Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:22])([F:23])[F:24])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccccc1NC1CCNCC1
Yield: 99.4 %

Procedure:
A solution of 4-(2-trifluoromethylphenylamino)piperidine-1-carboxylic acid tert-butyl ester (0.87 g, 2.52 mmol) in dichloromethane and trifluoroacetic acid (18 mL, 2:1) was stirred at ambient temperature overnight, the solvents were removed by evaporation. The residue was dissolved in ethyl acetate, and the resulting solution was washed with aqueous saturated NaHCO3 and brine, dried over anhydrous Na2SO4 and concentrated to give piperidin-4-yl-(2-trifluoromethylphenyl)amine (0.612 g, 99%) which was used directly for next step reaction without further purification. MS (ES+) m/z 245.0 (M+1).
Reaction SMILES: C(O)(=O)C(O)=O.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]([CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:14]([C:16]1[CH:36]=[CH:35][C:19]2[N:20]([CH3:34])[C:21]([CH2:23][NH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31](=[NH:33])[NH2:32])=[CH:27][CH:26]=3)=[N:22][C:18]=2[CH:17]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+].[CH2:50]([O:56][C:57](Cl)=[O:58])[CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]>C(C(C)=O)C.O>[CH3:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][O:56][C:57](/[N:33]=[C:31](\[NH2:32])/[C:28]1[CH:27]=[CH:26][C:25]([NH:24][CH2:23][C:21]2[N:20]([CH3:34])[C:19]3[CH:35]=[CH:36][C:16]([C:14]([N:13]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=4)[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:15])=[CH:17][C:18]=3[N:22]=2)=[CH:30][CH:29]=1)=[O:58]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCOC(=O)Cl
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Temperature: 15 °C

Procedure:
A solution of 1-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide oxalate compound of formula-3a (100 g) in a mixture of methyl ethyl ketone (1200 ml) and water (800 ml) was cooled to 12-18° C. Potassium carbonate (66.24 g) was added to the above reaction mixture and stirred for 15 minutes at 12-18° C. n-hexylchloroformate (28.95 g) was added to the reaction mixture and stirred for 4½ hours at 12-18° C. After completion of the reaction, the reaction mixture was quenched with water. Filtered the obtained solid, washed with methyl ethyl ketone and water. Dried the solid to get the title compound. Dichloromethane was added to the obtained compound and stirred for 15 minutes. Water was added to the reaction mixture and stirred for 20 minutes at 25-35° C. Both the organic and aqueous layers were separated, and the dichloromethane layer was washed with water followed by sodium chloride and then distilled off completely under reduced pressure. Acetone (600 ml) was added to the obtained residue and stirred for 45 minutes at 25-35° C. to obtain a clear solution. Water (500 ml) was added to the obtained solution and stirred for 45 minutes at 25-35° C. to get the solid. Filtered the solid, washed with water and finally with methyl tertiary butyl ether and then dried to get the pure title compound. Yield: 98 g; Purity by HPLC: 99.58%
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18]Br>CC(C)=O>[C:2]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:18][CH2:17]1)(=[O:1])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C(C)=O)CC1
Yield: 59.9 %

Procedure:
To a solution of ethyl 3-oxobutanoate (26 g, 200 mmol) in acetone (500 mL) was added potassium carbonate (82.8 g, 600 mmol) followed by 1,2-dibromoethane (45.12 g, 240 mmol). The reaction was refluxed for 24 hrs, then the reaction mixture was filtered. The filtrate was concentrated in vacuo, and the residue was purified by a silica gel column chromatography (1:50(v/v) EtOAc/n-hexane) to afford the title compound as colorless oil (18.7 g, 60%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].Br[CH2:11][CH2:12]Br.[OH-].[K+]>CS(C)=O>[C:3]([C:2]1([C:1]([O:7][CH2:8][CH3:9])=[O:6])[CH2:12][CH2:11]1)(=[O:4])[CH3:5]
Reactant: BrCCBr
Reactant: CCOC(=O)CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(=O)C1(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104 %

Procedure:
A mixture of ethyl acetoacetate (13.0 g, 99.9 mmol), 1,2-dibromoethane (13 mL, 151 mmol) and potassium hydroxide (14.0 g, 250 mmol) in dimethylsulfoxide (130 mL) was stirred at ambient temperature overnight. The mixture was poured into ice water and extracted with diethyl ether. The combined organic layers were washed with brine, and dried over sodium sulfate. Filtration and concentration gave 16.22 g of an oily material, which was purified by column chromatography (silica gel 80 g, 20% ethyl acetate in n-hexane) to give 12.97 g (83.1%) of 1, as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cccc(N)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100.3 %

