Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[C:16](=O)[C:15]3[C:14]([C:25]([O:27]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:31][NH2:32]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:9][C:10]3[C:15]4[C:16](=[N:31][NH:32][C:25](=[O:27])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[CH:17]2[C:18]2[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccc(F)cc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: Cn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccc(F)cc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
A mixture of ethyl 2-(4-fluorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (210 mg) in 85% hydrazine monohydrate (10 mL) and methanol (10 mL) was stirred at 45° C. for overnight. Methanol was removed under reduced pressure. The mixture was filtered and washed with water to give 8-(4-fluorophenyl)-9-(1-methyl-1H-imidazol-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one 36 mg, yield 19%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.42 (s, 3H), 4.66 (d, J=8.0 Hz, 1H), 4.95 (d, J=8.0 Hz, 1H), 6.72 (s, 1H), 6.89 (s, 1H), 7.11-7.17 (m, 3H), 7.30 (s, 1H), 7.40 (d, 1H), 7.43-7.44 (m, 2H), 7.58 (d, 1H), 12.17 (s, 1H); 19F-NMR (400 MHz, DMSO-d6) δ (ppm): −114.58; LC-MS (ESI) m/z: 362 (M+1)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[NH:17][C:18](=[S:21])[NH:19][CH:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31]>CC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]([S:21][CH:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[NH:19][CH:20]=2)[CH:8]=[C:9]([C:12]([CH3:14])([CH3:15])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(C)Br
Reactant: CC(C)(C)c1cc(-c2c[nH]c(=S)[nH]2)cc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)Sc1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c[nH]1
Yield: 39.7 %

Procedure:
By following the same procedure as in Example 10 using 1.8 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-thioxo-4-imidazoline, 30 ml of dry acetone, 0.99 g of potassium carbonate, and 1.3 g of ethyl α-bromopropionate and recrystallizing the product from a mixture of toluene and cyclohexane, 0.95 g of ethyl 2-[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-imidazolylthio]propionate was obtained.
Reaction SMILES: [N:1]#[C:2][NH2:3].Cl.[Cl:5][CH2:6][CH2:7][CH2:8][C:9]1[C:10]([CH3:15])=[N:11][NH:12][C:13]=1[CH3:14]>O.C(O)C>[ClH:5].[Cl:5][CH2:6][CH2:7][CH2:8][C:9]1[C:13]([CH3:14])=[N:12][N:11]([C:2]([NH2:3])=[NH:1])[C:10]=1[CH3:15]
Reactant: Cc1n[nH]c(C)c1CCCCl
Reactant: N#CN
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1nn(C(=N)N)c(C)c1CCCCl
Temperature: 80 °C
Reaction time: 24 h
Yield: 47.1 %

Procedure:
A solution of 0.17 g of cyanamide in 0.3 ml of water was added to a solution of 0.46 g of 4-(3-chloropropyl)-3,5-dimethyl-1H-pyrazole hydrochloride in 5 ml of ethanol, and the reaction mixture was stirred for one day at 80° C. the solvent was removed by distillation under reduced pressure, and the resulting residue was recrystallized from isopropanol-diisopropylether to obtain 0.13 g of 4-(3-chloropropyl)-3,5-dimethyl-1H-pyrazole-1-carboxamidine hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=1>COCCOCCOC>[CH3:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[CH:22]=1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: Cc1ccnc(Cl)c1
Solvent: COCCOCCOC
Product: Cc1ccnc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)c1

