Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([B:22]2[O:26][C:25]([CH3:28])(C)C(C)[O:23]2)=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=1)C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:30](C)([O-:32])=[O:31].[OH-].[Na+].Cl>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]2[B:22]([OH:23])[O:26][CH:25]([CH2:28][N+:30]([O-:32])=[O:31])[C:15]=2[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: CC1OB(c2c(C=O)cc(Cl)cc2OCCCOCc2ccccc2)OC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])CC1OB(O)c2c(OCCCOCc3ccccc3)cc(Cl)cc21
Reaction time: 12 h

Procedure:
To a solution of 3-(3-benzyloxy-propoxy)-5-chloro-2-(4,4,5-trimethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (3.4 g, 7.8 mmol) and nitromethane (1.7 mL, 31.3 mmol) in THF (20 mL) was added a solution of NaOH (0.025 M, 40 mL). After 12 h, 2 N HCl was added until pH was 1. The solution was diluted with EtOAc (150 mL), washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by silica gel column chromatography (4:1 hexanes-EtOAc mobile phase) to give the title compound product (1.7 g, 56%) as a colorless gel. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.39-7.28 (m, 5H), 6.92 (s, 1H), 6.83 (s, 1H), 5.85 (br s, 1H), 5.81 (dd, J=8.5, 3.9 Hz, 1H), 4.70 (dd, J=13.2, 3.9 Hz, 1H), 4.59 (s, 2H), 4.47 (dd, J=13.0, 8.7 Hz, 1H), 4.21-4.07 (m, 2 H), 3.71-3.60 (m, 2H), 2.10 (quin, J=5.7 Hz, 2H).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30]([CH2:33][C:34]([O:36]C)=[O:35])(=[O:32])=[O:31])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30]([CH2:33][C:34]([OH:36])=[O:35])(=[O:32])=[O:31])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CS(=O)(=O)CCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CS(=O)(=O)CCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
A mixture of methyl [[6-(3,4,5-triphenyl-lH-pyrazol-1-yl)hexyl]sulfonyl]acetate (0.94 g, 2 mmol), 3 N sodium hydroxide solution (2.43 mL, 7 mmol) and methanol (100 mL) was heated at reflux. After 20 minutes, the methanol was removed in vacu. the residue acidified with IN HCl and extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated to give a foam. Recrystallization from a mixture of dichloromethane and hexane (1:3) afford [[6-(3,4,5-triphenyl-lH-pyrazol-1-yl) hexyl]sulfonyl]acetic acid (0.80 g, 88%); m.p.=153.5°-155° C. MS(CI): m/e =459 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([CH3:22])=[C:4]([CH3:21])[C:5]2[O:9][CH2:8][CH:7]([C:10]3[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=3)[C:6]=2[C:19]=1[CH3:20].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC(C)([O-])C.[Na+].O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:23]([NH:30][C:2]1[C:3]([CH3:22])=[C:4]([CH3:21])[C:5]2[O:9][CH2:8][CH:7]([C:10]3[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=3)[C:6]=2[C:19]=1[CH3:20])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1Br)C(c1ccc(C(C)C)cc1)CO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(C)c2c(c(C)c1NCc1ccccc1)C(c1ccc(C(C)C)cc1)CO2
Reaction time: 0.25 h
Yield: 91 %

Procedure:
To a solution of 5-bromo-3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran obtained in Reference Example 18 (920 mg, 2.56 mmol) and benzylamine (0.34 mL, 3.07 mmol) in toluene (10 mL), were added palladium acetate (6 mg, 0.03 mmol) and BINAP (48 mg, 0.09 mmol) at room temperature, and the mixture was stirred under argon stream for 15 minutes. Sodium tert-butoxide (344 mg, 3.58 mmol) was added to the reaction solution at room temperature, and then the mixture was heated under reflux for 18 hours. Water was added to the reaction solution, which was extracted with ethyl acetate, the organic layer was washed with water and a saturated brine and then was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1) to obtain 900 mg (yield 91%) of the title compound as an oily matter. Oily matter.
Reaction SMILES: [CH2:1]([O:3][NH:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[N:11]([CH:22]=[N:23][CH:24]=2)[C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=1[F:21])=[O:6])[CH3:2].Cl.[CH:26]1(CON)C[CH2:27]1>>[CH:2]1([CH2:1][O:3][NH:4][C:5]([C:7]2[N:8]=[CH:9][C:10]3[N:11]([CH:22]=[N:23][CH:24]=3)[C:12]=2[NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])=[O:6])[CH2:27][CH2:26]1
Reactant: CCONC(=O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Reactant: NOCC1CC1
Agent: Cl
Product: O=C(NOCC1CC1)c1ncc2cncn2c1Nc1ccc(I)cc1F

