Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH:9]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:10]([N:12]1[CH2:16][CH:15]([O:17][C:18]2[C:27]3[C:22](=[C:23]([Cl:28])[CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]([O:29][CH2:30][CH3:31])[CH:19]=2)[CH2:14][CH:13]1[C:32]([NH:34][C:35]1([C:40]([OH:42])=[O:41])[CH2:37][CH:36]1[CH2:38][CH3:39])=[O:33])=[O:11])=O)(C)(C)C.Cl.[F:48][C:49]([F:68])([F:67])[C:50]1([O:54][C:55](=[O:66])OC2C=CC([N+]([O-])=O)=CC=2)[CH2:53][CH2:52][CH2:51]1.OS([O-])(=O)=O.[K+]>ClCCl.C(N(CC)CC)C>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:22]=1[N:21]=[C:20]([O:29][CH2:30][CH3:31])[CH:19]=[C:18]2[O:17][CH:15]1[CH2:16][N:12]([C:10](=[O:11])[CH:9]([NH:8][C:55]([O:54][C:50]2([C:49]([F:48])([F:67])[F:68])[CH2:51][CH2:52][CH2:53]2)=[O:66])[C:43]([CH3:44])([CH3:46])[CH3:45])[CH:13]([C:32]([NH:34][C:35]2([C:40]([OH:42])=[O:41])[CH2:37][CH:36]2[CH2:38][CH3:39])=[O:33])[CH2:14]1
Reactant: CCOc1cc(OC2CC(C(=O)NC3(C(=O)O)CC3CC)N(C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C2)c2cccc(Cl)c2n1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1(C(F)(F)F)CCC1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(OC2CC(C(=O)NC3(C(=O)O)CC3CC)N(C(=O)C(NC(=O)OC3(C(F)(F)F)CCC3)C(C)(C)C)C2)c2cccc(Cl)c2n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50.4 %

Procedure:
To 1-{[1-(2-tert-butoxycarbonylamino-3,3-dimethyl-butyryl)-4-(8-chloro-2-ethoxy-quinolin-4-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-ethyl-cyclopropanecarboxylic acid (200 mg, 0.3 mmol) in dichloromethane (4 mL) was added HCl (4N in dioxane) at room temperature. After 2 h, analysis of the reaction mixture by LC-MS showed complete conversion of starting material. At this point, the reaction was cooled to 0° C. and triethylamine (2 mL) was added dropwise, followed by carbonic acid 4-nitro-phenyl ester 1-trifluoromethyl-cyclobutyl ester (300 mg, 1 mmol). The reaction was allowed to warm to room temperature and stirred 14 h. The reaction mixture was then poured into a 1N solution of KHSO4(aq) and extracted with ethyl acetate. The combined organic extracts were washed with 1N KHSO4(aq), water, and brine, and subsequently dried over magnesium sulfate. Concentration, followed by purification by reverse phase HPLC and lyophilization gave 110 mg (50% yield) of 1-({4-(8-chloro-2-ethoxy-quinolin-4-yloxy)-1-[3,3-dimethyl-2-(1-trifluoromethyl-cyclobutoxycarbonylamino)-butyryl]-pyrrolidine-2-carbonyl}-amino)-2-ethyl-cyclopropanecarboxylic acid as a white powder. LCMS found 727.03 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH2:10]([NH:16][C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCN
Reactant: CCOC(=O)C(F)(F)F
Product: CCCCCCNC(=O)C(F)(F)F

Procedure:
In a manner similar to Example 6, ethyl trifluoroacetate (131 g, 0.92 m) was reacted with n-hexylamine. The resulting amide distilled at 64° C./0.2 mm Hg and amounted to 154 g.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.I[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])(=O)C.[K+]>CN(C)C(=O)C.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:7]1([C:5]2[S:1][CH:2]=[N:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1cscn1
Reactant: Ic1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: c1ccc(-c2cncs2)cc1
Temperature: 100 °C

