Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C@@H:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)[OH:11])[CH2:5][CH2:4]1.[N:24]1[C:33]2[NH:32][CH2:31][CH2:30][CH2:29][C:28]=2[CH:27]=[CH:26][C:25]=1[CH:34]=O.C(N(CC)CC)C.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>C(Cl)Cl.C(O)C>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[C:12]2[C@@H:10]([OH:11])[CH2:9][N:6]1[CH2:7][CH2:8][CH:3]([NH:2][CH2:34][C:25]2[CH:26]=[CH:27][C:28]3[CH2:29][CH2:30][CH2:31][NH:32][C:33]=3[N:24]=2)[CH2:4][CH2:5]1
Reactant: COc1ccc2nccc([C@@H](O)CN3CCC(N)CC3)c2c1
Reactant: O=Cc1ccc2c(n1)NCCC2
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2nccc([C@@H](O)CN3CCC(NCc4ccc5c(n4)NCCC5)CC3)c2c1
Reaction time: 36 h
Yield: 69 %

Procedure:
To a stirred solution of the mono hydrochloride salt of (R)-2-(4-aminopiperidin-1-yl)-1-(6-methoxyquinolin-4-yl) ethanol (1d) (0.34 g, 1.0 mmole) in CH2Cl2 (25 mL) and dry ethanol (10 mL) at RT was added 5,6,7,8-tetrahydro[1,8]naphthyridine-2-carboxaldehyde (prepared according to the procedure of WO 98/08840, 0.17 g, 1.0 mmole), triethylamine (0.10 g, 1.0 mmole), and granular Na2SO4 (approximately 200 mg). After 36 h, the reaction was filtered through a sintered-glass funnel and the filtrate was concentrated. The remaining residue was dissolved in dry ethanol and reacted with NaBH4 (0.04 g, 1.0 mmole). After 12 h at RT, the reaction was concentrated under vacuum and the residue was dissolved in a mixture of H2O (2 mL) and saturated aqueous NaHCO3 (10 mL). The aqueous solution was extracted with EtOAc (2×50 mL) and the combined organic phases were washed with brine then were dried over Na2SO4. Flash chromatography on silica gel (9:1 CHCl3/MeOH containing 5% NH4OH) afforded the title compound (0.31 g, 69%) as a white solid:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:17]3[C:12]([C:13]([NH2:18])=[N:14][CH:15]=[N:16]3)=[C:11]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[NH2:18][C:13]1[C:12]2=[C:11]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=[C:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[CH2:2][NH:1][S:36]([CH3:35])(=[O:38])=[O:37])[N:17]2[N:16]=[CH:15][N:14]=1
Reactant: NCc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)NCc1cccc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)c1
Yield: 8 %

Procedure:
Using a procedure similar to that of Example 5 and 7-(3-aminomethyl-phenyl)-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and methanesulfonyl chloride as starting materials, 18 mg (8%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 4.20 (s, 2 H), 2.90 (s, 2 H), 2.80 (s, 3 H); ES-MS m/z 524.3 [M+H]+, HPLC RT (min) 2.84.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12](=O)[CH2:13][CH3:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:16][NH:17][S:18](Cl)(=[O:20])=[O:19].[BH4-].[Na+]>>[CH2:13]([CH:12]1[C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[N:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[NH:1][S:18](=[O:20])(=[O:19])[N:17]1[CH3:16])[CH3:14]
Reactant: CCC(=O)c1ccc2cccnc2c1N
Reactant: CNS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Product: CCC1c2ccc3cccnc3c2NS(=O)(=O)N1C
Yield: 9 %

Procedure:
In a similar fashion using route 27 general procedure 71, 1-(8-amino-quinolin-7-yl)-propan-1-one 410 (300 mg, 1.6 mmol), N-methylsulfamyl chloride 213 (1 g, 7.7 mmol) and NaBH4 (20 mg, 0.54 mmol) gave the title compound (40 mg, 10%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][S:9]Cl)=[CH:4][CH:3]=1.[CH3:11][NH:12][C:13]([F:15])=[O:14]>>[CH3:11][N:12]([S:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:13]([F:15])=[O:14]
Reactant: ClSSc1ccc(Cl)cc1
Reactant: CNC(=O)F
Product: CN(SSc1ccc(Cl)cc1)C(=O)F

