Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[C:10]#[N:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH2:14].C(N(CC)CC)C>C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[C:10](=[S:14])[NH2:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C#N)NC(=O)OC(C)(C)C
Reactant: S
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(C)(C)C(N)=S
Reaction time: 19 h

Procedure:
2-tert-Butyloxycarbonylamino-2-methylpropiononitrile (80.00 g) in Benzene (700 ml) was stirred at 0° C., and saturated with hydrogen sulfide. To the reaction mixture was dropped triethyl amine (1000 ml) and bubbled hydrogen sulfide at ambient temperature for 9 hours, and left at the same temperature for 19 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogencarbonate, water and brine, and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo. The residue was washed with n-hexane, to give 2-tert-butyloxycarbonylamino-2-methylpropanethioamide (80.14 g).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([C:14]1[O:18][C:17]([CH2:19][CH2:20][NH:21][C:22]([NH:24][C:25]2[S:26][C:27]([C:31]3[CH:36]=[C:35]([CH3:37])[N:34]=[C:33]([S:38]([CH3:40])=[O:39])[N:32]=3)=[C:28]([CH3:30])[N:29]=2)=[O:23])=[N:16][CH:15]=1)[CH3:13]>ClCCl>[CH2:12]([C:14]1[O:18][C:17]([CH2:19][CH2:20][NH:21][C:22]([NH:24][C:25]2[S:26][C:27]([C:31]3[CH:36]=[C:35]([CH3:37])[N:34]=[C:33]([S:38]([CH3:40])(=[O:6])=[O:39])[N:32]=3)=[C:28]([CH3:30])[N:29]=2)=[O:23])=[N:16][CH:15]=1)[CH3:13]
Reactant: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(S(C)=O)n3)s2)o1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3cc(C)nc(S(C)(=O)=O)n3)s2)o1

Procedure:
Meta-chloroperoxybenzoic acid or m-CPBA (57-86% purity, 0.438 g, 1.8 mmol) is added in portions to a rapidly stirring solution of 1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[5-(2-methane-sulfinyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-urea (0.31 g, 0.74 mmol) in dry dichloromethane (5 ml) at room temperature. After 2 hours the mixture is diluted with dichloromethane and washed with aqueous sodium thiosulfite and brine. The organic extract is separated, dried over MgSO4 and the solvent is removed. Purification by chromatography on silica, eluting with EtOAc, MeOH (97:3) affords the titled compound.
Reaction SMILES: [CH:1]([C:7]1[C:8]([C:12]2[CH2:13][N:14](C)[CH2:15][CH2:16][CH:17]=2)=[N:9][O:10][CH:11]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:19](/B(O)O)=[CH:20]\CCCCCC.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1COCC1>[CH:1]([C:7]1[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][O:10][CH:11]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:19][CH3:20]
Reactant: CCCCCC/C=C/B(O)O
Reactant: CCCCC=Cc1conc1C1=CCCN(C)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCC=Cc1conc1-c1cccnc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
To anhydrous THF (20 ml) containing 64 (0.49 g, 2.17 mmol) (see Scheme 13), were added 1.5 eq of (E)-octene-1-ylboronic acid (0.51 g). The resulting mixture was stirred for 2 hours under N2. Successively were added 2 eq of K3PO4 (0.92 g), 2 mol % of Pd(OAc)2 (10 mg) and 4 mol % of S-Phos (36 mg). After the addition, the resulting solution was warmed at 65° C. for 18 hours under N2. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether/PE 1/1) to afford 3-(4 Oct-1-enyl-isoxazol-3-yl)-pyridine (compound 67B) as an oil (0.19 g, 34%). 1H-NMR (400 MHz, CDCl3): δ 8.9 (d, J=2 Hz, 1H), 8.72 (dd, J=5 Hz, 2 Hz, 1H), 8.49 (s, 1H), 7.9 (dt, J=8 Hz, 2 Hz, 1H), 7.45-7.40 (m, 1H), 6.11-5.99 (m, 2H), 2.21-2.13 (m, 2H), 1.46-1.38 (m, 2H), 1.37-1.21 (m, 6H), 0.91 (t, J=7 Hz, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:6]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:5]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:4][C@@H:3]1[OH:33].N1C=CN=C1.[C:39]([Si:43](Cl)([CH3:45])[CH3:44])([CH3:42])([CH3:41])[CH3:40]>C(Cl)Cl>[CH2:9]([O:8][C@H:7]1[C@H:6]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:5]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:4][C@H:3]([O:33][Si:43]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:45])[CH3:44])[C@@H:2]1[NH2:1])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)C[C@@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1N
Yield: 71.8 %

