Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](O)=[O:15])[C:9]2=[O:17])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=1.CN1CCOCC1>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:38][C:35]3[CH:34]=[CH:33][C:32]([Cl:31])=[CH:37][N:36]=3)=[O:15])[C:9]2=[O:17])=[CH:6][CH:7]=1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: Nc1ccc(Cl)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)Nc1ccc(Cl)cn1
Reaction time: 0.5 h

Procedure:
To a suspension of 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.168 g, 0.506 mmol; Example 58D) was added a catalytic amount of N,N-dimethylformamide followed by oxalyl dichloride (0.404 mL, 0.809 mmol). After stirring for 30 minutes, the reaction was concentrated and dried under high vacuum for 10 minutes. The residue was dissolved in dichloromethane (0.5 mL) and 5-chloropyridin-2-amine (0.052 g, 0.404 mmol) and 4-methylmorpholine (0.089 mL, 0.809 mmol) were added. After 30 minutes, the reaction was loaded onto a GraceResolv™ 40 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 10% ethyl acetate/hexanes to 40% ethyl acetate/hexanes (Flow=40 mL/minute) over 40 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 8.24-8.20 (m, 1H), 8.09 (d, J=8.8, 1H), 7.65 (dd, J=2.7, 8.8, 1H), 7.36-7.28 (m, 4H), 7.05-6.96 (m, 4H), 4.19 (s, 2H), 3.54 (t, J=6.5, 2H), 2.82 (t, J=6.5, 2H); MS (ESI+) m/z 442.0 (M+H)+.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([O:15][C:16](=[O:38])[NH:17][C@@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[C@H:20]([C:35](=O)[CH3:36])[CH2:19]1)([CH3:14])([CH3:13])[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1>[CH2:28]([O:27][C:25]([NH:24][C@H:21]1[CH2:22][CH2:23][C@@H:18]([NH:17][C:16](=[O:38])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:19][C@H:20]1[C:35]([CH3:36])=[CH2:1])=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(=O)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=C(C)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyltriphenylphosphoniumbromide (729 mg) was dissolved in THF (4 mL) and cooled to 0° C. prior to the addition of 0.5M potassium bis(trimethylsilyl)amide (3.7 mL) in toluene. After 1 h, (1R,3R,4S)-(4-benzyloxycarbonylamino-3-acetylcyclohexyl)carbamic acid tert-butyl ester (400 mg) in THF (4 mL) was added dropwise. The reaction was warmed to rt over 2 h, before it was quenched with saturated NH4Cl solution and extracted with EtOAc (3×) The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated. The resulting residue was purified by flash chromatography to provide tert-butyl (1R,3S,4S)-4-benzyloxycarbonylamino-3-(prop-1-en-2-yl)cyclohexylcarbamate (380 mg). MS (ES+)=389.2 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[NH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[C:43]([C:46]3[O:50][C:49]([NH:51][CH:52]([CH3:54])[CH3:53])=[N:48][N:47]=3)[CH:44]=2)[NH:39][CH:38]=1>CN(C=O)C>[CH:52]([NH:51][C:49]1[O:50][C:46]([C:43]2[CH:44]=[C:45]3[C:40](=[CH:41][CH:42]=2)[NH:39][CH:38]=[C:37]3[NH:36][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:6])=[N:47][N:48]=1)([CH3:54])[CH3:53]
Reactant: O=C(O)C1CC1
Reactant: CC(C)Nc1nnc(-c2ccc3[nH]cc(N)c3c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)Nc1nnc(-c2ccc3[nH]cc(NC(=O)C4CC4)c3c2)o1
Reaction time: 0.25 h
Yield: 11.1 %

