Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]([CH3:20])[C:10](=[O:21])[CH:9]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][CH:24]=1.[ClH:32]>CO>[ClH:32].[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH:31][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]([CH3:20])[C:10](=[O:21])[CH:9]=2)=[CH:25][CH:24]=1
Reactant: NCCc1ccc(F)cc1
Reactant: Cn1c(N2CCOCC2)nc(-c2ccncc2F)cc1=O
Agent: Cl
Solvent: CO
Product: Cn1c(N2CCOCC2)nc(-c2ccncc2NCCc2ccc(F)cc2)cc1=O
Temperature: 120 °C
Yield: 49 %

Procedure:
A suspension of 6-(3-fluoropyridin-4-yl)-3-methyl-2-(morpholin-4-yl)-3H-pyrimidin-4-one (0.60 g, 2.07 mmol), and 2-(4-fluorophenyl)ethylamine (2.9 g, 20.8 mmol) was heated at 120° C. for 8 hours. The resulting suspension was partitioned between chloroform and brine and the aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish a colorless oil. The methanol (10 ml) solution of resulting oil was treated with 4N hydrochloric acid (5 ml). The residue obtained by evaporation was washed by ethyl acetate to furnish 6-(3-(2-(4-fluorophenyl)ethylamino)pyridin-4-yl)-3-methyl-2-(morpholin-4-yl)-3H-pyrimidin-4-one hydrochloride (0.45 g, 1.01 mmol, 49%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23][CH3:24])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][C:11]#[N:12])=[C:4]([CH3:25])[CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:37])C=1>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23]([CH3:24])=[O:37])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][C:11]#[N:12])=[C:4]([CH3:25])[CH:3]=1
Reactant: CSCc1cccc2c(C(CCC#N)c3ccc(F)cc3C)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(F)ccc1C(CCC#N)c1c[nH]c2c(CS(C)=O)cccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
50 mg (0.14 mmol) of the compound from Example 46 were introduced into 10 ml of dichloromethane at RT, 35.0 mg (0.14 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 4 h. 2 ml of methanol were added, and the residue after concentration was taken up in dichloromethane and saturated aqueous sodium bicarbonate solution, the phases were separated, the organic phase was washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 24.6 mg (47% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(OC([NH:53][C@@H:54]([CH2:59][C:60]1[CH:65]=[CH:64][C:63]([O:66][CH3:67])=[CH:62][CH:61]=1)[C:55]([O:57][CH3:58])=[O:56])=O)(C)(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([O:8][CH2:9][C@H:10]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:11]([NH:53][C@@H:54]([CH2:59][C:60]1[CH:61]=[CH:62][C:63]([O:66][CH3:67])=[CH:64][CH:65]=1)[C:55]([O:57][CH3:58])=[O:56])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)OC(C)(C)C
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: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.08 h

Procedure:
To (S)-3-(benzyloxy)-2-((tert-butoxycarbonyl)amino)propanoic acid (1.00 g, 3.39 mmol) in DMF (10 mL) at 0° C. was added HATU (1.42 g, 3.73 mmol). The mixture was stirred for 5 min to dissolve the solids at which time (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-methoxyphenyl)propanoate (0.708 g, 3.39 mmol) and DIEA (1.77 mL, 10.2 mmol) was added. The reaction mixture was stirred at ambient temperature for 30 min then quenched with sodium bicarbonate (sat.), extracted with ethyl acetate (2×), dried with sodium sulfate, filtered, and concentrated to provide crude (S)-methyl 2-((S)-3-(benzyloxy)-2-((tert-butoxycarbonyl)amino)propanamido)-3-(4-methoxyphenyl)propanoate as a yellow oil that was carried forward without further purification. MS (EI) for C26H34N2O7, found 387.1 (M-Boc).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][O:6][C:7]([C:9]1C(C2C=CC=C([N+]([O-])=O)C=2)C(C(OC(C)C)=O)=C(C)[NH:13][C:14]=1[CH3:15])=[O:8].C(O)C>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][O:6][C:7](=[O:8])/[CH:9]=[C:14](\[NH2:13])/[CH3:15]
Reactant: CC1=C(C(=O)OCc2cccc(Cl)c2)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Solvent: CC(C)O
Solvent: CCO
Product: C/C(N)=C/C(=O)OCc1cccc(Cl)c1
Yield: 69 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoaceic acid isopropyl ester and 75 mmols of β-aminocrotonic acid 3-chlorobenzyl ester in 120 ml of isopropanol gave 2,6-dimethyl-3-isopropoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 3-chlorobenzyl ester of melting point 104° C (from ethanol).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[C:12]1([CH:18]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=2)[C:19](=[O:21])[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:20][C:19](=[O:21])[CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)C(CC=Cc1cccc(C)c1)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C=CCC(C(=O)C=Cc2ccc(Cl)cc2)c2ccccc2)c1

