Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][CH:11]=3)[N:6]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[C:5]=12.[H-].[Na+].Cl[C:23]1[N:27]([CH2:28][C:29](=[O:31])[CH3:30])[C:26]2[CH:32]=[CH:33][CH:34]=[CH:35][C:25]=2[N:24]=1.O>CN(C=O)C>[N:1]1[CH:2]=[CH:3][N:4]2[C:12]3[C:7](=[N:8][CH:9]=[CH:10][CH:11]=3)[N:6]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:23]4[N:27]([CH2:28][C:29](=[O:31])[CH3:30])[C:26]5[CH:32]=[CH:33][CH:34]=[CH:35][C:25]=5[N:24]=4)=[CH:15][CH:14]=3)[C:5]=12
Reactant: CC(=O)Cn1c(Cl)nc2ccccc21
Reactant: Oc1ccc(-n2c3ncccc3n3ccnc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Cn1c(Oc2ccc(-n3c4ncccc4n4ccnc34)cc2)nc2ccccc21
Reaction time: 0.17 h
Yield: 19.4 %

Procedure:
To a solution of 4-(9H-imidazo[1′,2′:1,2]imidazo[4,5-b]pyridin-9-yl)phenol (1.13 g) obtained in Example 9, step C) in DMF (10 ml) was added sodium hydride (60% in oil, 0.200 g) at room temperature by small portions. After stirring for 10 min, a solution of 1-(2-chloro-1H-benzimidazol-1-yl)propan-2-one (1.25 g) in DMF (5 ml) was added, and the obtained mixture was stirred under microwave irradiation at 180° C. for 1.5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) and recrystallized from methanol to give the title compound (0.371 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([OH:13])=[CH:11][C:10]([C:14]#[N:15])=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:17][N:18]1[C:22](=[O:23])[C:21]2[C:24]([CH:30]([CH3:32])[CH3:31])=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:20]=2[S:19]1(=[O:34])=[O:33].[F-].[K+].CN(C=O)C>O>[CH:30]([C:24]1[C:21]2[C:22](=[O:23])[N:18]([CH2:17][O:13][C:12]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[N:9]=[C:10]([C:14]#[N:15])[CH:11]=3)[S:19](=[O:34])(=[O:33])[C:20]=2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=1)([CH3:32])[CH3:31]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Reactant: N#Cc1cc(O)n(-c2ccc(Cl)cc2)n1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C#N)nn1-c1ccc(Cl)cc1)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
A mixture of 1-(4-chlorophenyl)-3-cyano-5-hydroxypyrazole (59.7 mg, 0.273 mmol), 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (93.7 mg, 0.27 mmol), KF (15.7 mg, 0.27 mmol) and DMF (5 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (50 mL) and extracted with ether (3×25 mL). The ether extracts were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20% ethyl acetate/hexane to afford 81 mg (62%) of 4-isopropyl-6-methoxy-2-[1-(4-chlorophenyl)-3-cyanopyrazol -5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =4-Cl--Ph; R2 =CN; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3), m.p. 135° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][N:26]=2)=[N:10]1.Cl.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH:33]1[CH2:38][OH:39]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH:33]2[CH2:38][OH:39])[NH:12][C:11]([C:22]2[S:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][N:26]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(CBr)NC(c2ncc(C(F)(F)F)s2)=NC1c1ccc(F)cc1Br
Reactant: OCC1COCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2CO)NC(c2ncc(C(F)(F)F)s2)=NC1c1ccc(F)cc1Br
Yield: 43.1 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(5-(trifluoromethyl)thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.74 g, 1.3 mmol) was reacted with morpholin-3-ylmethanol hydrochloride (0.23 g, 1.5 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellowish solid (0.34 g, 43%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[O:13][CH2:14][CH3:15].[OH-].[Na+].O>O1CCOCC1>[C:10]([C:8]1[CH:7]=[CH:6][C:5]([O:13][CH2:14][CH3:15])=[C:4]([CH:9]=1)[C:3]([OH:16])=[O:2])(=[O:12])[CH3:11]
Reactant: CCOc1ccc(C(C)=O)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1ccc(C(C)=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.3 %

