Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[N:16]=[C:15]([NH2:17])[N:14]=[C:13]([N:18]([CH3:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:12]=2)[N:7]=1)=[O:5])C.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)C>[CH2:26]([NH:33][C:4]([C:6]1[O:10][N:9]=[C:8]([C:11]2[N:16]=[C:15]([NH2:17])[N:14]=[C:13]([N:18]([CH3:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:12]=2)[N:7]=1)=[O:5])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1nc(-c2nc(N)nc(N(C)c3ccccc3)n2)no1
Reactant: NCc1ccccc1
Solvent: CCO
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(C(=O)NCc3ccccc3)n2)n1
Yield: 85 %

Procedure:
3-[4-Amino-6-(methyl-phenyl-amino)-[1,3,5]triazin-2-yl]-[1,2,4]oxadiazole-5-carboxylic acid ethyl ester (prepared in an analogous manner to Example 73, Example 73, 80 mg, 230 μmol), benzylamine (50 μL, 230 μmol) and ethanol (4 mL) were heated under reflux for 4 h. After evaporation of the solvent, the crude residue was loaded onto a 5 g isolute pre-pack silica column in a minimal amount of DCM and eluted with 10-30% ethyl acetate-heptane to give the title compound (79 mg, 85%).
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][CH3:7])[CH2:4][OH:5])[CH3:2].[CH2:10]([O:17][C:18]([NH:20][C@H:21]([C:25](O)=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:10]([O:17][C:18]([NH:20][C@H:21]([C:25]([O:5][CH2:4][C:3]([CH2:6][CH3:7])([CH2:1][CH3:2])[CH2:8][OH:9])=[O:26])[CH:22]([CH3:24])[CH3:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCC(CC)(CO)CO
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC(CC)(CO)COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a cooled solution of 2-ethyl-2-hydroxymethyl-butan-1-ol (33.1 g, 250 mmole), 4-dimethylaminopyridine (1.22 g, 10 mmole) and N-benzyloxycarbonyl-L-valine (12.6 g, 50 mmole) in 350 ml dichloromethane was added dropwise a solution of dicyclohexyl-carbodiimide (12.4 g, 60 mmole) in 50 ml dichloromethane. The mixture was stirred 2 days at room temperature and cooled. The urethane was filtered and the solution evaporated under reduced pressure. 350 ml ethyl acetate was added and the organic phase was washed twice with 5% acetic acid, 5% sodium-hydrogencarbonate and water. The organic phase was dried with sodium sulfat and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with dichloromethane/methanol. Yield 16.4 g=90%.
Reaction SMILES: N1C=CC=CC=1C(O)=O.[NH2:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:15][CH:14]=[CH:13][N:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].I[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39]>[Cu]I.CS(C)=O>[CH3:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]2[C:11]([NH2:10])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:18][CH:19]=1
Reactant: Nc1ncccc1-c1ccc(O)cc1
Reactant: Cc1ccccc1I
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: Cc1ccccc1Oc1ccc(-c2cccnc2N)cc1
Temperature: 130 °C
Reaction time: 5 h
Yield: 52.9 %

Procedure:
Copper(I) iodide (102 mg) was added to a mixture of picolinic acid (66.1 mg), 4-(2-aminopyridin-3-yl)phenol (500 mg), tripotassium phosphate (1710 mg), 1-iodo-2-methylbenzene (703 mg) and DMSO (8 mL). The mixture was stirred at 130° C. under nitrogen for 5 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). Water was added and the extracted organic layer was washed with brine. Silica-gel was added to the organic layer and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with EtOAc in hexane) to give the title compound (392.8 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]([C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH:29][CH2:30][C:31]([OH:33])=O)=[O:28])[CH:23]=[CH:24][CH:25]=1)([F:19])[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]([C:20]1[CH:21]=[C:22]([N:26]2[C:31](=[O:33])[CH2:30][NH:29][C:27]2=[O:28])[CH:23]=[CH:24][CH:25]=1)([F:19])[F:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CNC(=O)Nc1cccc(C(F)(F)COCCCCCCOCc2ccccc2)c1
Agent: Cl
Solvent: O
Product: O=C1CNC(=O)N1c1cccc(C(F)(F)COCCCCCCOCc2ccccc2)c1