Procedure:
To a solution of N-(t-butyloxycarbonyl)-3-nitrobenzylamine (13.8 g, 54.7 mmol) in dimethylformamide (200 mL) was added tin(II) chloride dihydrate (74.1 g, 328 mmol) and the reaction was stirred at room temperature for 48 hours. The dimethylformamide was removed under vacuum. The residue was resuspended in dichloromethane (300 ml), washed with brine (200 mL), filtered through a celite pad, and the solvent removed to provide 12.2 g of the title compound. (100%).
Reaction SMILES: [C:1]([C:3]1[NH:7][CH:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])#[N:2].[H-].[Na+].[NH2:24]OP(=O)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C>[NH2:24][N:7]1[C:3]([C:1]#[N:2])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6]1
Reactant: CCOC(=O)c1c[nH]c(C#N)c1-c1ccccc1[N+](=O)[O-]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(N)c(C#N)c1-c1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
A 3 L 3 neck round bottomed flask was fitted with a reflux condenser and overhead stirrer and charged with ethyl 5-cyano-4-(nitrophenyl)-1H-pyrrole-3-carboxylate (20 g, 70.11 mmol). To a rapidly stirred solution in DMF (1 L) was added NaH (5×500 mg, 98 mmol) portion wise over 20 min. The dark brown solution was allowed to stir for an additional 10 min. The aminating reagent ((aminooxy)(diphenyl)phosphine oxide) was added in one portion (21.26 g, 91.14 mmol). The reaction mixture immediately solidified. Upon heating to 60° C. the solids began to disperse. The mixture was eventually heated to 80° C. and stirred over night. The reaction mixture was cooled and the solids were filtered off. The filter cake was washed with EtOAc (200 mL) and the filtrate was concentrated in vacuo. The resulting solid was suspended in Et2O (300 mL) and filtered to provide a 69% yield of the product (14.37 g, 47.86 mmol) as a light tan powder. The product was used without further purification. 1H-NMR (DMSO-d6) δ 8.29-8.24 (m, 2H), 7.72 (s, 1H), 7.71-7.68 (m, 2H), 6.71 (s, 2H), 4.09 (q, J=7.2 Hz, 2H), 1.12 (t, J=7.2 Hz, 3H); HPLC RT=3.15 min.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([OH:5])[C:3]#[N:4].[Cl:7][CH2:8][CH2:9]O.CC(C)=O>O.[Cl-].[Cl-].[Zn+2]>[Cl:7][CH2:8][CH2:9][O:5][C:2]([CH3:6])([CH3:1])[C:3]#[N:4]
Reactant: CC(C)(O)C#N
Reactant: OCCCl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C#N)OCCCl
Temperature: 60 °C
Reaction time: 4 h
Yield: 46.6 %

Procedure:
Additional procedure. ZnCl2 (352.3 g 2.59 moles) was added to a 2 L round bottom flask equipped with a mechanical stirrer, nitrogen inlet-outlet, temperature probe, and condenser. Acetone cyanohydrin (110.0 g 1.29 moles) was slowly added to the stirred solid over 30 minutes keeping the temperature below 32° C. with external cooling. To the slurry, 2-chloroethanol (124.9 g 1.55 moles) was slowly added over 20 minutes keeping the temperature below 32° C. with external cooling. Acetone (3.75 g, 64.6 mmoles) was added and the mixture was heated to 60° C. After stirring for 4 h at 60° C., the reaction mixture was cooled to 30-35° C., diluted with water (1.10 L) and extracted with CH2Cl2 (1×440 mL and 1×220 mL). The combined CH2Cl2 extracts were washed with 0.5M sodium bicarbonate (330 mL), followed by water (3×330 mL). The dichloromethane solution was concentrated under vacuum to afford crude product (109 g). The crude product was purified by vacuum distillation (10 mm Hg) using a Vigreux column. The fraction boiling at 60-80° C. was collected to afford 2-(2-chloroethoxy)-2-methylpropanenitrile as colorless oil (88.7 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:5]=1[NH2:11].[Cu][C:14]#[N:15]>CN1CCCC1=O.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([C:14]#[N:15])[CH:7]=[CH:6][C:5]=1[NH2:11]
Reactant: COC(=O)c1cc(Br)ccc1N
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1cc(C#N)ccc1N
Temperature: 25 °C
Yield: 28.4 %