Procedure:
A solution of thiazole (10.0 g), iodobenzene (2.63 ml), tetrakis(triphenylphosphine)palladium (0) (1.36 g) and potassium acetate (3.46 g) in N,N-dimethylacetamide (100 ml) was stirred under heating at 100° C. overnight. The solvent was evaporated under reduced pressure, and added to the residue was ethyl acetate. The mixture was washed successively with water and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-90:10) to give 5-phenylthiazole (1.50 g) as a pale yellow solid. APCI-Mass m/Z 162 (M+H). (2) The above 5-phenylthiazole and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 100 to give 5-bromo-2-chloro-1-(5-phenyl-2-thiazolylmethyl)benzene as a yellow solid. APCI-Mass m/Z 364/366 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10](I)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>>[OH:1][C:2]1[CH:11]=[C:10]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: C#C[Si](C)(C)C
Product: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1O
Yield: 85.5 %

Procedure:
Following the basic procedure of Example 1(a), by reacting 34 g (122 mmol) of methyl 2-hydroxy-4-iodobenzoate with 34 ml (244 mmol) of trimethylsilylacetylene, 25.9 g (85%) of the expected compound were obtained in the form of a brown oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br-].[CH2:23]([Zn+])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:23]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Reactant: [Zn+]Cc1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Cc5ccccc5)nc34)cc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
Argon was bubbled through a slurry of bis(4-(di-tert-butylphosphino)-N,N-dimethylbenzenamine)palladium dichloride (Aldrich; 10.23 mg, 0.014 mmol), 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1, 0.043 g, 0.144 mmol), and benzylzinc bromide (0.5 M solution in THF; Aldrich; 1.155 ml, 0.578 mmol) in 1.5 mL THF for 2 min. The reaction mixture was sealed and heated to 70° C. After 1 h, the reaction was cooled to RT. The mixture was concentrated, dissolved in DMSO+1-2 drops TFA, filtered, and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 15-100% ACN/H2O with 0.1% TFA); product-containing fractions were concentrated in vacuo and the residue was treated with saturated aq. NaHCO3 and DCM. The aq. layer was extracted 3×DCM and combined organics dried over Na2SO4, filtered, and concentrated in vacuo to give 2-(2-benzylquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.026 g, 0.074 mmol, 50.9% yield): 1H NMR (400 MHz, DMSO-d6) δ ppm 12.17 (1H, br. s), 8.35 (1H, d, J=8.6 Hz), 8.14 (1H, dd, J=7.4, 1.4 Hz), 7.76 (1H, dd, J=8.0, 1.4 Hz), 7.50-7.60 (2H, m), 7.33-7.43 (4H, m), 7.24-7.30 (1H, m), 7.11 (1H, d, J=2.3 Hz), 6.94-7.00 (1H, m), 4.45 (2H, s), 3.38-3.46 (2H, m), 2.80 (2H, t, J=6.9 Hz). m/z (ESI, +ve) 353.9 (M+H)+.
Reaction SMILES: [ClH:1].CC([N:6]([C:10]1([C:16]([NH:18][C@@H:19]([CH2:33][CH3:34])/[CH:20]=[CH:21]/[C:22]([N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)=[O:23])=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)C(=O)[O-])(C)C>C(O)(C)C>[ClH:1].[NH2:6][C:10]1([C:16]([NH:18][C@@H:19]([CH2:33][CH3:34])/[CH:20]=[CH:21]/[C:22]([N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)=[O:23])=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: CC[C@@H](/C=C/C(=O)N1CCc2ccccc21)NC(=O)C1(N(C(=O)[O-])C(C)(C)C)CCOCC1
Agent: Cl
Solvent: CC(C)O
Product: CC[C@@H](/C=C/C(=O)N1CCc2ccccc21)NC(=O)C1(N)CCOCC1
Temperature: 65 °C
Yield: 89.4 %