Procedure:
A solution of Intermediate 60 (3.42 g, 7.4 mmol), water (20 mL) and concentrated HCl (5.5 mL) was heated at 140° C. for 12 hours. The reaction was cooled. The crude was extracted with ethyl acetate (50 mL) and washed with saturated solution of sodium bicarbonate (2×20 mL), water (2×20 mL) and brine (1×20mL), dried (Na2SO4) and concentrated. The titled compound was obtained (2.52 g, 76%) as oil.
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[C:4]([F:22])[C:5]2[C:15](=[O:16])[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][N:7]3[C@@H:8]([CH3:12])[CH2:9][O:10][C:11]=1[C:6]=23.[CH3:24][C:25]1[CH:30]=[C:29]([Sn](C)(C)C)[CH:28]=[C:27]([CH3:35])[N:26]=1>C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][C:25]1[CH:30]=[C:29]([C:2]2[C:3]([F:23])=[C:4]([F:22])[C:5]3[C:15](=[O:16])[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][N:7]4[C@@H:8]([CH3:12])[CH2:9][O:10][C:11]=2[C:6]=34)[CH:28]=[C:27]([CH3:35])[N:26]=1
Reactant: Cc1cc([Sn](C)(C)C)cc(C)n1
Reactant: CCOC(=O)c1cn2c3c(c(Br)c(F)c(F)c3c1=O)OC[C@@H]2C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CCOC(=O)c1cn2c3c(c(-c4cc(C)nc(C)c4)c(F)c(F)c3c1=O)OC[C@@H]2C
Temperature: 150 °C
Yield: 72.1 %

Procedure:
A mixture of 19.35 g ethyl (S)-10-bromo-8,9-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate, 16.20 g 2,6-dimethyl-4-(trimethylstannyl)pyridine, 0.88 g dichlorobis(triphenylphosphine)palladium in 200 ml ethanol was placed in a stainless steel Parr apparatus and the system flushed with nitrogen and pressurized to about 80 psi with nitrogen. The system was heated at 150° C. for 4 hours. The reaction mixture was cooled and concentrated in vacuo, and the residue was taken up in chloroform, filtered and chromatographed on silica gel using 5% methanol in chloroform to give 14.90 g ethyl (S)-10-(2,6-dimethyl-4-pyridinyl)-8,9-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate.
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.[N+:6]([C:9]1[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7].C(N(CC)CC)C.O>O1CCOCC1>[N+:6]([C:9]1[CH:10]=[C:11]([S:15]([NH:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7]
Reactant: NCC1CC1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccc(S(=O)(=O)NCC2CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
To a stirred solution of cyclopropylmethylamine (1.28 ml, 15 mmol) in dioxane (37 ml) was added at room temperature 3-nitrobenzenesulfonyl chloride (3.0 g, 14 mmol) and triethylamine (2.06 ml, 15 mmol). The light yellow suspension was stirred at room temperature for 4 h, poured into water (100 ml) and extracted with dichloromethane (3×75 ml). The combined organic layers were washed with water (100 ml) and brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (heptane/ethyl acetate 1:1) to yield 3-nitro-N-cyclopropylmethyl-benzenesulfonamide (3.08 g, 89%) as an off-white solid. MS (ISP) 254.9 [(M−H)−]; m.p. 91° C.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5](Cl)=[O:6].FF.Cl.[CH3:12][NH:13][O:14][CH3:15].C(N(CC)CC)C>ClCCl.O>[F:1][C:2]1([F:8])[CH2:4][CH:3]1[C:5]([N:13]([O:14][CH3:15])[CH3:12])=[O:6]
Reactant: O=C(Cl)C1CC1(F)F
Reactant: CNOC
Agent: Cl
Agent: FF
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1CC1(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.00 g (49.8 mmol) of 2,2-difluorocyclopropanecarbonyl chloride (described in the Journal of Fluorine Chemistry 1990, 49, 127-139) in 100 ml of dichloromethane were mixed with 6.32 g (64.8 mmol) of N,O-dimethylhydroxylamine hydrochloride and 18.1 ml (130 mmol) of triethylamine and stirred at RT overnight. Water was added to the reaction mixture, the phases were separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated. 5.73 g (70% of theory) of the title compound were obtained and were reacted without further purification.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=1B(O)O>>[OH:22][C:15]1[C:16]([O:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:25]3[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:24]=3[OH:23])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc(O)c(B(O)O)c1
Reactant: COc1cccc(-c2cccc(-c3cccc(Br)n3)n2)c1O
Product: COc1cccc(-c2cccc(-c3cccc(-c4cc(C)ccc4O)n3)n2)c1O
Yield: 20 %