Procedure:
2-Amino-5-bromobenzoic acid methyl ester (4.6 g, 20 mmol) and copper (I) cyanide (3.6 g, 40 mmol) were heated at 200° C. in N-methylpyrrolidinone (20 ml) for 4 h. After cooling to room temperature, the solution was diluted with water, extracted with ethyl acetate, the aqueous extract acidified with 2N hydrochloric acid and filtered. The organic layer was separated, dried over magnesium sulphate and evaporated. The residue was purified by flash column chromatography on silica eluting with 50% ethyl acetate in hexane to yield the title compound as a colourless oil (1.0 g). MS (+EI) m /z 176 [M+ ].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)c2cccc(F)c2)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
(3-fluorophenyl)(4-methoxyphenyl)methanone (1.0 g, 4.34 mmol) in 50 mL DCM at −78° C. while stirring was treated with 1M boron tribromide (13.03 mL, 13.03 mmol) dropwise over 20 minutes. The mixture was allowed to warm to 25° C. and stir for 18 hours. The mixture was treated with water (1 mL) and stirred for 5 minutes, followed by additional water (2 mL) and stirred for 10 minutes, and finally treated with more water (50 mL) and stirred for 20 minutes. The mixture was then extracted with DCM (50 mL×2). The organic layers were combined, dried, filtered, and the filtrate evaporated under reduced pressure. The residue was purified by flash chromatography to provide the title compound (0.69 g, 74% yield). 1HNMR (300 MHz, CD3OD) δ 6.92 (d, 2H, J=8.9 Hz), 7.26 (m, 1H), 7.41-7.58 (m, 3H), 7.79 (d, 2H, J=8.9 Hz); MS (DCI) m/z 217 (M+H)+, 234 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1)[CH3:11].[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[CH2:10]([O:12][C:13](=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:16]=1)[CH3:11]
Reactant: CCOC(=O)Cc1cccc(C=O)c1
Reactant: Cc1ccc(CN)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)Cc1cccc(CNCc2ccc(C)cc2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 107.9 %

Procedure:
A solution of 4-methylbenzylamine (0.097 mL, 0.76 mmol) and (3-formyl-phenyl)-acetic acid ethyl ester (138 mg, 0.72 mmol) in MeOH (2 mL) was stirred for 3 h at room temperature. The reaction was cooled to 0° C. and NaBH4 (43 mg, 1.15 mmol) was added. After stirring at room temperature for 10 minutes, a 1:1 mixture of saturated aqueous NaHCO3:H2 was added. The product was extracted into CH2Cl2 (3×) and the organic solution was dried over MgSO4, filtered, and concentrated to yield the title compound (231 mg). 1H NMR (400 MHz, CDCl3) δ 7.13–7.30 (m, 8H), 4.14 (q, 2H), 3.83 (d, 4H), 3.78 (s, 2H), 2.34 (s, 3H), 1.25 (t, 3H); MS 298 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[Br:9][C:10]1[CH:11]=[N:12][C:13](Cl)=[N:14][CH:15]=1.[H-].[Na+]>CN(C=O)C>[Br:9][C:10]1[CH:11]=[N:12][C:13]([O:1][CH2:2][CH2:3][N:4]2[CH2:8][CH2:7][CH2:6][CH2:5]2)=[N:14][CH:15]=1
Reactant: OCCN1CCCC1
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cnc(OCCN2CCCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.9 %

Procedure:
To a solution of N-2-hydroxyethylpyrrolidine (0.9 ml, 7.71 mmol) and 5-bromo-2-chloropyrimidine (1.2 g, 6.20 mmol), in DMF (7 ml), was added sodium hydride (60% in mineral oil, 0.35 g, 8.75 mmol). The mixture was stirred, under argon, at ambient temperature for 1 hour, before being heated to 90° C. and stirred for a further hour. The reaction mixture was then partitioned between ethyl acetate and water. The organics were separated, dried over magnesium sulfate and evaporated to dryness. The resultant oil was purified by flash chromatography on silica, eluting with an increasing gradient of methanol in dichloromethane (which contained 1% aqueous ammonia solution, 0.88 M) to give the title compound (640 mg, 38%); NMR Spectrum: (CDCl3) 1.76 (m, 4H), 2.39 (m, 4H), 3.90 (t, 2H), 4.48 (t, 2H), 8.50 (s, 2H); Mass Spectrum: M+H+ 272.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([NH:11]C(OC(C)(C)C)=O)[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].S(=O)(=O)(O)O.CN(C=O)C>CCOC(C)=O>[CH2:1]([O:3][C:4]([C@@:6]1([NH2:11])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: O=S(=O)(O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C[C@@H]1C[C@]1(N)C(=O)OCC
Temperature: 45 °C
Reaction time: 1 h

