Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[OH:21][C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>>[OH:21][C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:23]=1[C:24](=[O:25])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(=O)OC(C)(C)C
Reactant: Cc1ccc(C(=O)Cl)c(O)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Product: Cc1ccc(C(=O)CC(=O)OC(C)(C)C)c(O)c1

Procedure:
Prepared according to above procedure using diisopropylamine (3.8 mL, 28 mmol), nBuLi (21 mL, 1.2 M), tert-butyl acetate (2.1 mL, 16 mmol), 2-hydroxy-4-methylbenzoyl chloride (5 mmol, prepared from 760 mg 4-methyl-salicylic acid and SOCl2, 1.2 mL, heated to 47° C. in 12 mL toluene for 4 h) yielding 327 mg (26%) as white needles. mp=88-90° C.; IR (film) 1733.8; 1652.6; 1145.0 cm−1; 1H NMR (500 MHz, CDCl3) δ 11.95 (s, 1H); 7.54 (d, J=8.2 Hz, 1H); 6.81 (s, 1H); 6.72 (d, J=8.2, 1H); 3.88 (s, 2H); 2.36 (s, 3H); 1.45 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 198.5, 166.5, 163.0, 148.9, 130.5, 120.7, 118.8, 117.2, 82.6, 47.4, 28.1, 22.2; LRMS (electrospray): Mass calculated for C14H18O4, [M]+, 250.12. Found [M+23]+, 272.9.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C:18](=[O:20])[CH3:19])[CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.CSC>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C@@H:18]([OH:20])[CH3:19])[CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1cnc2cc(OCc3ccc(F)cc3)ccc2c1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: CSC
Solvent: Cc1ccccc1
Product: C[C@H](O)c1cnc2cc(OCc3ccc(F)cc3)ccc2c1
Temperature: -20 °C
Reaction time: 3 h
Yield: 17.2 %

Procedure:
To a cooled solution, −78° C., of 1-(7-((4-fluorobenzyl)oxy)quinolin-3-yl)ethanone (Example 42, 52 mg, 0.176 mmol) in toluene was added (S)-(−)-2-methyl-CBS-oxazaborolidine (97 mg, 0.352 mmol) followed by BH3.DMS (2 M in THF, 0.176 mL, 0.352 mmol). The reaction was warmed to −20° C. and stirred for 3 h before being quenched with MeOH. The reaction was warmed to ambient temperature and sat. NaHCO3 (aq.) solution was added. The aqueous layer was extracted with EtOAc and the combined organic fractions were washed with brine and concentrated under reduced pressure onto silica. Purification (FCC, SiO2, 0-5%, MeOH/DCM) afforded the title compound as a white solid (9 mg, 17%). 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J=2.3 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.61 (dd, J=5.5, 8.6 Hz, 2H), 7.51 (d, J=2.3 Hz, 1H), 7.33 (dd, J=2.5, 8.8 Hz, 1H), 7.28 (t, J=9.0 Hz, 2H), 5.44 (d, J=4.3 Hz, 1H), 5.29 (s, 2H), 5.01-4.91 (m, 1H), 1.47 (d, J=6.7 Hz, 3H). [M+H]=298.2.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[N:16]=[C:15]([N:17]4[CH2:23][C:22]([OH:25])([CH3:24])[CH2:21][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:19][CH2:18]4)[CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:41]2[CH:42]=[N:43][NH:44][CH:45]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:43]1[CH:42]=[C:41]([C:2]2[N:7]=[CH:6][C:5]3[CH:8]=[N:9][N:10]([C:11]4[N:16]=[C:15]([N:17]5[CH2:23][C:22]([OH:25])([CH3:24])[CH2:21][N:20]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH2:19][CH2:18]5)[CH:14]=[CH:13][CH:12]=4)[C:4]=3[CH:3]=2)[CH:45]=[N:44]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC1(O)CN(C(=O)OC(C)(C)C)CCN(c2cccc(-n3ncc4cnc(Cl)cc43)n2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC1(O)CN(C(=O)OC(C)(C)C)CCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)C1
Yield: 60 %