Procedure:
A solution of (1S,2S,3R,4R,5R)-2-amino-3,4-bis(benzyloxy)-5-(benzyloxymethyl)cyclohexanol (1 g, 2.23 mmol) and imidazole (338 mg, 3.35 mmol) in DCM (20 mL) was treated with tert-butylchlorodimethylsilane (371 mg, 2.46 mmol) for 12 h at room temperature. The reaction was quenched by addition of satd. aqueous NaHCO3 (5 mL), and was extracted by DCM (2×10 mL). The organic layers were combined, dried over anhydrous MgSO4, and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% of MeOH in DCM to give (1R,2R,3R,4R,6S)-2,3-bis(benzyloxy)-4-(benzyloxymethyl)-6-(tertbutyldimethylsilyloxy)cyclohexanamine as a yellow oil (0.9 g, 68%). MS (ES, m/z): 562.3; 1H NMR (300 MHz, CDCl3) δ 7.24-7.37 (m, 15H), 4.80-4.95 (m, 2H), 4.55-4.71 (m, 2H), 4.40-4.51 (m, 2H), 4.05 (s, 1H), 3.62-3.67 (m, 1H), 3.44-3.50 (m, 3H), 2.43-2.46 (m, 1H), 2.15 (s, 1H), 1.82-1.85 (m, 1H), 1.52-1.59 (m, 1H), 0.92 (s, 9H), 0.11 (s, 3H), 0.08 (s, 3H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1.[C:28](O)(=[O:31])[CH2:29][CH3:30]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1
Reactant: CCC(=O)O
Reactant: NC1CCC(CCN2CCN(c3nccc4ccoc34)CC2)CC1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4ccoc34)CC2)CC1

Procedure:
The title compound, white solid (64 mg, 83%), MS (ISP) m/z=385.4 [(M+H)+], mp 187.5° C., was prepared in accordance with the general method of example 6 from 4-[2-(4-furo[2,3-c]pyridin-7-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and propionic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)[O:3]1.C(N/C(=N/C(C)C)/O[C:26]([CH3:29])([CH3:28])[CH3:27])(C)C>C1COCC1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:19])([CH3:1])[O:3][B:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:17])=[CH:11][CH:10]=2)[O:5]1
Reactant: CC(C)/N=C(/NC(C)C)OC(C)(C)C
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2)OC1(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
2-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid (0.250 g, 0.954 mmol) was dissolved in 10 mls of dry THF. To this solution was added (Z)-tert-butyl N,N′-diisopropylcarbamimidate (3.82 g, 19.08 mmol) and the mixture was allowed to stir at room temperature for 16 hours. The mixture was then filtered, filtrate concentrated under reduced pressure and purified by a 50 g Snap cartridge (Biotage, 10% EtOAc/Hexanes) to give 280 mgs (92%) of tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate as a thick oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][CH:12]=[CH2:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:14][OH:15]>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][CH:12]([O:15][CH3:14])[CH3:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C=CCOC1CCN(C(C)=O)CC1
Reactant: CO
Product: COC(C)COC1CCN(C(C)=O)CC1

Procedure:
This compound was prepared similarly to Example F, starting from N-acetyl-4-allyloxypiperidine and mercuric acetate in methanol. To improve the conversion of starting material to product the mercuric acetate/methanol treatment was repeated twice to give N-acetyl-4-(2-methoxy-n-propoxy)piperidine, which was hydrolyzed in sodium hydroxide and methanol solution to give 4-(2-methoxy-n-propoxy)piperidine. A sample was characterized as the oxalate salt, m.p. 89°-91° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2.C1C(=O)N([Br:25])C(=O)C1.N(C(C)(CC(C)(OC)C)C#N)=NC(C)(CC(OC)(C)C)C#N.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClC(Cl)(Cl)Cl>[Br:25][CH2:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]([CH3:1])=[CH:11]2
Reactant: CCOC(=O)c1nc2ccc(C)cc2cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc2ccc(CBr)cc2cc1C
Temperature: 90 °C
Yield: 59.7 %