Procedure:
A solution of 153.2 g (600 mmol) of (1R,2S)-1-tert-butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid ethyl ester (commercially available from Synthetech Oregon, USA) in 80 mL of EtOAc was dosed to a solution of 65.1 g (630 mmol) of sulfuric acid in 480 mL of EtOAc at 20-25° C. The reaction mixture was stirred for 60 min at 42-48° C. After complete conversion the reaction mixture was cooled to 18-22° C. Then 127.5 g (1260 mmol) of TEA was dosed at 20-30° C. Finally 100 mL of DMF was added. The reaction mixture was used in the next step immediately after preparation.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([NH:11]C(OC(C)(C)C)=O)[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2].[ClH:19].O1CCOCC1>>[ClH:19].[CH2:1]([O:3][C:4]([C@@:6]1([NH2:11])[CH2:8][C@H:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Solvent: C1COCCO1
Product: C=C[C@@H]1C[C@]1(N)C(=O)OCC

Procedure:
N-BOC (1R,2S)-1-amino-2-vinylcyclopropanecarbox-ylic acid ethyl ester (8.5 g, 33.3 mmol) was stirred under an N2 atmosphere with 200 mL of 4N HCl/dioxane (Aldrich) at rt for 3 h. The solvent was removed under reduced pressure keeping the temperature below 40 C. This gave 6.57 g (˜100%) of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid ethyl ester hydrochloride as a light tan solid. 1H NMR (300 MHz, CD3OD) δ 1.31 (t, J=7.0 Hz, 3H), 1.69–1.82 (m, 2H), 2.38 (q, J=8.8 Hz, 1H), 4.29 (q, J=7.0 Hz, 2H), 5.22 (d, J=10.3 Hz, 1H), 5.40 (d, J=17.2 Hz, 1H), 5.69–5.81 (m, 1H). LC-MS (Method J, retention time: 0.58 min), MS m/z 156 (M++1).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[OH:12][C@H:13]1[CH2:17][NH:16][C@H:15]([C:18]([OH:20])=[O:19])[CH2:14]1.C([O-])(O)=O.[Na+].O>CCOCC>[CH2:5]([O:4][C:2]([N:16]1[CH2:17][C@H:13]([OH:12])[CH2:14][C@H:15]1[C:18]([OH:20])=[O:19])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.7 %

Procedure:
A solution of benzyl chloroformate (50 mL, 0.35 mol) in Et2O (160 mL) was added dropwise, during 10 min, to a rapidly stirred mixture of trans-4-hydroxy-L-proline (39.8 g, 0.308 mol), NaHCO3 (63.7 g, 0.758 mol) and H2O (660 mL). The reaction mixture was stirred at room temperature for 20 h. The layers were separated, and the aqueous layer was washed with Et2O (4×200 mL), cooled, and then acidified to pH 1-2 with concentrated hydrochloric acid The resulting emulsion was extracted with EtOAc (5×200 mL). Combined EtOAc extracts were washed in succession with H2O (3×500 mL) and brine (3×500 mL), dried over MgSO4, and then concentrated in vacuo to give intermediate (4) as a colorless foam (62.7 g, 78%). Additional reactions were carried out to give a total of 284 g of product suitable for further transformation.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7].[CH:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:12]([OH:19])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:6]([N:5]([CH2:8][CH3:9])[CH2:4][CH2:3][O:19][C:12]1[CH:11]=[CH:10][C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=1)[CH3:7]
Reactant: CCN(CC)CCCl
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C

Procedure:
88.7 g (515.41 mmol) of (2-chloroethyl)diethylamine hydrochloride are added at ambient temperature to a suspension of 71.7 g (515.41 mmol) of p-nitrophenol and 284.94 g (2.061 mol) of potassium carbonate in 600 mL DMF and the reaction mixture is heated to 80° C. for 8 hours. The reaction mixture is evaporated down and the residue poured onto water and extracted with ethyl acetate. The organic phase is extracted three times with water and dried over sodium sulfate. The desiccant is filtered off and the filtrate is evaporated down. Yield: 110.52 g (90% of theory); C12H18N2O3 (M=238.28); Rf value: 0.52 (silica gel, dichloromethane/methanol (10:1)).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[F:11].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(F)c1
Temperature: 85 °C
Yield: 99 %