Procedure:
Prepared by the procedure of Example II by reacting 4-chlorophenylthiosulfenyl chloride with methylcarbamoyl fluoride. b.p. 110°-113° C/0.3 Torr ND24 1.5959.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]3[C:17]4[N:16]=[CH:15][N:14]=[CH:13][C:12]=4[CH:11]=[CH:10][C:9]=3[C:4]=2[N:3]=[CH:2]1.[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])#[CH:19]>C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:21][Si:20]([C:18]#[C:19][C:4]1[CH:5]=[C:6]([C:13]2[C:12]3[CH:11]=[CH:10][C:9]4[C:4]5[N:3]=[CH:2][NH:1][C:5]=5[CH:6]=[CH:7][C:8]=4[C:17]=3[N:16]=[CH:15][N:14]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:23])[CH3:22]
Reactant: c1ncc2ccc3c(ccc4[nH]cnc43)c2n1
Reactant: C#C[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc(-c2ncnc3c2ccc2c3ccc3[nH]cnc32)c1
Reaction time: 3.5 h
Yield: 70.5 %

Procedure:
A slurry of 3.00 g (9.02 mmoles) of 6-bromophenyl)benzimidazoquinazoline, 100 mg of diacetatobis(triphenylphosphine)palladium[II] in 150 ml of 2:1 triethylamine-toluene was heated to 100° C. under argon and then treated with dropwise addition of 1.57 g (16.0 mmoles) of ethynyltrimethylsilane. After 3.5 hours, the mixture was cooled and filtered. The filtrate was diluted with 100 ml of ether, washed with 200 ml each of 5% hydrochloric acid and water, and then dried over magnesium sulfate. Concentrating the clear solution yielded a solid mass which upon trituration with hexane gave 2.21 g (56.5 mmoles, 70.5%) of 6-(m-trimethylsilylethynylphenyl)benzimidazoquinazoline: ir (KBr): 3077 (medium, sharp, C-H), 2960 (medium, sharp, SiCH), 2155 (strong, sharp, C≡C), 1621, 1587 (v. strong, sharp, C=N), 1524, 1456, 1441, 1355, 1325 (strong, sharp, C=C), 1247 (v. strong, sharp, Si--C) and 844 cm-1 (v. strong, broad, Si--C bending); mass spectrum (70 ev) m/e 391.
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6](=O)[C:7]([F:10])([F:9])[F:8])[CH2:3][CH2:2]1.Cl.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1>CC(O)=O>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:5][C:6]([C:7]([F:10])([F:9])[F:8])=[N:22]2)=[CH:17][CH:16]=1
Reactant: NNc1ccc(Br)cc1
Reactant: O=C(CC(=O)C(F)(F)F)C1CC1
Agent: Cl
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(C2CC2)n(-c2ccc(Br)cc2)n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 90.2 %

Procedure:
1-Cyclopropyl-4,4,4-trifluorobutane-1,3-dione (1.330 g) was added to a mixture of (4-bromophenyl)hydrazine hydrochloride (1.65 g) and AcOH (10 mL). The mixture was stirred at 120° C. for 1 hr. AcOH was removed in vacuo and the residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give 1-(4-bromophenyl)-5-cyclopropyl-3-(trifluoromethyl)-1H-pyrazole (2.2059 g) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:21]=[C:20]([O:22][C:23]3[CH:24]=[N:25][C:26]([NH:29][C:30]([NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[O:31])=[CH:27][CH:28]=3)[CH:19]=[CH:18][N:17]=2)=[CH:12][CH:11]=1)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][NH:2][C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:21]=[C:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33](=[O:38])[C:34]([CH3:36])([CH3:35])[CH3:37])=[O:31])=[N:25][CH:24]=3)[CH:19]=[CH:18][N:17]=2)=[CH:12][CH:11]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(-c2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)C)nc3)ccn2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(-c2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)C)nc3)ccn2)cn1
Temperature: 25 °C
Reaction time: 7 h
Yield: 75.6 %

