Reaction SMILES: S(Br)(C)(=O)=O.[Li]C(C)(C)C.[CH3:11][O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.[C:23]([O:27][C:28](=[O:37])[NH:29][CH2:30][C:31](N(OC)C)=[O:32])([CH3:26])([CH3:25])[CH3:24]>C1COCC1.C(Cl)Cl>[C:23]([O:27][C:28](=[O:37])[NH:29][CH2:30][C:31]([C:22]1[C:13]([O:12][CH3:11])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:32])([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1ccc2ccccc2n1
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Agent: CS(=O)(=O)Br
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1nc2ccccc2cc1C(=O)CNC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of mesyl bromide (17.23 mmol) in 10 mL of THF cooled to −78° C. was added a 1.7 M THF solution of tBuLi (34.5 mmol) dropwise. The mixture was left stirring at −78° C. for 1 h. The mixture was then allowed to reach 0° C. and a solution of 2-methoxyquinoline (12.9 mmol) in THF (40 mL) was added dropwise over 10 min. The resulting mixture was aged at 0° C. for 1 h, cooled to −78° C. and added dropwise with a solution of tert-butyl(2-(methoxy(methyl)amino)-2-oxoethyl)carbamate (4.31 mmol) in 20 mL of THF. The mixture was stirred at −78° C. for 30 min then left at room temperature over night. The mixture was diluted with DCM and washed with sat. aq. NaHCO3, dried (Na2SO4), concentrated under reduced pressure and the crude product was purified by flash chromatography (SiO2, Petroleum ether/EtOAc, from 5% to 40% EtOAc). Pooled fractions were concentrated under vacuum to title product (1.01 g). MS (ES) C17H20N2O4 requires: 316.35, found: 317.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.O.[NH2:13][NH2:14]>C(O)C>[NH:13]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:14]
Reactant: NN
Reactant: Clc1ccc2ccccc2n1
Solvent: O
Solvent: CCO
Product: NNc1ccc2ccccc2n1
Temperature: 0 °C

Procedure:
21.0 g (128.4 mmol) of 2-chloroquinoline are initially charged in 210 ml of ethanol. 64.3 g (1.3 mol) of hydrazine hydrate are added, and the mixture is stirred under reflux for 16 h. The mixture is then cooled to 0° C., and the solid formed is filtered off and washed with a little ethanol. The product is initially air-dried and then dried under high vacuum.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14](Cl)=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])([O-:3])=[O:2].[F-:21].[K+]>CS(C)=O>[N+:1]([C:4]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([F:21])=[CH:13][C:5]=1[O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])([O-:3])=[O:2]
Reactant: [F-]
Reactant: CCOC(=O)COc1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)COc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 89.9 %

Procedure:
A suspension of ethyl 2,4-dinitro-5-chlorophenoxyacetate (2.0 g) and potassium fluoride (0.57 g) in dimethylsulfoxide (10 g) was stirred at a temperature of 90° to 101° C. After cooling, the reaction mixture was diluted with ice water (200 ml) and extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution in order, dried over anhydrous magnesium sulfate and concentrated to give ethyl 2,4-dinitro-5-fluorophenoxyacetate (1.7 g; yield, 89.9%). M.P., 59.0°-59.5° C. (recrystallized from methanol).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:11](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[F:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccc(F)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1c(F)cccc1C=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a suspension of 3-fluoro-2-hydroxybenzaldehyde (5.328 g, 38.02 mmol) and potassium carbonate (7.88 g, 57.03 mmol) in acetone (60 mL) was added dimethyl sulphate (3.96 mL, 41.83 mmol). The resulting suspension was stirred at 60° C. for 2 h before being allowed to cool and then concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL) and water (50 mL). The organic phase was washed with saturated sodium bicarbonate (50 mL) with the resulting organic phase being dried (MgSO4) and the solvent evaporated in vacuo to give a pale yellow oil (6.262 g, 38.02 mmol, 100%). δH (300 MHz, CDCl3) 10.40 (1H, s, CHO), 7.60 (1H, d, Ar), 7.30 (1H), m, Ar), 7.10 (1H, m, Ar), 4.10 (3H, s, OCH3).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]([CH:16]=[CH2:17])=O.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1COCC1.C1CCN2C(=NCCC2)CC1>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:17][CH2:16][CH2:14][NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC=O
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: c1ccc(CNCCCN2CCC(Cc3ccccc3)CC2)cc1
Reaction time: 0.17 h
Yield: 35.4 %

Procedure:
To a solution of 4-benzylpiperidine (10.0 g, 57 mmol) and DBU (85 μl, 0.57 mmol) in THF (10 ml) was dropwise added a solution of acrolein (90%, 3.2 g, 57 mmol) in THF (2 ml) at −20° C. with stirring over a period of 10 minutes. The mixture was stirred for 1 hour while the temperature of the mixture was elevating from −20° C. to −10° C. To the mixture were added benzylamine (6.1 g, 57 mmol), sodium triacetoxyborohydride (24.2 g, 114 mmol), successively, at −10° C., and the mixture was stirred 19 hours while the temperature was elevated to room temperature. To the mixture was added aqueous solution of 2N-sodium hydroxide (100 ml) under ice cooling, and the mixture was stirred for 30 minutes and extracted with diethyl ether (100 ml, 80 ml×2). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was dissolved in 2-propanol (50 ml). To the solution was added 4N-hydrogen chloride in ethyl acetate (50 ml) with stirring, and the resulting precipitates were collected by filtration. The precipitates were washed with 2-propanol (20 ml×3), and dried under reduced pressure to give the titled compound as white crystals (6.5 g). To the white crystaline (2.0 g) obtained was added aqueous solution of 1N-sodium hydroxide (10 ml), and the resulting solution was extracted by ethyl acetate (10 ml, 8 ml×2). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the titled compound (1.6 g) as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1.[C:22](Cl)(=[O:26])[C:23]([CH3:25])=[CH2:24]>CCN(CC)CC>[Br:21][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:22](=[O:26])[C:23]([CH3:25])=[CH2:24])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:12]#[N:13])[CH:20]=[CH:19][CH:18]=1
Reactant: C=C(C)C(=O)Cl
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Yield: 52.8 %

Procedure:
Prepared from 0.500 g of 6-amino-4(3-bromophenylamino)quinoline-3-carbonitrile, 0.194 g of Et3N and 0.202 g of methacryloyl chloride in the same manner as Example 380. There was obtained 0.317 g of N-[4-(3-bromophenylamino)-3-cyanoquinolin-6-yl]-2-methylacrylamide as a yellow solid: mass spectrum (electrospray, m/e): M+H 406.8, 408.8.