Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]2[C:10]([C:13]([NH:15][C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[C:18]([CH3:33])=[N:19][N:20]4[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)=[O:14])=[CH:11][N:12]=[C:6]2[CH:5]=1)(=O)[CH3:2].[CH2:34]([CH2:36][NH2:37])[OH:35]>>[OH:35][CH2:34][CH2:36][NH:37][CH:1]([C:4]1[CH:9]=[CH:8][N:7]2[C:10]([C:13]([NH:15][C:16]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:17]=3[C:18]([CH3:33])=[N:19][N:20]4[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)=[O:14])=[CH:11][N:12]=[C:6]2[CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccn2c(C(=O)Nc3cccc4c3c(C)nn4Cc3cccc(C)n3)cnc2c1
Reactant: NCCO
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(C(C)NCCO)ccn45)cccc32)n1

Procedure:
Prepared from 7-acetyl-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (Example 79) and ethanolamine following procedure in Example 72, Step C. MS (ES+APCI) m/z=484 (M+H) detected.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].N1C=CC=CC=1.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([CH3:25])[C:16]=1[CH:26]([O:29][C:30]([CH3:36])([CH3:35])[C:31]([F:34])([F:33])[F:32])[CH2:27][OH:28]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:3]([O:28][CH2:27][CH:26]([C:16]1[C:17]([CH3:25])=[CH:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]=1[Cl:14])[O:29][C:30]([CH3:36])([CH3:35])[C:31]([F:32])([F:33])[F:34])(=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: Cc1cc2ccccc2c(Cl)c1C(CO)OC(C)(C)C(F)(F)F
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc2ccccc2c(Cl)c1C(COC(=O)C(C)(C)C)OC(C)(C)C(F)(F)F
Temperature: 25 °C

Procedure:
To a stirred solution of trimethylacetyl chloride (0.17 mL, 1.36 mmol) and 4-(Dimethylamino)pyridine (55 mg, 0.45 mmol) in pyridine (2.4 mL, 29.48 mmol), 2-(1-chloro-3-methylnaphthalen-2-yl)-2-(1,1,1-trifluoro-2-methylpropan-2-yloxy)ethanol (157 mg, 0.45 mmol) in CH2Cl2 (2.4 mL) was added at 0° C. The reaction mixture was allowed to warm to room temperature overnight. The mixture was quenched with water and concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give 2-(1-chloro-3-methylnaphthalen-2-yl)-2-(1,1,1-trifluoro-2-methylpropan-2-yloxy)ethyl pivalate. 1H-NMR: 400 MHz, (CDCl3) δ 8.26 (d, J=8.4 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.58-7.48 (m, 3H), 6.05 (dd, J=8.4, 5.2 Hz, 1H), 4.50 (dd, J=11.2, 8.4 Hz, 1H), 4.21 (dd, J=11.2, 4.8 Hz, 1H), 2.73 (s, 3H), 1.43 (s, 3H), 1.19 (s, 3H), 1.16 (s, 9H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[C:7]([CH2:9][Br:10])[CH:6]=[C:5]([CH2:11][Br:12])[CH:4]=1.F[B-](F)(F)F.[O:18]=[N+:19]=[O:20].O>CC#N>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][Br:12])[CH:6]=[C:7]([CH2:9][Br:10])[C:8]=1[N+:19]([O-:20])=[O:18]
Reactant: O=[N+]=O
Reactant: BrCc1cc(CBr)cc(CBr)c1
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1c(CBr)cc(CBr)cc1CBr
Reaction time: 0.33 h
Yield: 86.4 %