Procedure:
A mixture of tert-butyl methyl(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)-[2,3′-bipyridin]-6′-yl)carbamate (0.1 g, 0.192 mmol) and TFA (0.148 mL, 1.921 mmol) in DCM (4 mL) was stirred at RT for 7 h, then concentrated to dryness. The residue was treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness. The material was treated with 30% EtOAc/Hex, sonicated and the resulting solid collected via filtration to afford N-((5-((6′-(methylamino)-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide (61 mg, 76%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.21 (s, 1H), 10.42 (s, 1H), 8.69 (d, J=2.4 Hz, 1H), 8.44 (d, J=5.7 Hz, 1H), 8.27 (d, J=2.9 Hz, 1H), 8.09 (d, J=9.0 Hz, 1H), 8.02 (dd, J=8.8, 2.5 Hz, 1H), 7.75 (dd, J=9.0, 2.9 Hz, 1H), 7.39 (d, J=2.4 Hz, 1H), 6.83 (q, J=5.0 Hz, 1H), 6.73 (dd, J=5.7, 2.4 Hz, 1H), 6.48 (d, J=8.8 Hz, 1H), 2.80 (d, J=4.7 Hz, 3H), 1.21 (s, 9H); MS (ESI) m/z: 421.2 (M+H+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26]2[NH:29][N:30]=[C:31]([C:32](O)=[O:33])[C:25]=2[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH:10]1[CH2:11][CH2:12][N:13]([C:32]([C:31]2[C:25]3[CH2:24][N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:28][CH2:27][C:26]=3[NH:29][N:30]=2)=[O:33])[CH2:14][CH2:15]1
Reactant: Fc1ccc(Cl)c(C2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)O)c2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)N3CCC(c4cc(F)ccc4Cl)CC3)c2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.2 %

Procedure:
To a solution of 4-(2-chloro-5-fluorophenyl)piperidine hydrochloride (17, 70 mg, 0.28 mmol), 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (89 mg, 0.34 mmol), and diisopropylethylamine (0.15 mL, 0.84 mmol) in DMF (5.4 mL) was added EDCI (64 mg, 0.34 mmol) and HOBt (45 mg, 0.34 mmol). The resulting solution was stirred at ambient temperature for 24 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (4×20 mL). The combined organic extracts were washed with a saturated brine solution (8×20 mL), H2O (20 mL), and concentrated to dryness under reduced pressure. The obtained residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 100% EtOAc in hexanes) to give tert-butyl 3-(4-(2-chloro-5-fluorophenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (49) as a white solid (78 mg, 60%): 1H NMR (300 MHz, DMSO-d6) δ 12.96 (s, 1H), 7.48 (dd, J=8.7, 5.4 Hz, 1H), 7.34-7.21 (m, 1H), 7.16-7.06 (m, 1H), 5.28-5.11 (m, 1H), 4.77-4.57 (m, 1H), 4.53-4.38 (m, 2H), 3.66-3.52 (m, 2H), 3.30-3.04 (m, 2H, overlaps with H2O), 2.92-2.61 (m, 3H), 1.92-1.74 (m, 2H), 1.69-1.49 (m, 2H), 1.41 (s, 9H); ESI MS m/z 462 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:6]([CH3:18])[CH:5]=1)([O-])=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:31].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:31].[ClH:31].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:6]([CH3:18])[CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1NCCCCCCO
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Cc1cc(N)ccc1NCCCCCCO

Procedure:
The 6-(4-nitro-2-methylphenylamino)hexan-1-ol (11) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [CH2:1]([CH2:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1>>[CH2:1]([CH2:8][NH:9][CH:13]1[CH2:14][CH2:15][O:10][CH2:11][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCc1ccccc1
Reactant: O=C1CCOCC1
Product: c1ccc(CCNC2CCOCC2)cc1

Procedure:
The title compound was prepared according to Preparation 85 from N-benzylmethylamine and tetrahydro-4H-pyran-4-one. Purification of the crude material by chromatography using dichloromethane/methanol (98:2) as the eluent gave the title compound as a yellow oil. δH (CD3OD): 7.50–7.40 (5H, m), 4.08 (2H, m), 4.06-(2H, s), 3.49–3.40 (2H, ddd), 3.23–3.14 (1H, m), 2.51 (3H, s), 2.03–1.97 (2H, m), 1.89–1.76 (2H, m).
Reaction SMILES: Cl.[F:2][C:3]([F:20])([F:19])[C:4]1[CH:5]=[C:6]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([NH2:18])[CH:15]=[N:16][CH:17]=2)[CH:7]=[CH:8][CH:9]=1.Cl[C:22]([O:24][CH3:25])=[O:23]>>[CH3:25][O:24][C:22](=[O:23])[NH:18][C:14]1[CH:15]=[N:16][CH:17]=[C:12]([C:11]#[C:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:3]([F:2])([F:19])[F:20])[CH:5]=2)[CH:13]=1
Reactant: COC(=O)Cl
Reactant: Nc1cncc(C#Cc2cccc(C(F)(F)F)c2)c1
Agent: Cl
Product: COC(=O)Nc1cncc(C#Cc2cccc(C(F)(F)F)c2)c1
Yield: 48.6 %

