Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]2[C:10]([C:21]3[CH:26]=[C:25]([C:27]([O:29]N4C(=O)CCC4=O)=[O:28])[CH:24]=[CH:23][C:22]=3[C:37]([O-:39])=[O:38])=[C:11]3[C:19]([O:20][C:6]=2[CH:5]=1)=[CH:18][C:14](=[N+:15]([CH3:17])[CH3:16])[CH:13]=[CH:12]3)[CH3:3].[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-]>CS(C)=O.C([O-])([O-])=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>[CH3:17][N:15]([C:14]1[CH:13]=[CH:12][C:11]2[C:10]([C:21]3[CH:26]=[C:25]([C:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=3[C:37]([OH:39])=[O:38])=[C:7]3[C:6]([O:20][C:19]=2[CH:18]=1)=[CH:5][C:4](=[N+:2]([CH3:1])[CH3:3])[CH:9]=[CH:8]3)[CH3:16]
Reactant: CN(C)c1ccc2c(-c3cc(C(=O)ON4C(=O)CCC4=O)ccc3C(=O)[O-])c3ccc(=[N+](C)C)cc-3oc2c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Solvent: CS(C)=O
Product: CN(C)c1ccc2c(-c3cc(C(=O)[O-])ccc3C(=O)O)c3ccc(=[N+](C)C)cc-3oc2c1

Procedure:
A solution of 6-TAMRA-SE (0.75 mg, 1.4 μmol) in anhydrous DMSO (30 μL) was added to a solution of triphosphate dC.10 (1.6 μmol) in Na2CO3/NaHCO3 buffer (0.1 M, pH 9.2; 0.3 mL) and incubated at room temperature for 30 minutes. The reaction was purified with reverse-phase HPLC using a Perkin Elmer OD-300 C18 column (4.6×250 mm) to yield the 6-TAMRA labeled triphosphate WW2p080. Mobile phase: A, 100 mM triethylammonium acetate (TEAA) in water (pH 7.0); B, 100 mM TEAA in water/CH3CN (30:70). HPLC purification was achieved a linear gradient of 5-50% B for 40 minutes and then 50-90% B for 10 minutes. The concentration of WW2p080 was estimated by adsorption spectroscopy using the extinction coefficient of the 6-TAMRA dye (i.e., 65,000 at 555 nm).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([Cl:18])[N:3]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>CN(C)C=O>[Cl:18][C:4]1[N:3]=[C:2]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:11]2[C:6]([C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: Clc1nc(Cl)c2ccccc2c1-c1ccccc1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Clc1nc(-n2ccnc2)c2ccccc2c1-c1ccccc1

Procedure:
2.74 g (10 mmoles) of 1,3-dichloro-4-phenylisoquinoline abd 2.04 g (30 mmoles) of imidazole were heated for 3 hours to 150° C in 5 ml of dimethyl-formamide. Working up was effected as described uner 1d.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[CH:7]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:16][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[C:8]([N:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1)=[O:9]
Reactant: Cc1ccc(F)cc1C(=O)N1CCOCC1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1cc(F)ccc1CBr)N1CCOCC1
Yield: 38.3 %