Procedure:
To a solution of 5 g (0.014 mole) of the tribromide 8 in 100 ml of CH3CN was added, at room temperature and under argon atmosphere, in a dropwise fashion 3.72 g (0.028 mole) of nitronium tetrafluoroborate in 200 ml of CH3CN. The solution was then stirred for 20 minutes longer, poured into water and the mixture extracted with CH2Cl2. The CH2Cl2 extracts were washed with 10% NaHCO3, dried (Na2SO4) and solvents removed to afford 4.86 g (86%) of the desired nitro compound 27: NMR (CDCl3) 4.5 (s,6,--CH2Br), 7.55 (s,--C6H2).
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6](SC)[N:5]=[C:4]([CH2:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21]([OH:23])=[O:22])=[CH:16][CH:15]=[CH:14]3)[CH:3]=1>[Ni].CCO.O>[OH:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21]([OH:23])=[O:22])=[CH:16][CH:15]=[CH:14]3)[CH:3]=1
Reactant: CSc1nc(O)cc(Cc2ccc3c(C(=O)O)cccc3c2)n1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc2cc(Cc3cc(O)ncn3)ccc12
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
29 g Raney Nickel in EtOH are added to a solution of 5.08 mMol 6-(6-hydroxy-2-methylsulfanyl-pyrimidin-4-ylmethyl)-naphthalene-1-carboxylic acid in 220 ml EtOH and 170 ml water. The mixture is stirred for 3.5 h at 80° C., filtered hot and the residue is extensively washed with EtOH/H2O 1:1. Partial concentration in vacuo, acidification of the residue with 1 N HCl (pH=1), filtration of the precipitated product, washing with 50 ml 0.1 N HCl and drying (HV; 90° C.) gives the title compound. Additional product can be isolated from the filtrate by extraction with 3 Portions of EtOAc, washing of the organic layers with brine, drying (Na2SO4), concentration and chromatography (Combi Flash; CH2Cl2→CH2Cl2/MeOH+0.5% HOAc 19:1): TLC (CH2Cl2/MeOH+0.5% HOAc 9:1): Rf=0.17.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C@H:10]1[CH2:14][NH:13][C@H:12]([C:15]([NH:17][C:18]2([C:21]#[N:22])[CH2:20][CH2:19]2)=[O:16])[CH2:11]1.[CH2:23]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:37][CH2:36][CH:35]2[C:38]([O-])=[O:39])[CH2:30][CH2:29]1)=[O:27])[CH3:24].[Li+]>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C@H:10]1[CH2:14][N:13]([C:38]([CH:35]2[CH2:36][CH2:37][N:34]2[CH:31]2[CH2:30][CH2:29][N:28]([C:26]([O:25][CH2:23][CH3:24])=[O:27])[CH2:33][CH2:32]2)=[O:39])[C@H:12]([C:15](=[O:16])[NH:17][C:18]2([C:21]#[N:22])[CH2:20][CH2:19]2)[CH2:11]1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](Sc3ccc(F)cc3Cl)CN2)CC1
Reactant: CCOC(=O)N1CCC(N2CCC2C(=O)[O-])CC1
Agent: [Li+]
Product: CCOC(=O)N1CCC(N2CCC2C(=O)N2C[C@H](Sc3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-4-(2-chloro-4-fluorophenylthio)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 12A and lithium 1-(1-(ethoxycarbonyl)piperidin-4-yl)azetidine-2-carboxylate 20J carried out according to the general procedure L yielded ethyl 4-(2-((2S,4R)-4-(2-chloro-4-fluorophenylthio)-2-(1-cyanocyclopropylcarbamoyl)pyrrolidine-1-carbonyl)azetidin-1-yl)piperidine-1-carboxylate 1:1 epimers as a white solid (82%). MS ISP (m/e): 578.3/580.4 (100/38) [(M+H)]]+.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccc(OCCCCCCO)cc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Product: O=C(O)c1ccc(OCCCCCCOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3,4-Dihydro-2H-pyran (24.7 g) was added drop wise at room temperature to a solution of 4[(6-hydroxyhexyl)oxy]benzoic acid (35 g), toluene-4-sulfonic acid monohydrate (1.8) in diethylether (440 ml) and stirred at room temperature for 18 h. The resulting mixture was filtered over Hyflo Super Cel (FLUKA), organic solvents were removed in vacuum. The residue (60 g) was purified by column flash chromatography on silica gel using toluene/ethyl acetate (1:1) as eluent, to give after crystallisation from ethyl acetate/hexane (5:40) 4{[6(tetrahydro-2H-pyran-2-yloxy)hexyl]oxy}benzoic acid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][N:8]=1.[H-].[Na+].Cl[CH2:23][C:24]1[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[O:27][CH:28]=1.O>CN(C=O)C>[Cl:37][C:34]1[CH:35]=[CH:36][C:31](/[CH:30]=[CH:29]/[C:26]2[O:27][CH:28]=[C:24]([CH2:23][O:19][C:16]3[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][N:5]4[CH:6]=[CH:7][N:8]=[C:4]4[CH2:3][CH2:2][OH:1])=[CH:18][CH:17]=3)[N:25]=2)=[CH:32][CH:33]=1
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Reactant: ClCc1coc(/C=C/c2ccc(Cl)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(Cl)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To a solution of 4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl]butyl]phenol (130 mg) in DMF (4 ml), 60% oily sodium hydride (22 mg) was added under ice cooling. After stirring at room temperature for 30 minutes, (E)-4-chloromethyl-2-[2-(4-chlorophenyl)ethenyl]oxazole (140 mg) was added under ice cooling. After stirring at 0° C. for 1 hour, then at room temperature overnight, water was added under ice cooling. The precipitate was collected by filtration, washed with water, and dissolved in a mixture of THF-ethyl acetate. This solution was dried over magnesium sulfate, after which it was concentrated under reduced pressure. The residue was recrystallized from methanol-ethyl acetate-diethyl ether to yield the titled compound (168 mg) as colorless crystals.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]([NH:11][C:12]([C:14]1[S:15][C:16]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:17]=3[CH:18]=1)=[O:13])[CH2:4]2.C(N(CC)CC)C.[C:31]([Cl:34])(=[O:33])[CH3:32]>CN(C=O)C>[ClH:34].[N:3]12[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]1)[CH:5]([NH:11][C:12]([C:14]1[S:15][C:16]3[CH:22]=[CH:21][C:20]([NH:23][C:31](=[O:33])[CH3:32])=[CH:19][C:17]=3[CH:18]=1)=[O:13])[CH2:4]2
Reactant: Nc1ccc2sc(C(=O)NC3CN4CCC3CC4)cc2c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc2sc(C(=O)NC3CN4CCC3CC4)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
41.0 mg (0.12 mmol) of rac-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-amino-1-benzothiophene-2-carboxamide dihydrochloride and 36.8 mg (0.36 mmol) of triethylamine are dissolved in 1.5 ml of DMF. At 0° C., 14.3 mg (0.18 mmol) of acetyl chloride are added, and the mixture is stirred at RT overnight. The reaction mixture is purified by preparative HPLC. 29 mg (63% of theory) of the title compound are isolated.
Reaction SMILES: [Cl:1][C:2]1N=CN=[C:4]([NH:8][C:9]([C:11]2[N:12]([CH3:28])[S:13](=[O:27])(=[O:26])[C:14]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][C:15]=3[C:16]=2[OH:17])=[O:10])[CH:3]=1.Cl[C:30]1N=CN=[C:32](NC(C2NS(=O)(=O)C3C4C(=CC=CC=4)C=CC=3C=2O)=O)[CH:31]=1.CI>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[N:12]([CH3:28])[S:13](=[O:26])(=[O:27])[C:14]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][C:15]=3[C:16]=2[OH:17])=[O:10])[CH:30]=[CH:31][CH:32]=1
Reactant: CN1C(C(=O)Nc2cc(Cl)ncn2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Reactant: O=C(Nc1cc(Cl)ncn1)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Solvent: CI
Product: CN1C(C(=O)Nc2cccc(Cl)c2)=C(O)c2ccc3ccccc3c2S1(=O)=O