Procedure:
The title compound was prepared in an analogous fashion to N-ethoxy-5-(2-fluoro-4-iodophenylamino)imidazo[1,5-a]pyrazine-6-carboxamide, using O-(cyclopropylmethyl)-hydroxylamine hydrochloride as the starting material. 1H NMR (DMSO-d6, 400 MHz) δ ppm 11.82 (s, 1H), 10.36 (s, 1H), 8.82 (s, 1H), 7.95 (s, 1H), 7.91 (s, 1H), 7.73 (dd, J=10.4 Hz, 1.8 Hz, 1H), 7.44 (d, 8.4 Hz, 1H), 6.58 (t, J=8.4 Hz, 1H), 3.67 (d, J=7.2 Hz, 2H), 1.12 to 1.01 (m, 1H), 0.54-0.48 (m, 2H), 0.28-0.23 (m, 2H); LCMS (method D2): RT=1.33 min, [M+H]+=468.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[CH:14][C:13]=1[CH3:26].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:27])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][C:13]=1[CH3:26]
Reactant: COc1ccccc1NC(=O)Nc1ccc(CC(=O)OC(C)(C)C)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1C
Yield: 83.3 %

Procedure:
To a stirred solution of tert-butyl 4-[N′-(2-methoxyphenyl)ureido]-3-methylphenylacetate (1.32 g, 3.56 mmol) in CH2Cl2 (15 ml) was added trifluoroacetic acid (10 ml), and the resulting mixture was heated under reflux for 30 min. The mixture was concentrated in vacuo and added water to give precipitate which was collected by filtration. The crude solid was recrystallized from EtOH/hexane to give 4-[N′-(2-methoxyphenyl)ureido]-3-methylphenylacetic acid (932 mg, 83%) as a white powder. mp 260-264° C.; 1H-NMR (CD3OD) δ2.30 (s, 3 H), 3.55 (s, 2 H), 4.87 (s, 3 H), 6.87-6.92 (m, 2 H), 6.97-6.99 (m, 2 H), 7.10-7.24 (m, 2 H), 7.53-7.58 (m, 1 H), 8.04 (d, J=7.2 Hz, 1 H); MS (ESI) m/z 314 (M+).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:14]=[O:15])C1C=CC=CC=1.[C:16]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)([CH3:19])([CH3:18])[CH3:17].C(=O)(O)[O-].[Na+]>>[C:16]([C:20]1[S:21][C:22]([CH:14]=[O:15])=[CH:23][CH:24]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CN(C=O)c1ccccc1
Reactant: CC(C)(C)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc(C=O)s1
Temperature: 0 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
Phosphorus oxychloride (24.04 g, 0.157 mol) was added dropwise to N-methylformanilide (21.24 g, 0.157 mol) and a yellow solid was produced. This was cooled to 0° C. for 1/2 hour, then 2-t-butylthiophene (20 g, 0.143 mol) was added dropwise and the mixture stirred at room temperature for 3 hours. The mixture was poured into ice/water, neutralised with sodium bicarbonate and extracted into diethyl ether. The ethereal extracts were washed with water, dried over anhydrous sodium sulphate and the solvent removed to give a brown liquid. Purification by column chromatography (silica eluted with petroleum ether/ethyl acetate 9:1) gave 5-t-butyl-2-thiophenecarboxaldehyde (21.01 g, 87%) as a yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([CH3:25])([CH3:24])[C:18]([CH3:23])([CH3:22])[C:19]([NH2:21])=O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([CH3:25])([CH3:24])[C:18]([CH3:23])([CH3:22])[CH2:19][NH2:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C(N)=O)C(C)(C)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CN)C(C)(C)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 112.8 %