Procedure:
A 20% sodium hydroxide solution (5 ml.) is added to a stirred solution of p-chlorobenzaldehyde(14 g., 0.1 mole) and 3-phenyl-6-(m-methylphenyl)-5-hexen-2-one (25.24 g., 0.096 mole) in ethanol (250 ml.). The yellowish solid that separates on continued stirring is collected, washed with cold ethanol, and air-dried, yield 34.9 g., m.p. 89°-93°C. Recrystallization from ethanaol produces material with m.p. 95°-98°C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[CH:12]([CH3:17])[CH2:13][CH2:14][CH2:15]O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH2:15][CH2:14][CH2:13][CH:12]2[CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(CCCO)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC1CCCC1(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Yield: 51 %

Procedure:
The resulting 5-[(4-chlorophenyl)sulfonyl]-5-(2,5-difluorophenyl)-4-methyl-1-pentanol (isomer mixture) was dissolved in toluene (10 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (1.00 g, 4.14 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. After the reaction mixture was allowed to cool down, the residue obtained by concentrating the reaction mixture under reduced pressure was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=20:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with hexane, whereby the title compound (423 mg, 1.14 mmol, 51%) was obtained as a white powder.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([N+:26]([O-])=O)[C:7]([O:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][C:13]=3[O:24][CH3:25])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH3:29].O.O.[Sn](Cl)(Cl)(Cl)Cl.Cl>C(OCC)(=O)C>[NH2:26][C:6]1[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][C:13]=2[O:24][CH3:25])=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[C:3]([CH3:29])[N:2]2[CH3:1]
Reactant: CCOC(=O)Cc1ccc(Oc2ccc3c(cc(C)n3C)c2[N+](=O)[O-])c(OC)c1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(Oc2ccc3c(cc(C)n3C)c2N)c(OC)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A solution of 3.2 (35 mg, 0.088 mmol) and tin chloride dihydrate (159 mg, 0.70 mmol) dissolved in ethyl acetate (5 mL) was heated to 80° C. overnight. Alter 18 h, HPLC indicated no 3.2 remained and the reaction was poured into aqueous 5% hydrochloric acid solution. The resulting emulsion was filtered through a pad of Celite to remove fine solids, rinsing the solids with ethyl acetate and water. The biphasic filtrate was separated and the organic layer washed with saturated aqueous sodium bicarbonate solution, water and brine. The organic separation was stirred over magnesium sulfate, filtered and the filtrate concentrated in vacuo on a rotary evaporator to afford a dark brown, foamy solid.
Reaction SMILES: [CH3:1][C:2]([N+:13]([O-])=O)([CH3:12])[CH2:3][NH:4][CH2:5][C:6]([N+:9]([O-])=O)([CH3:8])[CH3:7]>CO.[Ni]>[CH3:8][C:6]([NH2:9])([CH3:7])[CH2:5][NH:4][CH2:3][C:2]([NH2:13])([CH3:1])[CH3:12]
Reactant: CC(C)(CNCC(C)(C)[N+](=O)[O-])[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CC(C)(N)CNCC(C)(C)N
Temperature: 25 °C