Procedure:
A mixture of 5-acetyl-2-ethoxybenzoic acid methyl ester (9.6 g, 0.043 mol), 5M aqueous sodium hydroxide solution (44 ml, 0.217 mol), water (80 ml) and 1,4-dioxan (80 ml) was stirred at room temperature for 18 hours. The solvent was removed by evaporation under vacuum, the residue dissolved in water (100 ml) and the resulting solution acidified to pH 1with concentrated hydrochloric acid. The aqueous mixture was extracted with ethyl acetate (4×100 ml) and the combined extracts dried (Na2SO4) and evaporated under vacuum. The resulting solid was crystallised form ethyl acetate to give the title compound as a colourless solid (5.4 g, 60%), m.p. 122°-125° C. Found: C,63.20; H,5.81. C11H12O4 requires C,63.45; H,5.81%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:42])[C:7]=1[C:8](=[O:41])[CH2:9][N:10]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=1)[C:11]([C:13]1[CH:14]=[N:15][N:16]([C@H:21]2[CH2:26][CH2:25][C@H:24]([C:27]([O:29]CC)=[O:28])[CH2:23][CH2:22]2)[C:17]=1[CH:18]([F:20])[F:19])=[O:12].Cl.O>O1CCOCC1>[Cl:42][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[C:8](=[O:41])[CH2:9][N:10]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=1)[C:11]([C:13]1[CH:14]=[N:15][N:16]([C@H:21]2[CH2:26][CH2:25][C@H:24]([C:27]([OH:29])=[O:28])[CH2:23][CH2:22]2)[C:17]=1[CH:18]([F:19])[F:20])=[O:12]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(Cl)cncc3Cl)Cc3cc(F)cc(F)c3)c2C(F)F)CC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(CN(Cc1cc(F)cc(F)c1)C(=O)c1cnn([C@H]2CC[C@H](C(=O)O)CC2)c1C(F)F)c1c(Cl)cncc1Cl
Temperature: 80 °C

Procedure:
To a solution of compound 20-3 (106 mg, 0.17 mmol) in dioxane (6 mL) was added 6 M HCl (6 mL) and heated at 80° C. for 16 h. The reaction mixture was cooled to room temperature, added H2O and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (2×10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (C18 silica gel, 75% CH3CN/water as eluent) to provide the compound of example 20 (36 mg, 62%) as a white solid. 1H NMR (DMSO-d6) rotamers present δ 8.76 and 8.69 (2H, 2×s); 7.77 and 7.67 (1H, 2×s); 7.45-7.00 (4H, m); 4.91-4.70 (4H, m); 4.36-4.29 (1H, m); 2.31-2.24 (1H, m); 2.06-2.02 (2H, m); 1.94-1.89 (4H, m); 1.56-1.45 (2H, m); LCMS (ESI): 599 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]3[S:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][O:37][CH3:38])[CH2:30][C:29]=3[CH:39]=2)[C:21]([Cl:40])=[CH:20][N:19]=1>>[Cl:40][C:21]1[C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]3[S:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][O:37][CH3:38])[CH2:30][C:29]=3[CH:39]=2)=[N:23][C:18]([NH:14][C:11]2[CH:12]=[CH:13][C:8]3[CH2:7][N:6]([CH2:15][CH3:16])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:9]=3[CH:10]=2)=[N:19][CH:20]=1
Reactant: CCN1CCN(CC)c2cc(N)ccc2C1
Reactant: COCCN1CCSc2ccc(Nc3nc(Cl)ncc3Cl)cc2C1
Product: CCN1CCN(CC)c2cc(Nc3ncc(Cl)c(Nc4ccc5c(c4)CN(CCOC)CCS5)n3)ccc2C1