Procedure:
To a stirred solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,3-trimethylbutanamide (159 mg, 0.47 mmol) in anhydrous THF (5 mL) was added a solution of LAH (1 M in diethylether, 1 mL, 1 mmol) under nitrogen at 0° C. The mixture was stirred at the same temperature for 1 hr and at rt for 22 hr. After an aqueous solution of sodium hydroxide (1 M, 10 mL) was added slowly, the mixture was stirred for 0.5 hr and filtered through a pad of celite that was then rinsed with dichloromethane. The filtrate was extracted with dichloromethane (4×10 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,3-trimethylbutan-1-amine (173 mg; 0.53 mmol, 110% yield) as a yellow foam solid that was used as such without further purification.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32]O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C(P(CCCC)CCCC)CCC.[NH:47]1[CH:51]=[N:50][CH:49]=[N:48]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[CH:27]=[CH:28][C:29]([CH2:32][N:47]5[CH:51]=[N:50][CH:49]=[N:48]5)=[CH:30][N:31]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: c1nc[nH]n1
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(CO)cn3)[nH]2)cc1)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(Cn4cncn4)cn3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of [6-(5-[1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl]-1H-pyrrol-2-yl)pyridin-3-yl]methanol (430 mg), tributylphosphine (280 mg), 1,2,4-triazole (76 mg) and tetrahydrofuran (30 mL) was added 1,1′-(azodicarbonyl)dipiperidine (350 mg) at room temperature, and the mixture was stirred at room temperature for 15 hr. To the mixture were added 1,2,4-triazole (76 mg) and tributylphosphine (280 mg), 1,1′-(azodicarbonyl)dipiperidine (350 mg) was further added at room temperature, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated, ethyl acetate was added to the residue, and the insoluble material was filtered off. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography to give the title compound as a crude product from a fraction eluted with ethyl acetate-methanol (100:0-90:10, volume ratio), and the crude product was subjected to preparative HPLC to give the title compound as an oil. The oil was crystallized from acetonitrile-diethyl ether, and further recrystallized from acetone-hexane to give the title compound (38 mg, yield 8%) as colorless crystals. MS: 518 (MH+). melting point 152-153° C.
Reaction SMILES: Cl[CH:2]([C:5]1[C:6]([CH3:21])=[N:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[CH:9][CH:10]=1)[CH2:3][CH3:4].[CH2:22]([O:24][C:25](=[O:40])[CH2:26][O:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([NH:38][CH3:39])=[CH:30][CH:29]=1)[CH3:23].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CS(C)=O>[CH2:22]([O:24][C:25](=[O:40])[CH2:26][O:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([N:38]([CH3:39])[CH:2]([C:5]2[C:6]([CH3:21])=[N:7][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=3)=[CH:9][CH:10]=2)[CH2:3][CH3:4])=[CH:30][CH:29]=1)[CH3:23]
Reactant: CCC(Cl)c1ccc(-c2cccc(C(F)(F)F)c2)nc1C
Reactant: CCOC(=O)COc1ccc(NC)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)COc1ccc(N(C)C(CC)c2ccc(-c3cccc(C(F)(F)F)c3)nc2C)c2ccccc12
Reaction time: 15 h

Procedure:
To 0.164 g (0.523 mmol) of [rac]-3-(1-chloro-propyl)-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine (see below 2C]) and 0.149 g (0.575 mmol) of the above prepared (4-methylamino-naphthalen-1-yloxy)-acetic acid ethyl ester, dissolved in 3.2 ml of abs. DMSO, were added successively 0.0867 g of K2CO3 (0.627 mmol) and 0.0856 g (0.575 mmol) of NaI. The reaction was allowed to proceed for 15 h at 60° C. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=9/1), yielded 0.043 g of the title compound as light yellow oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[NH:13][N:12]=[C:11]([C:14]([OH:16])=O)[CH:10]=2)[CH:6]=[CH:5][N:4]=1.[O:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[O:23][NH2:24].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH4+].[Cl-].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[NH:13][N:12]=[C:11]([C:14]([NH:24][O:23][CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)=[O:16])[CH:10]=2)[CH:6]=[CH:5][N:4]=1
Reactant: NOC1CCCCO1
Reactant: CSc1nccc(-c2cc(C(=O)O)n[nH]2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nccc(-c2cc(C(=O)NOC3CCCCO3)n[nH]2)n1
Yield: 47.7 %