Procedure:
6-(3-methoxyphenyl)-6′-(2-hydroxy-5-methyphenyl)-2,2′-was prepared from 6-bromo-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine and 2-hydroxy-5-methylphenyl boronic acid in 20% yield using method F; δH [2H6]-DMSO 13.57,(1H, b), 13.09,(1H, b), 8.33,(2H, t), 8.24,(2H, m), 8.15,(2H, m), 7.95,(1H, s), 7.70,(1H, d), 7.18,(1H, d), 7.10,(1H, d), 6.91,(2H, m), 3.84,(3H, s), 2.35,(3H, s), 385 (MH)+; HPLC retention time (system 1) 4.17 minutes.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.N#N.C(=O)=O.CC(C)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1C(=O)N([Br:40])C(=O)C1>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:13])[CH:11]([Br:40])[CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CCC(=O)c1ccc2occc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N#N
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(Br)C(=O)c1ccc2occc2c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To an oven dried roundbottom flask is added 1-(benzofuran-5-yl)propan-1-one (160 mg, 0.919 mmol) and dissolved in dry THF (5 ml). The flask is then cycled through a vacuum/N2 protocol and then cooled under N2 to −78° C. using dry ice/acetone. At this temperature, lithium bis(trimethylsilyl)amide (1M in hexanes) (1.378 ml, 1.378 mmol) is added and stirring continues for ˜30 mins. After this time, NBS (180 mg, 1.010 mmol) in THF (5 ml) is then added dropwise keeping the temp below −60° C. The mixture is left to warm to RT and stirring continued for ˜5 hr. After this time, LCMS looked to show ˜50% conversion to product. The raection is quenched by addition of NH4Cl and allowed to warm to RT. The contents are transferred to a separating funnel and extracted into EtOAc. The organic portion is washed with NaHCO3, water, brine, dried (MgSO4) and evaporated to give a clear oil. Purification by chromatography on silica gel (20 g) eluting with 100% iso-hexane followed by 5% EtOAc/iHex affords the title product as a clear oil. MS: m/z 253 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][N:16]3[CH:19]=[N:20][C:21]([C:22]([O:24]C)=[O:23])=[C:15]3[CH2:14]2)(=[O:12])=[O:11])=[C:5]([CH3:26])[CH:4]=1.[Li+].[OH-]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:26])[C:6]([S:10]([N:13]2[CH2:18][CH2:17][N:16]3[CH:19]=[N:20][C:21]([C:22]([OH:24])=[O:23])=[C:15]3[CH2:14]2)(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: COC(=O)c1ncn2c1CN(S(=O)(=O)c1c(C)cc(OC)cc1C)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C)c(S(=O)(=O)N2CCn3cnc(C(=O)O)c3C2)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
A mixture of methyl 7-(4-methoxy-2,6-dimethylphenylsulfonyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate (0.13 mmol, 1 equiv.), MeOH/H2O (1:1, 4 ml), and LiOH (0.551 mmol, 6 equiv.) was stirred for 16 h at 25° C. The organic solvent was removed in vacuo, and the resulting suspension was diluted with water (5 ml) and adjusted to an acidic pH value with 1N HCl at 0° C. Extraction with ethyl acetate (2×15 ml) was then carried out, and the combined organic phases were washed with sat. NaCl solution. The organic phase was dried over Na2SO4 and concentrated in vacuo to yield the product in the form of a light-yellow solid. This was used in the following stage without further purification. Yield: 63%
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:24](OCC)(=[O:30])[C:25](OCC)=[O:26]>CCOCC>[CH3:13][O:12][C:5]1[CH:4]=[C:3]2[C:2]([NH:1][C:24](=[O:30])[C:25](=[O:26])[N:14]2[CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(N)c(NCc2ccc(OC)cc2)cc1OC
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCOCC
Product: COC(=O)c1cc2[nH]c(=O)c(=O)n(Cc3ccc(OC)cc3)c2cc1OC
Yield: 71 %

Procedure:
The solution of methyl 5-amino-2-methoxy-4-(4-methoxybenzylamino)benzoate (30 g, 94.83 mmol) in diethyl oxalate (100 mL) was stirred for 3 h at reflux and then cooled with a water/ice bath and diluted with ether (500 mL). The product was collected by filtration to afford methyl 7-methoxy-1-[(4-methoxyphenyl)methyl]-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate as a light yellow solid (25.0 g, 71%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]=[O:8].[N+:9]([O-])([OH:11])=[O:10].[OH-].[Na+]>C(O)(=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[C:3]1[CH:7]=[O:8]
Reactant: Cn1cccc1C=O
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cn1cc([N+](=O)[O-])cc1C=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 49.6 %