Procedure:
A mixture of intermediate 41, (5-fluoro-2-methylphenyl)(morpholino)methanone, (2.1 g, 9.5 mmol) and N-bromosuccinimide (2.0 g, 11 mmol) in CCl4 (30 mL) was heated at reflux. To this mixture was added benzoylperoxide (242 mg, 1 mmol) and the mixture heated at reflux for 2 hrs. After cooling, the insoluble materials were filtered and the filtrate purified by column chromatography (SiO2, 0–10% ether in CH2Cl2) to give 1.1 g (Yield 38%) of the title compound as a clear oil: 1H NMR (300 MHz, CDCl3) δ ppm: 3.31 (2H, t, J=4.94 Hz) 3.55–4.02 (6H, m) 4.56 (2H, dd, J=128.81, 9.51 Hz) 6.89 (1H, dd, J=8.23, 2.74 Hz) 6.96–7.12 (1H, m) 7.33–7.49 (1H, m); LC/MS m/z 302 (M+H).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]2[CH:32]=[CH:31][C:14]([C:15]([NH:17][C@@H:18]3[CH2:26][C@:21]4([O:25][CH2:24][CH2:23][CH2:22]4)[CH2:20][C@@H:19]3[C:27](OC)=[O:28])=[O:16])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].Cl.[NH2:41][OH:42]>CO.C[O-].[Na+]>[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]2[CH:32]=[CH:31][C:14]([C:15]([NH:17][C@@H:18]3[CH2:26][C@:21]4([O:25][CH2:24][CH2:23][CH2:22]4)[CH2:20][C@@H:19]3[C:27]([NH:41][OH:42])=[O:28])=[O:16])=[CH:13][CH:12]=2)[CH2:3][CH2:2]1
Reactant: NO
Reactant: COC(=O)[C@H]1C[C@]2(CCCO2)C[C@H]1NC(=O)c1ccc(C2CCOc3ccccc32)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(N[C@@H]1C[C@@]2(CCCO2)C[C@@H]1C(=O)NO)c1ccc(C2CCOc3ccccc32)cc1
Reaction time: 1 h
Yield: 34 %

Procedure:
Methyl (5R,7S,8R)-8-{[4-(3,4-dihydro-2H-chromen-4-yl)benzoyl]amino}-1-oxaspiro[4.4]nonane-7-carboxylate from reaction 34f (0.095 g, 0.22 mmol) was dissolved in a solution of hydroxylamine hydrochloride, methanol and sodium methoxide, (2 mL) under nitrogen atmosphere at room temperature. The reaction was stirred for 1 h, made neutral with TFA, concentrated and purified by HPLC on a C-18 column eluting with an acetonitrile:water:TFA gradient, to give the title compound (0.032 g, 34%) as a white solid. MS found: (M+H)+=435.
Reaction SMILES: [C@@H]1(C2C=C3C(C=C(C(O)=O)C(=O)O3)=CC=2)O[C@H](CO)[C@H](O)[C@H](O)[C@H]1[OH:3].ON1C(=O)CCC1=O.[CH:34]1([N:40]=[C:41]=[N:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CN(C)C=O>[C:41]([NH:40][CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)([NH:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=[O:3]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)c1cc2ccc([C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)cc2oc1=O
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3.68 g (0.01 mol) of 7-β-galactosylcoumarin-3-carboxylic acid, supra, 2.30 g (0.02 mol) of N-hydroxy-succinimide, and 2.27 g (0.011 mol) of dicyclohexylcarbodiimide in 25 ml of dimethylformamide (DMF) was stirred under argon at room temperature for 1 hour. A thick precipitate of dicyclohexylurea formed and was removed by filtration. The clear filtrate was combined with 2.52 grams (g) of the hydrochloride salt of N-(tert-butyloxycarbonyl)-1,6-hexanediamine [Stahl et al, J. Org. Chem. 43:2285(1976)]. The solution was cooled to 0° C. and 2.8 ml (2.02 g, 0.02 mol) of triethylamine was added. The reaction was allowed to stir at room temperature for 2 hours, then filtered to remove the precipitate of triethylamine hydrochloride. Evaporation of the DMF under reduced pressure gave an oily residue that was stirred for 15 minutes with 100 ml of 2 N hydrochloric acid. The heavy precipitate that formed was filtered, washed with water, and dried.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]2[CH3:15])[N:6]=[C:5]([C:16]2[CH:21]=[CH:20][C:19]([NH:22]C(=O)OC(C)(C)C)=[CH:18][CH:17]=2)[N:4]=1.C(Cl)Cl>Cl.O1CCOCC1>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:5]2[N:4]=[C:3]([CH2:2][OH:1])[CH:8]=[C:7]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][C@@H:10]3[CH3:15])[N:6]=2)=[CH:17][CH:18]=1
Reactant: C[C@H]1COCCN1c1cc(CO)nc(-c2ccc(NC(=O)OC(C)(C)C)cc2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@H]1COCCN1c1cc(CO)nc(-c2ccc(N)cc2)n1
Reaction time: 18 h
Yield: 72 %

