Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=C2NC=CC=12.C[Sn](C)(C)[Sn](C)(C)C.[Sn].[CH3:19][Si:20]([CH3:39])([CH3:38])[CH2:21][CH2:22][O:23][CH2:24][N:25]1[C:29]2=[N:30][CH:31]=[C:32]([Sn](C)(C)C)[N:33]=[C:28]2[CH:27]=[CH:26]1.Br[C:41]1[C:42]([NH:49][C@H:50]2[CH2:55][CH2:54][CH2:53][N:52]([S:56]([CH3:59])(=[O:58])=[O:57])[CH2:51]2)=[N:43][C:44]([S:47][CH3:48])=[N:45][CH:46]=1>C1(C)C=CC=CC=1>[CH3:59][S:56]([N:52]1[CH2:53][CH2:54][CH2:55][C@H:50]([NH:49][C:42]2[C:41]([C:32]3[N:33]=[C:28]4[CH:27]=[CH:26][N:25]([CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:39])([CH3:38])[CH3:19])[C:29]4=[N:30][CH:31]=3)=[CH:46][N:45]=[C:44]([S:47][CH3:48])[N:43]=2)[CH2:51]1)(=[O:58])=[O:57]
Reactant: C[Si](C)(C)CCOCn1ccc2nc([Sn](C)(C)C)cnc21
Reactant: CSc1ncc(Br)c(N[C@H]2CCCN(S(C)(=O)=O)C2)n1
Agent: C[Sn](C)(C)[Sn](C)(C)C
Agent: [Sn]
Agent: c1cnc2[nH]ccc2n1
Solvent: Cc1ccccc1
Product: CSc1ncc(-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)c(N[C@H]2CCCN(S(C)(=O)=O)C2)n1
Temperature: 97.5 °C

Procedure:
A degassed toluene solution of 2-bromo-5-(2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (200 mg, 0.61 mmol) and 1,1,1,2,2,2-hexamethyldistannane (220 mg, 0.67 mmol) was treated with tetrakistriphenylphosphine palladium (0) (35 mg, 0.03 mmol) and heated to 95-100° C. for 2 hours. When LCMS indicated conversion to the tin product, 5-(2-trimethylsilanyl-ethoxymethyl)-2-trimethylstannanyl-5H-pyrrolo[2,3-b]pyrazine, (MS (ES+): 412), the reaction was treated with (5-bromo-2-methylsulfanyl-pyrimidin-4-yl)-((S)-1-methanesulfonyl-piperidin-3-yl)-amine (80 mg, 0.21 mmol) and additional tetrakistriphenylphosphine palladium (0) (35 mg, 0.03 mmol) and heated to 100° C. for 16 hours. The reaction was cooled, filtered through celite, evaporated and purified by flash chromatography (60% ethyl acetate/hexane+2% triethylamine) to give 60 mg of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methylsulfanyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine. MS (ES+): 550.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[N:6]=1.[Cl:14][C:15]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[Cl:14][C:15]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:16]=1[C:17]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([C:5]2[N:6]=[C:2]([CH3:1])[S:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:18]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: Cc1nc(-c2ccc(N)cc2)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccc(NC(=O)c3ccc(Cl)cc3Cl)cc2)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(2-methylthiazol-4-yl)aniline (0.05 g, 0.26 mmol) and 2,4-dichlorobenzoic acid (0.05 g, 0.26 mmol) in dimethylformamide (20 mL) and diisopropylethylamine (0.067 g, 0.09 mL, 0.52 mmol) at room temperature was added HATU (0.148 g, 0.39 mmol) in one portion. The reaction was stirred at room temperature for 4 hours, then poured in to water (200 mL) and stirred for 20 minutes. The product (0.094 g, 100%) as a light yellow solid was collected via filtration. LC-MS (M+H): 364. 1H NMR (400 MHz, dmso-d6): 10.67 (s, 1H), 7.95 (d, 2H), 7.87 (s, 1H), 7.80-7.77 (m, 3H), 7.69-7.58 (m, 2H), 2.74 (s, 3H).
