Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[C:21]([C:28]([O:30][CH3:31])=[O:29])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][C:13]([O:16][C:18]4[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[C:21]([C:28]([O:30][CH3:31])=[O:29])=[CH:20][CH:19]=4)=[CH:12][C:9]=3[CH2:10][CH2:11]2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(Cl)nc1C(=O)OC
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1C(=O)OC
Temperature: 80 °C

Procedure:
A mixture of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (1.5 g), dimethyl 6-chloro-2,3-pyridinedicarboxylate (1.58 g; Kenji Niiyama et al. Bioorg. Med. Chem. Lett. 12, 21, 2002, 3041-3054) and cesium carbonate (4.4 g) in dry DMF (30 ml) was heated at 80° C. for 3 h. The cooled mixture was partitioned between water (20 ml) and ethyl acetate (3×100 ml), the combined organic extracts were washed with brine (2×100 ml) and dried (Na2SO4). The solvent was evaporated to give an oil which was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.5:4.5:95) to afford the title compound (E231); MS (ES+) m/e 411 [M+H]+.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)=[CH:3][CH:2]=1.[C:17]([OH:27])(=[O:26])[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.CC(C)([O-])C.[K+]>CN(C)C=O>[C:17]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH:16][C:1]2[CH:2]=[CH:3][C:4]([C:7]3[O:8][C:9]4[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=4[CH:11]=3)=[CH:5][CH:6]=2)=[CH:20][CH:19]=1)([OH:27])=[O:26]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: Cc1ccc(-c2cc3ccccc3o2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(C=Cc2ccc(-c3cc4ccccc4o3)cc2)cc1

Procedure:
Proceeding in a manner similar to that described in Example 1 above, 2-(p-tolyl)benzofuran (2.08 g; 0.01 mole) was interacted with 2.25 g (0.01 mole) of the anil derivative of terephthalaldehydic acid in the presence of 6.72 g (0.06 mole) of potassium tert-butoxide in 150 ml of dimethylformamide. The resulting product was purified by sublimation to obtain 2-[4-(4-carboxystyryl)phenyl]benzofuran which melted at 348°-349°C. The wavelength of maximum excitation of this compound was 365 nm and the wavelength of maximum emission was 425 nm.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]1(B(O)O)[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1>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.COCCOC>[C:11]1([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: OB(O)C1=CCCCC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: O=[N+]([O-])c1cnccc1C1=CCCCC1
Yield: 82 %

Procedure:
A solution of 4-chloro-3-nitro pyridine (1 eq.), cyclohexenyl boronic acid (1.7 eq.), and Pd(dppf)Cl2—CH2Cl2 (0.05 eq) in 3:1 DME/2M Na2CO3, at a concentration of 0.1 M was heated at 95° C. for 16 hours. Upon cooling the reaction was partitioned between EtOAc and H2O, was washed with NaCl(sat.), dried over MgSO4, was filtered and the volatiles were removed in vacuo. The material was purified by SiO2 chromatography (20% EtOAc/hexanes eluant) to yield 4-cyclohexenyl-3-nitropyridine (82%). LCMS (m/z): 205.0 (MH+); LC Rt=3.84 min.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[H-].[Na+].[Br:9][C:10]1[CH:11]=[CH:12][C:13](F)=[C:14]([CH:17]=1)[C:15]#[N:16]>CN(C=O)C>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([O:4][CH2:3][C:2]([CH3:6])([CH3:5])[CH3:1])=[C:14]([CH:17]=1)[C:15]#[N:16]
Reactant: CC(C)(C)CO
Reactant: N#Cc1cc(Br)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)COc1ccc(Br)cc1C#N

Procedure:
After 2,2-dimethyl-1-propanol and sodium hydride were stirred at 0° C. in DMF, 5-bromo-2-fluorobenzonitrile was added thereto, followed by reaction at room temperature to obtain 5-bromo-2-(2,2-dimethylpropoxy)benzonitrile. NMRC: 3.67 (2H, s), 6.83 (1H, d), 7.64 (1H, d).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:14])[N:9]([CH3:13])[CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:15][N:16]1[CH:20]=[C:19]([NH:21][C:22]2[CH:27]=[C:26](I)[C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][N:23]=2)[C:18]([CH3:33])=[N:17]1>>[CH3:15][N:16]1[CH:20]=[C:19]([NH:21][C:22]2[CH:27]=[C:26]([NH:1][C:2]3[C:7]4[C:8](=[O:14])[N:9]([CH3:13])[CH2:10][CH2:11][O:12][C:6]=4[CH:5]=[CH:4][CH:3]=3)[C:25]([C:29]([F:31])([F:30])[F:32])=[CH:24][N:23]=2)[C:18]([CH3:33])=[N:17]1
Reactant: CN1CCOc2cccc(N)c2C1=O
Reactant: Cc1nn(C)cc1Nc1cc(I)c(C(F)(F)F)cn1
Product: Cc1nn(C)cc1Nc1cc(Nc2cccc3c2C(=O)N(C)CCO3)c(C(F)(F)F)cn1
Yield: 54.6 %

Procedure:
6-Amino-4-methyl-2,3-dihydro-1,4-benzoxazepin-5-one (151 mg, 0.79 mmol, see Example 3.22) and N-(1,3-dimethylpyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (150 mg, 0.39 mmol) were reacted using the procedure in Example 5.02. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent, followed by flash chromatography on silica gel eluting with 0 to 5% MeOH in EtOAc/DCM (1:1). The solvent was evaporated to dryness and triturated in a mixture of 30% tBuOMe in pentane to give the title compounds as a light white foam (95 mg, 54%). 1H NMR spectrum (500 MHz, CDCl3): 2.15 (s, 3H), 3.21 (s, 3H), 3.50 (t, 2H), 3.81 (s, 3H), 4.35 (t, 2H), 6.19 (s, 1H), 6.30 (s, 1H), 6.70 (dd, 1H), 7.19 (dd, 1H), 7.23 (dd, 1H), 7.38 (s, 1H), 8.20 (s, 1H), 9.21 (s, 1H); Mass spectrum: ESI+ MH+ 447.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C([Li:16])CCC.CCCCCC.[O:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Li:16])=[CH:3][CH:4]=1)([CH3:11])([CH3:10])[CH3:9].[CH2:26]1[CH2:27][O:23][CH2:24][CH2:25]1
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Li]c1ccc(C(C)(C)C)cc1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
Under an argon stream, 1-bromo-4-tert-butylbenzene (125 g, 587 mmol) and tetrahydrofuran (470 mL) were charged in a reactor, and cooled to −70° C. An n-butyl lithium/hexane solution (1.6 M, 367 mL, 587 mmol) was dropped to this solution over 90 minutes at −70° C. After dropping was completed, the solution was stirred at −70° C. for 2 hours to obtain a 4-tert-butylphenyllithium/THF solution. Under an argon stream, cyanuric chloride (50.8 g, 276 mmol) and tetrahydrofuran (463 mL) were charged in another reactor, and cooled to −70° C. The 4-tert-butylphenyllithium/THF solution prepared previously was slowly dropped to this solution while the solution was cooled so that the reaction temperature might be not more than −60° C. After dropping was completed, the reaction solution was stirred at −40° C. for 4 hours, and stirred at room temperature for 4 hours. Water (50 mL) was added to this reaction mixture to complete the reaction, and tetrahydrofuran was distilled off. Water (1 L) and chloroform (2 L) were added to this residue, and an organic layer was extracted. The organic layer was further washed with water (1 L), and subsequently the solvent was distilled off. This residue was dissolved in acetonitrile (600 mL), and an insoluble solid was removed by filtration at the time of heating. The obtained filtrate was condensed to approximately 100 mL, and cooled to −70° C. to filter and collect the solid deposited. The collected solid was dissolved in a mixed solvent of chloroform (200 mL)/hexane (600 mL), and purified with silica gel column chromatography (developing solvent: chloroform/hexane). The solvent was distilled off, and this residue was recrystallized from acetonitrile. Thereby, 4,6-bis(4′-tert-butylphenyl)-2-chloro-1,3,5-triazine (41.3 g, 109 mmol) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[NH:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:27](Cl)(=[O:30])[CH2:28][CH3:29]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH:21]3[CH:16]([CH2:17][CH2:18][CH2:19][CH:20]3[N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[N:15]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCNC2CCCC(N3CCCC3)C21
Reactant: CCC(=O)Cl
Solvent: ClCCl
Product: CCC(=O)N1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C2C(N3CCCC3)CCCC21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Under N2, 2-(3,4-dichlorophenyl)-1-[(4aRS,8SR,8aRS)-8-(pyrrolidin-1-yl)-perhydroquinoxalin-1-yl]-ethan-1-one (40.7 mg, 0.10 mmol) was dissolved in absolute CH2Cl2 (5 ml) and propionyl chloride (11.4 mg, 0.12 mmol) was added dropwise. The mixture was stirred at room temperature for 2.5 hours and then evaporated in vacuo. The residue was purified by flash chromatography (Ø 2 cm, CH2Cl2/MeOH/NH3 9:1:0.1, l=16 cm, V=3 ml). A yellow resin was obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]([C:11]1[CH:12]=[C:13]([CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])[CH:14]=[CH:15][C:16]([OH:18])=O)([CH3:10])[CH3:9].[CH3:27][C:28]([N:31]([C:33]([OH:35])=[O:34])[NH2:32])([CH3:30])[CH3:29]>C(Cl)Cl.CN(C)C=O>[CH3:27][C:28]([N:31]([C:33]([OH:35])=[O:34])[NH:32][C:16](=[O:18])[CH:15]=[CH:14][C:13]1[CH:12]=[C:11]([C:8]([CH3:7])([CH3:10])[CH3:9])[C:21]([OH:22])=[C:20]([C:23]([CH3:25])([CH3:24])[CH3:26])[CH:19]=1)([CH3:30])[CH3:29]
Reactant: CC(C)(C)N(N)C(=O)O
Reactant: CC(C)(C)c1cc(C=CC(=O)O)cc(C(C)(C)C)c1O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1cc(C=CC(=O)NN(C(=O)O)C(C)(C)C)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.6 %

Procedure:
Oxalyl chloride (2.9 g, 0.023 mole) is added dropwise to a stirred 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxycinnamic acid (4.3 g, 0.016 mole) in methylene chloride (30 ml) and N,N-dimethylformamide (0.5 ml . After one hour the solvent is removed in vacuo. The residue is dissolved in methylene chloride (30 ml) and added dropwise to a stirred 0° C. solution of 1,1-dimethylethyl hydrazinecarboxylic acid (4.5 g, 0.034 mole). After the addition is complete, the mixture is allowed to warm to room temperature and stir 18 hours. The mixture is concentrated in vacuo and the residue dissolved in methylene chloride (50 ml) and washed with aqueous 2M HCl, saturated aqueous NaCl, and dried MgSO4. Filtration and concentration gives a solid which was recrystallized from ethyl acetate/isopropyl ether to provide 4.6 g (6.1 g theor., 76%) of 1,1-dimethylethyl 2-[3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1-oxo-2-propenyl]hydrazinecarboxylic acid, mp 184° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:16])[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.Br[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[C:29]([F:32])([F:31])[F:30])[CH:20]=1>>[F:1][C:2]1[CH:3]=[C:4]([O:16][CH2:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[C:29]([F:30])([F:31])[F:32])[CH:20]=2)[CH:5]=[C:6]([C:8]2([O:14][CH3:15])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[CH:7]=1
Reactant: COC1(c2cc(O)cc(F)c2)CCOCC1
Reactant: FC(F)(F)c1cccc2cc(CBr)ccc12
Product: COC1(c2cc(F)cc(OCc3ccc4c(C(F)(F)F)cccc4c3)c2)CCOCC1
Yield: 36 %

Procedure:
Using the procedure described in Example 5, 4-(5-fluoro-3-hydroxyphenyl)-4-methoxytetrahydropyran was reacted with 2-bromomethyl-5-trifluoromethylnaphthalene to give 4-[5-fluoro-3-(5-trifluoromethylnaphth-2-ylmethoxy)phenyl]-4-methoxytetrahydropyran in 36% yield, as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:22]2[CH2:23][CH2:24][N:19]([C:13]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=3[CH3:11])[CH2:20][CH2:21]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Yield: 72.9 %

Procedure:
Using 4-bromobenzoyl chloride (25 g) and 1-(2,4-dimethylphenyl)piperazine (22 g) and by the reaction and treatment in the same manner as in Preparation Example 108, the title compound (31 g) was obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([CH3:12])=O.Cl.[NH2:14][OH:15].C(=O)([O-])O.[Na+].O>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10](=[N:14][OH:15])[CH3:12]
Reactant: NO
Reactant: CC(=O)c1cc2ccccc2o1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=NO)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Twenty six grams (g) (162 millimoles (mmol)) of commercially available 2-benzofuranylmethylketone was dissolved in 300 milliliters (ml) of methanol, and 16.9 g (243 mmol) of hydroxylamine hydrochloride and 20.4 g (243 mmol) of sodium hydrogencarbonate were added thereto. The resulting mixture was stirred at room temperature for 8 hours. Then, φml of water was added and the methanol was distilled away under reduced pressure. Precipitated crystals were filtered off and washed with water to yield 27.8 g of 2-benzofuranylmethylketone oxime having the following formula (yield, 98%). ##STR26##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[C:15]([CH3:23])[C:16]([OH:22])=[CH:17][CH:18]=3)[O:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[C:15]([CH3:23])[C:16]([O:22][C:24](=[O:26])[CH3:25])=[CH:17][CH:18]=3)[O:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2coc3c(C)c(O)ccc3c2=O)cc1OC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(-c2coc3c(C)c(OC(C)=O)ccc3c2=O)cc1OC
Temperature: 25 °C

Procedure:
3-(3,4-dimethoxy-phenyl)-7-hydroxy-8-methyl-chromen-4-one (9.82 g, 31 mmol), acetic anhydride (62 ml) and pyridine (6.2 ml) were combined in a round bottom flask and heated to reflux. The reaction was cooled to room temperature after 3 hours of heating, and a crystalline solid formed. The solid was filtered and rinsed with H2O (1 L). 1H NMR in d-CDCl3 indicated pale brown crystals was acetic acid 3-(3,4-dimethoxy-phenyl) -8-methyl-4-oxo-4H-chromen-7-yl ester in 90% purity (7.214 g, 71%).
Reaction SMILES: [OH-].[Li+].C([O:5][C:6]([C:8]1[C:12]([CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])=[C:11]([CH:20]=[O:21])[NH:10][C:9]=1[CH3:22])=[O:7])C.Cl>CO.O>[CH:20]([C:11]1[NH:10][C:9]([CH3:22])=[C:8]([C:6]([OH:7])=[O:5])[C:12]=1[CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:17])=[O:18])=[O:21]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCS(C)(=O)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1[nH]c(C=O)c(CCCS(C)(=O)=O)c1C(=O)O
Temperature: 65 °C
Yield: 86.8 %

Procedure:
Lithium hydroxide (179.6 mg, 7.5 mmol) was added to a suspension of 5-formyl 4-(3-methanesulfonyl-propyl)2-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (450 mg, 1.5 mmol) in methanol (6 mL) and water (6 mL). The mixture was heated under nitrogen in a 65° C. oil bath for 20 hours. The cooled reaction was adjusted to pH 2 using 1N HCl, the resulted precipitate was collected by vacuum filtration, washed with water and dried to give 356 mg (87%) of 5-formyl-4-(3-methanesulfonyl-propyl)-2-methyl-1H-pyrrole-3-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:13]2[CH:14]=[C:15]([C:18]3[O:22][C:21]([SH:23])=[N:20][N:19]=3)[CH:16]=[CH:17][C:12]=2[O:11][CH:10]=1.I[CH3:25]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:13]2[CH:14]=[C:15]([C:18]3[O:22][C:21]([S:23][CH3:25])=[N:20][N:19]=3)[CH:16]=[CH:17][C:12]=2[O:11][CH:10]=1
Reactant: Fc1ccc(F)c(-c2coc3ccc(-c4nnc(S)o4)cc23)c1
Reactant: CI
Product: CSc1nnc(-c2ccc3occ(-c4cc(F)ccc4F)c3c2)o1
Yield: 89 %

Procedure:
In the same manner as in Example 7 and using 5-[3-(2,5-difluorophenyl)-1-benzofuran-5-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(1H-indazol-5-yl)-1,3,4-oxadiazole-2-thiol and using iodomethane instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 89%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH2:25][CH2:26][CH:27]([OH:29])[CH3:28]>>[OH:29][CH:27]([CH3:28])[CH2:26][CH2:25][NH:24][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: CC(O)CCN
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCCC(C)O)cn1
Yield: 90 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using 4-amino-2-butanol instead of 2-aminoethyl isopropylether, to the title compound (221 mg, 90%) which was obtained as a white solid. MS: m/e=380.3 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]2[C:7]([CH2:10][CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[C:16]([C:22]([OH:24])=O)[NH:17]4)=[CH:8][O:9][C:5]=2[CH:4]=1.[NH2:27][CH:28]1[CH2:33][CH2:32][C:31]([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][C@H:40]([OH:43])[C@@H:39]([CH3:44])[CH2:38]2)([OH:34])[CH2:30][CH2:29]1>>[OH:34][C:31]1([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][C@H:40]([OH:43])[C@@H:39]([CH3:44])[CH2:38]2)[CH2:32][CH2:33][CH:28]([NH:27][C:22]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[C:13]([O:12][CH2:11][CH2:10][C:7]2[C:6]4[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[O:9][CH:8]=2)[CH:21]=[CH:20][CH:19]=3)=[O:24])[CH2:29][CH2:30]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Reactant: COc1ccc2c(CCOc3cccc4[nH]c(C(=O)O)cc34)coc2c1
Product: COc1ccc2c(CCOc3cccc4[nH]c(C(=O)NC5CCC(O)(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)coc2c1

Procedure:
This compound is synthesized analogously to example 1 from 4-[2-(6-methoxy-benzofuran-3-yl)-ethoxy]-1H-indole-2-carboxylic acid 16o and amine 14.
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH2:13][CH3:14])[CH3:12])[C:6]=1[O:15][C:16](=[O:18])[NH2:17])([CH2:3][CH3:4])[CH3:2]>CCCCCC.C(OCC)(=O)C>[C@H:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C@@H:11]([CH2:13][CH3:14])[CH3:12])[C:6]=1[O:15][C:16](=[O:18])[NH:17][C@@H:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1cccc(C(C)CC)c1OC(N)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC[C@@H](C)c1cccc([C@H](C)CC)c1OC(=O)N[C@H](C)c1ccccc1
Yield: 53 %

Procedure:
To an Agilent HPLC system fitted with a diode array detector and a 0.46 cm ID×25 cm long 10 mm KROMASIL Silica Column was charged 714 mg of racemic R-(+)-1-phenyl-ethyl)-carbamic acid-2,6-di-sec-butylphenyl ester dissolved in 10 ml of hexane/ethyl acetate (98:2) to give a 71.4 g/l feed solution. The sample was eluted with hexane/ethyl acetate (98:2) at 2 ml/min at 25° C. Fractions containing (R,R,R)-1-phenylethylcarbamic acid-2,6-di-sec-butylphenyl ester were collected and evaporated under reduced pressure at <55° C. At the highest loading, the (R,R,R)-stereoisomer was collected with a chiral purity of 98.7% diastereomeric excess (de) and a total yield of 53%.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9])[CH3:2].C(N(CC)CC)C.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOCCOCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 82 %

Procedure:
432 mg (3.22 mmol) of 2-(2-ethoxyethoxy)ethanol was dissolved in 40 ml of dichloromethane, and 0.6 ml (4.19 mmol) of triethylamine and 614 mg (3.22 mmol) of p-toluenesulfonyl chloride were added thereto. The mixture was stirred at room temperature for 15 hours. After the solvent was removed under reduced pressure, 40 ml of water was added thereto. The mixture was extracted with 30 ml of ethyl acetate. The solvent was removed under reduced pressure to give 760 mg (2.64 mmol) of the title compound in a yield of 82%.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH2:13])[CH2:9][CH2:10][C:11]#[CH:12].Cl[CH2:15][C:16]([N:18]1[CH2:37][CH2:36][C:21]2[N:22]=[C:23]([NH:26][CH:27]3[CH2:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:28]3)[N:24]=[CH:25][C:20]=2[CH2:19]1)=[O:17]>O1CCCC1>[CH2:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:35][CH:27]1[NH:26][C:23]1[N:24]=[CH:25][C:20]2[CH2:19][N:18]([C:16](=[O:17])[CH2:15][NH:13][CH2:8][CH2:9][CH2:10][C:11]#[CH:12])[CH2:37][CH2:36][C:21]=2[N:22]=1
Reactant: O=C(CCl)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reactant: C#CCCCN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCCCNCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 55 °C
Reaction time: 48 h
Yield: 99.7 %

Procedure:
Add triethylamine (0.434 mL; 2.0 equiv; 3.12 mmoles) followed by 4-pentyn-1-amine (0.194 mL; 1.50 equiv; 2.34 mmoles) to a solution of 2-chloro-1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]ethanone (0.534 g; 1.0 equiv; 1.56 mmoles) in tetrahydrofuran (5.19 mL). Stir for 48 hours at 55° C. The solution was directly concentrated to afford 1-[2-(indan-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-2-(pent-4-ynylamino)ethanone (0.606 g; 100%): MS (m/z): 390(M+1).
Reaction SMILES: [NH:1]([C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[NH2:2].C(N(CC)CC)C.[Cl:17][C:18]1[N:19]=[CH:20][C:21]([C:24](Cl)=[O:25])=[N:22][CH:23]=1>ClCCl>[Cl:17][C:18]1[N:19]=[CH:20][C:21]([C:24]([NH:2][NH:1][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:25])=[N:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(Cl)c1cnc(Cl)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC(=O)c1cnc(Cl)cn1
Reaction time: 16 h

Procedure:
1,1-dimethylethyl hydrazinecarboxylate (2.59 g, 19.58 mmol) and triethylamine (2.98 mL, 21.36 mmol) were dissolved in Dichloromethane (DCM) (50 mL). 5-chloro-2-pyrazinecarbonyl chloride (I47) (3.15 g, 17.80 mmol) dissolved in Dichloromethane (DCM) (50 mL) was added dropwise at 0° C. and the mixture allowed to reach room temperature over 16 hr. Solvents were removed in vacuo and the residue was partitioned between ethyl acetate (100 mL) and saturated sodium bicarbonate solution (50 mL). The aqueous phase was extracted with ethyl acetate (3×100 mL), combined extracts were washed with brine (100 mL) dried over anhydrous sodium sulfate and concentrated to a crude solid (5.05 g). The product was purified by flash chromatography (Isolera, 100 g, 0-100% Methanol:Dichloromethane (1:9)/Dichloromethane) to afford product in 4.63 g.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[C:8]3[N:22]=[CH:21][CH:20]=[CH:19][C:9]=3[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[C:6]2[CH:5]=[CH:4][N:3]=1.C(Cl)Cl.C([O-])([O-])=[O:27].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]2[C:8]3[N:22]=[CH:21][CH:20]=[CH:19][C:9]=3[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17]([CH3:18])=[O:27])[N:12]=3)=[C:6]2[CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: CSc1nccc(-c2c3cccnc3n3c(N)nccc23)n1
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)c1nccc(-c2c3cccnc3n3c(N)nccc23)n1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a cooled (0° C.) solution of 21 (20 mg, 0.07 mmol) in CH2Cl2 (5 ml) mCPBA (32 mg, 0.13 mmol) was added. The mixture was stirred for 30 min. A saturated aq. Na2S203 solution was added (1 ml) and was basified with saturated aq. Na2CO3. The organic layer was separated and the aqueous layer extracted with CH2Cl2. The organic solutions were dried and evaporated together to give 9-amino-5-(2-methanesulfinylpyrimidin-4-yl)pyrido[3′,2′:4,5]-pyrrolo[1,2-c]pyrimidine (20 mg, 90%).