Procedure:
tert-Butyl N-[4-[4-(hydroxymethyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]phenyl]carbamate (1.20 g) was dissolved in 4M hydrogen chloride in dioxane (5 mL) and dioxane (5 mL). The reaction was stirred for 18 hour then DCM (10 mL) added to help solubilise material. The reaction was stirred at 40° C. for a further 18 hours then evaporated to dryness. The solid was suspended in DCM (20 mL) and a mixture of a saturated aqueous solution of sodium hydrogen carbonate (6 mL) and water (4 mL) was added. The organics were separated, dried (MgSO4) and concentrated in vacuo to give the desired compound (648 mg) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:13]([C:16]1([CH3:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]1)(O)=[O:14]>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:13]([C:16]2([CH3:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]2)=[O:14])=[CH:4][CH:3]=1
Reactant: Fc1ccccc1
Reactant: CC1(C(=O)O)CCC(=O)O1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC1(C(=O)c2ccc(F)cc2)CCC(=O)O1
Temperature: 10 °C

Procedure:
To 0.5 moles of fluorobenzene and 0.2 moles of sulfuric acid at 80° C is added portionwise 0.2 , moles of gamma-carboxy-gamma-valerolactone (I). The mixture is kept at 80° C for an additional hour. The mixture is cooled to 10° C and 100 ml of ether is added. The mixture is poured onto ice and 100 ml of ether is added. The layers are separated and the aqueous layer is back extracted with ether and the ether extracts are combined. The combined ether extracts are washed with water, saturated sodium bicarbonate (twice), water, dried and concentrated to give the crude product (III).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][C:7]([C:10](=[O:28])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Cl>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[Cl:3][C:4]1[N:9]=[CH:8][C:7]([CH:10]([OH:28])[CH:11]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1ccc(Cl)nc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
To a solution of zinc chloride (9.89 g, 72.6 mmol) in diethyl ether (150 ml) was added sodium borohydride (5.49 g, 145 mmol), and the mixture was stirred at room temperature for 30 min. The insoluble material was filtered off, and a solution of ethyl 3-(6-chloro-3-pyridyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (14 g, 36.3 mmol) in diethyl ether (50 ml) was added to the filtrate. The mixture was stirred at room temperature for 30 min. 1N Hydrochloric acid was added to the reaction solution under ice-cooling to quench the reaction and water (200 ml) was added. The mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by medium pressure silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl(2RS,3RS)-3-(6-chloro-3-pyridyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate (9.32 g, 66%) as a colorless oil.
Reaction SMILES: [CH:1]([O:3][CH2:4][F:5])=[O:2].[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7]>>[CH2:6]([N:8]([CH2:9][CH3:10])[C:1](=[O:2])[O:3][CH2:4][F:5])[CH3:7]
Reactant: CCNCC
Reactant: O=COCF
Product: CCN(CC)C(=O)OCF
Reaction time: 1 h

Procedure:
In a 100 mL PFA-flask, fluoromethyl formate (27.0 g, 245 mmol) is given. Diethylamine (50.5 mL; 0.490 mmol) is added dropwise at about 0° C. The mixture is stirred for 1 hour. Solids are filtered off, and the resulting liquid is subjected to a distillation to isolate pure fluoromethyl N,N-diethylcarbamate.
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:7][CH:6]=2.[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>CS(C)=O>[C:16]([NH:20][C:2]1[C:3]([CH3:15])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:7][CH:6]=2)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)N
Reactant: CC(=O)c1cccc2nc(C)c(F)nc12
Solvent: CS(C)=O
Product: CC(=O)c1cccc2nc(C)c(NC(C)(C)C)nc12
Temperature: 65 °C
Yield: 91.3 %