Procedure:
490 g (2.23 mol) of bis-(2-methyl-2-nitropropyl)amine from reaction 1) are dissolved in 1200 ml of methanol and transferred into an autoclave. 60 g of Raney Ni are added. The autoclave is closed and purged with nitrogen. Then, hydrogen is added until the hydrogen pressure is 50 bars. That pressure is maintained at room temperature for 8 hours and, subsequently, the reaction mixture is heated to 50° C. at the same pressure. The catalyst is then separated off by filtration and the mixture is distilled under vacuum (100° C./33.3 mbar). A colourless oil is recovered (Boiling point: 110° C./5 mbar).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].Br.[NH2:38][CH:39]1[CH2:44][CH2:43][O:42][C:40]1=[O:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:38][CH:39]1[CH2:44][CH2:43][O:42][C:40]1=[O:41])=[O:24]
Reactant: NC1CCOC1=O
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Agent: Br
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NC2CCOC2=O)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 2-amino-4-butyrolactone hydrobromide.
Reaction SMILES: [CH:1]1([C:10]([OH:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:13]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[CH3:13][C:1]1([C:10]([OH:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(O)C1CCc2ccccc21
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCc2ccccc21
Temperature: -20 °C

Procedure:
A solution of indane-1-carboxylic acid (4.1 g, 25.3 mmol) in THF (30 ml) was added in portions to a solution of lithium diisopropylamide in THF (2M, 27.8 ml, 55.6 mmol) with stirring at −20° C. The solution was then stirred at 35° C. for 1 hour, then cooled again to −20° C. and a solution of methyl iodide (2.05 ml, 32.89 mmol) in THF (10 ml) was added. The light yellow solution was warmed at 35° C. for 4 hours before extracting between HCl (2M) and EtOAc to yield the crude product (4.5 g) as a brown oil. This mixture was chromatographed on HPLC with EtOAc/hexane to yield 1-methyl-1-indanecarboxylic acid (1 g) and recovered starting material (700 mg)
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]2=O.B.C1COCC1>C1COCC1>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2
Reactant: O=C1Nc2ccc(C(F)(F)F)cc2C1=O
Agent: B
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of 4 (6.75 g, 31.38 mmol) in dry THF (200 mL) at 0° C. under nitrogen atmosphere BH3.THF solution (82 mL, 1 M in THF) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched with 6N ice-cold aq. HCl (30 mL), made alkaline (pH 7-8) with 2 N NaOH, saturated with NaCl, extracted with EtOAc, the extracts were dried (MgSO4), concentrated. Purification by chromatoghraphy on silica gel using CH2Cl2 as eluent afforded (3.95 g, 68% yield) as an off white solid. 1H NMR (300 MHz, MeOH-d4): δ 7.87 (m, 1H), 7.51 (dd, 8.5, 0.8 Hz, 1H), 7.47 (d, 8.5 Hz, 1H), 7.37 (d, 3.2 Hz, 1H), 7.34 (dd, 8.5, 1.6 Hz, 1H), 6.57 (dd, 3.2, 0.8 Hz, 1H). MS m/z: 184 (M−1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Cl)=[N:7][CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH2:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:23]2[CH2:24][CH2:25][CH:20]([NH2:19])[CH2:21][CH2:22]2)=[N:7][CH:6]=1)[CH3:2]
Reactant: NC1CCNCC1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCC(N)CC2)nc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
6-chloronicotinic acid ethyl ester (4.27 g, 23 mmol) was dissolved in DMF (30 ml), and potassium carbonate (4.77 g, 35 mmol) and 4-aminopiperidine (2.76 g, 28 mmol) were added thereto, followed by stirring at 80° C. for 3 hours and at 100° C. for 1 hour. After the reaction mixture was cooled to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated sodium chloride, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was evaporated under reduced pressure, thereby obtaining 6-(4-aminopiperidin-1-yl)nicotinic acid ethyl ester (4.17 g, 73%) as a pale brown oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)[CH:3]=[O:4].[C:15](O)(=[O:17])[CH3:16]>>[C:15]([O:4][CH:3]=[C:2]([CH3:1])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)(=[O:17])[CH3:16]
Reactant: CC(C=O)Cc1ccc2c(c1)OCO2
Reactant: CC(=O)O
Product: CC(=O)OC=C(C)Cc1ccc2c(c1)OCO2

