Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:18]=[C:19]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:20]=1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][CH2:13][CH2:14][C:15]2[CH:16]=[C:17]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:18]=[C:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:20]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1cc(CCN)cc(Cc2ccc(F)cc2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc(Cc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 73.2 %

Procedure:
4-chlorobenzenesulphonyl chloride (352 mg) was added portionwise to a stirred solution of ethyl 3-(2-aminoethyl)-5-[(4-fluorophenyl)methyl]benzenepropanoate (500 mg) and triethylamine (0.25 ml) in dry dichloromethane (5 ml) at room temperature. The solution was stirred at room temperature for 5 hours and then washed with water and dried (MgSO4). The solvent was evaporated and the residue was chromatographed on silica gel. Elution with dichloromethane first gave impurity followed by pure product. The product fractions were combined and evaporated to give the title compound as an oil (560 mg); Rf 0.2 (SS 3). Found: C,62.08; H,5.47; N,2.73. C26H27ClFNO4S requires C,61.96; H,5.40; N,2.78%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=2)=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COc1cc(O)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Oc2ccc([N+](=O)[O-])cn2)ccc1C
Temperature: 115 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a solution of 4-methyl-3-(methyloxy)phenol (Intermediate 18, 400 mg) in dry N,N-dimethylformamide (15 mL), potassium carbonate (1200 mg, 8.69 mmol) and then 2-chloro-5-nitropyridine (551 mg, 3.47 mmol) were added and the reaction mixture was stirred for 2 hours at 115° C. The reaction was quenched with water (10 mL), diluted with brine (20 mL) and extracted with ethyl acetate (3 times 30 mL). The organic layer was washed with ice cold brine (2 times 30 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by silica gel chromatography (Biotage system, 100 g SNAP column) with a gradient cyclohexane/ethyl acetate from 10/0 to 8/2. Evaporation afforded the to title compound as a light yellow oil (570 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:32])[CH:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:27]3[C:26]4[C@H:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23][C:22]=4[S:21][C:20]=3[N:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:33][C:34]1[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=1.CN(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(C=O)C>[F:33][C:34]1[CH:35]=[CH:36][C:37]([NH:40][C:29]([CH2:28][C@@H:25]2[CH2:24][CH2:23][C:22]3[S:21][C:20]4[N:19]=[CH:18][N:17]=[C:16]([O:15][CH:12]5[CH2:13][CH2:14][CH:9]([N:8]([CH3:32])[C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][CH2:11]5)[C:27]=4[C:26]2=3)=[O:30])=[N:38][CH:39]=1
Reactant: Nc1ccc(F)cn1
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@H](CC(=O)O)CC4)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@H](CC(=O)Nc2ccc(F)cn2)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a solution of intermediate 22.4 (200 mg, 0.43 mmol, 1.00 equiv) in distilled DMF (8 mL) at room temperature under nitrogen was added 5-fluoropyridin-2-amine (55 mg, 0.49 mmol, 1.13 equiv), HATU (200 mg) and DIPEA (170 mg). The resulting solution was stirred for 2 h at room temperature and quenched with water and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column with ethyl acetate/petroleum ether (1:2 to 3:5) and purified to give tert-butyl N-(4-[[(3S)-3-[[(5-fluoropyridin-2-yl)carbamoyl]methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (23.1, 195 mg, 81%) as a yellow oil. MS: m/z 556 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[CH:5]=[C:4]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:16]>>[NH2:1][C:2]1[N:7]=[C:6]([Cl:16])[CH:5]=[C:4]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1nc(O)cc(-c2ccco2)n1
Product: Nc1nc(Cl)cc(-c2ccco2)n1

Procedure:
A solution of 2-amino-4-hydroxy-6-(2-furyl)pyrimidine (1.40 g, 7.9 mmol) in POCl3 (4 mL) was refluxed under argon for 2 h. The POCl3 was distilled; the residue was diluted with EtOAc and poured over iced saturated NaHCO3. The layers were separated and the aqueous was extracted with EtOAc (100 mL). The combined extracts was washed with saturated NaCl, dried (MgSO4), and the solvent removed at reduced pressure to afford 0.5 g of crude product, which was used without further purification. TLC (20% EtOAc/80% hexane) Rf 0.26; 1H-NMR (DMSO-d6) δ 6.68 (dd, J=1.7, 3.4 Hz, 1H), 6.94 (s, 1H), 7.25 (dd, J=1, 3.7 Hz, 1H), 7.91 (dd, J=0.8, 1.9 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22]Br)[CH3:19]>CN(C=O)C>[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22][O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:19]
Reactant: CCOC(CBr)OCC
Reactant: COc1ccc(O)c(C=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(OC)cc1C=O)OCC
Yield: 31.2 %