Procedure:
A suspension of tert-butyl 4-(6-(6-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-6-methyl-1,4-diazepane-1-carboxylate (330 mg, 0.72 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (140 mg, 0.72 mmol), Pd(dppf)Cl2 (53 mg, 0.072 mmol), and a solution of Na2CO3 (2.0 M, 0.72 mL) in 1,4-dioxane (10 mL) under argon in a sealed vial was heated in a microwave oven at 120° C. for an hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using DCM:MeOH (20:1˜10:1) as eluting solvents to afford tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-6-hydroxy-6-methyl-1,4-diazepane-1-carboxylate as a yellow solid (212 mg, 60%). MS (ESI) m/z: 491 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[NH:13][C:12]2=[O:22])[N:4]=1.CN1C=CN=C1.[F:29][CH:30]([F:35])[S:31](Cl)(=[O:33])=[O:32].O>ClCCl>[F:29][CH:30]([F:35])[S:31]([N:13]1[C:14]2[C:19](=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:11]([C:5]2[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([O:9][CH3:10])[N:6]=2)[C:12]1=[O:22])(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)C(F)F
Reactant: COc1ccc2c(c1)C(c1nc(OC)nc(OC)n1)C(=O)N2
Agent: Cn1ccnc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(c1)C(c1nc(OC)nc(OC)n1)C(=O)N2S(=O)(=O)C(F)F
Temperature: -10 °C

Procedure:
3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-5-methoxy-1,3-dihydro-2H-indol-2-one (1.0 g) and 1-methyl-1H-imidazole (0.51 g) are introduced as initial charge in 8 ml of dichloromethane and cooled to −10° C. under nitrogen. With stirring, difluoromethanesulfonyl chloride (0.66 g) is added dropwise in two portions and the mixture is stirred for 2.5 hours at −5 to −10° C. For the work-up, water is added and the mixture is stirred, and the solid is filtered off, washed with dilute hydrochloric acid and water and dried. This gives the title compound as a solid in an HPLC purity of 99% (0.91 g, 70% of theory). The UV absorption (maximum at 360 nm) verifies the N-sulfonylation of the product.
Reaction SMILES: [CH:1]1([N:4]([CH3:13])[C:5]2[N:9]=[C:8]([CH:10]=O)[N:7]([CH3:12])[N:6]=2)[CH2:3][CH2:2]1.[Cl-].[CH3:15][C:16]1[CH:21]=[C:20]([CH3:22])[N:19]2[N:23]=[C:24]([CH2:26][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:25]=[C:18]2[N:17]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH:1]1([N:4]([C:5]2[N:9]=[C:8]([CH:10]=[CH:26][C:24]3[N:25]=[C:18]4[N:17]=[C:16]([CH3:15])[CH:21]=[C:20]([CH3:22])[N:19]4[N:23]=3)[N:7]([CH3:12])[N:6]=2)[CH3:13])[CH2:3][CH2:2]1
Reactant: CN(c1nc(C=O)n(C)n1)C1CC1
Reactant: Cc1cc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2n1
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1cc(C)n2nc(C=Cc3nc(N(C)C4CC4)nn3C)nc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
To a solution of 3-(cyclopropyl(methyl)amino)-1-methyl-1H-1,2,4-triazole-5-carbaldehyde (45 mg, 250 μmol, Eq: 1.00) in tetrahydrofuran (2.3 ml) were added ((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)triphenylphosphonium chloride (115 mg, 250 μmol, Eq: 1.00) and DBU (95.0 mg, 94.1 μl, 624 μmol, Eq: 2.5). The resulting mixture was stirred for 18 hours at 25° C. TLC (Hep/EtOAC 1:1/UV 254 nm) showed no starting material left and new product spot. MS showed product peak also. The crude material was applied on silicagel and purified by flash chromatography over a 20 g silicagel column using heptane/ethyl acetate 1:1 as eluent to give Cyclopropyl-{5-[2-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-vinyl]-1-methyl-1H-[1,2,4]triazol-3-yl}-methyl-amine (30 mg, 37%) as light yellow waxy solid
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[CH:22][NH:21][C:20]=1[CH:33]=O>C(O)C.N1CCCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:20]2[NH:21][CH:22]=[C:23]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[O:25])[C:19]=2[CH3:18])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=C1C(=O)Nc2cccc(-c3ccc(Br)cc3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.9 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72.0 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-bromo-phenyl)-3-[3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (42.8 mg, 34%).
Reaction SMILES: Cl.Cl[C:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]1[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]=1.[CH3:23][O-:24].[Na+]>CO>[CH3:23][O:24][C:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]1[NH:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]=1
Reactant: C[O-]
Reactant: ClC(C1=NCCCCN1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(C1=NCCCCN1)(c1ccccc1)c1ccccc1

