Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH2:18])[CH:5]=[CH:6][C:7]=1[F:8].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH:23]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(#N)C.CC(O)=O>[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[CH2:23][NH:18][C:10]1[N:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=1
Reactant: Nc1nc2ccccc2n1-c1ccc(F)c(F)c1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: Fc1ccc(CNc2nc3ccccc3n2-c2ccc(F)c(F)c2)cc1F

Procedure:
1-(3,4-Difluorophenyl)-1H-benzoimidazol-2-ylamine, prepared as described in Procedure E (Scheme 5, Steps A-C), was dissolved in acetonitrile, added 3,4-difluorobenzaldehyde (1 eq), sodium triacetoxyborohydride (2 eq) and a catalytic amount of AcOH. The reaction mixture was heated in a sealed vial by means of MW irradiation at 100° C. for 25 min. Saturated aqueous NaHCO3 was added and the mixture extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered, concentrated in vacuo and purified by preparative LCMS to give the title compound as the free base (solid, mp 158.5-159.5° C.). MS(ES+) m/z 372 ([M+1]+, 100). 1NMR (DMSO-d6) δ 4.50 (d, 2H), 6.85-6.92 (m, 2H), 6.99-7.15 (m, 2H), 7.20-7.46 (m, 5H), 7.68-7.74 (m, 1H), 7.78-7.83 (m, 1H).
Reaction SMILES: [CH:1]1([C:4](=[O:26])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH2:15][N:16]3[C:20](=[O:21])[N:19]([CH:22]4[CH2:24][CH2:23]4)[N:18]=[N:17]3)[C:9]=2[Cl:25])=[O:7])[CH2:3][CH2:2]1.[CH:27](OCC)(OCC)[O:28][CH2:29][CH3:30]>C(OC(=O)C)(=O)C>[CH:1]1([C:4](=[O:26])[C:5](=[CH:27][O:28][CH2:29][CH3:30])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([CH2:15][N:16]3[C:20](=[O:21])[N:19]([CH:22]4[CH2:24][CH2:23]4)[N:18]=[N:17]3)[C:9]=2[Cl:25])=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(CC(=O)C1CC1)c1ccc(Cl)c(Cn2nnn(C3CC3)c2=O)c1Cl
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(Cl)c(Cn2nnn(C3CC3)c2=O)c1Cl)C(=O)C1CC1
Yield: 107.1 %

Procedure:
3-Cyclopropyl-1-{3-[(4-cyclopropyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)methyl]-2,4-dichlorophenyl}propan-1,3-dione (2.64 g) was dissolved in acetic anhydride (15 ml) and the solution, after adding triethyl orthoformate (2.12 g), was refluxed for 4 hours upon heating. The solvent was distilled off under reduced pressure and the residue was treated with toluene, which was distilled off under reduced pressure to obtain crude 3-cyclopropyl-1-{3-[(4-cyclopropyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)methyl]-2,4-dichlorophenyl}-2-ethoxymethylenepropan-1,3-dione (3.23 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][N:19](C(OCC4C=CC=CC=4)=O)[CH2:18][CH2:17]3)=[CH:11][C:10]2=[O:32])=[CH:5][CH:4]=1.I[Si](C)(C)C>C(Cl)Cl>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:11][C:10]2=[O:32])=[CH:5][CH:4]=1
Reactant: CSc1ccc(-n2ccc(OC3CCN(C(=O)OCc4ccccc4)CC3)cc2=O)cc1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: CSc1ccc(-n2ccc(OC3CCNCC3)cc2=O)cc1
Reaction time: 0.67 h
Yield: 73.3 %

Procedure:
To a stirring solution of benzyl 4-(1-(4-(methylthio)phenyl)-2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (367 mg, 0.815 mmol) in CH2Cl2 (5 mL) at 0° C. was added iodotrimethylsilane (0.33 mL, 2.4 mmol, Aldrich). The reaction was stirred for 40 min and then quenched at 0° C. with HCl (1N in H2O, 5 mL). To the resulting mixture was diluted with CH2Cl2 and extracted with H2O. The H2O layer was basified with NaOH (1N in H2O, 10 mL) and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to yield 189 mg crude product as an off-white solid. MS (ESI) 317 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][C:7]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18](Cl)=[O:19])[C:10]=2[O:9][C:8]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O.CC(C)=O>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:18]([C:17]1[C:10]2[O:9][C:8]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:7]([CH3:6])[C:12](=[O:13])[C:11]=2[CH:14]=[CH:15][CH:16]=1)=[O:19]
Reactant: NCCCO
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)Cl)cccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1c(-c2ccccc2)oc2c(C(=O)NCCCO)cccc2c1=O
Reaction time: 3 h

