Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]([CH2:7][C@@:8]2([CH3:34])[N:12]3[C:13]([C:16]([NH:18][C:19]4([C:22]([OH:24])=O)[CH2:21][CH2:20]4)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)[C:9]2=[O:33])=[CH:5][CH:4]=1)#[N:2].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC.[C:58]([O:62][C:63]([NH:65][NH:66][C:67]([C:69]1([NH2:72])[CH2:71][CH2:70]1)=[O:68])=[O:64])([CH3:61])([CH3:60])[CH3:59]>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[C:58]([O:62][C:63]([NH:65][NH:66][C:67]([C:69]1([NH:72][C:22]([C:19]2([NH:18][C:16]([C:13]3[N:12]4[C@@:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:36][CH:35]=5)([CH3:34])[C:9](=[O:33])[N:10]([C:25]5[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=5)[C:11]4=[N:15][CH:14]=3)=[O:17])[CH2:20][CH2:21]2)=[O:24])[CH2:71][CH2:70]1)=[O:68])=[O:64])([CH3:61])([CH3:59])[CH3:60]
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)O)CC3)n21
Reactant: CC(C)(C)OC(=O)NNC(=O)C1(N)CC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2cccnc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)C1(NC(=O)C2(NC(=O)c3cnc4n3[C@](C)(Cc3ccc(C#N)cc3)C(=O)N4c3cc(Cl)cc(Cl)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.3 %

Procedure:
To a solution of 1-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid (0.25 g, 0.48 mmol) in DMF (2 mL) was added HOAt (0.065 g, 0.48 mmol), EDC (0.092 g, 0.48 mmol), DMAP (0.005 g, 0.041 mmol), Et3N (0.066 mL, 0.48 mmol). The reaction allowed to stir for 10 min at room temperature. To this mixture was added N′-(1-amino-cyclopropanecarbonyl)-hydrazinecarboxylic acid tert-butyl ester (0.10 g, 0.48 mmol) and the reaction was heated at 70° C. for 15 h. The mixture was cooled to room temperature, diluted with water and extracted with EtOAc (3×50 mL). The combined extracts were washed with saturated NaHCO3, 2N HCl, brine and dried with MgSO4. The mixture was filtered and concentrated in vacuo to give N′-{1-[(1-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarbonyl)-amino]-cyclopropanecarbonyl}-hydrazinecarboxylic acid tert-butyl ester (0.33 g, 96%) as a yellow solid, m/z 721.9 [M+1]+.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2.[C:16]1([CH:22]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[C:31]1([CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH2:15][CH:2]([OH:1])[CH2:3][O:4][C:5]3[CH:14]=[CH:13][CH:12]=[C:11]4[C:6]=3[CH:7]=[CH:8][CH:9]=[N:10]4)[CH2:29][CH2:30]2)=[O:24])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: c1cc(OCC2CO2)c2cccnc2c1
Reactant: O=C(C(c1ccccc1)c1ccccc1)N1CCNCC1
Solvent: CCO
Product: O=C(C(c1ccccc1)c1ccccc1)N1CCN(CC(O)COc2cccc3ncccc23)CC1
Yield: 62.6 %

Procedure:
71 g of the above-mentioned 5-(2,3-epoxypropoxy) quinoline and 94 g of N-(2,2-diphenylacetyl)piperazine were dissolved in 1.5 l of ethanol and then the resulting solution was refluxed with heating for 3 hours. After the reaction, ethanol was evaporated and the residue was purified by chromatography. The elution was carried out with a solvent miture of chloroform:methanol=50:1 (volume ratio) and the targeted fraction was concentrated under reduced pressure to obtain 101 g of 5-[3-{4-(2,2diphenylacetyl)piperazin-1-yl}-2- hydroxypropoxy]quinoline (compound No. 1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH:17]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18]1.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH:22][CH2:21][CH2:20][CH:17]2[CH2:19][CH2:18]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)nn1
Reactant: NCCC1CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reaction time: 0.5 h