Procedure:
2-(Chlorodiphenylmethyl)-4,5,6,7-tetrahydro-1H-1,3-diazepine hydrochloride (0.003 mole) is stirred at room temperature for two days in dry methanol (25 ml) containing sodium methoxide (0.006 mole). After removal of the solvent the residue is dissolved in chloroform washed with water and dried over magnesium sulphate. Removal of the solvent gives the title compound.
Reaction SMILES: C([N:8]1[CH2:14][C:13]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([N+:15]([O-])=O)[CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH2:18]([C:13]1([NH2:15])[CH2:14][NH:8][CH2:9][CH2:10][NH:11][CH2:12]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])C1(Cc2ccccc2)CN(Cc2ccccc2)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: NC1(Cc2ccccc2)CNCCNC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Pd—C 10% was added to a solution of 5 (200 mg, 0.27 mmol) and ammonium formate (0.75 g, 12.0 mmol) in methanol (10.0 mL) and the mixture was stirred at 60° C. for 1 h. The catalyst was removed and the methanolic solution was concentrated to give the amine 6 as an oil, which was dried under vacuum to give a foamy solid. Yield: 95 mg (92%).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:22])=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH3:13])[N:8]=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:29]([CH:31]1[O:33][CH2:32]1)Br>CC(C)=O>[Br:1][C:2]1[C:3]([O:22][CH2:29][CH:31]2[CH2:32][O:33]2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[CH3:13])[N:8]=[CH:7]2
Reactant: BrCC1CO1
Reactant: CC(Cn1ncc2ccc(O)c(Br)c21)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(Cn1ncc2ccc(OCC3CO3)c(Br)c21)O[Si](C)(C)C(C)(C)C
Yield: 73.6 %

Procedure:
A suspension of the product from Step C (4.47 g, 11.6 mmol), potassium carbonate (2.25 g, 16 mmol), and epibromohydrine (1.59 mL, 19 mmol) in acetone (230 mL) was heated at reflux for 20 h. Additional epibromohydrine (1.5 mL, 17.9 mmol) was added and the mixture heated at reflux for 18 h. The solid was removed by filtration and the filtrate was concentrated to an oil which was dissolved in EtOAc (150 mL). This solution was washed with saturated aqueous ammonium acetate (150 mL), dried (MgSO4), and evaporated to a residue which was purified by chromatography (silica, 2% to 10% EtOAc/hexane) to afford an oil (3.77 g, 74%): LC/MS (+APCI) m/z 441, 443 (M+H).
Reaction SMILES: [C:1]([N:5]=[N:6][C:7](Cl)([CH2:9][C:10]([O:13][CH3:14])([CH3:12])[CH3:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:16]([O:21][OH:22])([CH2:19][CH3:20])([CH3:18])[CH3:17].[OH-].[K+].C(N=NC(O)(CC(OC)(C)C)C)(C)(C)C>>[C:1]([N:5]=[N:6][C:7]([O:22][O:21][C:16]([CH2:19][CH3:20])([CH3:18])[CH3:17])([CH2:9][C:10]([O:13][CH3:14])([CH3:12])[CH3:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)OO
Reactant: COC(C)(C)CC(C)(Cl)N=NC(C)(C)C
Agent: COC(C)(C)CC(C)(O)N=NC(C)(C)C
Agent: [K+]
Agent: [OH-]
Product: CCC(C)(C)OOC(C)(CC(C)(C)OC)N=NC(C)(C)C

Procedure:
The 2-t-butylazo-2-(t-amylperoxy)-4-methoxy-4-methylpentane was prepared in 97% crude yield from 7.78 grams (0.0331 moles) of 2-t-butylazo-2-chloro-4-methoxy-4-methylpentane, 5.35 grams (0.0464 moles) of 90% t-amyl hydroperoxide and 7.92 grams (0.0353 moles) of 25% potassium hydroxide solution. The procedure was the same as that described in Example XX. The infrared spectrum of the product indicated there was a small amount of 2-t-butylazo-2-hydroxy-4-methoxy-4-methylpentane present in the product.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][C:21](O)=[O:22])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:31][N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN>CN(C=O)C.O>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@@H:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][C:21](=[O:22])[NH:32][CH3:31])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)[C@@H](CC(=O)O)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Reaction time: 0.05 h
Yield: 94.7 %

