Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[O:13]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH2:15][C@@H:14]1[CH2:23]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:3][C:4]([C@@:6]1([CH3:12])[CH2:11][CH2:10][CH2:9][N:8]([CH2:23][C@@H:14]2[O:13][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][CH2:15]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@]1(C)CCCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccccc3O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@]1(C)CCCN(C[C@H]2COc3ccccc3O2)C1
Temperature: 120 °C
Yield: 80.1 %

Procedure:
A mixture of (S)-ethyl-3-methylpiperidine-3-carboxylate (7.23 g, 42.2 mmol), Toluene-4-sulfonic acid (R)-1-(2,3-dihydro-benzo[1,4]dioxin-2-yl)methyl ester (15.0 g, 44.3 mmol), potassium carbonate (6.42 g, 46.4 mmol) and N,N-dimethyl formamide (50 ml) was heated to 120° C. After 4 hours the reaction mixture was cooled down, water (35 ml) was added and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate layers were evaporated to dryness. Toluene (35 ml) was added to the evaporation residue and the mixture was extracted twice with 1M HCl. The combined acidic water layers were made basic with aq NaOH. The basic water layer was extracted twice with ethyl acetate and the combined ethyl acetate layers were evaporated to dryness to yield 10.8 g (76%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]([O:9][CH3:10])[C:5]([O:7][CH3:8])=[O:6].O[N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.N#N>O>[O:22]=[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20](=[O:21])[N:12]1[O:1][CH2:2][CH2:3][C@H:4]([O:9][CH3:10])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)[C@H](CCO)OC
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: COC(=O)[C@H](CCON1C(=O)c2ccccc2C1=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.6 %

Procedure:
To a solution of (S)-methyl 4-hydroxy-2-methoxybutanoate (46b, 1.48 g, 10.0 mmol) in CH2CT2 (25.0 mL) was added 2-hydroxyisoindolin-1,3-dione (1.63 g, 10.0 mmol) and triphenylphosphine (3.93 g, 15.0 mmol). The resultant mixture was cooled to 0° C. and diisopropylazodicarboxylate (2.95 ml, 15.0 mmol) was slowly added drop wise under N2 atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. To the reaction mixture, H2O (100 mL) was added and extracted with CH2Cl2. The organic layers washed with brine. Dried over anhydrous Na2SO4, filtered and concentrated to provide yellow oil, which was purified by flash chromatography (50% EtOAc-hexane) to afford (S)-methyl 4-(1,3-dioxoisoindolin-2-yloxy)-2-methoxybutanoate (46c, 1.25 g, 42%) as light yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.98-2.10 (m, 1H) 2.23-2.37 (m, 1H) 3.51 (s, 3H) 3.79 (s, 3H) 4.24 (dd, J=9.47, 3.66 Hz, 1H) 4.31-4.40 (m, 2H) 7.74-7.82 (m, 2H) 7.81-7.90 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH:21]([O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O)([CH3:23])[CH3:22]>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([O:24][CH:21]([CH3:23])[CH3:22])[CH:26]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: CC(C)Oc1cccc(C=O)c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(OC(C)C)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 3-isopropoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.91 min.; [M+H]+: 384.08 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH:13]=[C:12]([CH3:14])[C:11]([C:15]3[N:16]=[C:17]([NH2:20])[S:18][CH:19]=3)=[C:10]([CH3:21])[CH:9]=2)=[CH:5][CH:4]=1.[C:24]([O-])(=[O:26])[CH3:25].[Na+].O>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH3:21])[C:11]([C:15]3[N:16]=[C:17]([NH:20][C:24](=[O:26])[CH3:25])[S:18][CH:19]=3)=[C:12]([CH3:14])[CH:13]=2)=[CH:22][CH:23]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(Oc2cc(C)c(-c3csc(NC(C)=O)n3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of 4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-amine (2-1, 500 mg, 1.5 mmol) in acetic anhydride (2.0 mL) was added sodium acetate (125.7 mg, 1.5 mmol). The reaction was stirred at room temperature for 1.0 h. The solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give N-{4-(4-(4-methoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-yl}acetamide (2-2, 465 mg) as yellow oil in 82% yield: 1H NMR (500 MHz, DMSO-d6) δ 12.09 (s, 1H), 6.96-7.03 (m, 5 H), 6.64 (s, 2 H), 3.75 (s, 3 H), 2.15 (s, 3 H), 2.01 (s, 6 H). ESI-MS: m/z 368.9 (M+H)+.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH2:25]([CH2:27][NH2:28])[OH:26]>C1(C)C=CC=CC=1>[OH:26][CH2:25][CH2:27][NH:28][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(/C=C/c2c(-c3ccccc3)noc2C)nc1