Procedure:
Thereafter, the same operations as the procedure (a), the step (2) and the step (3) (procedure (c)) in Example 2 were carried out to provide 27.7 g of 2-methyl-3-(3,4-methylenedioxyphenyl)propanal. The amount of acetic acid contained in the resulting 2-methyl-3-(3,4-methylenedioxy-phenyl)propanal was 18 ppm.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]1>>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:29]5[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1
Reactant: Cn1cc(-c2cc3c(-c4cccc(F)n4)nn(C4CCCCO4)c3cn2)cn1
Reactant: OC1CCNCC1
Product: Cn1cc(-c2cc3c(-c4cccc(N5CCC(O)CC5)n4)n[nH]c3cn2)cn1
Yield: 56.1 %

Procedure:
Following the procedures as described in Example 189, 3-(6-fluoropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and piperidin-4-ol were reacted. The product was deprotected and purified to give 294 as a white solid (56.1% over two steps). 1H NMR (400 MHz, DMSO) δ 13.69 (broad s, 1H), 9.03 (s, 1H), 8.53 (s, 1H), 8.11 (s, 1H), 7.82 (s, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.42 (d, J=7.4 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 4.73 (d, J=3.2 Hz, 1H), 4.24-4.15 (m, 2H), 3.91 (s, 3H), 3.6-3.76 (m, 1H), 3.37-3.29 (m, 2H), 1.97-1.86 (m, 2H), 1.58-1.44 (m, 2H). LC/MS: m/z 376.2 [M+1]
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[CH3:20][O:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[NH2:24]>>[CH3:20][O:21][C:22](=[O:27])[C:23]([NH:24][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:26])[CH3:25]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Product: COC(=O)C(C)(C)NC(=O)c1ccc(N2CCCC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid (Example 14 a) and 2-methyl-alanine methyl ester as starting materials, MS (LC/MS): 362.2 [M+H]+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:12])=[C:4]([N:13]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=2)[S:14]([C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[N:3]=1.[H-].[Na+].[CH3:42][CH:43]([OH:45])[CH3:44].Cl>O1CCCC1.C(Cl)(Cl)Cl>[CH:43]([O:45][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:12])=[C:4]([N:13]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]([F:38])([F:39])[F:37])=[CH:31][CH:30]=2)[S:14]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:26][CH:27]=2)(=[O:16])=[O:15])[N:3]=1)([CH3:44])[CH3:42]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2nc(Br)c3ccccc3c2C)cc1
Reactant: CC(C)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Cc1c(N(Cc2ccc(OC(F)(F)F)cc2)S(=O)(=O)c2ccc(C(=O)O)cc2)nc(OC(C)C)c2ccccc12
Yield: 61.6 %