Procedure:
To a solution of ethyl 3,6-dimethylquinoline-2-carboxylate (1.0 g) in tetrachloromethane (10 ml) were added N-bromosuccimide (815 mg) and 2,2'-azobis (2,4-dimethyl-4-methoxyvaleronitrile) at ambient temperature under nitrogen atmosphere, and the mixture was heated at 90° C. for 1 hour. The reaction mixture was poured into 5% sodium thiosulfate solution and extracted with dichloromethane. The organic layer was washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (n-hexane--ethyl acetate) to give ethyl 6-bromomethyl-3-methylquinoline-2-carboxylate (802 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:18])[N:4]([C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[CH2:28]Br>CC(N(C)C)=O.O>[Cl:1][C:2]1[C:3](=[O:18])[N:4]([C:10]2[C:11]([F:17])=[CH:12][CH:13]=[CH:14][C:15]=2[F:16])[C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:28][C:27]1[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:26]=1[F:25]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: Cc1cc(O)c(Cl)c(=O)n1-c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-chloro-1-(2,6-difluorophenyl)-4-hydroxy-6-methylpyridin-2(1H)-one (0.27 g, 1.00 mmol) in DMA (5 mL) was added K2CO3 followed by the addition of 2,4-difluorobenzyl bromide (0.128 mL, 1 mmol). The reaction mixture stirred at room temperature for 2 hours and then was diluted in water. The reaction mixture was extracted with ethyl acetate, the organic extracts were dried over Na2SO4 and the filtrate was concentrated. The resulting residue was purified by flash column chromatography (ethyl acetate/hexane 3:4 v/v) to afford the desired product. 1H-NMR (CD3OD, 400 MHz) δ 7.60 (m, 2H), 7.25 (m, 2H), 7.04 (m, 2H), 6.71 (s, 1H), 5.36 (s, 2H), 2.11 (s, 3H); ES-HRMS m/z 398.0551 (M+H calculated for C19H13NO2F4Cl requires 398.0571).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)=[CH2:2].[C:12]([O:16][C:17](=[O:38])[NH:18][C:19]([C:21]1[S:22][C:23]([S:36][CH3:37])=[C:24]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31](Br)[CH:30]=2)(=[O:28])=[O:27])[CH:25]=1)=[NH:20])([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1.CCO>[C:12]([O:16][C:17](=[O:38])[NH:18][C:19](=[NH:20])[C:21]1[S:22][C:23]([S:36][CH3:37])=[C:24]([S:26]([C:29]2[CH:30]=[C:31]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH:1]=[CH2:2])[CH:32]=[CH:33][CH:34]=2)(=[O:28])=[O:27])[CH:25]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: C=Cc1ccccc1B(O)O
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C=Cc1ccccc1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1