Procedure:
To a stirred solution of 1-(3-fluoro-2-methylquinoxalin-5-yl)ethanone (126g) (13 g, 63.7 mmol) in DMSO (100 mL) was added t-BuNH2 (33.7 mL, 318 mmol). The reaction mixture was heated in an oil bath at 65° C. for 4 h. It was cooled to RT, treated with 100 mL of ice cold water. The precipitated light orange solid was collected, washed with water (2×15 mL), dried in a vacuum oven at 35° C. for 18 h to give 1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanone (606a) (14.96 g, 91% yield) which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 7.90 (dd, J=8.12, 1.66 Hz, 1H), 7.76 (dd, J=7.34, 1.66 Hz, 1H), 7.35 (t, J=7.73 Hz, 1H), 4.81 (br., 1H), 2.88 (s, 3H), 2.53 (s, 3H), 1.57 (s, 9H). m/z (ESI, +ve) 258.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1([CH2:6][CH3:7])[CH2:5][O:4]1)[CH3:2].[Br:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][CH2:5][C:3]([OH:4])([CH2:6][CH3:7])[CH2:1][CH3:2]
Reactant: CCC1(CC)CO1
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCC(O)(CC)COc1cccc(Br)c1
Temperature: 120 °C

Procedure:
2,2-Diethyloxirane (6.5 g of a 60% crude, 40 mmol), 3-bromophenol (5.7 g, 33 mmol), and cesium carbonate (12.0 g, 37 mmol) were combined in anhydrous DMSO (20 mL) in a sealed pressure tube and the reaction was stirred and heated at 120° C. for 2 d. Crude product was extracted from water with diethyl ether. The combined organic was washed with brine, dried over Na2SO4, filtered and concentrated under reduced vacuum. Purification by flash chromatography (0-20% EtOAc/hexanes gradient) gave 3-((3-bromophenoxy)methyl)pentan-3-ol as a colorless oil. Yield (7.1 g, 79%): NMR (400 MHz, CDCl3) δ 7.19 (t, J=8.0 Hz, 1H), 7.05-7.12 (m, 2H), 6.90-6.94 (m, 1H), 4.31 (s, 1H), 3.71 (s, 2H), 1.41-1.55 (m, 4H), 0.80 (t, J=7.6 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11](N(OC)C)=[O:12])[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:17].[CH2:18]([Mg]Br)[CH3:19]>>[Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11](=[O:12])[CH2:18][CH3:19])[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[Cl:17]
Reactant: CC[Mg]Br
Reactant: CON(C)C(=O)c1cc2c(Cl)c(Cl)ccc2s1
Product: CCC(=O)c1cc2c(Cl)c(Cl)ccc2s1

Procedure:
In a similar manner to Example 18, methyl thioglycolate (9.3 ml) was reacted with 2,3-dichloro-6-fluorobenzaldehyde (15.46 g) in dimethylformamide to give methyl 4,5-dichlorobenzo[b]thiophene-2-carboxylate (7.28 g) as an off-white solid which was hydrolysed, chlorinated and reacted with N,O-dimethylhydroxylamine hydrochloride to give 4,5-dichloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide (1.96 g) as a colourless solid. Reaction of this amide with ethylmagnesium bromide gave 1-(4,5-dichlorobenzo[b]thiophen-2-yl)propan-1-one (1.09 g) as an oil which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[N+:17]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd]>[CH2:1]([O:8][C:9](=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccncc1[N+](=O)[O-])OCc1ccccc1
Agent: [Pd]
Product: Nc1cnccc1CC(=O)OCc1ccccc1
Reaction time: 6 h
Yield: 72.6 %