Procedure:
To a stirred suspension containing 2-hydroxy-5-methoxybenzaldehyde (2.0 g, 13.16 mmol) and K2CO3 (2.18 g, 15.79 mmol) in DMF (20 mL), bromoacetaldehyde diethyl acetal (2.43 mL, 15.79 mmol) was added dropwise. The mixture was refluxed for 4 h. After cooling, the precipitate was filtered off and the solvent was evaporated in vacuo. The crude residue was adsorbed on silica gel and purified by flash chromatography. The product was eluted with hexane/EtOAc (4:1) to give the target compound 23 (1.10 g, 31%) as an oil. 1H NMR (500 MHz, CDCl3): δ: 10.49 (1H, s, CHO), 7.33 (1H, d, J=3.30 Hz, ArH), 7.12 (1H, dd, J=5.75 & 3.30 Hz, ArH), 6.97 (1H, d, J=9.05 Hz), 4.87 (1H, t, J=5.25 Hz, CH), 4.09 (2H, d, J=5.25 Hz, CH2), 3.81-3.78 (2H, m, CH2CH3), 3.67-3.64 (2H, m, CH2CH3), 1.26 (6H, t, J=7.05 Hz, 2×CH3).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:13]1[S:14][CH:15]=[C:16]([C:18]2[O:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[CH:22]=2)[N:17]=1)[C:6]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)=[O:7].C(N(CC)C(C)C)(C)C.[C:36]([N:39]1[CH2:47][CH2:46][CH:42]([C:43](Cl)=[O:44])[CH2:41][CH2:40]1)(=[O:38])[CH3:37]>C(Cl)(Cl)Cl>[C:36]([N:39]1[CH2:40][CH2:41][CH:42]([C:43]([NH:1][CH2:2][CH2:3][CH2:4][N:5]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[O:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[CH:22]=3)[N:17]=2)[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[O:7])=[O:44])[CH2:46][CH2:47]1)(=[O:38])[CH3:37]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: NCCCN(C(=O)c1cccs1)c1nc(-c2cc3ccccc3o2)cs1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCC(C(=O)NCCCN(C(=O)c2cccs2)c2nc(-c3cc4ccccc4o3)cs2)CC1
Temperature: 25 °C

Procedure:
A mixture of the amine prepared above (77 mg, 0.2 mmol) and N,N-diisopropylethylamine (139 μL, 0.8 mmol) was dissolved in chloroform (2 mL), and a portion of the solution (200 μL, 0.02 mmol) was added to a solution of 1-acetyl-isonipecotoyl chloride (7.6 mg, 0.04 mmol) in chloroform (200 μL). The reaction mixture was maintained at room temperature overnight.). The reaction mixture was maintained at room temperature overnight, then concentrated in vacuo. The resulting residue was dissolved in DMSO (200 μL) and subjected to HPLC purification (Method Z) to provide the title compound (4.5 mg) as a yellowish solid. LC/MS (ESI) m/z 537.1 [M+H]. HPLC retention time (Method C)=3.44 min.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2/[C:14](/[NH:17][OH:18])=[N:15]\[H])=[N:2]1.CC[C:25]([C:27](Cl)=[O:28])=O.C[OH:31].[OH-].[Na+]>N1C=CC=CC=1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[C:14]2[N:15]=[C:25]([C:27]([OH:28])=[O:31])[O:18][N:17]=2)=[N:2]1
Reactant: CCC(=O)C(=O)Cl
Reactant: [H]/N=C(/NO)c1ccccc1C=Cc1n[nH]c2ccccc12
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: O=C(O)c1nc(-c2ccccc2/C=C/c2n[nH]c3ccccc23)no1
Temperature: 90 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
(E)-2-[2-(1H-indazol-3-yl)vinyl]-N-hydroxybenzamidine (0.17 g, 0.60 mmol) was dissolved in pyridine (5.0 mL) and ethyloxalyl chloride (0.12 mL, 1.1 mmol) was added thereto, followed by stirring at 90° C. for 2 hours. Methanol and 2 mol/L aqueous sodium hydroxide solution were added to the mixture and the organic layer was extracted with ethyl acetate. The aqueous layer was neutralized by 6 mol/L hydrochloric acid and the precipitated solid was collected by filtration and then dried. The obtained solid was triturated in ethanol to obtain (E)-3-{2-[2-(1H-indazol-3-yl)vinyl]phenyl}[1,2,4]oxadiazole-5-carboxylic acid (0.12 g, 50%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][NH:17]3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[C:21]([O:25][C:26]([NH:28][C@@H:29]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41]([O:43][CH2:44][CH:45]2[C:57]3[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=3[C:51]3[C:46]2=[CH:47][CH:48]=[CH:49][CH:50]=3)=[O:42])=[CH:36][CH:35]=1)[C:30](O)=[O:31])=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(C(C)C)C(C)C)C.N1(O)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[CH:47]1[C:46]2[CH:45]([CH2:44][O:43][C:41](=[O:42])[NH:40][C:37]3[CH:38]=[CH:39][C:34]([CH2:33][C@H:29]([NH:28][C:26]([O:25][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:27])[C:30]([N:17]4[CH2:18][CH2:19][CH2:20][C@H:16]4[C:14]4[CH:13]=[N:12][CH:11]=[C:10]([C:8](=[O:9])[C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[CH:15]=4)=[O:31])=[CH:35][CH:36]=3)[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:51]=2[CH:50]=[CH:49][CH:48]=1
Reactant: O=C(c1ccc(F)cc1)c1cncc([C@@H]2CCCN2)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1)C(=O)N1CCC[C@H]1c1cncc(C(=O)c2ccc(F)cc2)c1
Reaction time: 16 h