Procedure:
1,2-Difluoro-4-nitrobenzene (8.0 g, 50 mmol) was added to morpholine (4.85 g, 55.7 mmol) and anhydrous potassium carbonate (3.85 g, 27.9 mmol) in acetonitrile (75 ml). The reaction was heated at 85° C. for 3 hours, cooled, filtered and the solid washed with EtOAc (50 ml). Evaporation of the filtrate, trituration with isohexane and filtration gave the title compound as a solid (11.2 g, 98%). NMR (CDCl3): 3.28 (t, 4H), 3.88 (t, 4H), 6.92 (t, 1H), 7.92 (dd, 1H), 8.00 (m, 1H); m/z 227.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1.[CH3:10][O-:11].[Na+]>CO>[NH2:1][C:2]1[C:7]([O:11][CH3:10])=[N:6][C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Cc1cnc(N)c(Br)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(C)cnc1N
Temperature: 25 °C
Yield: 75 %

Procedure:
2-Amino-3-bromo-5-methylpyrazine (0.374 g) was added to a freshly prepared solution of sodium methoxide in methanol (made by addition of sodium (0.115 g) to methanol (6 ml)). The reaction was heated under reflux for 18 hours, cooled to ambient temperature and the solvent removed by evaporation. Water (5 ml) was added to the residue and extracted with dichloromethane (3×20 ml). The combined organic extracts were dried (MgSO4) and the solvent removed by evaporation. The residue was purified by chromatography on silica gel, eluting with dichloromethane to give 2-amino-3-methoxy-5-methylpyrazine as a white crystalline solid (0.208 g, 75%), m.p. 67-69° C.; mass spectrum (+ve CI): 140 (M+H)+.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:34][CH2:35][CH:36]([O:39][CH3:40])[O:37][CH3:38]>C1COCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][C@H:12]([CH:13]([CH3:14])[CH3:15])[C:16]([NH:34][CH2:35][CH:36]([O:39][CH3:40])[O:37][CH3:38])=[O:18])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(CN)OC
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(CNC(=O)[C@H](NC(=O)OCc1ccccc1)C(C)C)OC
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
A solution of Cbz-D-Valine (500 g, 1.99 mol) and N-methylmorpholine (201.8 g, 1.99 mol) in anhydrous THF (8 L) was cooled to −15° C. and i-butyl chloroformate (299 g, 2.19 mol) was added dropwise under stirring. After 30 min, a solution of 1-amino-2,2-dimethyoxyethane (209.5 g, 1.99 mol) in THF (1 L) was added slowly and the temperature was maintained at −15° C. for 2 h. The reaction mixture was washed with brine (2 L) and the organic phase was concentrated to remove the THF. The residue was diluted with EtOAc (4 L), washed with 1N aq HCl (2×2 L), sat. aq. NaHCO3 (2 L) and sat. aq. Na2CO3 (2 L) and brine (1.5 L). After drying over Na2SO4, the organic solvent was removed under reduce pressure to afford (R)-benzyl(1-((2,2-dimethoxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate as a white solid (670 g, yield 99.5%), which was used for next step without further purification. LC-MS m/z 360.9 [M+Na]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17]Cl)[N:9]=[CH:8][CH:7]=[C:6]2[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[O:28])=[CH:22][CH:21]=1)#[N:2].[CH3:38][NH:39][CH3:40]>CN(C)C=O.[Cl-].[Na+].O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:39]([CH3:40])[CH3:38])[N:9]=[CH:8][CH:7]=[C:6]2[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[O:28])=[CH:22][CH:21]=1)#[N:2]
Reactant: CNC
Reactant: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OCCCCCl)c(C#N)cc34)cc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OCCCCN(C)C)c(C#N)cc34)cc2)cc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
N-(4-(6-Cyano-7-(4-chlorobutoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea (120 mg) was dissolved in dimethylformamide (3 ml), and then a 50% dimethylamine solution (93 μl) was added and the mixture was heated and stirred at 70° C. for 5 hours. The reaction solution was poured into saturated brine and extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate and concentrated. The residue was passed through NH silica gel (Fuji Silysia Chemical) and eluted with a solvent (ethyl acetate), and then further eluted with another solvent (ethyl acetate:methanol=10:1) and concentrated. The obtained solid was passed through Merck Silica Gel using tetrahydrofuran, and after eluting the insoluble portion with tetrahydrofuran and ethyl acetate, it was further eluted with solvents (tetrahydrofuran:methanol:triethylamine=10:1:1, ethyl acetate:methanol:triethylamine=10:1:1) and concentrated to obtain 10 mg of the title compound as a solid.