Procedure:
N-(6-Chloro-4-pyrimidyl)-4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide, m.p. 263° C (decomp.), from N-(6-chloro-4-pyrimidyl)-4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide and methyl iodide.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38](=[O:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C@@:22]([OH:29])([CH2:26][CH2:27][OH:28])[C:23]([OH:25])=O)=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].ClCCl.FC(F)(F)C(O)=O>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:18][C:19](=[O:20])[C@H:21]([C@@:22]2([OH:29])[CH2:26][CH2:27][O:28][C:23]2=[O:25])/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38](=[O:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)O)C(=O)OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@]2(O)CCOC2=O)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To No. 5214357, (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-(2-hydroxy-ethyl)-12-oxo-nonadec-4-enoic acid (20 mg, 0.0310 mmol) was added a mixture of dichloromethane/trifluoroacetic acid (9/1, v/v, 2 mL) and the mixture was stirred at room temperature for 1 hour. After confirming the consumption of the starting materials by LCMS, the organic solvent was distilled off under reduced pressure. The resulting residue was purified by preparative HPLC and then freeze-dried to obtain No. 5214805 (11 mg, 56% yield, white powder).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:16][N:15]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:25][N:26]1CCCC1=O.N>C1(C)C=CC=CC=1>[C:25]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:16][N:15]=3)=[CH:10][N:9]=2)=[CH:4][CH:3]=1)#[N:26]
Reactant: CN1CCCC1=O
Reactant: CCCCCc1cnc(-c2cnc(-c3ccc(Br)cc3)nc2)nc1
Agent: N
Solvent: Cc1ccccc1
Product: CCCCCc1cnc(-c2cnc(-c3ccc(C#N)cc3)nc2)nc1
Temperature: 40 °C