Procedure:
Prepared using General Procedures 7: To (R)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid (205.7 mg, 0.5 mmol) in DMF (5 mL) at 0° C. was added HATU (380 mg, 1.0 mmol). After stirring for 3 min, DIEA (277 μL, 1.5 mmol) and methylamine (40 wt % in water, 116 μL, 1.5 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was added to water (75 mL) and the precipitate was filtered and dried to give 201 mg (95%) of tert-butyl N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N4-methyl-D-asparaginate as a colorless semi-solid. LCMS-ESI (m/z) calculated for C24H28N2O5: 424.2. found 425.2 [M+H]+, tR=3.22 min (Method 16).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH:9]=[C:8]([C:10]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)[CH2:7][CH2:6][NH:5]1.[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27].[Cl-].[Na+]>O1CCCC1>[CH3:30][O:29][C:25]([CH2:26][CH2:27][N:5]1[CH2:6][CH2:7][C:8]([C:10]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=23)=[CH:9][C:4]1=[O:3])=[O:28]
Reactant: O=C1C=C(c2c(-c3ccccc3)nn3ccccc23)CCN1
Reactant: C=CC(=O)OC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CCN1CCC(c2c(-c3ccccc3)nn3ccccc23)=CC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.3 %

Procedure:
Sodium hydride (60%, 43.6 mg) was added to a mixture of 3-(2-oxo-1,2,5,6-tetrahydropyridin-4-yl)-2-phenylpyrazolo[1,5-a]pyridine (210 mg), methyl acrylate (93.8 mg) and tetrahydrofuran (2.1 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 1.5 hours. A saturated solution of sodium chloride (20 ml) was added to the reaction mixture and extracted with ethyl acetate (20 ml×2). The combined extract was washed with a saturated solution of sodium chloride (20 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of chloroform and ethyl acetate (10:1) to give 3-[1-[2-methoxycarbonylethyl)-2-oxo-1,2,5,6-tetrahydropyridin-4-yl]-2-phenylpyrazolo[1,5-a]pyridine (210.7 mg) as an oil.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:27]#[N:28])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:29][CH2:30][C:31]([CH3:38])([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CCO>[CH2:35]([O:34][C:32](=[O:33])[C:31]([CH3:38])([CH3:37])[CH2:30][NH:29][C:6]([C:8]1[N:9]=[C:10]([C:27]#[N:28])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH3:36]
Reactant: CCOC(=O)C(C)(C)CN
Reactant: CCCCOC(=O)c1nc(C#N)c2cc(Oc3ccc(C)cc3)ccc2c1O
Solvent: CCO
Product: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3ccc(C)cc3)ccc2c1O

Procedure:
1-Cyano-4-hydroxy-7-p-tolyloxy-isoquinoline-3-carboxylic acid butyl ester (19 mg, 0.05 mmol) and ethyl 3-amino-2,2-dimethylpropanoate (29 mg, 0.20 mmol) in EtOH (3 mL) were heated at 150° C. in a microwave for 1.5 hours. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 18 mg. MS: (−) m/z 446.33 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:43]=[CH:44][CH:45]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:29][C@@H:28]([C:30]3[CH:41]=[CH:40][C:33]4[O:34][C:35]([CH3:39])([CH3:38])[O:36][CH2:37][C:32]=4[CH:31]=3)[O:27][C:26]2=[O:42])[CH:9]=1)=[O:6].[C:46]1([S:52](Cl)(=[O:54])=[O:53])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:38][C:35]1([CH3:39])[O:34][C:33]2[CH:40]=[CH:41][C:30]([C@H:28]3[O:27][C:26](=[O:42])[N:25]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][CH2:14][C:10]4[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]5[CH:43]=[CH:44][CH:45]=[C:2]([NH:1][S:52]([C:46]6[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=6)(=[O:54])=[O:53])[CH:3]=5)[CH:13]=[CH:12][CH:11]=4)[CH2:29]3)=[CH:31][C:32]=2[CH2:37][O:36]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)c5cccc(N)c5)c4)C(=O)O3)ccc2O1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)c5cccc(NS(=O)(=O)c6ccccc6)c5)c4)C(=O)O3)ccc2O1
Reaction time: 2 h