Procedure:
Prepare essentially as described in EXAMPLE 158 using 5-(3-trifluoromethylphenylethynyl)-pyridin-3-ylamine hydrochloride, (prepared as described in EXAMPLE 155), (151 mg, 0.45 mmol) and methyl chloroformate (0.03 mL, 0.45 mmol) to give the title compound (70 mg, 49%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)=[O:14])=[CH:11][C:10]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[N-:43]=[N+:44]=[N-].[Na+].C([O-])(=O)C.[Na+].[OH-].[Na+]>Cl.O.C(OCC)(=O)C>[N:1]([C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=3)=[O:14])=[CH:11][C:10]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:4][CH:3]=1)=[N+:43]=[N-:44]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3Sc3ccc(N)cc3)ncnc2n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cc4)ccc3Sc3ccc(N=[N+]=[N-])cc3)ncnc2n1
Reaction time: 1 h
Yield: 32.2 %

Procedure:
A solution of the product of Example 13E (62.4 mg, 0.1066 mmol) in concentrated hydrochloric acid (2 mL) cooled to 0°-5° was treated dropwise with a solution of sodium nitrite (14.7 mg, 0.2131 mmol) in water (1 mL). After stirring at 0° for 1 hour, a solution of sodium azide (13.8 mg, 0.2131 mmol) and sodium acetate (72.6 mg, 0.885 mmol) in water (2 mL) was added dropwise at 0°, and the reaction stirred for 1 hour at 0°. The reaction was then diluted with water (25 mL) and ethyl acetate (50 mL), the aqueous pH was adjusted to 7-8 with 6N aqueous sodium hydroxide, the layers were separated, and the organic phase washed with brine (25 mL). The organic was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation under vacuum. The resultant residue was purified by silica gel flash chromatography using 30% ethyl acetate/methylene chloride as eluent to afford the title compound as a yellow solid (21 mg, 32%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.62 Hz, 6 H) 3.11-3.32 (m, 1 H) 7.10 (d, J=8.46 Hz, 2 H) 7.21 (d, J=8.46 Hz, 1 H) 7.41 (d, J=8.46 Hz, 2 H) 7.53 (d, J=8.82 Hz, 2 H) 7.63 (d, J=8.46 Hz, 1 H) 7.74 (d, J=9.19 Hz, 2 H) 7.81-7.91 (m, 1 H) 8.03 (d, J=1.10 Hz, 1 H) 8.58 (s, 1 H) 8.82 (d, J=8.46 Hz, 1 H) 10.23 (s, 1 H) 10.39 (s, 1 H); MS (ESI+) m/z 611/613 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[CH3:9][O:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2[C:20]([CH2:30]C(C)C)=[C:21](C)C=CC=2S([O-])(=O)=O)[CH:16]=[CH:17][CH:18]=1>[OH-].[Na+]>[CH3:9][O:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH2:19][CH:20]([CH3:30])[CH2:21][N:4]2[CH2:5][CH:6]([CH3:8])[O:7][CH:2]([CH3:1])[CH2:3]2)[CH:16]=[CH:17][CH:18]=1
Reactant: COCOc1cccc(-c2c(S(=O)(=O)[O-])ccc(C)c2CC(C)C)c1
Reactant: CC1CNCC(C)O1
Agent: [Na+]
Agent: [OH-]
Product: COCOc1cccc(CC(C)CN2CC(C)OC(C)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.4 %