Procedure:
To a solution of (4-fluoro-phenyl)-((S)-5-pyrrolidin-2-yl-pyridin-3-yl)-methanone (1.0 g, 3.7 mmol), (S)-2-tert-butoxycarbonylamino-3-[4-(9H-fluoren-9-ylmethoxycarbonylamino)-phenyl]-propionic acid (2.21 g, 4.4 mmol) and ethyldiisopropylamine (3 mL) in DMF (20 mL) was added a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1.67 g, 4.4 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (0.6 g, 4.4 mmol) in DMF (10 mL) and the reaction mixture was shaken for 16 hours. The reaction mixture was diluted with ethyl acetate (300 ml), washed sequentially with brine (2×) (300 mL), saturated aqueous bicarbonate solution (300 mL), brine (300 mL), water (300 mL), and brine (300 mL), then dried over Na2SO4/MgSO4, and concentrated in vacuo to provide the crude product [4-((S)-2-tert-butoxycarbonylamino-3-{(S)-2-[5-(4-fluoro-benzoyl)-pyridin-3-yl]-pyrrolidin-1-yl}-3-oxo-propyl)-phenyl]-carbamic acid 9H-fluoren-9-ylmethyl ester as a light yellow foam.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:22]=[CH:21][C:12]2[S:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][C:11]=2[C:10]=1[N+:23]([O-])=O)([C:3](OCC)=[O:4])=[O:2]>C(O)C.[Pd]>[CH2:19]([O:18][C:16]([C:14]1[S:13][C:12]2[CH:21]=[CH:22][C:9]3[N:8]=[C:1]([OH:2])[C:3]([OH:4])=[N:23][C:10]=3[C:11]=2[CH:15]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)C(=O)Nc1ccc2sc(C(=O)OCC)cc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2c(ccc3nc(O)c(O)nc32)s1
Yield: 62.9 %

Procedure:
A solution of 5-ethoxalylamino-2-ethoxycarbonyl-4-nitrobenzo[b]thiophene (0.84 g, 2.3 mmol) in ethanol was hydrogenated at atmospheric pressure and room temperature in the presence of 0.55 g of 5% palladium-on-charcoal. The catalyst was removed by filtration and washed with ethanol. The filtrate was heated to reflux for 11/2 h, and cooled. The resulting precipitate was collected by filtration and washed with ethanol to give 0.42 g (63%) of the title compound, m.p. 357°-363° C.; IR (KBr): 1680 cm-1 ; 1H-NMR (DMSO-d6): 1.36 (t, J=7 Hz, 3H, CH3), 4.37 (q, J=7 Hz, 2H, CH2), 7.33 (d, J=9 Hz, 1H, ArH), 7.73 (d, J=9 Hz, 1H, ArH), 8.83 (s, 1H, H-9), 12.06 and 12.30 (2 broad s, 2H, 2 OH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]([CH3:16])[NH:11][C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[H-].[Na+].Cl[CH2:20][C:21]([NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1)=[O:22]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]([CH3:16])[NH:11][C:12](=[O:15])[NH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:20][C:21]([NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1)=[O:22]
Reactant: CC1NC(=O)NN=C1c1ccc(O)c(Cl)c1
Reactant: COc1ccc(CCNC(=O)CCl)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCNC(=O)COc2ccc(C3=NNC(=O)NC3C)cc2Cl)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.6 %