Reactant: NCCO
Solvent: Cc1ccccc1
Product: Cc1onc(-c2ccccc2)c1/C=C/c1ccc(C(=O)NCCO)cn1
Temperature: 35 °C
Yield: 71.6 %

Procedure:
To a stirred solution of 6-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-nicotinic acid methyl ester (200 mg, 0.62 mmol) in toluene (0.5 mL) was added ethanolamine (46 mg, 0.75 mmol) and TBD (26 mg, 0.10 mmol), then the reaction mixture was warmed to 35° C. After 3 h the reaction mixture was concentrated. Purification by chromatography (silica, dichloromethane:methanol 100:0 to 93:7) afforded the title compound (155 mg, 71%) as a white solid after trituration with hexane/ethyl acetate. MS: m/e=350.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([CH2:11][OH:12])[C:4]=2[N:5]=[CH:6][N:7]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([CH:11]=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OCc1csc2c(Cl)ncnc12
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: O=Cc1csc2c(Cl)ncnc12
Temperature: 70 °C
Reaction time: 2 h

Procedure:
(4-Chlorothieno[3,2-d]pyrimidine-7-yl)methanol (215 mg, 0.99 mmol) and MnO2 (863 mg, 9.9 mmol, 10 eq) were dissolved in chloroform (10 mL) and stirred at 70° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered with Celite and concentrated to obtain the title compound as a white solid without further purification.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[C:15]3[N:14]=[C:13]([NH:16][CH:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[C:12]4[CH:23]=[CH:24][C:25](Br)=[CH:26][C:11]=4[C:10]=3[C:9](=[O:28])[NH:8][CH:7]=2)[CH2:3][CH2:2]1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][NH:40][CH:41]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.CN(C=O)C>[CH:1]1([C:4]#[C:5][C:6]2[C:15]3[N:14]=[C:13]([NH:16][CH:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[C:12]4[CH:23]=[CH:24][C:25]([C:37]5[CH:38]=[N:39][NH:40][CH:41]=5)=[CH:26][C:11]=4[C:10]=3[C:9](=[O:28])[NH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(Nc1nc2c(C#CC3CC3)c[nH]c(=O)c2c2cc(Br)ccc12)C(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(Nc1nc2c(C#CC3CC3)c[nH]c(=O)c2c2cc(-c3cn[nH]c3)ccc12)C(C)(C)C
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
4-(cyclopropylethynyl)-9-bromo-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one (750 mg, 1.711 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (664 mg, 3.42 mmol), and PdCl2(dppf)-CH2Cl2 adduct (279 mg, 0.342 mmol) were added to a vial, followed by DMF (1.71E+04 μl) and aqueous sodium carbonate (2M) (1711 μl, 3.42 mmol). The reaction was purged with argon (subsurface bubbling) for 10 min. The reaction mixture was heated in a microwave oven at 130° C. for 45 min. The mixture was then cooled to room temperature and diluted with DMSO (˜17 mL) and filtered through a syringe filter (filter was rinsed with DMSO). This solution was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA. The fractions were combined, neutralized with NaHCO3 (sat) and extracted with dichloromethane (2×300 mL). The combined organics were washed with water (200 mL), brine (200 mL) dried over anhydrous sodium sulfate, swirled for 10 min with 1 g MP-TMT Pd scavenger resin, filtered and dried under reduced pressure to give the title compound as a yellow solid. 1H NMR (500 MHz, CD3OD) δ 13.10 (s, 1H), 11.28 (d, 1H, J=6.5 Hz), 10.02 (d, 1H, J=1.5 Hz), 8.49 (d, 1H, J=9.0 Hz), 8.28 (s, 1H), 7.96 (s, 1H), 7.83 (dd, 1H, J=8.5, 1.5 Hz), 7.49 (d, 1H, J=6.5 Hz), 7.45 (d, 1H, J=9.0 Hz), 4.87 (m, 1H), 1.53 (m, 1H) 1.21 (d, 3H, J=7 Hz), 0.98 (s, 9H), 0.88 (m, 2H), 0.72 (m, 2H). LRMS (ESI) calc'd for (C26H28N5O) [M+H]+, 426.2; found 426.2.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:23])=[C:19]([CH2:21][OH:22])[CH:20]=1>CN(C=O)C.C(OCC)(=O)C>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([Cl:23])=[C:19]([CH:20]=1)[CH2:21][O:22][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: OCc1cc(Br)ccc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