Procedure:
The title compound is prepared following the procedures of WO, 00 55159 as follows. A mixture of (3-nitropyridin-4-yl)acetic acid benzyl ester (1.10 g, 5.23 mmol), 10% palladium on charcoal (200 mg) and denatured alcohol (100 mL) is stirred under an atmosphere of hydrogen for 6 hr. The catalyst is removed by filtration through a pad of Hi-Flo and the filtrate is concentrated to yield (3-aminopyridin-4-yl)acetic acid benzyl ester (0.92 g, 98% yield) as a yellow-brown oil. MS 181 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[Cl:14])[NH:6]1)=[O:4].[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH2:27][CH3:28])[C:24](O)=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N=C=NC(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[Cl:14])[N:6]1[C:24](=[O:25])[C@@H:23]([NH:22][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:27][CH3:28])=[O:4]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)C1Cc2c(Cl)cccc2N1
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2cccc(Cl)c2CC1C(=O)OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-chloroindoline-2(R/S)-carboxylic acid methyl ester (0.41 g, 1.94 mmol) and N-t-butoxycarbonyl-2(S)-aminobutyric acid (0.47 g, 2.33 mmol) dissolved in dried dichloromethane(10 ml) under nitrogen at 10° C., was added diisopropylcarbodiimide (0.36 ml, 2.33 mmol). The mixture was stirred at room temperature for 24 hours, then filtered. The filtrate was evaporated under vacuum to afford a brown solid which was purified by column chromatography on silica gel using 20:1 dichloromethane: diethyl ether as eluent. A white foam was obtained which was the mixture of two diastereomers.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:11]=[CH:10][N:9]=[C:8]([Cl:12])[C:5]2=[N:6][CH:7]=1.[CH3:13][O-:14].[Na+].CO>CN(C)C=O.O>[Cl:12][C:8]1[C:5]2=[N:6][CH:7]=[C:2]([O:14][CH3:13])[N:3]=[C:4]2[CH:11]=[CH:10][N:9]=1
Reactant: C[O-]
Reactant: Clc1cnc2c(Cl)nccc2n1
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cnc2c(Cl)nccc2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2,5-dichloropyrido[3,4-b]pyrazine (580 mg, 2.90 mmol) in N,N-dimethylformamide (10 mL) was added a 0.5-M solution of sodium methoxide in methanol (6.09 mL, 3.04 mmol), and the reaction was stirred at room temperature for 5 minutes. The solution was diluted with water and extracted with ethyl acetate. The organic layer was dried with sodium sulfate, filtered and concentrated to afford the title compound (550 mg, 2.81 mmol). MS m/z=196 (M+H).
Reaction SMILES: [C:1]([N:4]1[C:8]2([CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH2:7][CH2:6][CH:5]1[C:14]([OH:16])=O)(=[O:3])[CH3:2].[CH3:17][O:18][C:19]([NH:21][C@H:22]([C:26]([N:28]1[CH:32]([C:33]2[NH:34][CH:35]=[C:36]([C:38]3[CH:43]=[CH:42][C:41]([C:44]4[CH:49]=[CH:48][C:47](C5N=C([C@@H]6CCCN6C(=O)[C@H](C(C)C)NC(OC)=O)NC=5)=[CH:46][CH:45]=4)=[CH:40][CH:39]=3)[N:37]=2)[CH2:31][C:30]2(CCN(C(OC(C)(C)C)=O)CC2)[CH2:29]1)=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:20]>>[C:1]([N:4]1[C:8]2([CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH2:7][CH2:6][CH:5]1[C:14]([NH:4][CH2:5][C:14]([C:47]1[CH:46]=[CH:45][C:44]([C:41]2[CH:42]=[CH:43][C:38]([C:36]3[N:37]=[C:33]([C@@H:32]4[CH2:31][CH2:30][CH2:29][N:28]4[C:26]([C@@H:22]([NH:21][C:19](=[O:20])[O:18][CH3:17])[CH:23]([CH3:24])[CH3:25])=[O:27])[NH:34][CH:35]=3)=[CH:39][CH:40]=2)=[CH:49][CH:48]=1)=[O:16])=[O:16])(=[O:3])[CH3:2]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CCN(C(=O)OC(C)(C)C)CC2)CC1c1nc(-c2ccc(-c3ccc(-c4c[nH]c([C@@H]5CCCN5C(=O)[C@@H](NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Reactant: CC(=O)N1C(C(=O)O)CCC12CCOCC2
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3ccc(C(=O)CNC(=O)C4CCC5(CCOCC5)N4C(C)=O)cc3)cc2)c[nH]1)C(C)C
Yield: 132.4 %