Procedure:
The title compound was prepared from 1,4-Diethyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[8-(2-methoxy-ethyl)-6,7,8,9-tetrahydro-5-thia-8-aza-benzocyclohepten-2-yl]-amine in an analogous manner to example 730. Product was isolated as a tan solid (0.040 g, 42%). Mp 62-66° C. LCMS (m/e) 568 (M); 1H-NMR (DMSO, 400 MHz) δ 9.17 (s, 1H), 8.80 (s, 1H), 8.13 (s, 1H), 7.62-57 (m, 2H), 7.41-39 (d, 1H, J=8.85 Hz), 7.13-08 (m, 2H), 6.95-89 (d, 1H, J=8.34 Hz), 3.99 (s, 2H), 3.65-55 (s, 2H), 3.48-3.40 (q, 1H, J=5.79 Hz), 3.38-32 (t, 2H, J=5.56 Hz), 3.28-20 (m, 2H), 2.95-85 (m, 6H), 2.82-62 (m, 6H), 2.49-43 (t, 2H, J=5.81 Hz), 2.43-35 (m, 2H), 1.10-0.98 (m, 6H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[N:8]([C@@H:9]2[O:21][C@H:20]([CH3:22])[C@@H:15]([O:16]C(=O)C)[C@H:10]2[O:11]C(=O)C)[CH:7]=[N:6][C:5]=1[C:23]([O:25]C)=O)#[N:2].[NH3:27]>>[C:1]([CH2:3][C:4]1[N:8]([C@@H:9]2[O:21][C@H:20]([CH3:22])[C@@H:15]([OH:16])[C@H:10]2[OH:11])[CH:7]=[N:6][C:5]=1[C:23]([NH2:27])=[O:25])#[N:2]
Reactant: COC(=O)c1ncn([C@@H]2O[C@H](C)[C@@H](OC(C)=O)[C@H]2OC(C)=O)c1CC#N
Reactant: N
Product: C[C@H]1O[C@@H](n2cnc(C(N)=O)c2CC#N)[C@H](O)[C@@H]1O

Procedure:
A mixture of methyl 5-cyanomethyl-1-(5-deoxy-2,3-di-O-acetyl-β-D-ribofuranosyl)imidazole-4-carboxylate (2.20 g, 6.03 mmol) and liquid ammonia (30 ml) was placed in a steel bomb (40 ml) and heated at 100° for 7 hr. The ammonia was allowed to evaporate and the residue was subjected to a vacuum overnight to remove the last traces. The residue was absorbed on silica gel (5 g) and placed on a column of silica gel (60 g, packed in chloroform). Elution with chloroform-methanol (4:1) provided the pure product. Recrystallization from methanol provided colorless cubes (1.42 g, 88%); mp 173°-174° after drying at 100° for 3 hr; [α]D25 -47.8 C=1, H2O); uv λmaxpH 1 218 nm (ε 10,000), λmaxpH 7 233 nm (ε 10,200), λmaxpH 11 234 nm (ε 9,730); pmr (DMSO-d6): δ 1.35 (d,3,CH3), 5.66 (d,1,H1'), J = 5 Hz, 7.45 (d,2,NH2), 8.02 (s,1,C2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:18]=[C:12]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][N:11]2[N:10]=1.[CH2:19]([O:21][C:22]([C:24]1[CH:25]=[N:26][N:27]([CH3:32])[C:28]=1[C:29](O)=[O:30])=[O:23])[CH3:20]>>[CH2:19]([O:21][C:22]([C:24]1[CH:25]=[N:26][N:27]([CH3:32])[C:28]=1[C:29](=[O:30])[NH:17][C:14]1[CH:15]=[CH:16][N:11]2[N:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:18]=[C:12]2[CH:13]=1)=[O:23])[CH3:20]
Reactant: COc1ccccc1-c1nc2cc(N)ccn2n1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3ccccc3OC)nc2c1
Yield: 64.2 %