Procedure:
2,6-Dimethylmorpholine (10.0 g) was heated to 100° C. with stirring, and 3-(m-methoxymethoxyphenyl)-2-methylpropyl-p-toluenesulfonate (5.0 g) was dropwise added thereto in 1 hour. The reaction mixture was aged at 100° C. for 2 hours with stirring, cooled to room temperature, and after addition of 15% aqueous sodium hydroxide (50 ml), extracted with diethyl ether (50 ml×3). The organic layer was combined, washed with a saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to give 4-[3-(m-methoxymethoxyphenyl)-2-methylpropyl]-2,6-dimethylmorpholine (1.2 g).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[CH3:10][NH:11][CH2:12][CH2:13][NH2:14]>C(OCC)C>[F:9][C:2]([F:1])([F:8])[C:3]([NH:14][CH2:13][CH2:12][NH:11][CH3:10])=[O:5]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CNCCN
Solvent: CCOCC
Product: CNCCNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl trifluoroacetate (10 ml) in diethyl ether (20 ml) in an ice bath was added dropwise N-methylethylenediamine (7.4ml) for one hr. After addition, the reaction mixture was warmed to room temperature and stirred for 2 hr. Removal of ethyl ether from the reaction mixture gave the titled compound (14 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=1[CH3:25].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(Br)cc21
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: O
Solvent: CN1CCOCC1
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.4 %

Procedure:
To a mixture of 6-bromo-1-(1-methylethyl)-1H-indazole-4-carboxylic acid (0.52 g, 1.837 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (0.485 g, 2.57 mmol), 1-hydroxy-7-azabenzotriazole (0.375 g, 2.76 mmol) and EDC (0.528 g, 2.76 mmol) in dimethyl sulfoxide (15 mL) was added N-methylmorpholine (0.606 mL, 5.51 mmol) via syringe. The reaction was stirred at RT for 48 h. The contents were slowly diluted into 200 mL of water, stirred for 10 min, then allowed to sit for 20 min. The suspension was filtered. The collected solid was washed with about 50 mL of water, filtered, air dried for 15 min then dried in vac oven to afford the title compound (0.67 g, 85%), which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (d, J=6.57 Hz, 6H) 2.12 (s, 3H) 2.20 (s, 3H) 4.33 (d, J=5.05 Hz, 2H) 5.05 (quin, J=6.57 Hz, 1H) 5.89 (s, 1H) 7.71 (d, J=1.26 Hz, 1H) 8.20 (s, 1H) 8.37 (s, 1H) 8.62 (t, J=4.67 Hz, 1H) 11.54 (s, 1H). MS (ES) [M+H]+ 417.1.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6]C)=[O:5].CN(C)C=O.[CH2:13]([NH:15][C:16]([N:18]1[C:26]2[C:21](=[CH:22][C:23]([O:27][C:28]3[CH:33]=[CH:32][N:31]=[C:30]([N:34](C(OC4C=CC=CC=4)=O)[C:35](=O)[O:36]C4C=CC=CC=4)[CH:29]=3)=[CH:24][CH:25]=2)[CH:20]=[CH:19]1)=[O:17])[CH3:14]>C(N(CC)CC)C>[CH2:13]([NH:15][C:16]([N:18]1[C:26]2[C:21](=[CH:22][C:23]([O:27][C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35]([NH:2][CH2:3][C:4]([OH:6])=[O:5])=[O:36])[CH:29]=3)=[CH:24][CH:25]=2)[CH:20]=[CH:19]1)=[O:17])[CH3:14]
Reactant: COC(=O)CN
Reactant: CCNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)NCC(=O)O)c3)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 80.5 %

Procedure:
Methyl aminoacetate hydrochloride (292 mg, 2.33 mmol) was suspended in a solvent mixture of N,N-dimethylformamide (4 ml) and triethylamine (1 ml); phenyl N-(4-(1-(ethylamino)carbonyl-1H-5-indolyloxy)-2-pyridyl)-N-(phenoxycarbonyl)carbamate (250 mg, 0.466 mmol, Production example 55-1) was added thereto; and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in a solvent mixture of tetrahydrofuran (2 ml) and methanol (1 ml); and 4N aqueous solution of sodium hydroxide was added thereto while stirred at room temperature; and the reaction mixture was stirred for 1.5 hour at room temperature. After 1N hydrochloric acid was added, extraction was performed with ethyl acetate-tetrahydrofuran, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crystals were suspended in diethyl ether, filtered off, washed with dimethyl ether, and dried under aeration to yield the title compound as colorless crystals (149 mg, 0.375 mmol, 80.5%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13](=[O:15])(=[O:14])[C:12]3[CH:16]=C(C#N)[CH:18]=[CH:19][C:11]=3[CH2:10][CH2:9][C:8]=2[CH:22]=1)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[C:28]([OH:31])(=[O:30])[CH3:29]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13](=[O:14])(=[O:15])[C:12]3[CH:16]=[C:29]([C:28]([OH:31])=[O:30])[CH:18]=[CH:19][C:11]=3[CH2:10][CH2:9][C:8]=2[CH:22]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(=O)c1ccc2c(c1)CCc1ccc(C#N)cc1S2(=O)=O
Agent: O=S(=O)(O)O
Product: CC(=O)c1ccc2c(c1)CCc1ccc(C(=O)O)cc1S2(=O)=O
Temperature: 25 °C