Reaction SMILES: [CH2:1](C1C=CC=C(CC)C=1N)C.[CH2:12]([C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([CH3:25])[C:23]=1[OH:24])[C:17]([NH:19][OH:20])=[NH:18])[CH3:13]>>[CH2:12]([C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([CH2:25][CH3:1])[C:23]=1[OH:24])[C:17]([NH:19][OH:20])=[NH:18])[CH3:13]
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Reactant: CCc1cccc(CC)c1N
Product: CCc1cc(C(=N)NO)cc(CC)c1O

Procedure:
The title compound is prepared from commercially available 2,6-diethylaniline following literature procedures (G. G. Ecke, J. P. Napolitano, A. H. Filbey, A. J. Kolka, J. Org. Chem. 22 (1957) 639-642; and literature cited for 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine); LC-MS: tR=0.60 min; [M+1]+=209.46.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:11])=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[C:12](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Br)c(O)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(Cl)c(C#N)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
To a solution of 5-bromo-2-chloro-4-hydroxybenzonitrile (7.0 g, 30.11 mmol) in DMF (70 mL) was added cesium carbonate (19.62 g, 60.22 mmol, GLR Scientific) and MeI (3.74 mL, 60.22 mmol, Spectrochem). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with ice cold water (500 mL) and extracted with ethyl acetate (2×500 mL). The combined organic layer was washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude compound which was purified by column chromatography (silica gel 100-200 mesh and 0-4% EtOAc in hexane) to obtain 5-bromo-2-chloro-4-methoxybenzonitrile (5.5 g, 74.1%) as white solid. m/z (ESI) N/A (no ionization observed).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]2[CH2:11][O:10][C:9]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])=[N:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[C:9]1[O:10][CH2:11][CH:7]([C:5]2[S:6][C:2]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:3][CH:4]=2)[N:8]=1
Reactant: Fc1cccc(F)c1C1=NC(c2ccc(Br)s2)CO1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Fc1cccc(F)c1C1=NC(c2ccc(-c3ccccc3)s2)CO1
Temperature: 80 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 100 mg (0.3 mmol) of the product of Step D of Example 2 in 0.6 mL toluene was added successively 10.4 mg (0.009 mmol) of Pd (PPh3)4, 0.3 mL of 2.0 m sodium carbonate, and 44 mg (0.36 mmol) of phenylboronic acid in 0.15 mL of methanol. The mixture was stirred at 80° C. for 2 h. It was cooled and partitioned between 25 mL of 2.0 m sodium carbonate containing 2.5 mL of ammonium hydroxide solution and 25 mL of methylene chloride. The methylene chloride layer was washed with brine, dried (MgSO4), and concentrated. The residue was passed through a silica gel flash column eluting with ethyl acetate: hexanes (1:4) to give 85 mg of an oil. 1H-NMR (CDCl3) δ6.90-7.20 (m, 10H), 5.70 (dd,1H), 4.80 (t, 1H), 4.45 (t, 1H).