Procedure:
The product was prepared in the same manner as described in example 28 using 2-(2-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine (365 mg, 1.52 mmol) and 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (331 mg, 1.67 mmol) as starting material. The reaction affords 5-[2-(2-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (410 mg, 64.2%) as white solid. MS: m/z=421.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:19])[CH:11]=[C:10]([C:20](O)=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[N:29]=[CH:28][C:27]([C@H:30]([NH2:32])[CH3:31])=[CH:26][N:25]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:23][C:24]1[N:29]=[CH:28][C:27]([C@H:30]([NH:32][C:20]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH:13]=[C:12]([N:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[O:19])[CH:11]=2)=[O:21])[CH3:31])=[CH:26][N:25]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(N3CCCC3=O)c2)cc1
Reactant: Cc1ncc([C@@H](C)N)cn1
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
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3cnc(C)nc3)cc(N3CCCC3=O)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-methyl-5-(2-oxopyrrolidin-1-yl)biphenyl-3-carboxylic acid (58.0 mg, 0.000167 mol) in N,N-dimethylformamide (1 mL, 0.01 mol) was added (R)-1-(2-methylpyrimidin-5-yl)ethanamine (50.0 mg, 0.000364 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (150.0 mg, 0.0003945 mol) and N,N-diisopropylethylamine (150.0 uL, 0.0008612 mol). The reaction mixture was stirred for 16 hours at 25° C. Checked LC/MS, the reaction was completed. The DMF reaction solution was directly applied to prep. HPLC. The final product was yield a light color foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[C:24]([CH2:26][C:27](O)=[O:28])[N:25]=2)=[N:10]1.[CH:30]([NH2:33])([CH3:32])[CH3:31]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[C:24]([CH2:26][C:27]([NH:33][CH:30]([CH3:32])[CH3:31])=[O:28])[N:25]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(C)NC(c2nc(CC(=O)O)cs2)=NC1c1ccc(F)cc1Br
Reactant: CC(C)N
Product: CCOC(=O)C1=C(C)NC(c2nc(CC(=O)NC(C)C)cs2)=NC1c1ccc(F)cc1Br
Yield: 45 %

Procedure:
2-(2-(4-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-6-methyl-1,4-dihydropyrimidin-2-yl)thiazol-4-yl)acetic acid (3 g, 6.2 mmol) was reacted with isopropylamine (0.55 g, 9.3 mmol) according to the procedure as described in Example 62, Step B to give the title compound as a yellow solid (1.46 g, 45%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.N#N.[H-].[Na+].[CH:15]([Si:18](Cl)([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([Si:18]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:15]([CH3:17])[CH3:16])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Brc1ccc2cc[nH]c2n1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(Br)nc21
Reaction time: 0.67 h
Yield: 55.6 %

Procedure:
A 200-mL round-bottom flask was charged with 6-bromo-1H-pyrrolo[2,3-b]pyridine (2.961 g, 15.03 mmol) and THF (30 ml) to give a yellow solution. The flask was fitted with an N2 sweep, then sodium hydride (60% disperion in mineral oil) (0.721 g, 18.03 mmol) was added over 2 min, and the resulting mixture was stirred for 40 min. Triisopropylsilyl chloride (4.02 ml, 18.79 mmol) was added in one portion, and the mixture was stirred for 30 min before being concentrated in vacuo. The residue was taken up in saturated aq. sodium bicarbonate solution and extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (0 to 10% EtOAc/Heptane) to give 6-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (2.952 g, 8.35 mmol, 55.6% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ=7.72 (d, J=8.1 Hz, 1 H), 7.26 (d, J=3.5 Hz, 1 H), 7.18 (d, J=8.1 Hz, 1 H), 6.53 (d, J=3.5 Hz, 1 H), 1.81 (spt, J=7.5 Hz, 3 H), 1.13 (d, J=7.5 Hz, 18 H).
Reaction SMILES: C([O:4][C@@H:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[O:9][N:8]=1)[CH3:6])(=O)C.O.[OH-].[Li+]>C1COCC1.O>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[O:9][N:8]=[C:7]([C@H:5]([OH:4])[CH3:6])[CH:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)O[C@H](C)c1cc(-c2cccc(Cl)c2)on1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)c1cc(-c2cccc(Cl)c2)on1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
The title compound of Example 16.1 (56 g, 211 mmol) and lithium hydroxide monohydrate (10.6 g, 253 mmol) were mixed with THF/Water (7/5, 1.2 L) and stirred at RT over night. Reducing the volume of the mixture in vacuo to about half, followed by dilution with brine, extraction with ether and then drying over MgSO4 and in vacuo concentration gave crude product. The crude product was purified by flash column chromatography on silica using heptane/EtOAc (7:3) to give the title compound (40 g, 85%).
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].CI.[Br:9][C:10]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2>CN(C=O)C>[CH3:1][O:21][C:20]([C:17]1[CH:18]=[CH:19][C:10]([Br:9])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)=[O:22]
Reactant: O=C(O)c1ccc(Br)c2cccnc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(Br)c2cccnc12
Temperature: 45 °C