Procedure:
A solution of concentrated aq. HCl (0.23 mL, 2.76 mmol) was added to a solution of 1,1-dimethylethyl[4-({[(1S,2E)-4-(2,3-dihydro-1H-indol-1-yl)-1-ethyl-4-oxo-2-buten-1-yl]amino}carbonyl)tetrahydro-2H-pyran-4-yl]carbamate (251 mg, 0.549 mmol) in isopropanol (2.5 mL). The reaction flask was fitted with an air condenser, and the reaction mixture was heated to 65° C. (bath temp) for 1 h 45 min. The solvent was evaporated under reduced pressure. Water (5 mL) was added to the residue, and the mixture was concentrated under reduced pressure at 65° C. Water (2 mL) was added to the residue, and the mixture was lyophilized, giving 193.3 mg (89%) of the title compound. LC-MS m/z 358 (M+H)+, 0.68 (ret time). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.14 (br. s., 1H); 7.25 (d, J=7.03 Hz, 1H); 7.18 (t, J=7.53 Hz, 1H); 7.02-7.09 (m, 1H); 6.83 (dd, J=15.18, 6.65 Hz, 1H); 6.49 (d, J=14.8 Hz, 1H); 4.56 (d, J=7.28 Hz, 1H); 4.22 (br. s., 2H); 3.95 (d, J=7.53 Hz, 1H); 3.88-3.94 (m, 1H); 3.71-3.78 (m, 2H); 3.23 (br. s., 2H); 2.39-2.46 (m, 2H); 1.79-1.86 (m, 2H); 1.75 (s, 1H); 1.72 (d, J=8.28 Hz, 1H); 1.00 (t, J=7.40 Hz, 3H).
Reaction SMILES: [C:1]([NH:5][C:6]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[C:8](=[C:9]([C:18]3[CH:19]=[C:20]4[C:25](=[O:26])[N:24](CC5C=CC(OC)=CC=5OC)[CH2:23][CH2:22][N:21]4[CH:38]=3)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([NH:5][C:6]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[C:8](=[C:9]([C:18]3[CH:19]=[C:20]4[C:25](=[O:26])[NH:24][CH2:23][CH2:22][N:21]4[CH:38]=3)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN2CCn3cc(-c4cccc5c(=O)n(C)c(NC(C)(C)C)nc45)cc3C2=O)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(NC(C)(C)C)nc2c(-c3cc4n(c3)CCNC4=O)cccc2c1=O
Yield: 68.4 %

Procedure:
A solution of 2-(tert-butylamino)-8-(2-(2,4-dimethoxybenzyl)-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)-3-methylquinazolin-4(3H)-one (449a) (10 mg, 0.02 mmol) in 1 mL of DCM and 0.2 mL of TFA was heated in an oil bath at 50° C. for 4 h. The reaction mixture was concentrated under reduced pressure. The brown residue was partitioned between 25 mL of EtOAc and 3 mL of 0.5 N NaOH. The EtOAc layer was separated, washed with 5 mL of brine, and concentrated. The residue was purified on a silica gel column (1-5% MeOH in DCM) to afford 2-(tert-butylamino)-3-methyl-8-(1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-7-yl)quinazolin-4(3H)-one (449) (5 mg, 70% yield) as an off white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (1H, dd, J=7.8, 1.6 Hz), 7.70 (1H, dd, J=7.4, 1.6 Hz), 7.64 (1H, d, J=1.6 Hz), 7.60 (1H, br.), 7.10 (1H, d, J=1.6 Hz), 7.06 (1H, t, J=7.6 Hz), 5.74 (1H, s), 4.06 (2H, m), 3.46 (2H, t, J=7.1 Hz), 3.39 (3H, s), 1.45 (9H, s). m/z (ESI, +ve) 366.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[C:24]1(/[CH:30]=[CH:31]/B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:20]([C:14]1[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]2[C:5]3[CH:4]=[CH:3][C:2](/[CH:31]=[CH:30]/[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=1)[CH2:21][CH2:22][CH3:23]
Reactant: OB(O)/C=C/c1ccccc1
Reactant: CCCCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)C
Product: CCCCc1nc2c(N)nc3cc(/C=C/c4ccccc4)ccc3c2n1CC(C)C