Procedure:
A mixture of 2-(p-bromophenyl)-5'-pentyl-5,2'-bipyrimidinyl (5.0 g, 0.013 mol), N-methyl-2-pyrrolidone (100 mL) and cuprous cyanide (1.16 g, 0.013 mol) was heated under reflux for 5 hours, followed by cooling the reaction mixture down to 40° C., adding toluene (500 ml) and 28% aqueous ammonia (100 ml), separating the resulting layers, washing the toluene layer with water till the washing water became neutral, drying the toluene layer over anhydrous sodium sulfate, distilling off toluene, and three times recrystallizing the residual solids from toluene to obtain 2-(p-cyanophenyl)-5'-pentyl-5,2'-bipyrimidinyl (2.1 g, 0.006 mol).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N+:3]=1[O-].CO.[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>>[C:13]([O:16][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[N:3]=1)(=[O:15])[CH3:14]
Reactant: Cc1ccc(F)c(Br)[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)OCc1ccc(F)c(Br)n1
Temperature: 120 °C

Procedure:
A solution of 2-bromo-3-fluoro-6-methylpyridine 1-oxide (585 mg) in acetic anhydride (4.98 mL) was stirred while heating at 120° C. for 4 hr. After returning the solution to room temperature, methanol (25 mL) was gradually added dropwise thereto. After the solvent was distilled off under reduced pressure, the acetic anhydride was evaporated with methanol. The resulting residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=88:12-0:100) to afford (6-bromo-5-fluoropyridin-2-yl)methyl acetate (269 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][C:19]([NH:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH2:24]Cl)=[O:20].O>CN(C)C=O>[CH3:17][O:18][C:19]([NH:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH2:24][O:1][C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:20]
Reactant: COC(=O)Nc1cccc(C)c1CCl
Reactant: O=[N+]([O-])c1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Nc1cccc(C)c1COc1cccnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
A mixture of 3-hydroxy-2-nitropyridine (3.08 g) and potassium carbonate (3.04 g) in N,N-dimethylformamide (31 ml) was stirred at room temperature for 15 minutes and then 2-methoxycarbonylamino-6-methylbenzyl chloride (4.7 g) was added. After being stirred for 6 hours, the mixture was poured into water and the resulting precipitates were collected by filtration, washed with water, and air-dried to give 3-(2-methoxycarbonylamino-6-methylbenzyloxy)-2nitropyridine (6.35 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:35]1([CH2:41][CH2:42][S:43][CH:44]([C:48](O)=[O:49])[C:45](O)=[O:46])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[OH:49][C:48]1[CH:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:16][CH:15]=2)[O:19][C:45](=[O:46])[C:44]=1[S:43][CH2:42][CH2:41][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(OCCCc2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(OCCCc3ccccc3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-(3-phenylpropoxy)acetophenone (1.28 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (57 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 139°-142° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.04 (m, 2 H), 2.84 (m, 4 H), 2.98 (t, 2 H), 4.40 (t, 2 H), 6.68 (s, 1 H), 7.18 (m, 12 H), 7.75 (d, 2 H), 11.86 (bs, 1 H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21]([OH:23])=O)=[CH:6][N:5]2[C:24]=1[CH3:25].[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.C(Cl)Cl.[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>C(OC(=O)C)C.C(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([NH:10][CH2:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:19][CH3:20])=[CH:8][C:7]([C:21]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[O:23])=[CH:6][N:5]2[C:24]=1[CH3:25]
Reactant: C1COCCN1
Reactant: CCc1cccc(C)c1CNc1cc(C(=O)O)cn2c(C)c(C)nc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCc1cccc(C)c1CNc1cc(C(=O)N2CCOCC2)cn2c(C)c(C)nc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.1 %

Procedure:
2,3-Dimethyl-8-(2-ethyl-6-methylbenzylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid (0.15 g, 0.44 mmol) and o-Benzotriazol-1-yl-N,N,N′,N′-Tetramethyluronium tetrafluoroborate (TBTU)(0.14 g, 0.44 mmol) were added to methylene chloride (10 ml). Morpholine (0.12 g, 1.4 mmol) was added and the reaction mixture was stirred at ambient temperature for 1.5 h. The reaction mixture was added to a column with silica gel and purification by chromatography using ethylacetate:methylene chloride (1:1) as eluent gave 0.12 g (66%) of the desired product.
Reaction SMILES: CO.[CH:3]([N:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:17]C)=[O:16])=[CH:11][CH:10]=1)[OH:7])([CH3:5])[CH3:4].[OH-].[Na+]>O>[CH:3]([N:6]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1)[OH:7])([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccc(CN(O)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(O)Cc1ccc(C(=O)O)cc1
Reaction time: 18 h
Yield: 83.6 %