Procedure:
To a suspension of 6-chloropyridazine-3-carboxylic acid (4.1 g, 25.8 mmol) from Step 1 and DMF (50 μL) in CH2Cl2 (60 mL) at r.t. was added oxalyl chloride (5.0 mL, 57.1 mmol) and the mixture was refluxed for 30 min. Volatile materials were removed in vacuo to give the crude acid chloride as a pale yellow solid. The acid chloride was dissolved in CH2Cl2 (40 mL) and added to a solution of cyclopropylethylamine (2.4 g, 28.2 mmol) and Et3N (11 mL, 78 mmol) in CH2Cl2 at 0° C. over a period of about 15 min. After further stirring for 30 min, the mixture was diluted with more CH2Cl2, washed successively with 10% HCl, saturated aqueous NaHCO3, water, dried (Na2SO4) and concentrated. Chromatography over silica gel and elution with hexanes-EtOAc (2:1) gave the title compound as a white powder. 1H NMR (500 MHz, Acetone-d6): δ 0.12 (d, 2H), 0.47 (t, 2H), 0.80 (s, 1H), 1.57-1.61 (m, 2H), 3.58-3.62 (m, 2H), 8.02 (d, 1H), 8.31 (d, 1H), 8.62 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([CH3:10])[CH:9]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:7]=[C:8]([CH3:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(C)n[nH]1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)nn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.5 %

Procedure:
To a stirring solution of 21.91 g (13.63 mmol) of 5-methyl-2H-pyrazole-3-carboxylic acid methyl ester, prepared as in Part A, in 50 mL of DMF is added 2.88 g (20.44 mmol, 1.5 equiv) of K2CO3, followed by 1.95 mL (16.35 mmol, 1.2 equiv) of benzyl bromide. The reaction mixture is stirred 15 min at RT then heated at 50° C. for 20 h. The reaction is cooled to RT, poured into 100 mL 1N HCl, and extracted with Et2O (2×100 mL). The organic layers were washed with H2O (2×100 mL), dried (MgSO4), and the solvent removed in vacuo. Purification of the crude material by silica gel flash column chromatography using a gradient elution of hexane/EtOAc 10/1 to 1/1 afforded 833 mg of 2-Benzyl-5-methyl-2H-pyrazole-3-carboxylic acid methyl ester as a yellow oil: 1H NMR (CDCl3, 300 MHz) δ7.42-7.25 (m, 5H), 6.68 (s, 21H), 5.74 (s, 2H), 3.86 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[CH3:17])=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][C@H:13]1[CH2:14][CH2:15][CH2:16][N:12]1[CH2:11][C@H:9]1[CH2:10][C@@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=2)=[CH:3][CH:4]=1
Reactant: C[C@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(Br)cc1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: C[C@H]1CCCN1C[C@H]1C[C@@H]1c1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 90 °C

Procedure:
To a solution of 1-[(1S,2S)-2-(4-bromo-phenyl)-cyclopropylmethyl]-2(S)-methyl-pyrrolidine (the product of Example 1D, 50 mg, 0.17 mmol) in isopropyl alcohol (4 mL) under an atmosphere of nitrogen was added 4-cyanophenylboronic acid (30 mg, 0.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (6 mg, 8.5 μmol) and potassium carbonate (59 mg, 0.43 mmol). The mixture was heated to 90° C. for 5 hours, cooled to ambient temperature and partitioned between ethyl acetate (25 mL) and H2O (10 mL). The separated organic layer was washed with brine, dried (MgSO4), filtered, concentrated under reduced pressure and chromatographed on silica gel eluting with 3% methanol (containing 10% concentrated NH4OH) in dichloromethane to provide the title compound. 1H NMR (300 MHz, CD3OD) δ 1.01 (m, 1H), 1.13 (m, 1H), 1.25 (d, J=6 Hz, 3H), 1.36 (m, 1H), 1.54 (m, 1H), 1.89 (m, 3H), 2.11 (m, 1H), 2.30 (m, 1H), 2.65 (m, 1H), 2.79 (m, 1H), 3.27 (dd, J=12 Hz, J=6 Hz, 1H), 3.40 (m, 1H), 7.22 (d, J=9 Hz, 2H), 7.59 (d, J=6 Hz, 2H), 7.78 (s, 4H). MS (DCl—NH3) m/z 317 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[C:5]([OH:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:7]=[CH:8][CH:9]=1.Br[CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+].FC(F)OC1C(OCC(C)(C)C)=C(/C=C/C2N=C3N(C=2C(O)=O)C=CS3)C=CC=1>CN(C)C=O>[F:27][CH:2]([F:1])[O:3][C:4]1[C:5]([O:26][CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]3[C:20]=2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2O)nc2ccccn12
Reactant: CC(C)CCBr
Agent: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2OCCC(C)C)nc2ccccn12
Yield: 101 %