Procedure:
Following the procedure outlined for Examples 41–107, reaction of 2-vinyl-phenylboronic acid (30 mg, 0.20 mmol, Aldrich Chemical Company), {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (50 mg, 0.1 mmol, as prepared in Example 27, step c), tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol, Strem Chemicals, Inc., Newburyport, Mass.), Na2CO3 (400 μL, 2M aqueous), and toluene/EtOH mixture (2:1, 1.2 mL) afforded 25 mg (50%) after purification (1:3 EtOAc/hexanes, 2000μ SiO2 plate) of the title compound as a white foam.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8]C)[C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].B(Br)(Br)Br.Cl>ClCCl>[OH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11]
Reactant: COc1cccc(I)c1S(N)(=O)=O
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: NS(=O)(=O)c1c(O)cccc1I
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
0.50 g (1.60 mmol) of 2-iodo-6-methoxybenzenesulfonamide are introduced in 10 ml of dichloromethane at room temperature and this initial charge is cautiously admixed with 0.6 g (2.40 mmol) of boron tribromide. The reaction solution is stirred at room temperature for a further 45 min and then added to 2 N hydrochloric acid. Following extraction with dichloromethane, the organic phase is dried and evaporated. This gives 0.43 g (90% of theory) of 2-hydroxy-6-iodobenzenesulfonamide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:15]([OH:17])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[Na].Cl.C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][CH2:28][C:29](Cl)=[O:30]>O.[Ni](Cl)Cl.O1CCCC1.CO>[CH3:26][O:27][CH2:28][C:29]([NH:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:15]([OH:17])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[O:30]
Reactant: COCC(=O)Cl
Reactant: O=C(O)C1(c2ccc([N+](=O)[O-])cc2)CCCC1
Agent: Cl[Ni]Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COCC(=O)Nc1ccc(C2(C(=O)O)CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
13 g (20 mmol) of triphenylphosphine complex of nickel (II) chloride were added to a solution of 25.3 g (100 mmol) of 1-(4-nitrophenyl)cyclopentanoic acid in 200 ml of a 1:1 by volume mixture of methanol and tetrahydrofuran cooled in an ice bath. 10 g of sodium boronhydride were added to the cooled mixture in small portions over 10 minutes. The resulting mixture was then stirred at room temperature for 20 minutes, at the end of which time the reaction mixture was poured into 500 ml of water and the pH was then adjusted to 4 with concentrated hydrochloric acid. This caused the precipitation of crystals of 1-(4-aminophenyl)cyclopentanecarboxylic acid which were collected by filtration. 22.2 g (150 mmol) of potassium carbonate and 100 ml of tetrahydrofuran were then added to a suspension of the crystalline product in 100 ml of water which had been cooled in an ice bath, after which 9.0 ml (100 mmol) of methoxyacetyl chloride were added. After stirring the resulting mixture at the same temperature for 30 minutes, 200 ml of water were added, the mixture was washed with ether and the pH of the ether extract was then adjusted to 4 with concentrated hydrochloric acid. This mixture was allowed to stand at room temperature for 2 hours and the resulting crystals were collected by filtration to afford 25.4 g (yield 91.6%) of the desired compound as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].O[CH2:11][CH:12]([CH2:14]O)O>>[CH3:9][C:7]1[CH:6]=[C:5]2[C:3](=[C:2]([Br:1])[CH:8]=1)[N:4]=[CH:14][CH:12]=[CH:11]2
Reactant: OCC(O)CO
Reactant: Cc1ccc(N)c(Br)c1
Product: Cc1cc(Br)c2ncccc2c1

Procedure:
2-bromo-4-methylaniline and glycerol can be combined to form 6-methyl-8-bromoquinoline,
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=[O:14].C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:34][O:35][C:36]1[CH:37]=[C:38](/[CH:48]=[CH:49]/[C:50](O)=[O:51])[CH:39]=[N:40][C:41]=1[N:42]1[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]1>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[CH3:34][O:35][C:36]1[CH:37]=[C:38](/[CH:48]=[CH:49]/[C:50]([NH:1][N:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:3]2=[O:14])=[O:51])[CH:39]=[N:40][C:41]=1[N:42]1[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]1
Reactant: COc1cc(/C=C/C(=O)O)cnc1-n1cnc(C)c1
Reactant: NN1CCCN(c2ccccc2)C1=O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/C(=O)NN2CCCN(c3ccccc3)C2=O)cnc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-Amino-3-phenyl-tetrahydropyrimidin-2-one synthesized by the same method as in Example 232 at room temperature (111 mg; ESI-MS; m/z 192 [M++H]), IPEA (0.41 mL), EDC (166 mg) and HOBT (117 mg) were added to a solution of (E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylic acid (300 mg) in DMF (6 mL). The reaction solution was stirred at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system, then ethyl acetate-methanol system) to obtain 250 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:50]1[C:54]2[CH:55]=[CH:56][C:57]([C:59]3[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=3)=[CH:58][C:53]=2[CH2:52][CH2:51]1>CN(C=O)C>[O:50]1[C:54]2[CH:55]=[CH:56][C:57]([C:59]3[CH:60]=[C:61]([NH:65][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:62]=[CH:63][CH:64]=3)=[CH:58][C:53]=2[CH2:52][CH2:51]1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2ccc3c(c2)CCO3)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5c(c4)CCO5)c3)c(=O)oc12
Temperature: 25 °C
Yield: 95.4 %