Procedure:
A MeOH solution (75 mL) of N-isopropyl-N-(4-carbomethoxybenzyl)-hydroxylamine (13.2 g, 59.1 mmol) was heated to 60° C. and treated with NaOH (2.46 g, 61.5 mol) in water 50 (mL). The reaction was allowed to stir for 18 h under argon and was then filtered, concentrated to remove most of the MeOH, diluted with water (100 mL), an acidified to pH-4.5 with conc H2SO4. The white solid was stirred at ambient temperature for 3 h, isolated by filtration, washed with copious amounts of water and then dried in vacuo at 60° C. to give 10.34 g (83%) N-isopropyl-N-(4-carboxybenzyl)hydroxylamine. mp 201°-202° C.(dec). 1H NMR (DMSO-d6) δ 12.6 (br, 1), 7.83 (d, J=8.1 Hz, 2), 7.49 (s, 1), 7.41 (d, J=8.1 Hz, 2), 3.72 (s, 2), 2.85 (sept, J=6.4 Hz, 1), 1.02 (d, J=6.4 Hz, 6).
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.Cl.[CH2:21]([O:23][C:24](=[O:28])[CH2:25][CH2:26][NH2:27])[CH3:22].C(N(CC)CC)C>C(O)(=O)C>[CH2:21]([O:23][C:24]([CH2:25][CH2:26][N:27]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]1[CH2:6][N:5]1[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]2[C:1]1=[O:19])=[O:28])[CH3:22]
Reactant: CC(=O)CCC(=O)CN1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCOC(=O)CCn1c(C)ccc1CN1C(=O)c2ccccc2C1=O

Procedure:
3.9 g (0.015 mol) of 6-phthalimido-2,5-hexanedione, 3.1 g (0.02 mol) of β-alanine ethyl ester hydrochloride and 3 ml (0.02 mol) of triethylamine are stirred in 80 ml of glacial acetic acid at 50° C. for 8 hours and the mixture is worked up as in Example 27.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5]1.[NH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35]>C(O)(C)C.C(O)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:20][N:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][CH2:23][CH2:22]4)[CH2:5][CH2:6]3)=[N:11][O:12][C:13]=2[CH:18]=1.[F:19][C:17]1[CH:16]=[CH:15][C:14]2[C:10]([CH:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:20][N:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][CH2:23][CH2:22]4)[CH2:5][CH2:6]3)=[N:11][O:12][C:13]=2[CH:18]=1
Reactant: c1ccc2c(c1)CCCN2
Reactant: Fc1ccc2c(C3CCN(CC4CO4)CC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CC(C)O
Product: OC(CN1CCC(c2noc3cc(F)ccc23)CC1)CN1CCCc2ccccc21

Procedure:
A stirred mixture of N-(2,3-epoxypropyl)-4-(6-fluoro-1,2-benzisoxazol-3yl)piperidine (2.41 g, 8.73 mmol), 1,2,3,4-tetrahydroquinoline (1.33 g, 10 mmol, in isopropyl alcohol (50 ml) was heated at reflux for 6 hours. The solution was cooled and the solvent was removed on a rotary evaporator. The crude solid was purified by flash chromatography over a silica gel column (SiO2, 40 g, eluted with methylene chloride DCM, and 1-3% MeOH in DCM). The product thus purified weighed 2.0 g. This material was dissolved in ethanol and was treated with a solution of fumaric acid (567 mg, 1.0 eq) in ethanol. The solids collected were recrystallized again from ethanol (50 ml) to yield 1.0 g of white crystals, as a hemifumarate, m.p. 170°-171° C.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH:3]=1.C(OC([NH:32][C@H:33]([C:35](O)=[O:36])[CH3:34])=O)(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1.FC(F)(F)C(O)=O>>[NH2:32][CH:33]([CH3:34])[C:35]([NH:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][C:5]=2[O:4][CH:3]=1)=[O:36]
Reactant: CS(=O)(=O)Nc1cc2occ(N)c(=O)c2cc1Oc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: CC(N)C(=O)Nc1coc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c1=O

Procedure:
3-Amino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was reacted with N-tert-butoxycarbonylalanine in the presence of dicyclohexylcarbodiimide. The reaction product was treated with trifluoroacetic acid to obtain 3-(2-aminopropionyl)amino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.