Procedure:
Alkylation of Intermediate 12 (400 mg, 1.069 mmol) with 1-bromo-3-methylbutane (193.8 mg, 1.283 mmol) in presence of potassium carbonate (163 mg, 1.175 mmol) in anhydrous N,N-dimethylformamide (4 mL) as described in Intermediate 7A, Step 1 gave 480 mg of the compound as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.94 (d, J=6.9, 6H), 1.40-1.47 (m, 3H), 1.64-1.71 (m, 2H), 1.88-1.95 (m, 1H), 3.97-4.03 (m, 2H), 4.40-4.48 (m, 2H), 7.12-7.20 (m, 2H), 7.21 (t, J=74.7 Hz, 1H), 7.22-7.28 (m, 1H), 7.53-7.62 (m, 2H), 7.74 (d, J=8.4 Hz, 1H), 7.94 (d, J=15.9 Hz, 1H), 8.04 (d, J=16.2 Hz, 1H), 9.23 (d, J=6.3 Hz, 1H); ESI-MS (m/z) 445.25 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:33]=[CH:32][C:27]5[O:28][CH2:29][CH2:30][O:31][C:26]=5[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:34][N:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[C:40](Cl)=[O:41]>C1COCC1.C(Cl)Cl>[O:28]1[C:27]2[CH:32]=[CH:33][C:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[C:8]([C:4]5[CH:3]=[C:2]([NH:1][C:40]([C:36]6[N:35]([CH3:34])[CH:39]=[CH:38][CH:37]=6)=[O:41])[CH:7]=[CH:6][CH:5]=5)=[N:9][N:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=45)[CH:22]=[CH:21][N:20]=3)=[CH:25][C:26]=2[O:31][CH2:30][CH2:29]1
Reactant: Cn1cccc1C(=O)Cl
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)OCCO4)n2)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1cccc1C(=O)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)OCCO4)n2)c1
Yield: 91.2 %

Procedure:
To a solution of {4-[2-(3-amino-phenyl)-pyrazolo[1,5-a]pyridin-3-yl]-pyrimidin-2-yl}-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amine (105 mg, 0.24 mmol) in 5 mL THF was added N-methylpyrrole carbonyl chloride (37 mg, 0.26 mmol). When TLC showed the reaction to be complete, the solution was diluted with DCM and washed with a solution of saturated NaHCO3 and with brine. The organic phase was dried over MgSO4 and concentrated. The residue was triturated with diethyl ether to give the title compound as a yellow solid (119 mg, 92%). 1H NMR (400 MHz, d6-DMSO) δ 9.90 (s, 1H), 9.80 (s, 1H), 8.87 (d, J=6.8 Hz, 1H), 8.50 (s, 1H), 8.14 (d, J=6.0 Hz, 1H), 8.05 (s, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.51 (m, 1H), 7.43 (m, 1H), 7.27-7.22 (m, 2H), 7.17 (t, J=6.8 Hz, 1H), 7.05-7.04 (m, 2H), 7.00 (s, 1H), 6.81 (d, J=8.4 Hz, 1H), 6.47 (d, J=6.0 Hz, 1H), 6.08-6.07 (m, 1H), 4.22 (m, 4H), 3.85 (s, 3H) ppm. HRMS calculated C31H25N7O3 [M+H]+ 544.2097 found 544.2101.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH3:9])[O:4][C@H:3]1[O:10][C@H:11]([CH3:34])[CH2:12][CH2:13][C:14]([O:16][C@H:17]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:18][NH:19][C:20](=[O:27])[CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[O:15].[Li+].[OH-].O.C(O)(=O)C>O1CCCC1.O1CCOCC1>[OH:1][C@@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH3:9])[O:4][C@H:3]1[O:10][C@H:11]([CH3:34])[CH2:12][CH2:13][C:14]([O:16][C@H:17]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:18][NH:19][C:20](=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15]
Reactant: COC(=O)CCC(=O)NC[C@H](OC(=O)CC[C@@H](C)O[C@@H]1O[C@@H](C)[C@H](O)C[C@H]1O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: C[C@H](CCC(=O)O[C@@H](CNC(=O)CCC(=O)O)c1ccccc1)O[C@@H]1O[C@@H](C)[C@H](O)C[C@H]1O
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 28.6 %