Procedure:
K2CO3 (61.3 g, 444.0 mmol) and methyl iodide (63.1 g, 444.0 mmol) were added to a stirred suspension of 5-bromoquinoline-8-carboxylic acid (28.0 g, 111.0 mmol) in DMF (250 mL) at r.t. The reaction mixture was heated at 45° C. for 36 h, cooled to r.t, filtered the solids, washed with ethyl acetate (100 mL). The filtrate was diluted with water, extracted with ethyl acetate (3×300 mL) and washed with water (3×100 mL). The ethyl acetate layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate in hexanes (0-20%) to afford methyl-5-bromoquinoline-8-carboxylate as a cream color solid (20.5 g, 70% for 2 steps). 1H NMR (400 MHz, CDCl3) δ 9.07 (dd, J=4.3, 1.5 Hz, 1H), 8.60 (dd, J=8.7, 1.6 Hz, 1H), 7.88 (s, 2H), 7.58 (dd, J=8.6, 4.0 Hz, 1H), 4.05 (s, 3H)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:12])[O:9][CH2:10][CH3:11])[CH2:3][CH2:2]1.[O:13]1[CH2:28][CH:14]1[CH2:15][O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH2:19][CH2:20][C:21](=[O:27])[NH:22]2.[ClH:29]>C(O)C>[ClH:29].[OH:13][CH:14]([CH2:28][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([O:9][CH2:10][CH3:11])=[O:12])[CH2:5][CH2:6]1)[CH2:15][O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH2:19][CH2:20][C:21](=[O:27])[NH:22]2
Reactant: O=C1CCc2c(cccc2OCC2CO2)N1
Reactant: CCOC(=O)NC1CCNCC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)NC1CCN(CC(O)COc2cccc3c2CCC(=O)N3)CC1
Temperature: 25 °C
Yield: 56.5 %

Procedure:
Ethyl 4-piperidylcarbamate (2 g), from Preparation 4, and 5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril (2.54 g), from Preparation 5, were dissolved in ethanol (50 mL) and the resulting solution was heated under reflux for 6 hours and then cooled to room temperature. Concentrated hydrochloric acid (1 mL) was added. A white product precipitated, which was collected by filtration. The crude product was recrystallized from ethanol to yield 2.8 g (56.5%) of 3,4-dihydro-5-[2-hydroxy-3-(4-(ethoxycarbonylamino)-1-piperidyl)propoxy]carbostyril hydrochloride, m.p. 232°-234° C. (dec.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH:18][CH3:19])(=[O:17])=[O:16])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH2:21]1[N:30]2[C@H:24]([CH2:25][O:26][CH2:27][C:28]3[CH:34]=[C:33]([NH2:35])[CH:32]=[CH:31][C:29]=32)[CH2:23][CH2:22]1>>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH:18][CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:35][C:33]2[CH:32]=[CH:31][C:29]3[N:30]4[C@H:24]([CH2:25][O:26][CH2:27][C:28]=3[CH:34]=2)[CH2:23][CH2:22][CH2:21]4)=[N:3][CH:4]=1
Reactant: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)COC[C@@H]1CCCN21
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)COC[C@@H]2CCCN32)ncc1Cl