Procedure:
7-Bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and trans-2-phenylvinylboronic acid were coupled according to the general procedure described in Part J of Example 1. Recrystallization from toluene followed by chromatography on silica gel (8% methanol in CH2Cl2) afforded 2-butyl-1-isobutyl-7-[(E)-2-phenylethenyl]-1H-imidazo[4,5-c]quinolin-4-amine, m.p. 215-216° C.
Reaction SMILES: [CH3:1][C@@H:2]1[C@:26]2([O:32][CH2:31][C@H:29]([CH3:30])[CH2:28][CH2:27]2)[O:25][C@H:4]2[CH2:5][C@@H:6]3[C@@:20]([CH3:21])([C@@H:3]12)[C@H:19]([OH:22])[C:18](=[O:23])[C@H:17]1[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[C@:15]1([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:24])[CH2:11]2.[C:33]([Si:37]([CH3:40])([CH3:39])Cl)([CH3:36])([CH3:35])[CH3:34].N1C=CN=C1>CN(C=O)C>[Si:37]([O:24][C@H:12]1[CH2:13][CH2:14][C@@:15]2([CH3:16])[C@@H:10]([CH2:9][CH2:8][C@@H:7]3[C@@H:17]2[C:18](=[O:23])[C@@H:19]([OH:22])[C@@:20]2([CH3:21])[C@H:6]3[CH2:5][C@@H:4]3[O:25][C@@:26]4([O:32][CH2:31][C@H:29]([CH3:30])[CH2:28][CH2:27]4)[C@@H:2]([CH3:1])[C@@H:3]32)[CH2:11]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:40])[CH3:39]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4C(=O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4C(=O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
Using the procedure described in J. Am. Chem. Soc., 1972, 94, 6190, (3β,5α,12β,25R)-spirostan-3,12-diol-11-one (see preparation G6) was silylated with t-butyldimethylchlorosilane and imidazole in DMF to give the title compound.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23]O)=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:25]1[CH:29]=[N:28][CH:27]=[N:26]1>>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:25]4[CH:29]=[N:28][CH:27]=[N:26]4)=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1nc[nH]n1
Reactant: OCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Product: C(=C/c1nc(COc2ccc(CCn3cncn3)cc2)co1)\c1ccccc1
Yield: 75 %

Procedure:
In substantially the same manner as in Working Example 1, 2-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]ethanol was allowed to react with 1,2,4-triazole to give 1-[2-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]ethyl]-1,2,4-triazole. The yield was 75%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 136-137° C.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:33]([O:37][C:38](=[O:48])[NH:39][C:40]1([CH2:46]O)[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38](=[O:48])[NH:39][C:40]1([CH2:46][N:18]2[C:17](=[O:22])[C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:23]=[CH:24][C:25]([C:27]([F:29])([F:28])[F:30])=[CH:26][C:3]=3[C:2]([F:31])([F:1])[F:32])[N:7]=[CH:8]4)[S:20][C:19]2=[O:21])[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)NC1(CO)CCOCC1
Reactant: O=C1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)NC1(CN2C(=O)SC(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)C2=O)CCOCC1