Procedure:
442 mg of 6-(3-chloro-4-hydroxyphenyl)-4,5-dihydro-5-methyl-1,2,4-triazin-3(2H)-one [prepared as described in step (a) above] were added to a stirred suspension of 85 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) in 7 ml of anhydrous dimethylformamide, whilst ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the ice-cooled suspension were then added 472 mg of α-chloro-N-[2-(3,4-dimethoxyphenyl)ethyl]acetamide (prepared as described in Preparation 1), and the reaction mixture was stirred at room temperature for 1 hour and then at 100° C. (bath temperature) for a further 1 hour. The dimethylformamide used as the solvent was removed by evaporation under reduced pressure, and then the mixture was diluted with ethyl acetate. It was then washed with water and with a saturated aqueous solution of sodium chloride, dried and concentrated by evaporation under reduced pressure. The residue was collected by filtration and then recrystallized from a mixture of chloroform and ethyl acetate, to give 326 mg of the title compound as a white powder melting at 167°-169° C. (with decomposition).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.[H-].[Na+].[H][H].[F:23][C:24]([F:37])([F:36])[O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](Cl)=[O:34])=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>CN(C=O)C.O>[OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:4](=[O:18])[C:3]=1[C:33](=[O:34])[CH2:32][C:29]1[CH:30]=[CH:31][C:26]([O:25][C:24]([F:36])([F:23])[F:37])=[CH:27][CH:28]=1
Reactant: [H][H]
Reactant: O=C(Cl)Cc1ccc(OC(F)(F)F)cc1
Reactant: O=c1cc(O)c2cccnc2n1-c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccc(OC(F)(F)F)cc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
In accordance with a process described in JP-61-246183A, 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one was synthesized. To a suspension of the synthesized compound (893 mg, 3.7 mmol) in DMF (16 mL) was added sodium hydride (purity of about 60%, 360 mg, 9.0 mmol, 2.4 eq.), and the mixture was stirred until no more hydrogen was generated. Then, 4-trifluoromethoxyphenylacetyl chloride (1.2 eq.) was added thereto, and the mixture was stirred at a room temperature for 3 hours. To the mixture was added water and further added a saturated sodium hydrogencarbonate solution, and the resulting mixture was subjected to extraction with dichloromethane. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off from the extract. The resulting residue was purified by a flash column chromatography to give 4-hydroxy-1-phenyl-3-(4-trifluoromethoxyphenylacetyl)-1,8-naphthyridin-2(1H)-one (383 mg, yield 23%).
Reaction SMILES: NC(N)=O.[Br-:5].[C:6](C1C=CC=CN=1)(=[O:8])[CH3:7].[N:15]1[CH:20]=[CH:19][CH:18]=[CH2+:17][CH:16]=1>>[C:6]([C:17]1[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=1)(=[O:8])[CH3:7].[Br:5][CH2:7][C:6]([C:17]1[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=1)=[O:8]
Reactant: CC(=O)c1ccccn1
Reactant: [Br-]
Reactant: C1=CN=C[CH2+]=C1
Agent: NC(N)=O
Product: CC(=O)c1cccnc1
Product: O=C(CBr)c1cccnc1

Procedure:
Furthermore, it is known that 2,6-bis(2'-pyridyl)-pyridine is formed as a byproduct besides 2-(2'-pyridyl)-pyridine in the reaction of pyridine with potassium peroxydisulfate (East German Patent No. 23,118) or with pyridine-N-oxide in the presence of Pd-Pt-catalysts (Yakugaku Zasshi Vol. 93 (1973) pages 144-148). Also in the heating of pyridine in the presence of Raney nickel there is formed as byproduct 2,6-bis(2'-pyridyl)-pyridine and in the same manner there is formed in the heating of substituted pyridines the corresponding substituted compounds (J. Chem. Soc. (1956) pages 616-620). 2,6-Bis(3-pyridyl)-pyridine is produced when 3-acetyl pyridine is reacted with dimethylamine hydrochloride and formaldehyde to form an aminoketone and this aminoketone is further reacted with 3-pyridinium acetyl pyridine bromide obtained from 3-acetyl pyridine by way of 3-bromoacetyl pyridine (Synthesis (1976) pages 1-24).
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.Cl.[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]([OH:33])=[O:32])[CH2:27][CH2:26]1.N12CCCN=C1CCCCC2>CN(C)C=O>[CH3:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]([O:33][CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:11])[N:3]2[C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=3)[N:13]=2)=[O:32])[CH2:27][CH2:26]1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: CN1CCC(C(=O)O)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CN1CCC(C(=O)OC2c3ccccc3C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Yield: 42.7 %

Procedure:
Working as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (9.9 g) in anhydrous dimethylformamide (100 cc), 1methyl-4-piperidinecarboxylic acid hydrochloride (5.4 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (10.7g), and after the residue obtained has been recrystallized twice successively in ethanol and then in acetonitrile, 2-(7-chloro-1,8-naphthyridin-2-yl)-1-oxo-3-isoindolinyl 1-methyl-4-piperidinecarboxylate (5.6 g), m.p. 136° C. and then 157° C., is obtained.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Cl[C:9]1[CH:16]=C[C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.C[N:18](C=O)C>O>[CH:1]1([CH2:4][O:5][C:12]2[CH:11]=[CH:10][C:9]([C:16]#[N:18])=[N:14][CH:13]=2)[CH2:3][CH2:2]1
Reactant: OCC1CC1
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(OCC2CC2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
Cyclopropylmethanol (0.120 mL, 1.504 mmol) was added to a suspension of sodium hydride (60% in mineral oil) (0.072 g, 1.805 mmol) in DMF (4 mL) at room temperature. The mixture was stirred at room temperature for 30 min, 4-chlorobenzonitrile (0.139 g, 1.002 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with water and extracted with EtOAc (3 times). The organic extracts were combined, washed with water (2 times), brine (2 times), dried and evaporated under vacuum. The crude residue was purified by flash chromatography (hexane:EtOAc 9:1 to 85:15) to afford the title compound (0.120 g, 69%). Method B HPLC-MS: MH+ requires m/z=175. Found: m/z=175, Rt=1.73 min (100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([CH3:13])=[CH:7][CH:8]=2)[NH:3]1.[H][H]>[Rh]>[CH3:1][C:2]1([CH3:14])[CH2:11][CH:10]([CH3:12])[CH:9]2[CH:4]([CH2:5][CH:6]([CH3:13])[CH2:7][CH2:8]2)[NH:3]1
Reactant: [H][H]
Reactant: CC1=CC(C)(C)Nc2cc(C)ccc21
Agent: [Rh]
Product: CC1CCC2C(C)CC(C)(C)NC2C1
Reaction time: 24 h

Procedure:
2,2,4,7-tetramethyldecahydroquinoline was prepared by reacting 125 grams of 2,2,4,7-tetramethyl-1,2-dihydroquinoline with hydrogen using 3 grams of rhodium at 5% by weight on charcoal as the catalyst and operating at 185° C., a 1000 psig pressure, for 24 hours. The desired product was confirmed by NMR spectral analysis and its carbon, hydrogen, nitrogen content (calculated contents for C13H25N is the same as above and analyzed contents were 78.95% carbon, 13.30% hydrogen, and 6.80% nitrogen). The product was 95% pure as determined by vapor pressure chromotography and boiled at about 65° C. at 1 mm of Hg.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][CH:28]([CH2:31][C:32]([OH:34])=O)[CH2:29][N:30]=1)=[CH:9]2.Cl.C[N:37](C)CCCN=C=NCC.CN(C)C=O>O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:17])=[O:18])[CH:14]=1)[NH:11][C:10]([C:26]1[S:27][CH:28]([CH2:31][C:32]([NH2:37])=[O:34])[CH2:29][N:30]=1)=[CH:9]2
Reactant: CCN=C=NCCCN(C)C
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CC(=O)O)S3)cc2c1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CC(N)=O)S3)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 40.1 %

Procedure:
A mixture of (2-{5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (200 mg), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (90 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (120 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-methanol (100:0-90:10, volume ratio) to give colorless crystals. The crystals were recrystallized from acetone-hexane to give the title compound (80 mg, yield 55%) as a colorless powder. melting point 100-102° C.
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1O)=[CH:15][CH:14]=[CH:13][CH:12]=2)([O-:7])=[O:6].CN(C=O)C.[NH2:24][CH2:25][CH2:26][CH2:27][OH:28]>C(Cl)Cl>[N+:5]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[NH:24][CH2:25][CH2:26][CH2:27][OH:28])=[CH:15][CH:14]=[CH:13][CH:12]=2)([O-:7])=[O:6]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Reactant: NCCCO
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCO
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (6.3 mL) was added to a mixture of 3-nitroquinolin-4-ol (15 g) and DMF (6.9 mL) in DCM (200 mL). The mixture was heated under reflux for 3 h then cooled to 0° C. 3-Amino-1-propanol (7.3 mL) was added slowly followed by dropwise addition of TEA (36 mL) and the mixture stirred at rt for 3 h. The precipitate was filtered, washed with DCM then water. The DCM filtrate was washed with water and evaporated under reduced pressure then combined with the filtered solid. The combined solids were triturated with ether and filtered to give a yellow solid, 19.2 g