Procedure:
To a solution of cyclopropanecarboxylic acid (55 mg, 0.642 mmol) in DMF (6 mL) was added EDC.HCl (167 mg, 0.875 mmol), HOBt (118 mg, 0.875 mmol) and triethylamine (0.244 mL, 1.75 mmol). The mixture was stirred for 15 min, then 5-(3-amino-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (150 mg, 0.583 mmol) was added and the mixture was stirred for 16 h at RT. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified with basic alumina chromatography to give N-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1H-indol-3-yl)cyclopropane carboxamide (21 mg, 11%). MS (ESI, pos. ion) m/z: 326.2 (M+1); 1H-NMR (300 MHz, DMSO-d6): δ 11.13 (s, 1H), 10.43 (s, 1H), 8.37 (brs, 1H), 7.75 (d, 1H, J=2.1 Hz), 7.41-7.55 (m, 3H), 3.70-3.76 (m, 1H), 1.92-1.97 (m, 1H), 1.21 (d, 6H, J=6.6 Hz), 0.77-0.79 (m, 4H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([OH:18])[CH2:14][CH2:15][S:16][CH3:17])[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](F)[C:23]=1[Cl:29].CCO>CN(C=O)C.Cl>[Cl:21][C:22]1[C:23]([Cl:29])=[CH:24][CH:25]=[CH:26][C:27]=1[O:18][CH:13]([CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][CH2:15][S:16][CH3:17]
Reactant: Fc1cccc(Cl)c1Cl
Reactant: CSCCC(O)C1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CSCCC(Oc1cccc(Cl)c1Cl)C1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-(1-Hydroxy-3-methylsulfanylpropyl)pyrrolidine-1-carboxylic acid t-butyl ester (49 mg, 180 μmol) was dissolved in DMF (550 μL). 60% NaH in oil (60:40, NaH:mineral oil, 8.5 mg, 210 μmol) was slowly added, and the mixture was stirred for 15 minutes at room temperature. 1,2-Dichloro-3-fluorobenzene (62 μL, 530 μmol) was added, and the resulting mixture was heated at 90° C. for 24 hours. The reaction was quenched with MeOH, and DMF/MeOH was removed in vacuo. The product was dissolved in 1.25M HCl in EtOH (1.4 mL, 1.8 mmol) and stirred overnight at room temperature. The product was then purified by preparative HPLC to yield the title compound as a mixture of all 4 stereoisomers (R,R, R,S, S,S, and S,R) as mono-TFA salts (20 mg, 100% purity). MS m/z: [M+H] calcd for C14H19Cl2NOS, 320.06. found 320.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]([OH:18])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)[CH3:24].ClCCl.CO.N>>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:16](=[O:18])[C:15]#[C:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[CH:13][CH:12]=2)=[CH:30][CH:31]=1)[CH3:24]
Reactant: COCCN(C)Cc1ccc(N)cc1
Reactant: O=C(O)C#Cc1ccc(-c2ccc(Cl)cc2)cc1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COCCN(C)Cc1ccc(NC(=O)C#Cc2ccc(-c3ccc(Cl)cc3)cc2)cc1

Procedure:
Prepared analogously to Example 3.8. from (4′-chlorobiphenyl-4-yl)propynoic acid and 4-{[(2-methoxyethyl)methylamino]methyl}phenylamine. Yield: 150 mg (35% of theory); melting point: 130° C.-133° C.; C26H25ClN2O2 (M=432.94); calc.: molecular ion peak (M+H)+: 433/435 (Cl); found: molecular ion peak (M+H)+: 433/435 (Cl); Rf value: 0.50 (silica gel, dichloromethane/methanol/ammonia (90:10:1)).
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:22][CH2:23][CH:24]([OH:31])[CH2:25][NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:12]([CH:21]=1)[C:13]([CH2:15][CH2:16][C:17](OC)=[O:18])=O)(=[O:6])[CH3:5]>C(O)(=O)C>[C:4]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:22][CH2:23][CH:24]([OH:31])[CH2:25][NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:12]([C:13]2[CH2:15][CH2:16][C:17](=[O:18])[NH:2][N:3]=2)[CH:21]=1)(=[O:6])[CH3:5]
Reactant: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1OCC(O)CNC(C)(C)C
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(OCC(O)CNC(C)(C)C)c(C2=NNC(=O)CC2)c1
Yield: 85 %

Procedure:
Hydrazine hydrate (0.0785 ml, 0.00157 mole) was added to a stirred solution of methyl 3-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)benzoyl]propionate (0.21 g, 0.0005 mole) in glacial acetic acid (2 ml) and the solution was heated under reflux for 90 minutes. The residue after evaporation was treated with an excess of sodium bicarbonate solution and the solution evaporated to dryness under reduced pressure. The residue was extracted with dichloromethane and the dried extract evaporated to dryness. An aqueous solution of the residue was washed with two small portions of dichloromethane and then evaporated to an oily residue, which with ethyl acetate gave 6-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (0.16 g, 80%, m.p. 165°-168°).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH:23]3[CH2:27][CH2:26][N:25]([C:30](=[O:32])[CH3:31])[CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:20])=[O:21])=[N:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CCNC2)c2cnccc12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCC(n2c(Cn3nc(S(C)(=O)=O)c4ccncc43)nc3cc(Cl)ccc32)C1
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 1-{[5-chloro-1-(pyrrolidin-3-yl)-1H-benzimidazol-2-yl]methyl}-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (30 mg, 0.07 mmol), acetic anhydride (0.1 mL) in 8 mL of DCM was added DMAP (3 mg, 0.025 mmol). The mixture was stirred for 1 h. Then 20 mL of DCM and then 10 mL of water was added. The organic phase was washed with water, NaHCO3 and dried over anhydrous Na2SO4. The solvent was evaporated to give the residue which purified by preparative-HPLC to afford the title compound (15 mg, yield: 50%) as a pale solid.
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH2:15])=[C:4]([N+:16]([O-])=O)[CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH2:15])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: CN1CCN(c2cc(N)c([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2cc(N)c(N)cc2F)CC1
Yield: 100 %

Procedure:
21.2 g of 4-fluoro-5-(4-methylpiperazin-1-yl)-2-nitrophenylamine in solution in 800 mL of methanol are hydrogenated under 1 bar of hydrogen pressure in the presence of 2.1 g of palladium-on-charcoal at 25° C. for 16 hours. The reaction crude is filtered through celite and the filtrate is concentrated under vacuum in a rotary evaporator. 18.7 g of 4-fluoro-5-(4-methylpiperazin-1-yl)benzene-1,2-diamine in the form of a black oil are isolated. 1H NMR (400 MHz, DMSO-d6, δ in ppm), for this batch, all the signals are broad with: 2.19 (s, 3H); 2.40 (m, 4H); 2.79 (m, 4H); 4.22 (s, 2H); 4.31 (s, 2H); from 6.24 to 6.33 (m, 2H). EI mass spectrum: m/z=224: M+. (base peak)—m/z=209: (M—CH3)+—m/z=153: (M−C4H9N)+—m/z=70: C4H8N+—m/z=43: C2H5N+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:23][CH3:24])=[C:11]([CH:13]3[C:19](=[O:20])[CH:18]4[CH2:21][CH:15]([CH2:16][CH2:17]4)[C:14]3=[O:22])[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:23][CH3:24])=[C:11]([C:13]3[C:14](=[O:22])[CH:15]4[CH2:21][CH:18]([CH2:17][CH2:16]4)[C:19]=3[O:20][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCc1sc(-c2ccc(Cl)cc2)nc1C1C(=O)C2CCC(C2)C1=O
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1sc(-c2ccc(Cl)cc2)nc1C1=C(OC(=O)C(C)(C)C)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of the 3-[2-(4-chlorophenyl)-5-ethylthiazol-4-yl]bicyclo[3.2.1]octane-2,4-dione (100 mg, 0.28 mmol) in dichloromethane (5 ml) and triethylamine (140 μl, 1 mmol) is added pivaloyl chloride (123 μl, 1 mmol) at room temperature. The reaction mixture is stirred overnight at room temperature. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 2,2-dimethylpropionic acid 3-[2-(4-chlorophenyl)-5-ethylthiazol-4-yl]-4-oxobicyclo[3.2.1]oct-2-en-2-yl ester (101 mg)
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[CH2:5][C:6]2=[O:11].[N+:13]([O-])([OH:15])=[O:14]>CCOCC>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[CH:5]([N+:13]([O-:15])=[O:14])[C:6]2=[O:11]
Reactant: Cc1cccc2c1C(=O)CC2=O
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Product: Cc1cccc2c1C(=O)C([N+](=O)[O-])C2=O
Reaction time: 0.17 h

Procedure:
To a stirred suspension of 4-methyl-1,3-indanedione (1.02g.0.006 mole) in anhydrous ether (5 ml) at ca 10°C was added dropwise and with stirring fuming nitric acid (2.0 ml). After 10 mins. a clear, dark solution formed followed by precipitation of a bright yellow solid. The mass was filtered and washed with 5N hydrochloric acid. Recrystallisation from water/hydrochloric acid afforded the title compound, m.p. 108°-9°C. (Found; C, 56.16; H, 3.74; N, 6.32; C10H7NO4.1/2H2O requires; C, 56.07; H, 3.76; N, 6.54%).
Reaction SMILES: [CH:1]1[C:6](N=C=S)=[CH:5][C:4]2[C:10]([O:12][C:13]3([C:23]4[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=4[O:21][C:15]4[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]3=4)[C:3]=2[CH:2]=1)=[O:11].O>CN(C=O)C.B([O-])([O-])[O-]>[CH:1]1[CH:6]=[CH:5][C:4]([C:10]([OH:12])=[O:11])=[C:3]([C:13]2[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[O:21][C:22]3[C:23]=2[CH:24]=[CH:25][C:26]([CH:27]=3)=[O:28])[CH:2]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: [O-]B([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Reaction time: 8 h

Procedure:
A solution of fluorescein isothiocyanate (Aldrich) 10 μl of 10% solution in DMF) was added to the aminooligonucleotide (0.25 A260 units) in 0.2 M borate buffer, pH 8.6, 100 μl). The mixture was shaken in the dark overnight; then water (400 μl) was added and the mixture was desalted by gel filtration on a NAP-5 column (Pharmacia). The filtrate (1 ml) was collected, concentrated, and repurified by gel filtration. Reversed phase HPLC showed that the oligomers were converted essentially completely to the fluorescein conjugated derivatives: for the derivative of 3'-amino-oligomer 18, elution time 21.5 min (compared to 19.0 min for the starting amino-oligomer); for the derivative of 5'3'-diamino-oligomer 19, elution time 23.6 min (compared to 18.5 min for the starting diaminooligomer). The UV spectra show the presence of both the thymidine and fluorescein moieties: for derivative of 18, λmax 266, 456, 480 nm, λmin 240, 332, 468 nm; for derivative of 19, λmax 266, 460, 482, μmin 250, 332, 470 nm.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9](C(OC)=O)[C:10]([O:12]C)=[O:11])=[C:5]([N+:18]([O-:20])=[O:19])[CH:4]=1.O>CS(C)=O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[C:5]([N+:18]([O-:20])=[O:19])[CH:4]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)Cc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 5 h
Yield: 92.7 %

Procedure:
6M Aqueous hydrochloric acid (200 mL) was added to a stirred solution of dimethyl 2-(4-bromo-2-nitrophenyl)malonate (preparation 1a, 55.45 g, 170 mmol) in dimethylsulphoxide (250 mL) at room temperature and then mixture was warmed to 130° C. with stirring. After 5 hours, the mixture was cooled and water (400 mL) was added with stirring and the mixture was left to cool overnight. The precipitate was filtered, washed with water and dried in vacuo to give the title compound (41.0 g, 94%) as a white solid.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]#[C:10][CH2:11][OH:12])[CH2:5][CH2:4]1.[Cl:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[Cl:13][C:14]1[N:15]=[N:16][C:17]([N:2]([CH3:1])[C@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]#[C:10][CH2:11][OH:12])[CH2:7][CH2:8]2)=[CH:18][CH:19]=1
Reactant: CN[C@H]1CC[C@H](C#CCO)CC1
Reactant: Clc1ccc(Cl)nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(c1ccc(Cl)nn1)[C@H]1CC[C@H](C#CCO)CC1
Temperature: 80 °C

Procedure:
A mixture of 0.67 g (4 mmol) trans-3-(4-Methylamino-cyclohexyl)-prop-2-yn-1-ol, 2.76 g (18 mmol) of 3,6-dichloropyridazine and 1.76 ml (13.6 mmol) N-ethyldiisopropylamine was heated for 3.5 h at 80° C., diluted with 1 ml DMF and heated for 4 days at 80° C. and one day at 120° C. The reaction was cooled, evaporated and partitioned between aqueous saturated NaHCO3/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (NaSO4) and evaporated. Flash chromatography on silica gel (MeCl2/Et2O 95:5 to 9:1) gave 0.61 g (54%) of trans-3-{4-[(6-Chloro-pyridazin-3-yl)-methyl-amino]-cyclohexyl}-prop-2-yn-1-ol, MS: 280 (MH+, 1Cl).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([OH:18])[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[C:19]1([N:25]=[C:26]=[S:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH3:1][N:2]([CH2:3][CH:4]([OH:18])[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2)[C:26]([NH:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[S:27]
Reactant: S=C=Nc1ccccc1
Reactant: CNCC(O)COc1ccc2[nH]c(=O)ccc2c1
Solvent: CCO
Product: CN(CC(O)COc1ccc2[nH]c(=O)ccc2c1)C(=S)Nc1ccccc1
Reaction time: 1 h

Procedure:
To a suspension of 6-(3-methylamino-2-hydroxypropoxy)carbostyril (0.7 g) in ethanol (10 ml) is added phenylisothiocyanate (0.35 ml) at room temperature, and the mixture is stirred at the same temperature for 1 hour. The insoluble product is collected by filtration and recrystallized from chloroform-methanol to give 6-[3-(1-methyl-3-phenylthioureido)-2-hydroxypropoxy]carbostyril (0.83 g), as white powder, m.p. 185.0°-186.5° C. (decomp.).
Reaction SMILES: C(OC(O[CH2:9][CH3:10])OCC)C.[NH:11]([C:13]1C=[N:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[NH2:12]>>[CH:13]1[N:14]2[C:15]3[C:20]([N:21]=[CH:9][C:10]2=[N:12][N:11]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: NNc1cnc2ccccc2n1
Reactant: CCOC(OCC)OCC
Product: c1ccc2c(c1)ncc1nncn12

Procedure:
One hundred ml. of triethylorthoformate was mixed with 8.98 g. of 2-hydrazinoquinoxaline. The mixture was stirred at reflux and cooled as in the example above, and 9 g. of crude product was collected. After recrystallization from ethanol, the product was identified as s-triazolo[ 4,3-a]quinoxaline, m.p. 238°-39° C. The final yield was 5 g.
Reaction SMILES: [C-:1]#[N:2].[Na+].[Br:4][C:5]1[C:6]([CH3:12])=[N:7][C:8](F)=[CH:9][CH:10]=1.O>CS(C)=O>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([C:1]#[N:2])=[N:7][C:6]=1[CH3:12]
Reactant: Cc1nc(F)ccc1Br
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(C#N)ccc1Br
Temperature: 100 °C
Reaction time: 2 h
Yield: 14.5 %

Procedure:
NaCN (4 g, 82 mmol) was added to a solution of 3-bromo-6-fluoro-2-methyl-pyridine (4 g, 21 mmol) in DMSO (100 mL) The mixture was stirred for 2 h at 100° C., poured into H2O (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layers were dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, 10 g, eluting with 10% ethyl acetate in petroleum ether) to give the title compound (0.6 g, 15%) as white solid; MS (D): m/e=197.0 [M+H]+.
Reaction SMILES: [Sn](Cl)Cl.[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2C=C[C:15]([NH2:18])=[C:14]([N+:19]([O-])=O)[CH2:13]2)=[CH:8][CH:7]=1)#[N:5].[CH2:22](O)[CH3:23]>O>[NH2:19][C:14]1[CH:15]=[N:18][CH:22]=[CH:23][C:13]=1[NH:12][C:9]1[CH:8]=[CH:7][C:6]([C:4]#[N:5])=[CH:11][CH:10]=1
Reactant: CCO
Reactant: N#Cc1ccc(N2C=CC(N)=C([N+](=O)[O-])C2)cc1
Agent: Cl[Sn]Cl
Solvent: O
Product: N#Cc1ccc(Nc2ccncc2N)cc1
Temperature: 0 °C