Procedure:
To prepare pasc#9, a solution of 18 (6.6 mg, 14 μmol) in dry tetrahydrofuran (200 μl) was treated with a mixture of LiOH (0.3 mg, 12 μmol) and water (80 μl) in 1,4-dioxane (400 μl). After stirring at 60° C. for 5 minutes, the solution was acidified with glacial acetic acid and concentrated in vacuo. HPLC purification (see Methods) of the crude reaction mixture afforded 4-(((R)-2-(((R)-4-(((2R,3R,5R,6S)-3,5-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)pentanoyl)oxy)-2-phenylethyl)amino)-4-oxobutanoic acid (pasc#9) (1.8 mg, 4 μmol, 29%) as a colorless oil.
Reaction SMILES: N[C:2]1[C:3]([CH2:9][C:10]#[N:11])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([O-])(O)=[O:13].[Na+]>Cl>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][N:6]=1)[NH:11][C:10](=[O:13])[CH2:9]2
Reactant: N#CCc1cc(Cl)ncc1N
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Product: O=C1Cc2cc(Cl)ncc2N1
Yield: 46 %

Procedure:
(5-Amino-2-chloro-4-pyridyl)acetonitrile (1.40 g, 8.4 mmol) was taken up in 6N HCl solution (100 mL) and heated between 50° and 100° C. for 2 hours. After cooling, the solution was adjusted to pH 7 by addition of solid NaHCO3 and extracted with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was subjected to flash chromatography on silica gel using ethyl acetate as eluant. (Some methanol was used to help dissolve the solid). Fractions containing the desired product were combined and concentrated to leave the title compound as a solid (650 mg, 46%), m.p. 230° C. (dec.) The NMR spectrum indicated that this material contained a small amount of the by-product, 2-amino-5-chloro-6-azaindole in addition to the title compound. Nonetheless, this material was used in the next step without further purification.
Reaction SMILES: [ClH:1].Cl.Br[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][CH:17]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:16][CH2:15]3)=[CH:6][N:5]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:40][O:41][C:42]1[CH:47]=[CH:46][C:45](OB(O)O)=[CH:44][CH:43]=1>O.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.C(O)C>[ClH:1].[ClH:1].[CH3:25][N:24]([CH2:23][CH2:22][CH:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][CH2:10][C:7]3[CH:6]=[N:5][C:4]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[O:41][CH3:40])=[CH:9][CH:8]=3)[CH:13]=2)[CH2:18]1)[CH3:26]
Reactant: CN(C)CCC1CCc2cc(OCc3ccc(Br)nc3)ccc2C1
Reactant: COc1ccc(OB(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COc1ccccc1-c1ccc(COc2ccc3c(c2)CCC(CCN(C)C)C3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 166.2 %