Imidazole (5.22 g) and tert-butyldimethylsilyl chloride (8.64 g) were added to a solution of (5-bromo-2-chlorophenyl)methanol (8.47 g) in DMF (80 ml). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed twice with water. The aqueous layer was again extracted with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (12.6 g).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1)=[O:4].[H-].[Na+].[CH3:21]I.[ClH:23]>CN(C)C=O.O.CCOCC>[ClH:23].[CH3:1][N:2]([CH3:21])[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: CI
Reactant: CNC(=O)CCCCCc1cccc2cncn12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(C)C(=O)CCCCCc1cccc2cncn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.45 g of 5-[5-(N-methylcarbamoyl)pentyl]imidazo[1,5-a]pyridine in 25 ml of dimethylformamide is treated with 0.011 mole of sodium hydride (obtained by washing 0.53 g of 50% NaH dispersion in mineral oil with hexane) and warmed briefly on a steam bath. Methyl iodide (1.56 g) is added to the cooled yellow solution. The mixture is stirred at room temperature for 2 hours, diluted with water and extracted first with a 1:1 mixture of ethyl acetate and ether and subsequently with chloroform. The residue obtained on evaporation of the combined extracts to dryness is dissolved in ether and treated with ethanolic hydrochloric acid. The precipitated salt is collected, recrystallized first from acetonitrile/ethyl acetate and then from ethanol/ether to yield 5-[5-(N,N-dimethylcarbamoyl)pentyl]imidazo[1,5-a]pyridine hydrochloride melting at 166°-71°.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][CH2:19][NH2:20]>C(OC(=O)C)C>[CH2:1]([NH:8][CH2:9][C:10]([NH:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][CH2:19][NH:20][C:10](=[O:12])[CH2:9][NH:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CNCc1ccccc1
Reactant: NCCCNCCN
Solvent: CCOC(C)=O
Product: O=C(CNCc1ccccc1)NCCCNCCNC(=O)CNCc1ccccc1
Reaction time: 1 h

Procedure:
The p-nitrophenyl ester of N-benzylglycine (2 g) and N-(2-aminoethyl)-1,3-propanediamine (0.18 g) are dissolved in ethylacetate (30 ml). After standing for 1 hour, the mixture is filtered, evaporated and resulting solid triturated with diethyl ether. Recrystallisation of the product from ethanol yields N-[2-(benzylaminoacetamido)-ethyl]-3-(benzylaminoacetamido)-propylamine as a solid, νmax (nujol) 1680, 1630, 1540 cm-1 ; δ(d6DMSO) 1.5 (quintet, 2H), 2.5 (m, 4H), 3.1 (q, 4H), 3.6 (d, 4H), 5.0 (s, 4H), 7.3 (s, 10H), 7.4 (m, 2H), 7.7 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.C(COC)OC.B([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])(O)O.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C.[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2]>[Br:8][C:4]1[N:3]=[C:2]([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=2[NH:25][C:26](=[O:31])[C:27]([CH3:29])([CH3:28])[CH3:30])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1ccc(NC(=O)C(C)(C)C)c(B(O)O)c1
Reactant: Brc1cccc(Br)n1
Agent: [Pd+2]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)C(C)(C)C)c(-c2cccc(Br)n2)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 75.5 %

Procedure:
A mixture of 24 g (0.1 mol) 2,6-dibromopyridine, 0.250 g palladium bis(triphenylphosphine) dichloride, and 40 mL dimethoxyethane was stirred under nitrogen for 20 min, after which 12 g (0.05 mol) N-(2-borono4-methylphenyl)-2,2-dimethylpropanamide and a solution of 26 g sodium bicarbonate in 300 mL water was added, and the mixture heated to reflux for 5 h. After cooling to 50° C., 50 mL ethyl acetate was added and stirred until it reached room temperature. The reaction mixture was diluted with 300 mL ethyl acetate and washed successively with water and brine. The organic extracts were dried over magnesium sulfate, filtered, and evaporated to dryness. The crude product was purified by chromatography on silica using 20:1 chlorobutane/ethyl acetate mixture as eluent to yield 13.1 g of the title compound as light tan crystals melting at 120°-126° C. 1H NMR (CDCl3): δ 1.28 (s,9H), 2.40 (s,3H), 7.30-8.4 (6H), 10.9 (s,1H,NH).