Reaction SMILES: Br.[Br:2][CH2:3][C:4]1[CH:15]=[N:14][C:7]2[N:8]=[C:9]([NH2:13])[N:10]=[C:11]([NH2:12])[C:6]=2[CH:5]=1.CCO[CH2:19][CH3:20].[CH3:21]C(O)=O>>[Br:2][CH2:3][C:4]1[CH:15]=[N:14][C:7]2[N:8]=[C:9]([NH2:13])[N:10]=[C:11]([NH2:12])[C:6]=2[C:5]=1[CH2:21][CH2:19][CH3:20]
Reactant: CCOCC
Reactant: CC(=O)O
Reactant: Nc1nc(N)c2cc(CBr)cnc2n1
Agent: Br
Product: CCCc1c(CBr)cnc2nc(N)nc(N)c12

Procedure:
The hydroxymethyl compound 2,4-diamino-5-propylpyrido[2,3-d]pyrimidine-6-methanol (III-1) was treated with dry HBr in AcOH as reported for 6-(bromomethyl)-2,4-diaminopyrido [2,3-d]pyrimidine (III-2, where R1 is H). Addition of Et2O caused precipitation of yellow solid which was collected with the aid of Et2O and dried in vacuo to afford the HBr salt of the product (III-3).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH:24]1[CH2:26][CH:25]1[C:27]1([OH:30])[CH2:29][CH2:28]1>>[CH3:15][C:13]1([CH3:16])[CH2:14][CH:9]([NH:8][C:4]2[N:3]=[C:2]([C:23]3[S:19][C:20]([CH:24]4[CH2:26][CH:25]4[C:27]4([OH:30])[CH2:29][CH2:28]4)=[CH:21][CH:22]=3)[CH:7]=[CH:6][N:5]=2)[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12]1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: OC1(C2CC2c2cccs2)CC1
Product: CC1(C)CC(Nc2nccc(-c3ccc(C4CC4C4(O)CC4)s3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared analogous to Method C, starting from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 2′-thiophen-2-yl-bicyclopropyl-1-ol (prepared by cyclopropanation of 2-thiophen-2-yl-cyclopropanecarboxylic acid methyl ester, J. Org. Chem. 1993, 502).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=[CH:39][CH:38]=2)[C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])[CH2:26][CH2:25][NH:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N>C(Cl)Cl>[CH2:16]([C@@H:23]1[CH2:28][C@@H:27]([N:29]([CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]=[CH:39][CH:38]=2)[C:30](=[O:35])[C:31]([F:33])([F:34])[F:32])[CH2:26][CH2:25][N:24]1[C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: N
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(Cc1ccc(Cl)cc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
96 mg (0.56 mmol) of 4-chlorophenylacetic acid are reacted in analogy to Example 2j first with 58 μl (0.795 mmol) of thionyl chloride and subsequently with 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine to give the product. TLC: methylene chloride/methanot/conc. ammonia (700:50: 1) Rf =0.39, FD-MS: M+ =580.
Reaction SMILES: C(OC1C=CC(C([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C:24](=[O:47])[C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:46])[CH2:33][C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=4[C:42]([F:45])([F:44])[F:43])=[CH:27][CH:26]=3)=[CH:18][CH:17]=2)=O)=CC=1)CCCCCC.CO.[OH-].[Na+].CC(O)=O>C1COCC1>[OH:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:48][C:49]([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:50])[C:24](=[O:47])[C:25]2[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:46])[CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=3[C:42]([F:44])([F:45])[F:43])=[CH:29][CH:30]=2)=[CH:20][CH:21]=1
Reactant: CCCCCCCOc1ccc(C(=O)Oc2ccc(CN(CC(=O)OC(C)(C)C)C(=O)c3ccc(NC(=O)Cc4ccc(OC)cc4C(F)(F)F)cc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(O)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