Procedure:
(4-{5-[1-(2,4-Bis-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-ylmethyl}tetrahydro-2H-pyran-4-yl)carbamic acid tert-butyl ester was prepared from 5-[1-(2,4-bis-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]thiazolidine-2,4-dione (from Example 6) and (4-hydroxymethyltetrahydro-2H-pyran-4-yl)carbamic acid tert-butyl ester following General Procedure J.
Reaction SMILES: BrC1C=CC(OC)=C(C)C=1.C1(CCN2CCNCC2)C=CC=CC=1.[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36](Br)=[CH:35][C:34]=1[F:40])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH:41]1([CH2:47][CH2:48][CH2:49][N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>>[CH2:25]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N:53]2[CH2:54][CH2:55][N:50]([CH2:49][CH2:48][CH2:47][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[CH2:51][CH2:52]2)=[CH:35][C:34]=1[F:40])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C1CCC(CCCN2CCNCC2)CC1
Reactant: Fc1cc(Br)ccc1OCc1ccccc1
Agent: COc1ccc(Br)cc1C
Agent: c1ccc(CCN2CCNCC2)cc1
Product: Fc1cc(N2CCN(CCCC3CCCCC3)CC2)ccc1OCc1ccccc1
Yield: 111.4 %

Procedure:
Production Example 9 was repeated except that 5-bromo-2-methoxytoluene and 1-(2-phenylethyl)piperazine were replaced with 1-benzyloxy-4-bromo-2-fluorobenzene (1.42 g) and 1-(3-cyclo-hexylpropyl)piperazine (1.28 g), respectively, to provide crude 1-(4-benzyloxy-3-fluorophenyl)-4-(3-cyclohexylpropyl)piperazine (2.31 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]2[N:3]=1.[CH3:13][N:14]([CH3:25])[CH2:15][CH2:16][O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.O.ClCCl>O1CCOCC1>[CH3:13][N:14]([CH3:25])[CH2:15][CH2:16][O:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([CH:11]=[O:12])=[C:4]3[N:3]=2)=[CH:20][CH:19]=1
Reactant: O=Cc1cnn2ccc(Cl)nc12
Reactant: CN(C)CCOc1ccc(N)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN(C)CCOc1ccc(Nc2ccn3ncc(C=O)c3n2)cc1
Temperature: 120 °C

Procedure:
To 5-chloropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.276 mmol) in dioxane was added 4-(2-(dimethylamino)ethoxy)aniline (149 mg, 0.829 mmol). The mixture was heated in microwave 100 minutes at 120° C. Water and dichloromethane were added, and the product was extracted into dichloromethane. The organic layer was dried over Na2SO4 and concentrated under reduced pressured to yield 5-(4-(2-(dimethylamino)ethoxy)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde. LCMS (M+1=408)
Reaction SMILES: [C:1]([C:3]1[CH:16]=[C:15]([F:17])[C:14]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:13][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)#[N:2].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH:16]=[C:15]([F:17])[C:14]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:27])([F:28])[F:26])[N:20]([CH3:29])[C:19]2=[O:30])=[CH:13][C:4]=1[O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[O:12][CH2:32][C:33]([O:35][CH3:36])=[O:34])#[N:2]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(O)c3)c(C#N)cc2F)c1=O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1cccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2C#N)c1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 69.4 %