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([CH3:17])([CH3:16])[C:13](N)=[O:14])=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[CH2:18]([OH:20])[CH3:19]>>[CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([CH3:17])([CH3:16])[C:13]([O:20][CH2:18][CH3:19])=[O:14])=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: CCO
Reactant: CC(C)(C(N)=O)c1ccc(C(=O)C2CC2)cc1
Product: CCOC(=O)C(C)(C)c1ccc(C(=O)C2CC2)cc1

Procedure:
Dissolve 2-(4-cyclopropanecarbonyl-phenyl)-2-methyl-propionamide (100 mg) in ethanol and bubble in hydrochloride gas for 5 minutes while stirring. Reflux for 10 hours, distill off the ethanol and extract into ethyl acetate. Evaporate the solvent in vacuo to give the title compound as an oil (50 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[S:17][C:18]([CH:21]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=5[Cl:34])[N:22]5[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]5)=[CH:19][N:20]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[C:36]([O:38][C@H:39]1[CH2:44][C@@H:43]([CH3:45])[CH2:42][CH2:41][C@@H:40]1[CH:46]([CH3:48])[CH3:47])=[O:37]>ClCCl.CN(C)C1C=CN=CC=1.CO>[C:36](=[O:37])([O:38][C@H:39]1[CH2:44][C@@H:43]([CH3:45])[CH2:42][CH2:41][C@@H:40]1[CH:46]([CH3:48])[CH3:47])[O:27][C@@H:24]1[CH2:25][CH2:26][N:22]([CH:21]([C:18]2[S:17][C:16]([NH:15][C:13]([C:10]3([C:8]4[CH:7]=[CH:6][C:5]5[O:1][CH2:2][O:3][C:4]=5[CH:9]=4)[CH2:12][CH2:11]3)=[O:14])=[N:20][CH:19]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[CH2:23]1
Reactant: CC(C)[C@H]1CC[C@H](C)C[C@@H]1OC(=O)Cl
Reactant: O=C(Nc1ncc(C(c2ccccc2Cl)N2CC[C@@H](O)C2)s1)C1(c2ccc3c(c2)OCO3)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)[C@H]1CC[C@H](C)C[C@@H]1OC(=O)O[C@@H]1CCN(C(c2cnc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)s2)c2ccccc2Cl)C1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2-chlorophenyl)((R)-3-hydroxypyrrolidin-1-yl)methyl)thiazol-2-yl)-cyclopropanecarboxamide (3.00 g, 6.02 mmol) was suspended in 200 mL of anhydrous dichloromethane containing N,N-dimethylpyridin-4-amine (2.20 g, 18.0 mmol), (1S,2R,5S)-2-Isopropyl-5-methylcyclohexyl chloroformate (1.91 mL, 9.00 mmol) was slowly added to the suspension and the resulting mixture was heated to reflux for 16 hours. The resulting pale yellow solution was allowed to cool to room temperature, diluted with 20 mL of methanol, and then evaporated to dryness. The crude reaction mixture was separated on 330 g of silica gel utilizing a gradient of 0-5% methanol in dicholoromethane to yield the pure product as a pale yellow solid (2.008 g, 2.9529 mmol, 49.1%). ESI-MS m/z calc. 679.3, found; 680.5 (M+1)+; Retention time 3.88 minutes.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]=2[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=1.[H-].[Na+].[CH2:20]([O:22][CH2:23][CH2:24]Br)[CH3:21]>CN(C=O)C>[CH3:13][C:10]1([CH3:12])[CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]2[CH:5]=[C:4]([CH:16]=[O:17])[CH:3]=[C:2]([O:1][CH2:21][CH2:20][O:22][CH2:23][CH3:24])[C:11]1=2
Reactant: CC1(C)CCC(C)(C)c2c(O)cc(C=O)cc21
Reactant: CCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCCOc1cc(C=O)cc2c1C(C)(C)CCC2(C)C
Reaction time: 1 h

Procedure:
36 g (156 mmol) of 4-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carbaldehyde are dissolved in 400 mL of anhydrous DMF. 6.5 g (163 mmol) of 60% sodium hydride are added portionwise and the reaction medium is stirred for 1 hour. 25 g (163 mmol) of 2-ethoxyethyl bromide are added portionwise and the medium is stirred at room temperature for 2 hours and then hydrolysed and extracted with ethyl ether. The organic phase is washed with 1N sodium hydroxide solution, and then three times with water. The residue obtained is purified by chromatography (eluent: heptane). A yellow oil is obtained (m=40.7 g; yield =86%).