Procedure:
Suspend 2.2 g. of 8-acetyl-3-cyano-10,11-dihydrodibenzo[b,f]thiepin-5,5-dioxide in 60 ml. of acetic acid and 60 ml. of 50% sulfuric acid. Reflux under a nitrogen atmosphere for 6 hours. Cool to room temperature. Evaporate the acetic acid, dilute with water and separate the solids by filtration. Wash with water and air dry. Suspend the solid in ether (200 ml.), stir at room temperature and filter to obtain the title product. (m.p. 219°-221° C.)
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Br[C:16]1[CH:17]=[C:18]([C:23]2[C:24]([C:30]#[N:31])=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH:19]=[C:20]([F:22])[CH:21]=1>>[F:29][C:26]1[CH:25]=[C:24]([C:30]#[N:31])[C:23]([C:18]2[CH:17]=[C:16]([C:12]3[N:4]4[CH:5]=[CH:6][C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:2]([F:1])[C:3]4=[N:14][CH:13]=3)[CH:21]=[C:20]([F:22])[CH:19]=2)=[CH:28][CH:27]=1
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Reactant: N#Cc1cc(F)ccc1-c1cc(F)cc(Br)c1
Product: CC(C)(O)c1ccn2c(-c3cc(F)cc(-c4ccc(F)cc4C#N)c3)cnc2c1F
Yield: 20.5 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol (58 mg, 0.3 mmol) and 3′-bromo-4,5′-difluorobiphenyl-2-carbonitrile (106 mg, 0.36 mmol) were coupled following the procedure in Example 6 to afford 4,3′-difluoro-5′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]-biphenyl-2-carbonitrile (25 mg, 20%) as a white solid: δH (500 Ndz, CDCl3) 1.74 (6H, s), 2.07 (1H, s), 7.22-7.26 (2H, m), 7.35 (1H, d, J 9), 7.39-7.45 (1H, m), 7.51-7.57 (3H, m), 7.76 (1H, s), 8.35 (1H, d, J 7); m/z (ES+) 408 (100%, [MH]+).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([CH3:14])([CH3:13])/[C:4](/O)=[CH:5]/[C:6](=[O:11])/[CH:7]=[CH:8]/[O:9]C.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[F:16][C:2]([F:1])([F:15])[C:3]([C:4]1[O:9][CH:8]=[CH:7][C:6](=[O:11])[CH:5]=1)([CH3:13])[CH3:14]
Reactant: CO/C=C/C(=O)/C=C(\O)C(C)(C)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)(c1cc(=O)cco1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.8 %

Procedure:
To a mixture of (1E,4Z)-7,7,7-trifluoro-5-hydroxy-1-methoxy-6,6-dimethylhepta-1,4-dien-3-one (1 g, 4.20 mmol) in toluene (5 mL) was added TFA (0.647 mL, 8.40 mmol). The mixture was stirred at 25° C. for 16 h. Then the mixture was concentrated to afford 2-(1,1,1-trifluoro-2-methylpropan-2-yl)-4H-pyran-4-one (800 mg, 3.10 mmol, 73.9% yield). TLC (PE/EA=1:1, Rf=0.2): 1H NMR (400 MHz, CD3OD): δ 8.12 (d, J=6.0 Hz, 1H), 6.53 (d, J=2.4 Hz, 1H), 6.39 (dd, J=2.4, 6.0 Hz, 1H), 1.53 (s, 6H). ES-LCMS m/z 207.1 (M+H).