Procedure:
5-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazole-3-carboxylic acid (60 mg, 0.25 mmol) was reacted in dry DCM/DMF 9:1 mixture (2 mL) with O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (44.6 mg, 0.38 mmol), EDC.HCl (73 mg, 0.38 mmol), HOBt (51.5 mg, 0.38 mmol) and DIPEA (0.087 mL, 0.51 mmol) at r.t. for 4 h. The reaction was worked up with water, NH4Cl sat. sol., NaHCO3 sat. sol. and extracted with AcOEt. The organic layer was washed with brine dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by silica gel flash chromatography eluting with DCM/MeOH 19/1 to provide 5-[2-(methylsulfanyl)pyrimidin-4-yl]-N-(tetrahydro-2H-pyran-2-yloxy)-1H-pyrazole-3-carboxamide 40 mg (48%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)=[O:4].[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[C:10]([NH:15][S:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N+:16]([O-:18])=[O:17])(=[O:26])=[O:27])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COC(=O)c1ccnc2c(N)cccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccnc2c(NS(=O)(=O)c3ccccc3[N+](=O)[O-])cccc12
Yield: 93.5 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-amino-quinoline-4-carboxylic acid methyl ester (Intermediate 475) (370 mg, 1.38 mmol), 2-nitrobenzenesulfonyl chloride (530 mg, 2.3 mmol), DMAP (cat.), pyridine (0.44 ml, 5.4 mmol) and DCM (15 ml) gave the title compound (500 mg, 70%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A magnetically stirred solution of tert-butyl 2-formyl-4-(trifluoromethoxy)phenylcarbamate (18.36 g, 60.14 mmol) in methanol (200 mL) was treated with sodium borohydride (2.3 g, 60.14 mmol), the mixture was quickly cooled in a dry ice/acetone bath, then allowed to warm to 0° C., and stirred for 1 h. The reaction was quenched with water (50 mL), the methanol was stripped, and the aqueous was extracted with diethyl ether (300 mL). The organic phase was washed successively with saturated ammonium chloride (2×100 mL), water (100 mL), and brine (100 mL), dried over sodium sulfate, and concentrated in-vacuo to a colorless solid, which was used as-is in the next step. 1H NMR (500 MHz, DMSO) δ ppm 1.46 (s, 9 H) 4.52 (d, J=5.50 Hz, 2 H) 5.55 (m, 1 H) 7.21 (d, J=8.80 Hz, 1 H) 7.34 (s, 1 H) 7.59 (d, J=8.25 Hz, 1 H) 8.68 (s, 1 H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][CH2:8][N:9]2[C@H:13]([CH3:14])[CH2:12][O:11][C:10]2=[O:15])=[CH:4][CH:3]=1.[CH:16]1([CH2:22][CH2:23][CH2:24][C:25]#[CH:26])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C.O>CN(C)C=O.[Cu]I.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>[CH:16]1([CH2:22][CH2:23][CH2:24][C:25]#[C:26][C:2]2[S:6][C:5]([CH2:7][CH2:8][N:9]3[C@H:13]([CH3:14])[CH2:12][O:11][C:10]3=[O:15])=[CH:4][CH:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C[C@@H]1COC(=O)N1CCc1ccc(Br)s1
Reactant: C#CCCCC1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H]1COC(=O)N1CCc1ccc(C#CCCCC2CCCCC2)s1
Temperature: 80 °C
Reaction time: 2 h
Yield: 10 %

Procedure:
(4R)-[2-(5-Bromothiophen-2-yl)]ethyl-4-methyloxazolidin-2-one (450 mg, 1.55 mmol) obtained in Example 1 (g) was dissolved in dimethylformamide (4.5 ml), and 5-cyclohexylpent-1-yne (50% xylene solution) (1.4 g, 4.65 mmol), triethylamine (2.16 ml, 15.5 mmol), copper (I) iodide (30 mg, 0.16 mmol) and dichlorobis(triphenylphosphine)palladium (109 mg, 0.16 mmol) were added thereto, and then the reaction mixture was stirred for 2 hours at 80° C. under a nitrogen atmosphere. The reaction solution was poured into water, extracted with ethyl acetate, and the ethyl acetate layer was washed with a saturated aqueous sodium chloride solution. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the solvent was concentrated in vacuo, and the residue was purified by chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=4:1-3:2) to afford the title compound (56 mg, 82% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][N:17]([CH2:20][N:21]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[N:22]4)[C:16](=[O:30])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][N:17]([CH2:20][N:21]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[N:22]4)[C:16](=[O:30])[N:15]=3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1nc(N2CCC(O)(c3ccc(Cl)cc3)CC2)ncn1Cn1ccc(C(F)(F)F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1nc(N2CC=C(c3ccc(Cl)cc3)CC2)ncn1Cn1ccc(C(F)(F)F)n1
Yield: 56.5 %