Procedure:
From 1-(4-nitro-phenyl)-piperazine and 2-chloro-4-methylpyridine, by heating in diglyme to give 1-(4-methyl-pyridin-2-yl)-4-(4-nitro-phenyl)-piperazine then catalytic hydrogenation over Raney nickel in methanol.
Reaction SMILES: [C:1]([C:3]1[C:4](F)=[C:5]([F:22])[CH:6]=[C:7]2[C:12]=1[N:11]([CH:13]1[CH2:15][CH2:14]1)[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][C:8]2=[O:21])#[N:2].Cl.Cl.[NH2:26][CH2:27][C:28]12[CH2:35][NH:34][CH2:33][CH:32]1[CH2:31][CH2:30][O:29]2.C(N(CC)CC)C>C(#N)C>[NH2:26][CH2:27][C:28]12[CH2:35][N:34]([C:4]3[C:3]([C:1]#[N:2])=[C:12]4[C:7]([C:8](=[O:21])[CH:9]=[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:11]4[CH:13]4[CH2:15][CH2:14]4)=[CH:6][C:5]=3[F:22])[CH2:33][CH:32]1[CH2:31][CH2:30][O:29]2
Reactant: NCC12CNCC1CCO2
Reactant: CCOC(=O)c1cc(=O)c2cc(F)c(F)c(C#N)c2n1C1CC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(=O)c2cc(F)c(N3CC4CCOC4(CN)C3)c(C#N)c2n1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
350 mg (1.21 mmol) of ethyl 8-cyano-1-cyclopropyl-6,7-difluoro-1,4-dihydro4-oxo-quinolinecarboxylate and 260 mg (1.2 mmol) of (1SR,5RS)-1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]octane dihydrochloride in 30 ml of absolute acetonitrile are admixed with 470 mg (4.64 mmol) of triethylamine and stirred at room temperature overnight. The mixture is concentrated and the residue is purified chromatographically (silica gel; dichloromethane/methanol 9:1). 450 mg (86% of theory) of ethyl 7-([1SR,5RS]-1-aminomethyl-2-oxa-7-azabicyclo[3.3.0]oct-7-yl)-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinolinecarboxylate are isolated, melting point: 193° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([NH2:11])[CH:9]=[CH:10][C:2]=1[Cl:1]
Reactant: CO
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(N)ccc1Cl
Temperature: 86 °C
Yield: 93 %

Procedure:
2-Chloro-5-aminobenzoic acid (1.5 g, 8.74 mmol) was dissolved in methanol (8 ml) and sulphuric acid (1 ml) was added drop wise with stirring. The reaction mixture was then heated to 86° C. for 18 hr then allowed to cool to room temperature before solvent was removed in vacuo. The resultant purple solid was then dissolved in water and 5M NaOH solution was added until pH 7 was reached. This was then washed with ethyl acetate. The organics were dried over Na2SO4 and solvent was removed in vacuo to give the title compound as a purple oil (1.51 g, 8.12 mmol, 93%): LCMS: [M+H]+=186, Rt=0.88 min, 95% purity.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15](OC)=[O:16])=[CH:12][C:11]=3[CH:19]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH3:20].Cl>O>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]([NH2:20])=[O:16])=[CH:12][C:11]=3[CH:19]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: N
Reactant: COC(=O)c1cc2cc(N3CCNCC3)ccc2o1
Agent: Cl
Solvent: O
Product: NC(=O)c1cc2cc(N3CCNCC3)ccc2o1
Reaction time: 11 h
Yield: 73.1 %

Procedure:
Methyl 5-(1-piperazinyl)benzofuran-2-carboxylate (37 g) was added to saturated methanolic ammonia solution (1850 ml) at 25-30° C., the mixture was stirred for 6 to 16 hours at the same temperature. The reaction mass was distilled under vacuum to remove the solvent after completion of the reaction. Water (148 ml) was added to the resulting residue, followed by adjusting the pH to 2-4 with concentrated HCl and then filtering the aqueous layer. The pH of the resulting aqueous layer was adjusted to 9-10 with ammonium hydroxide solution. The separated solid was filtered, washed with water (100 ml) and then dried to produce 25.5 g of 5-(1-piperazinyl)benzofuran-2-carboxamide (Purity by HPLC: 99%; Yield: 73.1%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[C:6]([CH3:14])([CH2:8][CH2:9][C:10](Cl)([CH3:12])[CH3:11])[CH3:7].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOCC.CCCCCC>[Br:15][C:16]1[CH:21]=[C:20]2[C:19](=[CH:18][CH:17]=1)[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][C:6]2([CH3:14])[CH3:7]
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: Brc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Reaction time: 0.33 h
Yield: 83 %

Procedure:
Aluminum chloride (700 mg, 5.25 mmol) was added slowly to a solution of 2,5-dichloro-2,5-dimethylhexane (11 g, 60 mmol) in bromobenzene (90 mL) at 0° C. After stirred for 20 min, the mixture was diluted with 100 mL of ether:hexane (1:1), washed with ice-water (1×10 mL), 10% HCl (1×10 mL) and brine (1×10 mL), dried (MgSO4) and concentrated to afford a brown oil. The crude was then distilled using Coughler distillation to yield the title compound (13.2 g, 83% yield) as a white solid:
Reaction SMILES: 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.[OH:34][CH2:35][CH2:36][O:37][C:38]1[CH:46]=[C:45]2[C:41]([CH:42]=[C:43]([C:47]([OH:49])=O)[NH:44]2)=[CH:40][CH:39]=1.[NH2:50][CH2:51][C:52]1[C:53]([F:69])=[C:54]([O:59][C:60]2[CH:61]=[C:62]([CH:65]=[C:66]([Cl:68])[CH:67]=2)[C:63]#[N:64])[C:55]([Cl:58])=[CH:56][CH:57]=1>CN(C=O)C>[Cl:58][C:55]1[CH:56]=[CH:57][C:52]([CH2:51][NH:50][C:47]([C:43]2[NH:44][C:45]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[C:38]([O:37][CH2:36][CH2:35][OH:34])[CH:46]=3)=[O:49])=[C:53]([F:69])[C:54]=1[O:59][C:60]1[CH:61]=[C:62]([C:63]#[N:64])[CH:65]=[C:66]([Cl:68])[CH:67]=1
Reactant: O=C(O)c1cc2ccc(OCCO)cc2[nH]1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
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: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4ccc(OCCO)cc4[nH]3)c2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
HATU (0.070 g, 0.186 mmol) and DIPEA (0.024 mL, 0.186 mmol) were added to a solution 6-[(2-hydroxyethyl)oxy]-1H-indole-2-carboxylic acid (0.041 g, 0.186 mmol) and 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.057 g, 0.186 mmol) in DMF. This solution was stirred 2 h at room temperature. The mixture was partitioned between water and EtOAc, the organic layer was separated, washed with a 15% solution of Na2CO3, dried over MgSO4 and filtered. The EtOAc was evaporated to yield a residue which upon trituration in EtOAc afforded the title compound (0.041 g, 42%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.38 (s, 1H), 8.88 (t, 1H), 7.80 (s, 1H), 7.43-7.53 (m, 4H), 7.37 (t, 1H), 7.08 (s, 1H), 6.85 (s, 1H), 6.68 (d, 1H), 4.83 (t, 1H), 4.53 (d, 2H), 3.94 (t, 2H), 3.71 (q, 2H). MS m/z 512 (M−1).
Reaction SMILES: [F:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:21][CH2:22][C:23]4C=CC=[CH:25][N:24]=4)[C:15]4[C:20]([C:11]3=[N:10][N:9]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:4]=1.C[N:30]1[C:34](CO)=[N:33]C=N1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>>[F:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:12]3[N:13]=[C:14]([O:21][CH2:22][C:23]4[N:24]([CH3:25])[N:33]=[CH:34][N:30]=4)[C:15]4[C:20]([C:11]3=[N:10][N:9]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:4]=1
Reactant: FCc1cc(-c2nnc3c4ccccc4c(OCc4ccccn4)nn23)no1
Reactant: Cn1ncnc1CO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: Cn1ncnc1COc1nn2c(-c3cc(CF)on3)nnc2c2ccccc12

Procedure:
The title-compound was prepared from the product of Example 66 part c (150 mg, 0.5 mmol) and 2-methyl-1,2,4-triazole-3-methanol (61 mg, 0.53 mmol) (prepared using the conditions of Itoh and Okongi, EP-A-421210) using the procedure given in Example 1 using lithium bis(trimethylsilyl)amide (0.59 ml, 1.0M in tetrahydrofuran) as the base (80 mg, 43%), mp 250-252° C.; 1H NMR (360 MHz, d6-DMSO) δ 4.01 (3H, s, CH3), 5.76 (2H, d, J=47 Hz, CH2), 5.83 (2H, s, CH2), 7.70 (1H, d, J=3.5 Hz, Ar—H), 7.96 (1H, m, Ar—H), 8.02 (1H, s, Ar—H), 8.13 (1H, m, Ar—H), 8.25 (11H, d, J=7.8 Hz, Ar—H), 8.59 (1H, d, J=7.9 Hz, Ar—H); MS (ES30) m/e 381 [MH]+; Anal. Found. C, 52.31; H, 3.36; N, 28.64. C17H13N8O2F.0.15CH2Cl2 requires C, 52.40; H, 3.41; N, 28.51%.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH:14]=O)=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.Cl.[NH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]([O:26]CC)=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH2:14][N:19]2[CH2:20][CH2:21][O:22][CH2:23][C:24]2=[O:26])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Reactant: CCOC(=O)COCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(OC)c1nc2c(cc1CN1CCOCC1=O)CCCN2
Reaction time: 1 h

Procedure:
A mixture of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 1.50 g, 5.40 mmol), ethyl 2-(2-aminoethoxyl)acetate hydrochloride (intermediate 105, 1.24 g, 6.75 mmol) and triethylamine (0.97 ml, 7.02 mmol) in 1,2-dichloroethane (25 ml) at room temperature was stirred for 1 h and then sodium triacetoxyborohydride (1.83 g, 8.63 mmol) was added. The reaction mixture was stirred for 18 h at room temperature and additional sodium triacetoxyborohydride (0.92 g, 4.32 mmol) was added. After a further 5 h stirring at room temperature the reaction mixture was partitioned between saturated aqueous NaHCO3 solution and DCM, the mixture extracted with DCM (3×), the combined organic layers dried over Na2SO4 and evaporated. The residue was applied to a 80 g RediSep® silica and purified by normal phase chromatography, eluting with a gradient from DCM to 10% MeOH in DCM. Product containing fractions were combined and evaporated to give the title compound as an yellow solid. (UPLC-MS 6) tR 0.42; ESI-MS 322.2 [M+H]+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([C:27](O)=[O:28])[CH:24]=[C:23]([CH3:30])[CH:22]=2)=[C:17]([CH3:31])[C:16]=1[CH:32]1[C:45]2[C:44](=[O:46])[CH2:43][C:42]([CH3:48])([CH3:47])[CH2:41][C:40]=2[O:39][C:38]2[CH2:37][C:36]([CH3:50])([CH3:49])[CH2:35][C:34](=[O:51])[C:33]1=2.[CH3:52][S:53]([NH2:56])(=[O:55])=[O:54].N12CCCN=C1CCCCC2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([C:27]([NH:56][S:53]([CH3:52])(=[O:55])=[O:54])=[O:28])[CH:24]=[C:23]([CH3:30])[CH:22]=2)=[C:17]([CH3:31])[C:16]=1[CH:32]1[C:33]2[C:34](=[O:51])[CH2:35][C:36]([CH3:49])([CH3:50])[CH2:37][C:38]=2[O:39][C:40]2[CH2:41][C:42]([CH3:48])([CH3:47])[CH2:43][C:44](=[O:46])[C:45]1=2
Reactant: COc1ccc(-c2cc(C)cc(C(=O)O)n2)c(C)c1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reactant: CS(N)(=O)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(-c2cc(C)cc(C(=O)NS(C)(=O)=O)n2)c(C)c1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
1,1′-Carbonyldiimidazole (99.5 mg, 0.61 mmol) was added to a solution of the 6-[4-methoxy-2-methyl-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]-4-methylpyridine-2-carboxylic acid produced in Example 32-3 (250 mg, 0.47 mmol) in DMF (5 ml) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 1 hour and 30 minutes. Thereafter, methanesulfonamide (58.4 mg, 0.61 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.092 ml, 0.61 mmol) were added to the resulting solution at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 2 hours. Thereafter, an aqueous solution of citric acid (454 mg, 2.36 mmol) was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer thus obtained was washed with water, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel column chromatography (methanol:dichloromethane=0:1 to 1:9, v/v). The solid thus obtained was washed with diethyl ether, followed by collection by filtration and drying, to obtain the title compound (230 mg, yield: 80%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[CH3:8].F[C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1>CC(N(C)C)=O>[CH3:8][CH:3]1[N:2]([CH3:1])[CH2:7][CH2:6][N:5]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=2)[CH2:4]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: CC1CNCCN1C
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(N2CCN(C)C(C)C2)cc1
Temperature: 150 °C
Yield: 32.5 %

Procedure:
1,2-Dimethylpiperazine (2.284 g, 20.00 mmol) and ethyl 4-fluorobenzoate (1.467 mL, 10 mmol) were dissolved in DMA (12 mL) and sealed in a microwave tube. The reaction was heated to 150° C. for 90 mins in the microwave reactor and cooled to room temperature. The reaction mixture was heated for a further 30 mins at 150° C. and cooled to room temperature. The reaction mixture was evaporated and the crude product was purified by silica column chromatography, eluting with 5% MeOH in DCM with 0.1% 0.880 ammonia. Pure fractions were evaporated to dryness to afford ethyl 4-(3,4-dimethylpiperazin-1-yl)benzoate (0.853 g, 32.5%) as a colourless waxy solid.
Reaction SMILES: B(Br)(Br)[Br:2].[CH2:5]1[O:13][CH2:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2>C(Cl)Cl>[Br:2][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[CH2:12][OH:13]
Reactant: c1ccc2c(c1)COC2
Reactant: BrB(Br)Br
Solvent: ClCCl
Product: OCc1ccccc1CBr
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of 1M BBr3 in CH2Cl2 (49.2 mL, 49.2 mmol) cooled at 0° C. was added dropwise over 45 minutes a solution of phthalan (17.40 g, 142.6 mmol) in CH2Cl2 (30 mL). After the addition, the mixture was heated to reflux (oil bath) for 1 hour, then cooled to room temperature and quenched with water (50 mL). The mixture was washed with H2O (100 mL), 50% saturated NaHCO3 (100 mL), H2O (100 mL), brine, dried (MgSO4) and concentrated in vacuo to give a brownish solid, which was crystallized from EtOAc/hexane to afford 16.442 g of the title compound of this step as a light yellow crystalline compound. The mother liquor was concentrated and the residue crystallized (EtOAc/hexane) to yield an additional 6.30 g of the title compound of this step (total amount of product: 22.742 g, 80% yield).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Br:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=O)[CH2:8]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:31][NH:32][C:33]([NH:35][OH:36])=[NH:34].[ClH:37]>C(O)C>[ClH:37].[Br:1][C:2]1[S:3][C:4]([Br:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[CH:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[N:31][NH:32][C:33](=[NH:34])[NH:35][OH:36])[CH2:8]1
Reactant: Cc1ccnc2c1C(=O)CC(c1cc(Br)sc1Br)C2
Reactant: N=C(NN)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)NO)CC(c1cc(Br)sc1Br)C2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a mixture of 7-(2,5-dibromothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.07 g) and 1-amino-3-hydroxyguanidine p-toluenesulfonate (58 mg) were added ethanol (1.5 ml) and concentrated hydrochloric acid (0.04 ml), and the mixture was stirred at 90° C. for 2 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added 0.2N sodium hydroxide solution (10 ml). The mixture was extracted with ethyl acetate (30 ml) and tetrahydrofuran (20 ml). The organic layer was washed with water, to which was added concentrated hydrochloric acid (0.02 ml). The mixture was concentrated, and to the residue was added ethanol (1 ml). To the solution was added ether (0.2 ml), and the mixture was stirred for 3 hours. Precipitated crystals were filtered, washed with a mixture of ethanol/ether and dried to give 7-(2,5-dibromothiophen-3-yl)-5-(1-hydroxyguanidin-3-yl)imino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 126) (0.27 g) as pale yellow crystals.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[Cl:10][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[CH:21](O)[CH2:22][CH2:23][C:24]1([C:41]([O:43][CH3:44])=[O:42])[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][S:32][C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[F:40])[CH2:26][CH2:25]1)=[CH:18][C:17]([O:46][CH3:47])=[CH:16][CH:15]=2.C(=O)([O-])O.[Na+]>ClCCl>[Cl:10][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[CH:21]([F:7])[CH2:22][CH2:23][C:24]1([C:41]([O:43][CH3:44])=[O:42])[CH2:25][CH2:26][N:27]([CH2:30][CH2:31][S:32][C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[F:40])[CH2:28][CH2:29]1)=[CH:18][C:17]([O:46][CH3:47])=[CH:16][CH:15]=2
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)C1(CCC(O)c2c(Cl)cnc3ccc(OC)cc23)CCN(CCSc2cc(F)ccc2F)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C1(CCC(F)c2c(Cl)cnc3ccc(OC)cc23)CCN(CCSc2cc(F)ccc2F)CC1
Temperature: 5 °C

Procedure:
0.1 cm3 of diethylaminosulfur trifluoride was added to a solution of 0.25 g of methyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)-hydroxypropyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-4-carboxylate in 10 cm3 of dichloromethane, with stirring and under an inert atmosphere, at a temperature in the region of 5° C. After stirring for 7 hours at a temperature in the region of 20° C., saturated sodium hydrogen carbonate solution was added to the reaction mixture. The aqueous phase was extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under atmospheric pressure, on a column of silica gel (particle size 70-200μ; mass: 15 g), eluting with 60 cm3 of dichloromethane, then with 45 cm3 of a mixture of ethyl acetate/dichloromethane (1/9 by volume), then with 30 cm3 of a mixture of ethyl acetate/dichloromethane (2/8 by volume) and then with 210 cm3 of a mixture of ethyl acetate/dichloromethane (3/7 by volume) and then with ethyl acetate. Fractions 24 to 26 were combined and then concentrated to dryness according to the same conditions as above. 0.08 g of methyl 4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)-fluoropropyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-4-carboxylate was obtained in the form of a thick yellow oil.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][C:40]=2B(O)O)[CH:35]=[CH:34][CH:33]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:24][S:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([NH:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[C:40]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:41]=1[N:32]=[CH:33][CH:34]=[CH:35]2)(=[O:14])=[O:13])(=[O:22])=[O:23]
Reactant: OB(O)c1cccc2cccnc12
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cccc4cccnc34)c2c1
Yield: 1.8 %

Procedure:
2-Methylsulfonyl-N-(3-quinolin-8-yl-1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 59 from 2 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 1.17 g of 8-quinolineboronic acid, 80 ml of dimethylformamide, 7.5 ml of a saturated aqueous sodium hydrogencarbonate solution and 98 mg of tetrakis(triphenylphosphine)palladium[0]. 30 mg of 2-methylsulfonyl-N-(3-quinolin-8-yl-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of a pale yellow solid melting at 219° C. (analysis C23H18N4O4S2% calculated C, 57.73; H, 3.79; N, 11.71; O, 13.37; S, 13.4. % found C, 57.10; H, 4.11; N, 11.19; S, 11.94).