Procedure:
A mixture of (+)-6-(2-bromopyridin-5-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin dihydrochloride (0.2 g), toluene (8 ml), ethanol (1 ml), 2M aqueous sodium carbonate (1 ml) was stirred at room temperature for 10 min. 4-methoxyphenylboric acid (89 mg), and tetrakis(triphenylphosphine)palladium (27 mg) was added and the reaction mixture was heated under reflux under argon for 15 hr and cooled. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate:hexane=1:4) and then converted into its dihydrochloride, which was recrystallized from ethanol-ethyl acetate to obtain the titled compound (176 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([O:26]C)=[O:25])=[O:19])=[CH:13][CH:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[OH-].[Na+].Cl>CO.C1COCC1.O.[Cl-].[Na+].O>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([OH:26])=[O:25])=[O:19])=[CH:13][CH:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COC(=O)c1cccc(NC(=O)Nc2ccc(-c3csc4ncnc(N)c34)cc2)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Nc1ncnc2scc(-c3ccc(NC(=O)Nc4cccc(C(=O)O)c4)cc3)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.4 %

Procedure:
A suspension of Example 348A (0.5 g, 1.19 mmol) in methanol (50 mL) and THF (20 mL) was treated with 2N NaOH (3.6 mL, 7.2 mmol), stirred at room temperature for 4 hours, and heated to reflux for 1 hour. The mixture was cooled to room temperature, diluted with water, acidified to pH 3 with 4N HCl, and diluted with brine resulting in the formation of a precipitate. The solid was collected by filtration and dried to give 0.417 g of the desired product. MS (ESI(+)) m/e 406 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 7.41 (m, 3H); 7.55 (s, 1H); 7.56 (d, J=6.0 Hz, 1H); 7.66-7.71 (m, 3H); 8.14 (s, 1H); 8.47 (s, 1H); 9.30 (s, 1H); 9.32 (s, 1H).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([O:25][C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[CH:31]([CH:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1)([CH3:33])[CH3:32]>>[CH:31]([CH:34]1[CH2:39][CH2:38][CH:37]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:20]4[CH:21]=[C:22]([O:25][C:26]([F:28])([F:27])[F:29])[CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:11]2)[CH2:36][CH2:35]1)([CH3:33])[CH3:32]
Reactant: CC(C)C1CCC(=O)CC1
Reactant: O=C(CNc1noc2ccc(OC(F)(F)F)cc12)NC1CNC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1CCC(N2CC(NC(=O)CNc3noc4ccc(OC(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethoxy-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and 4-isopropyl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: O=C(O)c1cnn2c(Nc3cccc(F)c3Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc(F)c3Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 29.9 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-chloro-3-fluorophenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (77 mg, 0.16 mmol) obtained in step 2 and ethanesulfonamide (84 mg, 0.80 mmol), the title compound (28 mg, 28%) was obtained.
Reaction SMILES: [ClH:1].[Si]([O:9][CH2:10][CH2:11][N:12]1[C:16]2[N:17]=[C:18]([C:47]#[N:48])[N:19]=[C:20]([C:21]3[CH:42]=[CH:41][C:24]([O:25][CH2:26][CH2:27][CH:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)=[C:23]([C:43]([F:46])([F:45])[F:44])[CH:22]=3)[C:15]=2[CH:14]=[CH:13]1)(C(C)(C)C)(C)C>O1CCOCC1>[ClH:1].[OH:9][CH2:10][CH2:11][N:12]1[C:16]2[N:17]=[C:18]([C:47]#[N:48])[N:19]=[C:20]([C:21]3[CH:42]=[CH:41][C:24]([O:25][CH2:26][CH2:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[C:23]([C:43]([F:46])([F:45])[F:44])[CH:22]=3)[C:15]=2[CH:14]=[CH:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(-c3nc(C#N)nc4c3ccn4CCO[Si](C)(C)C(C)(C)C)cc2C(F)(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1nc(-c2ccc(OCCC3CCNCC3)c(C(F)(F)F)c2)c2ccn(CCO)c2n1
Reaction time: 1 h