Prepared using General Procedure 9: To a stirring solution of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)phenyl 4-(heptyloxy)benzoate INT-6 (2.53 g, 3.20 mmol) in THF (10 mL) and MeOH (50 mL) was added 2N NaOH (3.2 mL). The reaction mixture was stirred at room temperature for 10 min. The reaction mixture was acidified with AcOH. The crude mixture was concentrated then diluted with DCM (150 mL) and washed with brine (200 mL). The organic layer was concentrated and purified by chromatography (EA/hexanes) to afford 1.64 g (88%) of tert-butyl 2-(N-(4-hydroxybenzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-9. LCMS-ESI (m/z) calculated for C30H31F3N2O6: 572; found 571 [M−H]−, tR=2.30 min. (Method 3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30].[CH2:33]([N:35](CC)[CH2:36][CH3:37])[CH3:34].C([O-])([O-])=O.[K+].[K+].N1CCCC1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([NH2:19])=[O:18])[CH:16]=2)[NH:13][N:12]=[C:11]3[CH:20]2[CH2:25][CH2:24][N:23]([S:29]([CH2:28][CH2:27][N:35]3[CH2:36][CH2:37][CH2:34][CH2:33]3)(=[O:31])=[O:30])[CH2:22][CH2:21]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCNCC3)n[nH]c12
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCN4CCCC4)CC3)n[nH]c12
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 15.1 %

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 16. Thus, 5-(3-fluorophenyl)-3-(4-piperidinyl)-1H-indazole-7-carboxamide (Intermediate 15) (75 mg, 0.167 mmol) was reacted with 2-chloro-1-ethanesulfonyl chloride (17 uL, 0.167 mmol) in the presence of triethyl amine (93 uL, 0.665 mmol) in DMF (2 mL) at 0° C. After 10 mins, K2CO3 (46 mg, 0.334 mmol) and pyrrolidine (41 uL, 0.501 mmol) were added. The reaction mixture was heated to 100° C. overnight. The resulting suspension was filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to afford the title compound (12.6 mg, 15% for 2 steps).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:3]1.[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:14][N:3]1[C:2](=[O:1])[CH2:6][CH2:5][N:4]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a mixture of 1,1-dimethylethyl 3-oxo-1-pyrazolidinecarboxylate (1.00 g, 5.37 mmol) and potassium carbonate (0.89 g, 6.44 mmol) in DMF (10 ml) was added iodomethane (2 M in MTBE, 3.22 ml, 6.44 mmol). The reaction mixture was stirred at rt for 2 h. LCMS indicated completion of the reaction. The mixture was diluted with ethyl acetate/hexanes (1:1, 150 ml) and washed with water (5×50 ml), brine (50 ml), dried (Na2SO4) and concentrated to provide 1,1-dimethylethyl 2-methyl-3-oxo-1-pyrazolidinecarboxylate (0.57 g, 53.0%). LCMS: (M+H)+ 201.0.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([B:9]2[O:13][CH2:12][CH2:11]O2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:15]1[CH:20]=[CH:19]C=[CH:17][C:16]=1COCOC>>[B:9]1([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])[C:17]2[CH:16]=[CH:15][CH:20]=[CH:19][C:11]=2[CH2:12][O:13]1
Reactant: N#Cc1cccc(B2OCCO2)c1
Reactant: COCOCc1ccccc1Br
Product: N#Cc1cccc(B2OCc3ccccc32)c1

Procedure:
This was prepared as per the procedure in Example 11, from 2-(3-cyanophenyl)-[1,3,2]-dioxaborolane and 1-bromo-2-((methoxymethoxy)methyl)benzene to afford white crystalline product.