Procedure:
N-methylpyrrol-2-carboxaldehyde (5 g) was dissolved in anhydrous acetic acid (50 ml), and to an ice-cold of the solution was slowly added dropwise nitric acid (1.84 ml) with stirring. The mixture was stirred at this temperature for 1 hour, and then at room temperature for 18 hours. After confirming the completion of the reaction, to the mixture was added an ice-water (200 ml), followed by slowly adding solid sodium hydroxide (20 g) thereto and stirring for 1 hour. The obtained mixture was extracted with ether (150 ml×3). The obtained organic layer was washed with aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure and purified by column-chromatography (ethyl acetate/hexane=1/4) to yield the compound 22-1 (3.5 g, 49.6%).
Reaction SMILES: [CH2:1]([C:4]1[O:8][C:7]([NH2:9])=[N:6][CH:5]=1)[CH2:2][CH3:3].[C:10]1([CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](Cl)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:20]1([CH:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:17]([NH:9][C:7]2[O:8][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][N:6]=2)=[O:18])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCCc1cnc(N)o1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CCCc1cnc(NC(=O)C(c2ccccc2)c2ccccc2)o1

Procedure:
The title compound, white solid, m.p. 122° C. and MS: m/e=320.2 (M+) was prepared in accordance with the general method of example 44a from 5-propyl-oxazol-2-ylamine and 2,2-diphenylacetic acid chloride.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][CH:5]([CH:7](O)[CH3:8])[CH2:4][O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:30][N:31]1[C:35](=[O:36])[C:34]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:33]2[C:32]1=[O:41].CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:10][C:2]1([CH3:1])[O:6][CH:5]([CH2:7][CH2:8][O:30][N:31]2[C:35](=[O:36])[C:34]3[C:33](=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:32]2=[O:41])[CH2:4][O:3]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(O)C1COC(C)(C)O1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OCC(CCON2C(=O)c3ccccc3C2=O)O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
To a vigorously stirring suspension of 1,2,4-butanetriol (5.8 g, 54.6 mmol) in dichloromethane (20 mL) was added 2,2-dimethoxypropane (6.8 mL, 54.6 mmol) and catalytic p-toluenesulfonic acid. After 5 minutes, the solution became homogenous and was allowed to stir for an additional 30 minutes. The reaction mixture was then concentrated in vacuo to afford (2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethanol (7.72 g, 96.7%). To a stirring solution of (2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethanol (6.95 g, 47.5 mmol), triphenylphosphine (12.5 g, 47.5 mmol) and N-hydroxyphthalimide in freshly distilled tetrahydrofuran (200 mL) at 0° C. was slowly added (over 20 minutes) diethylazodicarboxylate. The dark red solution was allowed to stir for 2 hours at 0° C. and then allowed to warm to room temperature while stirring for 17 hours. The yellow solution was concentrated in vacuo and dissolved in chloroform (100 mL). The solids were filtered and filtrate concentrated. This filtration was repeated twice. The remaining yellow oil was purified on silica gel eluting with hexanes-ethyl acetate (4:1) to afford 2-[2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-isoindole-1,3-dione (8.1 g, 58.7%). To a stirring solution of 2-[2-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-isoindole-1,3-dione (0.86 g, 2.95 mmol) in dichloromethane (10 mL) at 0° C. was added methylhydrazine (0.16 mL, 2.95 mmol). The resultant solution was allowed to warm to room temperature and stirred for 3 days. The resulting suspension was diluted with diethyl ether (20 mL) and filtered. The filtrate concentrated in vacuo to afford O-(2,2-dimethyl-[1,3]dioxolan-4-ylethyl)-hydroxylamine (0.36 g, 75.3%): 1H NMR (400 MHz; CDCl3) δ 4.18 (quint, 1H, J=5.9), 4.07 (dd, 1H, J=5.9, 7.8), 3.86 (t, 2H, J=6.2), 3.56 (t, 1H, J=7.6), 1.89 (m, 2H), 1.36 (s, 3H), 1.20 (s, 3H); MS(APCI+)=162.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][C:42]=1[O:43][CH:44]([CH3:46])[CH3:45])[C:5]([NH:7][C@@H:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29]=[C:30]3[C:35]([CH:36]([OH:38])[CH3:37])=[CH:34][CH:33]=[CH:32][N:31]3[CH:39]=2)=[CH:24][CH:23]=1)[CH2:9][N:10]1C(=O)C2C(=CC=CC=2)C1=O)=[O:6].O.NN>C(O)C>[NH2:10][CH2:9][C@@H:8]([NH:7][C:5](=[O:6])[C:4]1[CH:40]=[CH:41][C:42]([O:43][CH:44]([CH3:45])[CH3:46])=[C:2]([Cl:1])[CH:3]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29]=[C:30]3[C:35]([CH:36]([OH:38])[CH3:37])=[CH:34][CH:33]=[CH:32][N:31]3[CH:39]=2)=[CH:24][CH:23]=1
Reactant: CC(C)Oc1ccc(C(=O)N[C@@H](Cc2ccc(-c3cn4cccc(C(C)O)c4n3)cc2)CN2C(=O)c3ccccc3C2=O)cc1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)Oc1ccc(C(=O)N[C@H](CN)Cc2ccc(-c3cn4cccc(C(C)O)c4n3)cc2)cc1Cl
Temperature: 57 °C
Yield: 99.8 %