Procedure:
A 4 M solution of hydrogen chloride in dioxane (1 ml) was added to a solution of tert-butyl 4-(2-{4-[7-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-cyano-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-(trifluoromethyl)phenoxy}ethyl)piperidine-1-carboxylate (150 mg) in dioxane (1 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. After the reaction mixture was concentrated under reduced pressure, the precipitate was washed with diisopropyl ether, and collected by filtration, whereby 7-(2-hydroxyethyl)-4-{4-[2-(piperidin-4-yl)ethoxy]-3-(trifluoromethyl)phenyl}-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile monohydrochloride (110 mg) was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH:7]([OH:9])[C:6]2[CH:10]=[CH:11][S:12][C:5]=2[CH2:4][CH2:3]1.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1F>>[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:9][CH:7]1[CH2:8][N:2]([CH3:1])[CH2:3][CH2:4][C:5]2[S:12][CH:11]=[CH:10][C:6]1=2
Reactant: CN1CCc2sccc2C(O)C1
Reactant: Fc1ccccc1Br
Product: CN1CCc2sccc2C(Oc2ccccc2Br)C1

Procedure:
The same method as in Example 1 was conducted using 6-methyl-5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-4-ol (Reference Example 28) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-bromo-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[I:12]N1C(=O)CCC1=O>C1COCC1.[Cl-].[Na+].O>[NH2:1][C:2]1[S:3][C:4]([I:12])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1csc(N)n1
Reactant: O=C1CCC(=O)N1I
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1nc(N)sc1I
Reaction time: 1.5 h
Yield: 84 %

Procedure:
A solution of 14.53 g of 2-amino-4-ethoxycarbonylthiazole in 200 ml of THF was cooled in ice under an argon atmosphere, 20.0 g of N-iodosuccinimide was added to the cooled solution, and the mixture was stirred at the same temperature for 1.5 hr. Brine was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1 to 1:2) to give 21.12 g of 2-amino-4-ethoxycarbonyl-5-iodothiazole.
Reaction SMILES: C(C1SC(C=O)=CC=1)#N.Br.C([S:14][C:15](=[NH:26])[NH:16][N:17]=[CH:18][C:19]1[S:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=1)C=C>C(O)CO.COC>[C:24]([C:21]1[S:20][C:19]([CH:18]=[N:17][NH:16][C:15]([NH2:26])=[S:14])=[CH:23][CH:22]=1)#[N:25]
Reactant: C=CCSC(=N)NN=Cc1ccc(C#N)s1
Agent: Br
Agent: COC
Agent: N#Cc1ccc(C=O)s1
Solvent: OCCO
Product: N#Cc1ccc(C=NNC(N)=S)s1

Procedure:
In the same manner, there were obtained with good yields: 2. 5-Cyano-thiophen-2-aldehyde-S-ethyl-isothiosemicarbazonehydroiodide melting at 145° C (free base 94° C) from 5-cyan0-thiophen-2-aldehyde and S-ethyl-isothiosemicarbazide-hydroiodide. 3. 5-Cyano-thiophen-2-aldehyde-S-n-propyl-isothiosemicarbazonehydroiodide melting at 174° C (free base 75° C) from 5-cyano-thiophen-2-aldehyde and S-n-propyl-isothiosemicarbazide-hydroiodide. 4. 5-Cyano-thiophen-2-aldehyde-S-allyl-isothiosemicarbazone-hydrobromide melting at 169° C (free base 126° C) from 5-cyano-thiophen-2-aldehyde and S-allyl-isothiosemicarbazide-hydrobromide. 5. 5-Cyano-thiophen-2 -aldehyde-S-benzyl-isothiosemicarbazonehydrobromide melting at 208° C (free base 130° C) from 5-cyano-thiophen-2-aldehyde and S-benzyl-isothiosemicarbazide-hydrobromide. 6. The above-mentioned compounds were also obtained by the reaction of 5-cyano-thiophen-2-aldehyde-thiosemicarbazone with the corresponding alkyl- or aralkyl-halides in ethylene-glycol-monomethyl ether at 50° -60° C.