Reaction SMILES: N[C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.O=S(Cl)Cl.[S:13](=[N:15]S(C)(=O)=O)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[S:13]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH:8]=[N:15]1
Reactant: Cc1ccccc1N
Reactant: CS(=O)(=O)N=S=O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: c1ccc2sncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of o-toluidine (10 g, 93.4 mmol) in 50 mL toluene was added SOCl2 (12.1 g, 102 mmol) dropwise at 0° C. After the addition was complete, the reaction mixture was heated to reflux and stirred overnight. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure to give a yellow oil. The oil was dissolved in toluene (100 mL), then a solution of N-sulfinylmethanesulfonamide (20.6 g, 146 mmol) was added dropwise, followed by pyridine (7.3 g, 93.4 mmol). The mixture was heated to reflux and stirred at that temperature overnight. Toluene was then removed under reduced pressure, the residue was dissolved in EtOAc (200 mL) and washed with water (2×200 mL). The organic layer was washed with brine, dried and evaporated to give the crude product. The crude product was purified by column chromatography (3% EtOAc/PE) to afford 6.2 g title compound as colorless oil. 1H NMR (CHLOROFORM-d) δ 9.22 (s, 1H), 7.88 (d, J=9.7 Hz, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.46 (ddd, J=8.9, 6.5, 1.2 Hz, 1H), 7.26 (dd, J=7.9, 6.6 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:28][C:17]3=[CH:18][N:19]=[C:20]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:29]1([S:32](Cl)(=[O:34])=[O:33])[CH2:31][CH2:30]1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:28][C:17]3=[CH:18][N:19]=[C:20]([N:22]4[CH2:23][CH2:24][N:25]([S:32]([CH:29]5[CH2:31][CH2:30]5)(=[O:34])=[O:33])[CH2:26][CH2:27]4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(N4CCNCC4)ncc3O2)CC1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(N4CCN(S(=O)(=O)C5CC5)CC4)ncc3O2)CC1

Procedure:
The title compound is prepared by treatment of 4-(5-piperazin-1-yl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester with cyclopropylsulfonyl chloride in dichloromethane in the presence of triethylamine. LC (method 10): tR=1.47 min; Mass spectrum (ESI+): m/z=493 [M+H]+.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:25][C:26]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)=[CH:31][C:27]=1[C:28]([OH:30])=O.[F:47][CH2:48][CH:49]([O:52][CH:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)[CH2:50][F:51].C(N(CC)CC)C>CN(C)C=O>[F:51][CH2:50][CH:49]([O:52][CH:53]1[CH2:54][CH2:55][N:56]([C:28]([C:27]2[CH:31]=[C:32]([CH:33]=[CH:34][C:26]=2[F:25])[CH2:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39](=[O:46])[NH:38][N:37]=2)=[O:30])[CH2:57][CH2:58]1)[CH2:48][F:47]
Reactant: FCC(CF)OC1CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(OC(CF)CF)CC1
Temperature: 20 °C
Reaction time: 24 h
Yield: 16.1 %

Procedure:
O-Benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (0.227 g, 0.60 mmol) was added in one portion to 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (0.137 g, 0.46 mmol), 4-(1,3-difluoropropan-2-yloxy)piperidine (28) (0.082 g, 0.46 mmol) and triethylamine (0.194 mL, 1.38 mmol) in N,N-dimethylformamide (3 mL) at 20° C. under air. The resulting solution was stirred at 20° C. for 24 hours. The crude mixture was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound as a colourless gum (34 mg, 15.90%); 1H NMR (400.132 MHz, DMSO) δ 1.10-1.19 (1H, m), 1.21-1.30 (1H, m), 1.46-1.55 (2H, m), 1.62-1.70 (2H, m), 2.78-2.86 (1H, m), 3.54-3.60 (1H, m), 3.69-3.79 (2H, m), 4.11 (2H, s), 4.15-4.20 (1H, m), 4.22-4.32 (2H, m), 4.34-4.39 (1H, m), 6.97-7.02 (1H, m), 7.13-7.20 (2H, m), 7.59-7.69 (2H, m), 7.76 (1H, d), 8.05 (1H, d), 12.34 (1H, s); m/z (LC-MS, ESI+), RT=1.99 (M+H 460).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[N:34]1[CH:35]=[CH:36][N:37]2[C:42]([CH2:43][CH2:44]O)=[CH:41][CH:40]=[CH:39][C:38]=12.[C:46]([OH:49])(=[S:48])[CH3:47]>O1CCCC1.CN(C)C=O>[C:46]([S:48][CH2:44][CH2:43][C:42]1[N:37]2[CH:36]=[CH:35][N:34]=[C:38]2[CH:39]=[CH:40][CH:41]=1)(=[O:49])[CH3:47]