Procedure:
To a suspension of ethyl 4-({(1-bromo-4-methylisoquinolin-3-yl)[4-(trifluoromethoxy)-benzyl]amino}sulfonyl)benzoate (93.5 mg, 0.15 mmol) prepared in Example 9-(1) and sodium hydride (60.0 mg, 1.5 mmol) in tetrahydrofuran (2 mL) was added 2-propanol (0.115 mL, 1.5 mmol) under argon atmosphere, and the mixture was heated to reflux for 4 hours. The mixture was neutralized by 2 mol/L hydrochloric acid, and then thereto was added chloroform. The mixture was stirred, and then separated. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/chloroform=2%→10%) to give 4-({(1-isopropoxy-4-methylisoquinolin-3-yl) [4-(trifluoromethoxy)benzyl]amino}sulfonyl)benzoic acid (53.1 mg, 58%) as a brown powder.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][C:8]([CH2:11][OH:12])=[CH:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.O1CCCC1.[H][H]>[C].[Pd].CO>[CH2:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: OCC1=CCC2(CCCC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: OCC1CCC2(CCCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
To a solution of spiro[4.5]dec-7-en-8-yl-methanol (0.7 g) obtained in Step 4 in a mixed solvent of tetrahydrofuran (7 mL)-methanol (7 mL) was added 5% palladium carbon (70 mg), followed by stirring the reaction mixture at room temperature under normal pressure in an atmosphere of hydrogen for 1.5 hours and then under increased pressure of 0.3 MPa in an atmosphere of hydrogen for 3 hours. Then, the reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was dissolved in methanol (5 mL). To the solution was added sodium borohydride (0.14 g), followed by stirring the reaction mixture at room temperature for 30 minutes. After addition of 1N aqueous hydrochloric acid solution, the reaction mixture was extracted with ethyl acetate twice. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:4) to give spiro[4.5]dec-8-yl-methanol (0.528 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(O[C:12]([S-])=[S:13])C.[K+].O.Cl>N1C=CC=CC=1>[O:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[N:1]=[C:12]1[SH:13]
Reactant: CCOC(=S)[S-]
Reactant: Nc1ncccc1O
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: Sc1nc2ncccc2o1
Yield: 67.4 %

Procedure:
2-Amino-3-hydroxypyridine (5.51 g) was dissolved in pyridine (100 mL), and potassium ethylxanthate (8.82 g) was added thereto. The mixture was refluxed for 2 hr. Iced water (400 mL) was added to the reaction mixture, and concentrated hydrochloric acid (40 mL) was added thereto. The mixture was extracted with chloroform and the extract was washed with brine and concentrated under reduced pressure to give 1,3-oxazolo[4,5-b]pyridine-2-thiol (5.13 g) as a pale-brown powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Br:15])[CH:9]=2)=[O:5])[CH3:2].[C:16]([O:20][C:21]([N:23]1[CH2:27][C@H:26]([CH3:28])OS1(=O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:26]([CH3:28])[CH2:27][NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Br:15])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(Br)cc2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Product: CCOC(=O)c1cc2ccc(Br)cc2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound, ISP-MS: m/e=425.3, 427.3 (M+H+), was prepared in accordance with the general method of example 12b) from 6-bromo-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH2:13][CH:14]=[CH2:15])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].B1C2CCCC1CCC2.C([O-])(=[O:28])C.[Na+].OO>C1COCC1>[OH:28][CH2:15][CH2:14][CH2:13][C:2]([CH3:16])([CH3:1])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: C=CCC(C)(C)C(=O)OCc1ccccc1
Reactant: CC(=O)[O-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(CCCO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of benzyl 2,2-dimethylpent-4-enoate (5.74 g, 26.3 mmol, prepared according to Step A) in THF (100 mL) was added a solution of 9-BBN (63.1 mL, 31.6 mmol, 0.5 M in THF) over 20 minutes, while under nitrogen. The reaction was allowed to stir at ambient temperature for 17 hours. An aqueous solution of sodium acetate (7.3 g, 89 mmol, in 18 mL of water) was then added, followed by the slow addition of aqueous hydrogen peroxide (18 mL, 30% by weight solution) with occasional chilling in a 0° C. bath. This mixture was allowed to stir at ambient temperature for 1.5 hours, before being extracted with ethyl acetate. The combined organics were washed with saturated brine. The organics were then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of MeOH:DCM—1:99 to 10:90, to give the title compound. MS: m/z=237 (M+1).