Procedure:
According to a modification of the method of Pharm. Helv. Acta, 1975, 50, 188., tin dichloride dibydrate (56.4 g, 250 mmol) was added to a suspension of N-(4-cyanophenyl)-4-amino-3-nitropyridine (12.0 g, 50 mmol) in 2N aqueous bydrochloric acid (35 ml), water (150 ml) and ethanol (75 ml) and the resulting mixture was heated to reflux for 10 minutes under nitrogen. The mixture was cooled in ice, poured into ice-cold 2N aqueous sodium bydroxide (400 ml) and filtered. The creamy-coloured solid was washed with 2N aqueous sodium hydroxide and water, and then dried in a vacuum desiccator. The product, 3-amino-4-(4'-cyanophenyl)aminopyridine, 9.31 g, gradually turns reddish brown on exposure to light and air.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:17][CH:16]=2)=[O:14])=[CH:7][CH:6]=1)=[O:4].Cl.[NH2:29]O>CO.C(OCC)(=O)C>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[O:14][N:29]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[CH:12]=2)=[CH:16][CH:17]=1)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCOc1ccc(C(=O)CC(=O)c2ccc(C(=O)OC)cc2)cc1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)OC)cc3)no2)cc1
Yield: 74.6 %

Procedure:
The solution of 1-(4-Methoxycarbonylphenyl)-3-(4-pentyloxyphenyl)propane-1,3-dione (1.00 g) and hydroxylamine hydrochloride (567 mg) in methanol (10 ml) was refluxed for 10 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (50 ml×2), brine (50 ml). The organic layer was dried over magnesium sulfate and the solvents were removed under reduced pressure. The residue was triturated with acetonitrile (10 ml), collected by filtration, and dried under reduced pressure to give Methyl 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoate (0.74 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21]([OH:23])=O)[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]1([C@H:31]([NH2:33])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([C@H:31]([NH:33][C:21]([C:20]2[CH:24]=[C:16]([N:14]3[CH2:13][C@@H:11]4[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@@H:10]4[CH2:15]3)[CH:17]=[N:18][CH:19]=2)=[O:23])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Product: C[C@@H](NC(=O)c1cncc(N2C[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C2)c1)c1ccccc1

Procedure:
The product from Example 33B and (R)-1-phenylethanamine were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 437 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[N:7]([NH2:8])[C:6](=[O:9])[C:5]([C:10]2([CH2:13][CH3:14])[CH2:12][CH2:11]2)=[N:4][N:3]=1.O.[CH3:16]I.CO>[OH-].[Na+]>[CH3:16][S:1][C:2]1[N:7]([NH2:8])[C:6](=[O:9])[C:5]([C:10]2([CH2:13][CH3:14])[CH2:12][CH2:11]2)=[N:4][N:3]=1
Reactant: CCC1(c2nnc(S)n(N)c2=O)CC1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC1(c2nnc(SC)n(N)c2=O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6 g of 3-mercapto-4-amino-6-(1-ethylcyclopropyl)-1,2,4-triazin-5(4H)-one is dissolved in 14.2 ml of 2 N NaOH and 20 ml of H2O in the cold state. To the solution is added a solution consisting of 4.8 g of methyl iodide and 35 ml of CH3OH. The solution is stirred for 3 hours at room temperature; H2O is added and the solution is subsequently extracted 3 times with 50 ml of ethyl acetate each time. The organic phase is separated, dried, and evaporated to dryness. The residue (5.7 g) is recrystallized from 0 ml of toluene/petroleum ether (40°-65° C.)=1:1. There is thus obtained 4 g of white crystals of the formula ##STR3## having a melting point of 93°-95° C. The n-propyl derivative can be prepared in a similar manner.