Procedure:
To a dichloromethane solution (1.0 mL) of 4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-1-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-1,3,5-triazin-2(1H)-one (14 mg, 0.03 mmol) synthesized in Reference Synthesis Example 91a, trifluoroacetic acid (0.5 mL) was added and the resultant mixture was stirred at room temperature for 3 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure and to the resultant concentrate, water and saturated sodium hydrogen carbonate aqueous solution were added. A deposited solid was washed with water and was dried under reduced pressure to obtain the title compound (7.4 mg, yield: 55%).
Reaction SMILES: CC[N:3]=C=NCCCN(C)C.[Cl:12][C:13]1[S:39][C:16]2[NH:17][C:18]([C:20]([NH:22][CH:23]3[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]([CH2:33][CH:34](O)CO)[C:24]3=[O:38])=[O:21])=[CH:19][C:15]=2[CH:14]=1.ClC1SC2NC(C(NC3CC4C(=CC=CC=4)N(C[C@@H](O)CO)C3=O)=O)=CC=2C=1>C(Cl)Cl>[Cl:12][C:13]1[S:39][C:16]2[NH:17][C:18]([C:20]([NH:22][CH:23]3[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]([CH2:33][C:34]#[N:3])[C:24]3=[O:38])=[O:21])=[CH:19][C:15]=2[CH:14]=1
Reactant: O=C(NC1Cc2ccccc2N(CC(O)CO)C1=O)c1cc2cc(Cl)sc2[nH]1
Reactant: CCN=C=NCCCN(C)C
Agent: O=C(NC1Cc2ccccc2N(C[C@@H](O)CO)C1=O)c1cc2cc(Cl)sc2[nH]1
Solvent: ClCCl
Product: N#CCN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Reaction time: 18 h
Yield: 21 %

Procedure:
EDCI (1.09 g, 5.65 mmol) was added to a suspension of 5-Carboxy-2-chloro-6H-thieno[2,3-b]pyrrole (Method 9, 1.04 g, 5.13 mmol) and (3-amino-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetonitrile (Method 13; 1.29 g, 5.13 mmol) in DCM (30 mL) and the reaction stirred for 18 hours. The reaction was evaporated and the residue was partitioned between DCM:MeOH (9:1) (100 mL) and aqueous K2CO3 (25 mL). The organic layer was then separated, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (DCM to DCM:MeOH (9:1)) to give a brown solid. The solid was triturated with refluxing Et2O (25 mL) and the solid filtered, washed with Et2O (25 mL) then hexane (25 mL) to afford the title compound (414 mg, 21%) as a pale brown solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][C@@H:6]([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][C:11]([Cl:32])=[N:12][C:13]=3[NH:17][CH2:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:5]([OH:33])[C@@H:4]1[OH:34].C(N(C(C)C)CC)(C)C.[CH:44]1([C:48](Cl)=[O:49])[CH2:47][CH2:46][CH2:45]1>C1COCC1>[Cl:32][C:11]1[N:10]=[C:9]2[C:14]([N:15]=[CH:16][N:8]2[C@@H:6]2[CH2:7][C@H:3]([NH:2][C:48]([CH:44]3[CH2:47][CH2:46][CH2:45]3)=[O:49])[C@@H:4]([OH:34])[C@H:5]2[OH:33])=[C:13]([NH:17][CH2:18][CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:12]=1
Reactant: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O)C1CCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 46.6 %

Procedure:
A solution of (1S,2R,3S,5R)-3-amino-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopentane-1,2-diol hydrochloride (Intermediate JJ3) (100 mg, 0.2 mmol) in dry THF (1 ml) is treated with diisopropylethylamine (0.17 ml, 1 mmol) and cyclobutanecarboxylic acid chloride (0.023 ml, 0.2 mmol) and the mixture is stirred at room temperature for 48 hours. The solvent is removed under reduced pressure. The residue is purified by reverse-phase chromatography eluting with a gradient system of acetonitrile (0.1% TFA): water (0.1% TFA) (0:100 by volume) gradually changing to acetonitrile (0.1% TFA): water (0.1% TFA) (100:0 by volume) to afford the title compound (51 mg). LCMS (electrospray): m/z [MH+] 547.26. 1H nmr (MeOD, 400 MHz); 8.00 (s, 1H), 7.40-7.25 (m, 8H), 7.20-7.15 (m, 2H), 4.70 (m, 1H), 4.50 (m, 2H), 4.20 (m, 2H), 3.95 (m, 1H), 2.85 (m, 1H), 2.30 (m, 2H), 2.20 (m, 2H), 2.05 (m, 2H), 1.90 (m, 1H).