Reactant: CC(O)=S
Reactant: OCCc1cccc2nccn12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)SCCc1cccc2nccn12
Reaction time: 0.17 h

Procedure:
To a solution of triphenyl phosphine (4.20 g) in tetrahydrofuran (30 ml) was added dropwise, at −15° C., diisopropyl azodicarboxylate (3.16 ml). The mixture was stirred for 10 minutes at the same temperature. To the reaction mixture were, then, added a solution of 2-(imidazo[1,2-a]pyridin-5-yl)ethanol (1.00 g) in dimethylformamide (20 ml) and thioacetic acid (1.14 ml). The reaction mixture was stirred for 0.5 hour at −15° C. and, then, for 20 hours at room temperature. The reaction mixture was concentrated, which was diluted with ethyl acetate and washed with water, a saturated aqueous solution of sodium hydrogencarbonate and, then, with a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate and concentration. The concentrate was purified by means of a column chromatography (carrier: silica gel, developing solvent: ethyl acetate-hexane, 1:1) to afford the title compound (0.52 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:39])[N:15]([C:25]2[CH:29]=[C:28]([C:30]#[C:31][C:32]([CH3:35])([CH3:34])[CH3:33])[S:27][C:26]=2[C:36]([OH:38])=[O:37])[C:16]([CH:18]2[CH2:23][CH2:22][CH:21]([CH3:24])[CH2:20][CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[CH3:33][C:32]([CH3:34])([CH3:35])[C:31]#[C:30][C:28]1[S:27][C:26]([C:36]([OH:38])=[O:37])=[C:25]([N:15]([C:16]([CH:18]2[CH2:19][CH2:20][CH:21]([CH3:24])[CH2:22][CH2:23]2)=[O:17])[N:14]([CH3:39])[CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:29]=1
Reactant: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)N(C)C2CCN(C(=O)OC(C)(C)C)CC2)CC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)N(C)C2CCNCC2)CC1
Yield: 0 %

Procedure:
Crude 4-[N′-[2-carboxy-5-(3,3-dimethyl-but-1-ynyl)-thiophen-3-yl]-N-methyl-N′-(4-methyl-cyclohexanecarbonyl)-hydrazino]-piperidine-1-carboxylic acid tert-butyl ester (220 mg, 500 mmol) (Example 127) was treated with TFA (3 mL, 4.6 mmol) at 60° C. for 10 min. After cooling, toluene (2-3 mL) was added and the mixture was concentrated, this was repeated several times, and a portion of this crude material was purified by HPLC (Gemini column, 35% acetonitrile:water, 2 min, 35-50% acetonitrile:water, 2 min, 50-95% acetonitrile: water 13 min, both solvents containing 0.1% trifluoroacetic acid). This resulted in 20 mg of the title compound as a white powder (bis-TFA salt): MS (m/z): 460.2 [M−H]+; HPLC retention time: 3.15 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.[SH:21][CH2:22][C:23](O)=[O:24]>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([N:18]2[C:23](=[O:24])[CH2:22][S:21][CH:9]2[C:8]2[CH:11]=[CH:12][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)CS
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(C2SCC(=O)N2c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Yield: 57.6 %

Procedure:
4-methanesulfonylbenzaldehyde and 150 mg(1.18 mmol) of 4-chloroaniline were added and stirred in 10 ml of toluene and the mixture was heated and refluxed for 4 hours in the Dean-Stark trap apparatus. 0.083 ml(1.19 mmol) of mercaptoacetic acid was added to the reaction mixture and was heated and refluxed for 5 hours. The reaction mixture was cooled to room temperature and the solvent was distilled under reduced pressure and discarded, and then the resultant was diluted in 20 ml of ethyl acetate. The resultant was washed with 20 ml of 2N-hydrochloric acid, 20 ml of saturated sodium bicarbonate solution, and saturated sodium chloride solution and dried on anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate/n-hexane=1:1, v/v ) to give 230 mg of the title compound as an white crystal(yield 57.6%).