Procedure:
3-Amino-N-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]benzamide (200 mg) in pyridine (5 ml) under nitrogen was treated with benzenesulfonyl chloride (0.045 ml) and the mixture was stirred at 20° for 2 h. Sat. sodium bicarbonate solution (30 ml) was added and the mixture was extracted with dichloromethane (2×20 ml). The combined extracts were dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica gel. Elution with EtOAc-dichloromethane (1:1) gave the title compound (155 mg). LCMS RT=3.72 min, ES+ve 758 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:17]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)(=[O:19])[CH3:18]>CN(C=O)C>[C:17]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:2]2[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=2)=[CH:23][CH:22]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Oc2ccc([N+](=O)[O-])nc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a solution of 5-bromo2-nitropyridine (2.03 g, 10.0 mmol) in DMF (30 mL) was added Cs2CO3 (4.9 g, 15.0 mmol) followed by 4-acetylaminophenol (1.66 g, 11.0 mmol) in DMF (30 mL) at 0° C. then stirred at room temperature overnight. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over. Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography and recrystalization from ethyl acetate gave 5-(4-acetamidophenoxy)-2-nitropyridine (1.62 g, 59%). Hydrogenation of 5-(4-acetamidophenoxy)-2-nitropyridine (879.0 mg, 3.22 mmol) with 5% Pd—C in MeOH (80 mL) gave the title compound (575.7 mg, 74%): MS m/e 244 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][N:14](C)[CH3:15])[CH2:9][CH2:8][CH2:7]2.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>ClCCl.O.C(=O)([O-])[O-].[K+].[K+]>[F:1][C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][N:14]([CH3:15])[C:21](=[O:22])[O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:9][CH2:8][CH2:7]2
Reactant: CN(C)CCN1CCCc2cc([N+](=O)[O-])cc(F)c21
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CN(CCN1CCCc2cc([N+](=O)[O-])cc(F)c21)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a stirred solution of 2-(8-fluoro-6-nitro-3,4-dihydroquinolin-1(2H)-yl)-N,N-dimethylethanamine (500 mg, 1.871 mmol) in Dichloromethane (8 ml) at room temperature was added phenyl chloroformate (0.352 ml, 2.81 mmol) via a syringe dropwise, slowly. The resulting solution was stirred overnight at room temperature. The reaction mixture was then diluted with water and potassium carbonate (dilute) and extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed in 0-50% ethyl acetate in hexanes, giving the desired phenyl 2-(8-fluoro-6-nitro-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)carbamate (576 mg, 1.543 mmol, 82% yield). 1H NMR (DMSO-d6) δ 7.85-7.76 (m, 1H); 7.75-7.70 (m, 1H); 7.34 (t, J=7 Hz, 1H); 7.22-7.16 (m, 1H); 6.99-6.95 (m, 2H); 3.77-3.65 (m, 3H); 3.60-3.54 (m, 1H); 3.43 (t, J=5.5 Hz, 2H); 3.02, 2.93 (2s, 3H); 2.75 (t, J=5.8, 2H); 1.90-1.81 (m, 2H). ESI-MS (m/z, %): 374 (MH+, 100).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][CH2:5][CH:6]=[O:7].[O:10]1CCOCC1.[Se](=O)=O.O>C(O)(=O)C>[F:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](=[O:10])[CH:6]=[O:7]
Reactant: C1COCCO1
Reactant: O=CCCCC(F)(F)F
Agent: O=[Se]=O
Solvent: CC(=O)O
Solvent: O
Product: O=CC(=O)CCC(F)(F)F
Temperature: 90 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Combine 5,5,5-trifluoropentanal (2.01 g, 14.35 mmol), 1,4-dioxane (10 mL), selenium dioxide (1.62 g, 1.0 eq), water (0.51 mL), and acetic acid (0.69 mL). Heat the mixture at 90° C. and stir overnight. Allow the reaction mixture to cool to room temperature. Filter, wash the solids with dioxane. Combine the filtrate and washings to give 5,5,5-trifluoro-2-oxopentanal (2.21 g, 100%). GCMS m/z=154.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[NH2:7].[C:13](Cl)(=[O:17])[C:14](Cl)=[O:15]>>[CH3:12][O:11][C:9]1[CH:10]=[C:4]([O:3][CH3:2])[CH:5]=[C:6]2[C:8]=1[C:13](=[O:17])[C:14](=[O:15])[NH:7]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(N)cc(OC)c1
Agent: Cl
Product: COc1cc2c(c(OC)c1)C(=O)C(=O)N2
Yield: 46 %

Procedure:
3,5-Dimethoxyaniline hydrochloride (80.21 g, 0.424 mol) was added cautiously to oxalyl chloride (136 ml, 1.56 mol) and the solution heated at reflux for 3 hours. The solution was cooled and concentrated in vacuo. Methanol (300 ml) was added to the residue and the mixture heated at reflux for 1 hour. The reaction was allowed to cool, and the resulting precipitate filtered and washed with methanol to yield 4,6-dimethoxyisatin (40.4 g, 46%) as a yellow solid.