Reaction SMILES: [O:1]=[C:2]1[C:6]2=[CH:7][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4][N:3]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][C:34](OC)=[O:35].[BH4-].[Li+].CO.[Cl-].[NH4+].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C(=O)(O)[O-].[Na+]>C(OCC)C.ClCCl.O>[OH:35][CH2:34][CH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N:3]1[C:2](=[O:1])[C:6]2=[CH:7][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:5]2=[N:4]1
Reactant: COC(=O)Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: O=c1c2cn(Cc3ccc(-n4cccn4)cc3)c3ccccc3c-2nn1-c1ccccc1CCO
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Methyl [2-(3-oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)phenyl]acetate (Example 533, 0.10 g, 0.21 mmol) was suspended in diethyl ether (6 mL) and dichloromethane (9 mL), cooled to 0° C. and treated with lithium borohydride (4.9 mg, 0.23 mmol, 1.1 equiv) and then methanol (9.2 μL, 0.23 mmol, 1.1 equiv). The mixture was stirred at 0° C. for 15 minutes and then warmed to ambient temperature. After 20 minutes, the mixture was treated with additional lithium borohydride (10 mg, 0.46 mmol, 2.2 equiv) and methanol (20 μL, 0.46 mmol, 2.2 equiv) and stirred for an additional 1 hour at ambient temperature. The mixture was treated with ammonium chloride (3 mL, aqueous saturated) and stirred at ambient temperature for 15 minutes. The mixture was poured into water (20 mL) and extracted with dichloromethane (3×50 mL). The combined organic extracts were treated with dichloro-5,6-dicyanobenzoquinone (DDQ, 52 mg, 0.46 mmol, 2.2 equiv) and stirred for 45 minutes at ambient temperature. The mixture was treated with sodium bicarbonate (50 mL, aqueous saturated) and vigorously stirred for 30 minutes, partitioned and the aqueous layer was further extracted with dichloromethane (1×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate containing 5% methanol), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.13 (1H, s), 8.46 (1H, d, J=2.5 Hz), 8.19 (1H, d, J=7.6 Hz), 7.84 (2H, d, J=8.5 Hz), 7.77 (1H, d, J=8.5 Hz), 7.73 (1H, d, J=1.4 Hz), 7.64-7.59 (1H, m), 7.53 (1H, t, J=7.2 Hz), 7.48 (2H, d, J=8.5 Hz), 7.43 (1H, br d, J=6.9 Hz), 7.39-7.33 (3H, m), 6.53 (1H, m), 5.77 (2H, s), 4.61 (1H, t, J=5.2 Hz), 3.58-3.53 (2H, m), 2.77 (2H, t, J=7.4 Hz) ppm; high resolution mass spectrometry (ES+) m/z 462.1912 [(M+H)+; calculated for C28H24N5O2: 462.1925].
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([C:6]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15]C)[C:8]=2[CH:7]=1)(=[O:5])=[O:4].B(Br)(Br)Br>>[CH3:1][N:2]([CH3:17])[S:3]([C:6]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([OH:15])[C:8]=2[CH:7]=1)(=[O:5])=[O:4]
Reactant: COc1cccc2oc(S(=O)(=O)N(C)C)cc12
Agent: BrB(Br)Br
Product: CN(C)S(=O)(=O)c1cc2c(O)cccc2o1
Yield: 97.7 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 5 using 2-(N,N-dimethylsulfamoyl)-4-methoxybenzo(b)furan (1.30 g) and boron tribromide (2.6 ml), the title compound (1.20 g) was obtained as colorless crystals, melting point 150–153° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.Br[C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:14][O:13][C:11](=[O:12])[CH:10]([CH3:16])[CH2:15][N:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]1=[O:8]
Reactant: COC(=O)C(C)(C)Br
Reactant: O=c1cc(Br)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)Cn1ccc(Br)cc1=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 4-bromo-1H-pyridin-2-one (0.50 g), methyl 2-bromoisobutyrate (0.45 mL), and potassium carbonate (0.68 g) in dimethylformamide (5 mL) was stirred at 60° C. for 3 h. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 70:30->50:50) to afford the title compound. Yield: 0.53 g (67% of theory); Mass spectrum (ESI+): m/z=274/276 (Br) [M+H]+. Additionally 2-(4-bromo-pyridin-2-yloxy)-2-methyl-propionic acid methyl ester was obtained {Yield: 0.15 g; Mass spectrum (ESI+): m/z=274/276 (Br) [M+H]+}