Procedure:
This compound was prepared in an analogous fashion to 169 from 1-acetyl-8-oxa-1-azaspiro[4.5]decane-2-carboxylic acid (171) (56 mg, 0.25 mmol) and methyl {(1S)-1-[((2S)-2-{4-[4′-(aminoacetyl)-4-biphenylyl]-1H-imidazol-2-yl}-1-pyrrolidinyl)carbonyl]-2-methylpropyl}carbamate dihydrochloride (1) (142 mg, 0.25 mmol) to afford the title compound as an off-white solid (118 mg, 67% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:22]([CH2:23][C:24]([OH:26])=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:10][CH:9]=1.Cl.Cl.[CH3:29][N:30]([CH3:38])[C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:22]([CH2:23][C:24]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([N:30]([CH3:38])[CH3:29])=[CH:32][CH:33]=3)=[O:26])[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[N:15]=2)=[CH:12][CH:13]=1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: CN(C)c1ccc(N)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ccc(NC(=O)Cn2c(-c3ccc(Cl)cc3)nc3cccnc32)cc1
Temperature: 60 °C
Yield: 12.7 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (2.21 g, 0.0174 mole) was added slowly dropwise to a stirred and cooled (0°-10° C.) suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.0174 mole) in 50 ml of dimethylformamide. After the addition was complete, the reaction solution was heated at 60° C. for 5 hrs. This acylchloride solution was added dropwise to a stirred and cooled (<10° C.) suspension of N,N-dimethyl-1,4-phenylenediamine dihydrochloride (3.64 g, 0.0174 mole), triethylamine (5.27 g, 0.052 mole), and 75 ml of dimethylformamide. The reaction mixture was stirred at room temperature overnight. The reaction mixtue was poured into 1800 ml of water and refrigerated overnight. The solid was collected by filtration and dried. The solid was recrystallized twice from isopropyl alcohol, collected by filtration, washed with water, and dried under high vacuum at 98° C. overnight to give 0.9 g (12.7%) of crystals, mp 245°-246.5° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl.Cl[CH2:12][CH2:13][CH2:14][N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19]>O>[CH2:20]([N:15]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH2:13][CH2:12][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:21][CH2:22][CH3:23]
Reactant: Oc1ccccc1
Reactant: CCCCN(CCCC)CCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCN(CCCC)CCCOc1ccccc1
Yield: 91.4 %

Procedure:
The process is performed in the same manner as previously (Example 13), starting with 138 g (1.466 mol; 1.15 eq.) of phenol, 109.5 g (2.738 mol; 2.15 eq.) of NaOH, 530 ml of distilled water and 308.9 g (1.275 mol; 1 eq.) of N-(3-chloropropyl)-N,N-dibutylamine hydrochloride. The mixture is refluxed for 16 hours. The oil formed is separated out by settling and washed with 500 ml of water and then diluted with 500 ml of MTBE and washed with 500 ml of 2% HCl. The MTBE phase is concentrated under vacuum and the oil is dried by azeotropic distillation with DCM. 307.1 g of the crude derivative N,N-dibutyl-N-(3-phenoxypropyl)amine are obtained.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH:15]([CH3:31])[CH2:16][CH2:17][CH2:18][C:19]1[N:20]=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:22][C:23]=1[CH3:24].Cl>O1CCCC1>[CH3:24][C:23]1[O:22][C:21]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:20][C:19]=1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:31][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1oc(-c2ccccc2)nc1CCCC(C)Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCCCc1nc(-c2ccccc2)oc1C)C(=O)OCC
Reaction time: 0.17 h
Yield: 87.5 %

Procedure:
To 35 ml of dry tetrahydrofuran, 650 mg of 60% sodium hydride was added, and 3.9 g of diethyl malonate was added dropwise with stirring under ice-cooling. After the stirring was continued for 10 minutes, 4-(4-bromopentyl)-5-methyl-2-phenyloxazol (2.5 g) was added. The mixture was stirred for 10 minutes at room temperature and then heated to reflux for 12 hours. The reaction solution was poured into ice-cold water, neutralized with dilute hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane: ethyl acetate=10:1) to provide 2.75 g of the objective compound as colorless oil.