Procedure:
Following an analogous procedure to that described in Example 5, the reaction of 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzenesulfonamide and (S)-(2,3,3a,4-Tetrahydro-1H,6H-5-oxa-10b-aza-benzo[e]azulen-8-yl)amine gave 2-{5-Chloro-2-[(S)-(2,3,3a,4-tetrahydro-1H,6H-5-oxa-10b-aza-benzo[e]azulen-8-yl)amino]-pyrimidin-4-ylamino}-N-methyl-benzenesulfonamide, upon purification by flash chromatography (Dichloromethane:MeOH 98:2) followed by trituration with Et2O, as solid (32%)2-{5-Chloro-2-[(S)-(2,3,3a,4-tetrahydro-1H,6H-5-oxa-10b-aza-benzo[e]azulen-8-yl)amino]-pyrimidin-4-ylamino}-N-methyl-benzenesulfonamide; 1H NMR (400 MHz, DMSO-d6) δ9.30 (s, 2H), 8.56 (m, 1H), 8.22 (s, 1H), 7.79 (m, 2H), 7.63 (m, 1H), 7.44 (s, 1H), 7.34 (m, 1H), 7.28 (m, 1H), 6.81 (d, J=8.71 Hz, 1H0, 4.53 (d, J=13.04 Hz, 1H), 4.27 (d, J=13.01 Hz, 1H), 3.88 (d, J=9.54 Hz, 1H), 3.31-3.19 (2m along with water peak, 2H), 2.88 (m, 1H), 2.43 (d, J=4.73 Hz, 3H), 2.07 (m, 1H), 1.84 (m, 1H), 1.47 (m, 1H); MS (m/e) 501, 502 (M+H); mp 187-188° C.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:36][NH:37][CH3:38]>O>[CH3:36][N:37]([CH3:38])[C:2]1[C:11]2[N:12]=[C:13]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCC(CCn2c(-c3ccccc3)nc3c(Cl)nc4ccccc4c32)CC1
Solvent: O
Product: CN(C)c1nc2ccccc2c2c1nc(-c1ccccc1)n2CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 0.69 g of tert-butyl 4-[2-(4-chloro-2-phenyl-1H-imidazo[4,5-c]-quinolin-1-yl)ethyl]-1-piperidinecarboxylate and 7 ml of 50% aqueous dimethylamine solution was stirred in a sealed tube at 80° C. of outer temperature for 2 hours. The reaction solution was added with water and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried, and the solvent was evaporated. The residue was washed successively with isopropanol and diisopropyl ether to give 0.52 g of colorless crystals. Recrystallization from isopropanol gave colorless crystals having the melting point of from 170.5 to 171.5° C.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Br:19]Br>O1CCCC1.ClCCl>[Br:19][C:4]([CH3:3])([C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13]
Reactant: CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: BrBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(Br)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred suspension of sodium hydride (1.7g, 80% dispersion in oil) in tetrahydrofuran (60 ml) under an atmosphere of nitrogen was added di-t-butyl methylmalonate (11.52g). The mixture was stirred at 60°-70° for 1.5 hours to give a clear solution. This solution was cooled to -25°, and to it was rapidly added a solution of bromine (2.6 ml) in dichloromethane (30ml). The solution was allowed to warm to ambient temperature, then concentrated. The residue in ether was washed with water, dried, and fractionally distilled under reduced pressure to give the title compound b.p. 78°-86°/1.0 mm Hg, (7.56g, 49%); νmax (CHBr3) 1730cm-1 (CO2But); τ (CDCl3) values include 8.05 (s, C(CH3)3) and 8.53 (2s, CH3 and C(CH3)3).
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[Cl:24])=O>>[Cl:24][C:23]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[C:16]1[N:1]=[C:2]([C:3]2[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=2[CH3:8])[S:13][CH:15]=1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: O=C(CBr)c1cnccc1Cl
Product: COC(=S)c1cc(-c2nc(-c3cnccc3Cl)cs2)c(C)s1
Yield: 80.4 %

Procedure:
240 mg (0.970 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was reacted with 2-bromo-1-(4-chloro(3-pyridyl))ethan-1-one (1.06 mmol; 250 mg) in a manner similar to Example 22, step (a) to afford 286 mg (77% yield) of methyl 4-[4-(4-chloro(3-pyridyl))(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.