Procedure:
A mixture of 3-chloro-N-[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide (2.10 g, 3.30 mmol) and hydrazine monohydrate (0.83 g, 16.5 mmol) in ethanol (30 mL) was heated at 57° C. overnight. The reaction was cooled, diluted with ethanol, filtered, and concentrated to give the title compound (1.67 g, 100%) as a pale yellow powder. MS (ES+) m/e 507 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH2:13][CH3:14])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[F:15][B-:16]([F:19])([F:18])[F:17].[CH2:20]([O+](CC)CC)[CH3:21]>>[F:15][B-:16]([F:19])([F:18])[F:17].[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][CH2:13][CH3:14])=[C:6]([CH:10]=1)[C:7](=[NH:9])[O:8][CH2:20][CH3:21]
Reactant: CCCOc1ccc(F)cc1C(N)=O
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Product: CCCOc1ccc(F)cc1C(=N)OCC

Procedure:
reaction of 5-fluoro-2-propoxybenzamide (16.40 g) with triethyloxonium tetrafluoroborate yielded ethyl 5-fluoro-2-propoxybenzimidate tetrafluoroborate which on reaction with a saturated solution of ethanolic ammonia yielded 5-fluoro-2-propoxybenzamidine (8.40 g);
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][CH:7]=1.[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30]O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][O:17][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1)([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Nc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCCC1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1COC(c1cccc(N)c1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-(3-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (1.30 g), 2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.04 g), PPh3 (2.64 g) and molecular sieves 4 Å in THF (100 mL) was added diethyl diazocarboxylate (1.55 mL) slowly. The reaction was stirred at RT for 4 h and at reflux for overnight. After filtration to remove solids, the filtrate was concentrated and the residue was taken into Et2O. The organic phase was washed with saturated NaHCO3 and brine. The organic layer was dried over MgSO4 and evaporated to give a crude compound as very viscous brown oil, which was purified by chromatography through silica gel (500 g, 30% to 50% EtOAc in hexanes) to afford 2-[1-(3-amino-phenyl)-2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a light brown oil.
Reaction SMILES: FC(F)(F)C(O[C:6](=[O:11])[C:7](F)(F)F)=O.[Br:14][C:15]1[C:16]([Cl:23])=[CH:17]C(C)=[N+:19]([O-])[CH:20]=1.CO>C(Cl)Cl>[Br:14][C:15]1[C:16]([Cl:23])=[CH:17][C:7]([CH2:6][OH:11])=[N:19][CH:20]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(Cl)c(Br)c[n+]1[O-]
Solvent: CO
Solvent: ClCCl
Product: OCc1cc(Cl)c(Br)cn1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
3.0 mL trifluoroacetic anhydride were added dropwise at 10° C. to 2.6 g (12 mmol) 5-bromo-4-chloro-2-methylpyridine-1-oxide in 30 mL DCM. The reaction mixture was stirred for 5 days at RT. After the addition of MeOH the reaction mixture was evaporated down, the residue was combined with 15% potassium carbonate solution and extracted several times with EtOAC. The combined organic phases were dried on sodium sulphate and evaporated down.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]1[C:7]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][O:16][C:8]=2[NH:9][C:10](=[O:15])[C:11]=1C(O)=O.[OH-].[Na+]>O>[CH:6]1[C:7]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][O:16][C:8]=2[NH:9][C:10](=[O:15])[CH:11]=1
Reactant: O=C(O)c1cc2c([nH]c1=O)OCc1ccccc1-2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1ccc2c([nH]1)OCc1ccccc1-2
Temperature: 0 °C

Procedure:
To a mixture of 60 ml of concentrated sulfuric acid and 15 ml of water, add 22.2 gm of 4,6-dihydro-3H[2]benzopyrano-[3,4-b]pyridin-3-one-2-carboxylic acid. Heat the system at reflux for 24 hours. Cool the system and pour the solution into 1 liter of ice/water. Neutralize the solution with 10N NaOH solution. Extract the solution with 300 ml of chloroform and dry the organic solution over anhydrous magnesium sulfate. Filter the solution and remove the solvent by stripping to give 4,6-dihydro-3H[2]-benzopyrano-[3,4-b]pyridin-3-one.