Procedure:
32 mg of 3-{2-cyano-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol (described later, produced in Intermediate Production Example 9) was dissolved in 0.5 ml of acetonitrile, and to this 13 mg of methyl bromoacetate and 13 mg of anhydrous potassium carbonate were added, then, the mixtures was stirred for 1.5 hours at 60° C. The reaction solution was cooled to room temperature, then, the reaction solution was subjected to silica gel column chromatography to obtain 26 mg of methyl [3-{2-cyano-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate [Compound 5-22 of the present invention].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:31])[CH:12]2[CH2:30][N:16]3[C:17]4[C:22]([C:23]([C:24](=O)[C:25]([O:27][CH3:28])=[O:26])=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+].CC(O)=O>CO.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:31])[CH:12]2[CH2:30][N:16]3[C:17]4[C:22]([C:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)C(=O)c1c2n(c3ccccc13)CC(N(C)S(=O)(=O)c1ccc(F)cc1)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Cc1c2n(c3ccccc13)CC(N(C)S(=O)(=O)c1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
To a solution of 0.8 g of the product of Step 10 in 100 mL of MeOH and 20 mL of THF was added 0.3 g of NaBH4. After stirring for 1 h at room temperature, 2 mL of AcOH was added and the reaction mixture was concentrated and the residue was portioned between 50 mL of brine and 150 mL of EtOAc. The organic layer was separated and dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was dissolved in 5 mL of CH2Cl2, and treated with 5 mL of Et3SiH and 3 mL of TFA. After stirring for 30 min at room temperature, the reaction mixture was concentrated and the residue was purified by Combiflash eluted with a gradient up to 70% EtOAc/hexane to give 0.3 g of the title compound. 1H NMR (500 MHz, acetone-d6) δ 8.10 (m, 2H), 7.45-7.52 (m, 3H), 7.27 (d, 1H), 7.10 (m, 1H), 7.01 (m, 1H), 4.53 (m, 1H), 4.18 (m, 1H), 3.88 (t, 1H), 3.60 (s, 3H), 3.13 (m, 1H), 2.97 (s, 3H), 2.86 (m, 1H), 1.90-2.00 (m, 1H), 1.70 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:12]3[O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=4[Cl:38])[C@@H:15]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[C@@:13]3([CH3:39])[OH:14])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH4+:40].[OH-]>O1CCOCC1>[NH2:40][C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([C@@H:12]3[O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=4[Cl:38])[C@@H:15]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[C@@:13]3([CH3:39])[OH:14])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1cc(I)c2c(Cl)ncnc21
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1cc(I)c2c(N)ncnc21
Yield: 88 %

Procedure:
To a compound 6.2 (5 g, 6.7 mmol) in dioxane (100 mL) was added conc. NH4OH (100 mL). The mixture was heated in a stainless steel autoclave at 100° C. for 3 h, then cooled and evaporated in vacuo. The crude mixture was dissolved in 100 mL of CH2Cl2 and washed with water and brine, dried over MgSO4, filtered and concentrated to provide crude product. The crude product was then purified on a silica gel column with 5% MeOH in CH2Cl2 as eluent to give 4.32 g of 6.3 as white foam (yield 88%).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].[CH3:25][O:26][CH2:27][CH2:28]Br>>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:28][CH2:27][O:26][CH3:25])=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: COc1cc2c(OC(C)C)nc(Nc3cc(C)[nH]n3)cc2cc1O
Reactant: COCCBr
Product: COCCOc1cc2cc(Nc3cc(C)[nH]n3)nc(OC(C)C)c2cc1OC

Procedure:
Similar procedure as described in example 328 was used, starting from 1-Isopropoxy-7-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol and 2-bromoethyl methyl ether to give [1-Isopropoxy-7-methoxy-6-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 387(MH+).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:33]=[CH:32][C:9]([O:10][C:11]2[C:12]([CH:26]([OH:31])[C:27](OC)=[O:28])=[CH:13][C:14]3[N:18]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[NH:16][C:15]=3[CH:25]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([S:3]([C:6]1[CH:33]=[CH:32][C:9]([O:10][C:11]2[C:12]([CH:26]([OH:31])[CH2:27][OH:28])=[CH:13][C:14]3[N:18]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[NH:16][C:15]=3[CH:25]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2C(O)C(=O)OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2C(O)CO)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a tetrahydrofuran (1.5 ml) solution of methyl (6-(4-(ethylsulfonyl)phenoxy)-2-pyridin-2-yl-1H-benzimidazol-5-yl)(hydroxy)acetate (30 mg) obtained in Example 31 (step 2), added was lithiumaluminium hydride (10 mg), and the reaction liquid was stirred at 0° C. for 10 minutes. Sodium sulfate 10-hydrate was added to the reaction liquid, and stirred overnight at room temperature. Then, the residue was removed through filtration through Celite, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through reversed-phase middle-pressure liquid chromatography (ODS-AS-360-CC (by YMC), mobile phase: water/acetonitrile/0.1% trifluoroacetic acid), and the resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and saturated saline water in that order, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound.