Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:30][O:31][C:32](=[O:64])[C@H:33]([CH2:56][C:57]1[CH:62]=[CH:61][C:60]([OH:63])=[CH:59][CH:58]=1)[NH:34][C:35](=[O:55])[C@H:36]([CH:52]([CH3:54])[CH3:53])[NH:37][C:38](=[O:51])[C@H:39]([CH2:44][CH2:45][CH2:46][NH:47][C:48](=[NH:50])[NH2:49])[NH:40][N+:41]([O-:43])=[O:42]>C(Cl)Cl>[CH3:30][O:31][C:32](=[O:64])[C@H:33]([CH2:56][C:57]1[CH:62]=[CH:61][C:60]([OH:63])=[CH:59][CH:58]=1)[NH:34][C:35](=[O:55])[C@H:36]([CH:52]([CH3:54])[CH3:53])[NH:37][C:38](=[O:51])[C@H:39]([CH2:44][CH2:45][CH2:46][NH:47][C:48](=[NH:49])[NH2:50])[N:40]([C:11](=[O:13])[CH2:10][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:9])[N+:41]([O-:43])=[O:42]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)N)N[N+](=O)[O-])C(C)C
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(=N)N)N(C(=O)CN(C)C(=O)OC(C)(C)C)[N+](=O)[O-])C(C)C
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
8.84 g of t-butoxycarbonylsarcosine is dissolved in 200 ml of methylene chloride. 10.5 ml of N-methylmorpholine is added to the solution. The solution is cooled to -70° C. 6.1 ml of isobutyl chloroformate is then added. The reaction mixture is warmed up to -15° C. and stirred for 5 minutes. The reaction mixture is again cooled to -70° C. 25.5 g of nitroarginylvalyltyrosine methyl ester hydrochloride is added to the reaction mixture. The reaction mixture is allowed to warm to room temperature, and then is stirred for 16 hours. The reaction mixture is extracted three times with 0.5 M potassium bisulfate and once with brine. The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and stripped of solvent. The residue is dissolved in 200 ml of ethyl ether. The ether solution is added to cold rapidly stirring Skellysolve B. The white precipitate is filtered and dried to afford the product t-butoxycarbonylsarcosylnitroarginylvalyltyrosine methyl ester.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5](=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)[C:6]([O:8]C)=[O:7]>O.CO>[CH3:3][O:4][C:5](=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=Cc1cccc([N+](=O)[O-])c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
A solution of potassium hydroxide (2.0 g, 35.9 mol) in water (25 ml) was added to a stirred solution of methyl 2-methoxy-3-(3-nitrophenyl)acrylate (8.1 g, 34.2 mmol) in methanol (150 ml) and the resulting mixture was stirred at RT overnight. A further quantity of KOH (0.5 g, 8.9 mmol) in water (10 ml) was added and the mixture heated to 80° C. for 1 hr. The methanol was then evaporated in vacuo and the residue diluted with water (200 ml). The solution was washed with dichloromethane (2×100 ml), filtered through a pad of celite and then acidified by the addition of 3M HCl to pH 3. The mixture was refrigerated for 18 h then the precipitated solid was collected by filtration, washed with water (3×30 ml) and dried in vacuo at 40° C. to give 2-methoxy-3-(3-nitrophenyl)acrylic acid as a yellow solid (6.4 g, 84%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([CH3:10])[N:4]=[CH:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:24][C:25](=[NH:27])[CH3:26]>CN(C=O)C>[CH3:1][N:2]1[C:6]([C:7]2[O:9][N:27]=[C:25]([CH3:26])[N:24]=2)=[C:5]([CH3:10])[N:4]=[CH:3]1
Reactant: CC(=N)NO
Reactant: Cc1ncn(C)c1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1noc(-c2c(C)ncn2C)n1
Temperature: 80 °C
Reaction time: 16 h
Yield: 61.3 %

Procedure:
A solution of 3,5-dimethyl-3H-imidazole-4-carboxylic acid (1.0 g, 7.14 mmol) and 1,1′-carbonyldiimidazole (1.74 g, 10.7 mmol) in DMF (35 ml) was stirred at RT for 3 h. N-hydroxy-acetamidine (0.68 g, 9.18 mmol) was added, the reaction mixture was stirred at 16 h at 80° C., evaporated and dissolved in acetic acid (30 ml). The solution was stirred at 100° C. for 2 h, evaporated, poured into sat. NaHCO3 solution (50 ml) and extracted with dichloromethane (7×30 ml). The combined organic layers were washed with brine (70 ml), dried (MgSO4) and evaporated to give the title compound (0.78 g, 61%) as a white solid, m.p. 95° C. and MS: m/e=178.2 (M+).
Reaction SMILES: [ClH:1].C(O/[CH:5]=[C:6]1\[C:7](=O)[C:8]2[C:13]([O:14][C:15]3\1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2)C.[CH3:22][NH:23][NH2:24]>C(O)C>[ClH:1].[CH3:22][N:23]1[CH:5]=[C:6]2[C:15]3([O:14][C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:7]2=[N:24]1)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3
Reactant: CNN
Reactant: CCO/C=C1\C(=O)c2ccccc2OC12CCNCC2
Agent: Cl
Solvent: CCO
Product: Cn1cc2c(n1)-c1ccccc1OC21CCNCC1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 51.8 %

Procedure:
(Z)-3-(Ethoxymethylene)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (2.46 g, 7.94 mmol) in ethanol (24.6 mL) was treated with methylhydrazine (423 μL, 7.94 mmol). The reaction mixture was heated at 70° C. for 1 h and then at 100° C. for 10 min. The mixture was allowed to cool to room temperature overnight. The yellow solid was filtered off and was washed with ethanol to give 2-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]hydrochloride (1.20 g, 74%). ESI-MS m/z calc. 255.1. found 256.3 (M+1)+; Retention time: 0.65 minutes. 1H NMR (400 MHz, DMSO) δ 9.01 (s, 2H), 7.75 (s, 1H), 7.61 (dd, J=7.5, 1.2 Hz, 1H), 7.28-7.20 (m, 1H), 7.10-6.99 (m, 2H), 3.89 (s, 3H), 3.28-3.18 (m, 4H), 2.18-2.02 (m, 4H).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([C:24]([F:27])([F:26])[F:25])[CH:16]=3)(=[O:14])=[O:13])[CH:9]=[CH:10][C:5]=2[CH2:4][O:3]1>[Pd].CCO>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]3[CH2:4][O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)(=[O:13])=[O:14])=[CH:16][C:17]=1[C:24]([F:25])([F:27])[F:26]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)cc1C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)cc1C(F)(F)F

Procedure:
A suspension of N-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-nitro-3-trifluoromethyl-benzenesulfonamide (212 mg, 0.53 mmol), 10% Pd/C (50 mg), and abs. EtOH (100 mL) was shaken in a Parr apparatus at rt under an atmosphere of H2 (50 psi) for 2 h. The mixture was filtered through Celite (washing with EtOH) and then a 0.2 μM filter. The filtrate was concentrated in vacuo at 40° C. and the residue was recrystallized (MeCN/H2O) to give the title compound as a white solid; yield 122 mg (62%). mp 178-179° C.; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.98 (s, 1H), 9.22 (s, 1H), 7.65-7.64 (m, 1H), 7.54-7.51 (m, 1H), 7.48-7.47 (m, 1H), 7.28-7.26 (m, 1H), 7.16-7.14 (m, 1H), 6.82-6.79 (m, 1H), 6.49 (s, 2H), 4.88 (s, 2H); 19F NMR (376 MHz, DMSO-d6) δ (ppm): −63.0 (s); MS (ESI) m/z=371 (M−1, negative); HPLC purity: 98.02% (MaxPlot 200-400 nm), 98.34% (220 nm).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][NH2:19])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1.[CH3:21][C:22](=O)[CH2:23][C:24](=O)[CH3:25]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([N:18]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:21])=[N:19]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1
Reactant: Cn1cnc2c(Nc3ccc(Br)cc3)nc(NN)nc21
Reactant: CC(=O)CC(C)=O
Product: Cc1cc(C)n(-c2nc(Nc3ccc(Br)cc3)c3ncn(C)c3n2)n1

Procedure:
Was prepared according to Example 9 from (4-bromo-phenyl)-(2-hydrazino-9-methyl-9H-purin-6-yl)-amine and 2,4-pentanedione.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])=[O:25])[C:6]1=[O:32].Cl[C:34]([O:36][CH3:37])=[O:35].C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:30]([O:29][CH2:28][CH2:27][NH:26][C:24]([C:7]1[C:6](=[O:32])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:34](=[O:35])[O:36][CH3:37])[C:14]2[C:9]([C:8]=1[OH:23])=[N:10][CH:11]=[C:12]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH:13]=2)=[O:25])[CH3:31]
Reactant: COC(=O)Cl
Reactant: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN)c1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCNC(=O)OC)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(3-aminopropyl)-N-[2-(ethyloxy)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (15 mg, 0.034 mmol), methyl chloroformate (2.6 μL, 034 mmol) and diisopropylethyl amine (30 μL, 0.17 mmol) in anhydrous DMF (1.5 mL) was stirred under nitrogen at ambient temperature overnight. The crude reaction mixture was evaporated in vacuo and purified by reverse phase chromatography eluting with 10-90% aqueous CH3CN containing 0.1% formic acid to provide the product as a white solid: 1H NMR (CDCl3) δ 10.29 (2H, b), 8.57 (1H, s), 7.36 (1H, s), 7.13-7.18 (2H, m), 7.00-7.05 (2H, m), 5.60 (2H, b), 4.23 (2H, t, J=7 Hz), 4.13 (2H, s), 3.67 (3H, s), 3.63 (2H, b), 3.56 (2H, q, J=7 Hz), 3.11 (2H, b), 1.74-1.81 (2H, m), 1.24 (3H, t, J=7 Hz); ES+ MS: 501 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][N:13]2[C:15]([CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:16][N:17]=[C:12]2[C@@H:11]([NH2:23])[CH2:10]1.[O:24]=[C:25]1[NH:33][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[C@:26]21[CH2:41][C:40]1[C:35](=[CH:36][CH:37]=[C:38]([C:42](O)=[O:43])[CH:39]=1)[CH2:34]2.ON1C2N=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][N:13]2[C:15]([CH2:18][C:19]([F:22])([F:20])[F:21])=[CH:16][N:17]=[C:12]2[C@@H:11]([NH:23][C:42]([C:38]2[CH:39]=[C:40]3[C:35](=[CH:36][CH:37]=2)[CH2:34][C@:26]2([C:27]4[C:28](=[N:29][CH:30]=[CH:31][CH:32]=4)[NH:33][C:25]2=[O:24])[CH2:41]3)=[O:43])[CH2:10]1
Reactant: O=C(O)c1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: N[C@H]1C[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: O
Product: O=C(N[C@H]1C[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21)c1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reaction time: 0.42 h
Yield: 76.9 %

Procedure:
To a solution of (6S,8S)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-8-amine (7.0 mg, 0.023 mmol) in N,N-dimethylforinamide (105 μL) was added (2R)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylic acid (6.5 mg, 0.023 mmol), 1-hydroxy-7-azabenzotriazole (0.3 mg, 2.1 μmol), N-methylmorpholine (2.56 μL, 0.023 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.46 mg, 0.023 mmol). The mixture was stirred 25 min. Water was added, and the mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→15% water/acetonitrile with 0.1% trifluoroacetic acid) giving the title compound (10.5 mg). HRMS 594.1931 (M+1). 1H NMR (500 MHz, DMSO): δ 11.10 (s, 1H); 8.84 (d, J=8.6 Hz, 1H); 8.07 (dd, J=5.3, 1.6 Hz, 1H); 7.83 (s, 1H); 7.79 (d, J=8.0 Hz, 1H); 7.40-7.36 (m, 2H); 7.32-7.28 (m, 2H); 7.22 (dd, J=7.3, 1.6 Hz, 1H); 6.92 (s, 1H); 6.88 (dd, J=7.3, 5.3 Hz, 1H); 4.34 (d, J=7.9 Hz, 1H); 3.80 (t, J=10.3 Hz, 4H); 3.40 (d, J=16.3 Hz, 2H); 3.19 (dd, J=16.4, 3.5 Hz, 2H); 2.33-2.29 (m, 2H).
Reaction SMILES: [OH-].[Na+].Cl.Cl.[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([CH2:15][S:16][C:17](=N)N)[CH:6]=1.BrC[CH2:22][CH2:23][Cl:24]>O>[Cl:24][CH2:23][CH2:22][CH2:17][S:16][CH2:15][C:7]1[CH:6]=[N:5][C:14]2[C:9]([CH:8]=1)=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: ClCCCBr
Reactant: N=C(N)SCc1cnc2ccccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCCCSCc1cnc2ccccc2c1
Temperature: 70 °C
Reaction time: 20 h
Yield: 17.9 %

Procedure:
A 10 N aqueous solution of sodium hydroxide (40.8 cc) is added in the course of 9 minutes, and whilst allowing the temperature to rise to 10° C., to a solution, cooled to 1° C., of 2-(quinol-3-ylmethyl)-isothiourea dihydrochloride (59.2 g) in distilled water (100 cc). After heating for 20 minutes at a temperature of about 70° C. and then cooling to 12° C., a 10 N aqueous solution of sodium hydroxide (25 cc) is added dropwise in the course of 5 minutes. 1-Bromo-3-chloropropane (33.6 g) is then added and stirring is continued for 20 hours at a temperature of about 20° C. The reaction mixture is then extracted three times with methylene chloride (400 cc in total). The organic extracts are combined, washed with distilled water (100 cc), dried over anhydrous sodium sulphate and concentrated under reduced pressure (20 mm Hg; 2.7 kPa) at 35° C. so as to bring the volume to about 100 cc. The solution thus obtained is chromatographed on neutral silica gel (250 g) contained in a column of diameter 3.8 cm. Elution is carried out with methylene chloride (1500 cc), one 600 cc fraction and one 900 cc fraction being collected. The latter fraction is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 35° C. Quinol-3-ylmethyl 3-chloropropyl sulphide (9.2 g) is thus obtained in the form of a yellow oil.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[O:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:38]2[CH2:39][CH2:40][N:35]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:36][CH2:37]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: c1ccc(Oc2ccccc2N2CCNCC2)cc1
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3Oc3ccccc3)CC2)c(OC)nc1C
Yield: 69 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-phenoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:17]=[CH:16][C:11](/[C:12](/[NH2:15])=[N:13]/[OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[F-].[CH2:23]([N+](CCCC)(CCCC)CCCC)[CH2:24]CC>C1COCC1>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]3[N:15]=[C:23]([CH3:24])[O:14][N:13]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: N/C(=N\O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)no1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 12.2 %

Procedure:
(Z)-4-(4-(Trifluoromethyl)phenoxy)-N′-hydroxybenzamidine (79 mg, 0.23 mmol) was placed under nitrogen and THF was added. Then tetrabutylammonium fluoride (67 μL, 0.23 mmol) was added dropwise and the solution was stirred at room temperature for 92 hours 40 minutes. The product was purified by column chromatography over silica gel (EtOAc/Hex 1:12) to give a white solid (9.0 mg, 12%). 1H NMR (500 MHz, CDCL3) δ(ppm): 2.66 (3H, s), 7.11-7.14 (4H, m), 7.62 (2H, d, J=8.4 Hz), 8.08 (2H, d, J=9.0 Hz). 13C NMR (125 MHz, CDCL3) δ(ppm): 12.61 (CH3), 119.0 (CH), 119.7 (CH), 122.9, 125.3, 126.0 (C, q, J=32.5 Hz), 127.5 (CH, q, J=3.8 Hz), 129.6 (CH), 158.7, 159.6, 167.9, 176.8. 19F (282 MHz, CDCL3) δ(ppm): −61.89 (3F, s). MS (FAB+): 321 (MH+). HRMS for C16H11F3N2O2 (MH+): calculated: 320.0773; found 320.0779.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:15])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[CH:20]=[C:21]([NH2:32])[CH:22]=[CH:23][C:24]=1[S:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:18][C:19]1[CH:20]=[C:21]([NH:32][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:15])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:22]=[CH:23][C:24]=1[S:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=1
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Reactant: CCOc1cc2c(Cl)c(C#N)cnc2cc1F
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: CCOc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F

Procedure:
Following the procedure of Example 1, a mixture of 2.4 g (9.72 mmol) 4-chloro-6-ethoxy-7-fluoro-3-quinolinecarbonitrile, 2.56 g (10.7 mmol) of 3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)phenylamine and 1.2 g (10.38 mmol) of pyridine hydrochloride are refluxed in 2-ethoxyethanol (30 mL) at 110°0 C. for 1 hour to yield 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)sulfanyl]phenyl}amino)-6-ethoxy-7-fluoro-3-quinolinecarbonitrile as a pink solid, mp 251-254° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([F:10])([F:9])[F:8])[N:4]([CH3:11])[N:3]=1.[N:12]([O-])=O.[Na+].[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>Cl.O>[NH:1]([C:2]1[CH:6]=[C:5]([C:7]([F:8])([F:10])[F:9])[N:4]([CH3:11])[N:3]=1)[NH2:12]
Reactant: O=N[O-]
Reactant: Cn1nc(N)cc1C(F)(F)F
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: Cn1nc(NN)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 77.9 %

Procedure:
To a solution of 1.0 g (6.06 mmol) 3-amino-1-methyl-5-trifluoromethylpyrazole in 15 ml 6N hydrochloric acid, 0.52 g (7.44 mmol) sodium nitrite in 2 ml water was added slowly dropwise at 5° C. The mixture was stirred for 1.5 hours at the same temperature. Then 3.35 g (14.85 mmol) tin chloride (SnCl2.2H2O) in 3 ml concentrated hydrochloric acid was added dropwise. The mixture was warmed to room temperature, stirred for 2 hours and made basic by addition of 8N caustic soda under ice cooling. The residue was extracted with methylene chloride, dried over sodium sulfate and concentrated. 0.85 g 3-hydrazino-1-methyl-5-trifluoromethylpyrazole was obtained which was treated without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][S:16]([O-:18])=[O:17].[Na+]>CN(C=O)C>[CH3:15][S:16]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12])(=[O:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 120 °C
Yield: 63.5 %

Procedure:
A mixture of 2-fluoro-5-nitro-benzotrifluoride (0.50 g, 2.4 mmol) and sodium methanesulfinate (0.25 g, 2.4 mmol) in anhyd DMF (1.0 mL) was heated at 120° C. with stirring. After 18 h the reaction mixture was cooled, concentrated and chromatographed (silica, EtOAc/Hex, 0:100 to 40:60) to give 2-methanesulfonyl-5-nitro-benzotrifluoride (0.41 g, 64%) as a white solid: 1H-NMR (CDCl3) δ 8.76 (1H, d, J=2.0), 8.62 (1H, dd, J=2.0, 8.8), 8.57 (1H, d, J=8.8), 3.26 (3H, s). The title compound was prepared from 2-methanesulfonyl-5-nitro-benzotrifluoride in a manner similar to that described in Example 3A: 1H-NMR (DMSO-d6) δ 10.14 (1H, s), 8.50 (1H, d, J=2.0), 8.35 (1H, dd, J=2.0, 8.6), 8.16 (1H, d, J=8.8), 8.02 (1H, d, J=7.8), 7.92 (1H, app t, J=7.8), 7.82 (1H, app t, J=7.8), 7.52 (1H, d, J=7.8), 6.69 (1H, s), 3.26 (3H, s), 2.15 (3H, s), 1.89 (3H, s); MS (ESI): 505 (MH+). B. In a manner similar to that described for Example 5A, the following compound was prepared by replacing 2-fluoro-5-nitro-benzotrifluoride with 3-chloro-4-fluoro-nitrobenzene:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.[CH3:14][N:15]([CH3:20])[CH2:16][C:17](O)=[O:18].N1C=CC=CC=1.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl.CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[C:10]([C:11]=1[C:17](=[O:18])[CH2:16][N:15]([CH3:20])[CH3:14])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Nc1cc2ccccc2c(=O)[nH]1
Reactant: CN(C)CC(=O)O
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CN(C)CC(=O)c1c(N)[nH]c(=O)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.9 %

Procedure:
3-Amino-2H-isoquinolin-1-one (9.0 g), dimethylglycine hydrochloride (10.2 g) and pyridine (22.7 mL) were suspended in methylene chloride (100 mL), and 2-chloro-1,3-dimethylimidazolinium chloride (12.4 g) was added under ice-cooling. Then the mixture was stirred at room temperature for 2 hrs. After the completion of the reaction, the reaction mixture was dissolved in a mixed solvent (chloroform and lo methanol 10:1), washed with aqueous potassium carbonate solution and the organic layer was dried over magnesium sulfate. The solvent was evaporated, and the obtained residue was purified by silica gel column chromatography. The fraction eluted with chloroform:methanol was concentrated, and the precipitated crystals were collected by filtration to give 3-amino-4-(2-(dimethylamino) acetyl)-2H-isoquinolin-1-one (5.5 g). This compound was dissolved in chloroform-methanol mixed solvent, and 4N hydrogen chloride-dioxane was added. The precipitated crystals were collected by filtration, and recrystallized from ethanol-water mixed solvent to give 3-amino-4-(2-(dimethylamino)acetyl)-2H-isoquinolin-1-one hydrochloride monohydrate (4.5 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][C:25]1[N:26]=[CH:27][S:28][C:29]=1[C:30](O)=[O:31]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:30]([C:29]3[S:28][CH:27]=[N:26][C:25]=3[CH3:24])=[O:31])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: Cc1ncsc1C(=O)O
Product: Cc1ncsc1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 4-methyl-thiazole-5-carboxylic acid. LC-MS (basic): tR=0.73 min; [M+H]+=457.8.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](Cl)(=[O:7])[CH3:6].[Cl:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(Cl)Cl>[Cl:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:5](=[O:7])[CH3:6])=[CH:15][CH:14]=1
Reactant: CC(=O)Cl
Reactant: ClCCCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(CCCCl)cc1
Temperature: -7 °C

Procedure:
84 mL of CH2Cl2 and 14.4 g (1.1 eq.) of aluminum trichloride (AlCl3) are placed in a reactor at 20° C. with stirring. The reaction medium is cooled to −7° C. and 8.5 g (1.1 eq.) of acetyl chloride are then added. The mixture is stirred for 30 minutes and 15 g of 1-chloro-3-phenylpropane are then added at 0° C. At the end of the reaction, the reaction mixture is poured over about 30 minutes with vigorous stirring into 75 mL of 5% hydrochloric acid solution. The mixture is stirred for 1 hour at 10° C., the phases are then separated by settling and the aqueous phase is extracted with CH2Cl2. The organic phases are combined and washed successively with 2N HCl solution, 1N sodium hydroxide solution and water.