Procedure:
DIEA (0.014 mL, 0.078 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.016 g, 0.071 mmol) and HATU (0.030 g, 0.078 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2,3-dihydro-benzofuran-5-yl)-phenylamine (0.015 g, 0.071 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.028 g of product in 94% yield: LCMS (ESI) m/z 414 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[NH:14][N:15]=[C:16]([CH3:17])[C:11]3=[C:10]([C:18]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[O:19])[CH:9]=2)=[CH:4][CH:3]=1.[CH:26]1(C2C3C(C(O)=O)=CC(C4C=CC(O)=CC=4)=NC=3NN=2)C[CH2:27]1.C1(C2NN=C(N)C=2)CC1.COC(=O)C(C)=O.OC1C=CC(C=O)=CC=1.N1(C(OC(C)(C)C)=O)CCNCC1>>[CH:17]1([C:16]2[C:11]3[C:12](=[N:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=4)=[CH:9][C:10]=3[C:18]([N:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)=[O:19])[NH:14][N:15]=2)[CH2:27][CH2:26]1
Reactant: O=C(O)c1cc(-c2ccc(O)cc2)nc2[nH]nc(C3CC3)c12
Reactant: Cc1n[nH]c2nc(-c3ccc(O)cc3)cc(C(=O)N3CCNCC3)c12
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: COC(=O)C(C)=O
Agent: Nc1cc(C2CC2)[nH]n1
Product: O=C(c1cc(-c2ccc(O)cc2)nc2[nH]nc(C3CC3)c12)N1CCNCC1

Procedure:
[3-Cyclopropyl-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone was prepared following a similar procedure as described for the synthesis of example 53, [6-(4-Hydroxy-phenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl]-piperazin-1-yl-methanone, using 3-cyclopropyl-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (obtained as described in example 41, steps (a) and (c) employing 5-cyclopropyl-1H-pyrazol-3-ylamine, pyruvic acid methyl ester and 4-hydroxybenzaldehyde as the starting materials) and tert.butyl 1-piperazine carboxylate as starting materials.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][O:19][CH2:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.FC(F)(F)C(O)=O>>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][O:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)CCOCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCOCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 76.5 %

Procedure:
A mixture of tert-butyl 3-[(6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl)methoxy]propanoate (2.80 g, 6.8 mmol) and trifluoroacetic acid (15 ml) was stirred at 0° C. for 3 hrs. The mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate-hexane to give the titled compound (1.78 g, 74%), which was recrystallized from ethanol to give prisms (1.66 g, 69%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[S:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].C([C:28]1[C:29]([N:35]=[CH:36][N:37]([CH3:39])C)=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=1)#N.NC1C=C(C=CC=1SC1C=CC(O)=CC=1)C(NC1C=CC(Br)=CC=1)=O>>[CH2:8]([NH:7][C:5](=[O:6])[C:4]1[CH:15]=[CH:16][C:17]([S:18][C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)=[C:2]([NH:1][C:39]2[C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[N:30][C:29]=3[N:35]=[CH:36][N:37]=2)[CH:3]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccc1Sc1ccc(O)cc1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Agent: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Product: Cc1ccc2c(Nc3cc(C(=O)NCc4ccccc4)ccc3Sc3ccc(O)cc3)ncnc2n1
Yield: 54 %

Procedure:
The product of Example 35A was reacted with the product of Example 9B using the procedure of Example 22C substituting the product of Example 35A for the product of Example 22B and substituting the product of Example 9B for the product of Example 8E to provide the crude title compound which was purified by column chromatography on silica gel using methanol/dichloromethane as eluent to provide the title product (50 mg, 54%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.67 (s, 3 H) 4.45 (d, J=5.88 Hz, 2 H) 6.78-6.96 (m, 1 H) 6.83 (d, J=8.46 Hz, 2 H) 7.15-7.40 (m, 7 H) 7.55 (d, J=7.35 Hz, 1 H) 7.73 (d, J=5.88 Hz, 1 H) 7.90 (s, 1 H) 8.56 (s, 1 H) 8.80 (d, J=8.09 Hz, 1 H) 9.01 (s, 1 H) 9.94 (s, 1 H) 10.14 (s, 1 H); MS (ESI+) m/z 494(M+H)+, (ESI−) m/z 492 (M−H)−.