Procedure:
A solution of 7.6 ml of 3-aminopropanol in 50 ml of water was added dropwise over a period of 30 minutes to a suspension of 30 g of 3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carbonyl chloride and 15.2 g of potassium carbonate in 400 ml of acetone. The thick suspension was stirred for 3 hours at 20°-25° C. The solvents were removed in vacuo and the residue was taken up in 300 ml of water. After stirring for 1 hour, the precipitate was collected by suction filtration and washed with water. The crude product was purified by crystallization from 95% ethanol to give 23.8 g of the title compound, melting point 191°-193° C. Another 4.7 g of the title compound was obtained by concentration in vacuo of the crystallization liquors.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][C:9]([NH:11][C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[NH:22][NH:23]C(OC(C)(C)C)=O)=[CH:19][CH:18]=[CH:17][CH:16]=3)=O)OCCO1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.Cl.[OH-].[Na+]>C(O)CCC.O>[CH3:1][C:2]1[CH2:7][CH2:8][C:9]2=[N:11][C:12]3[CH:13]=[N:14][C:15]4[C:20]([C:21]=3[N:22]2[N:23]=1)=[CH:19][CH:18]=[CH:17][CH:16]=4
Reactant: CC(C)(C)OC(=O)NNc1c(NC(=O)CCC2(C)OCCO2)cnc2ccccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Product: CC1=Nn2c(nc3cnc4ccccc4c32)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.6 %

Procedure:
A solution of tert-butyl 2-(3-{[3-(2-methyl-1,3-dioxolan-2-yl)propanoyl]amino}quinolin-4-yl)hydrazinecarboxylate (6.83 g, 16.4 mmol) and pyridinium p-toluenesulfonate (0.10 g, 0.41 mmol) in 1-butanol (125 mL) was heated to 140° C. under an atmosphere of nitrogen. After 3 h, the reaction mixture was cooled to ambient temperature, treated with HCl (38 mL, 4.3 M in ethanol) and heated (115° C.). After 1 h, the reaction mixture was concentrated under reduced pressure to give a brown solid. The solid was dissolved in water (50 mL) and treated with 50% NaOH aqueous solution until the pH of the liquid was 13. A tan solid was collected by vacuum filtration. The solid was dissolved in dichloromethane (150 mL) and washed with water (2×30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield 1.96 g of 10-methyl-8,9-dihydropyridazino[1′,6′:1,2]imidazo[4,5-c]quinoline as a light brown solid.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][CH:24]([OH:26])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:27][C:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[N:30](C2CCCCO2)[N:29]=1>>[OH:26][CH:24]1[CH2:25][N:22]([C:3]2[C:2]([C:31]3[NH:30][N:29]=[C:28]([CH3:27])[CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC(O)C2)c(Br)c1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)n(C2CCCCO2)n1
Product: Cc1cc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC(O)C2)[nH]n1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 37 using 5-bromo-6-(3-hydroxyazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 37.1) and 3-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Stage 41.1) to afford a white lyophilizate. HPLC (Condition 7) tR=5.50 min, UPLC-MS (Condition 3) tR=0.89 min, m/z=434.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.29 (s, 3H) 3.59-3.67 (m, 2H) 3.99-4.08 (m, 2H) 4.37-4.45 (m, 1H) 6.21 (s, 1H) 7.35 (d, J=8.99 Hz, 2H) 7.82-7.89 (m, J=9.40 Hz, 2H) 8.11 (d, J=1.96 Hz, 1H) 8.66 (d, J=2.35 Hz, 1H) 10.28 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[F:13].C([Mg]Br)(C)C.[C:19](=[O:21])=[O:20]>C1COCC1>[F:13][C:3]1[CH:4]=[C:5]([O:8][C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:7][C:2]=1[C:19]([OH:21])=[O:20]
Reactant: O=C=O
Reactant: Fc1cc(OC(F)(F)F)ccc1Br
Agent: CC(C)[Mg]Br
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OC(F)(F)F)cc1F
Reaction time: 3 h
Yield: 87 %

Procedure:
A solution of 1-bromo-2-fluoro-4-(trifluoromethoxy)benzene (8 g, 30.8 mmol) in 170 mL of THF was cooled to −40° C., and then i-PrMgBr (0.4 mol/L in THF, 91 mL) was injected. After being stirred for 3 h, CO2 was injected for 2 h at 0° C. The mixture was washed with 1M HCl aqueous solution, separated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, and concentrated under reduced pressure. The residue was washed with petroether to give the title compound (6 g, 87% yield): 1H NMR (400 MHz, CDCl3): δ ppm 7.05-7.12 (m, 2H), 8.10 (t, J=8.4 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22]>>[F:14][C:15]1[CH:20]=[C:19]([C:11](=[O:13])[CH2:10][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[CH:18]=[CH:17][C:16]=1[O:21][CH3:22]
Reactant: COc1ccccc1F
Reactant: COc1ccc(CC(=O)O)cc1F
Product: COc1ccc(CC(=O)c2ccc(OC)c(F)c2)cc1F
Yield: 77.5 %

Procedure:
Using 3-fluoro-4-methoxyphenylacetic acid and 2-fluoroanisole as starting materials, the procedures of Preparation Example 7 were repeated likewise, whereby the title compound was obtained in a yield of 77.5%.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]1([C:21]([F:24])([F:23])[F:22])[CH2:20][O:19]1)=[O:15].[CH3:25][NH2:26]>O1CCCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([OH:19])([CH2:20][NH:26][CH3:25])[C:21]([F:24])([F:22])[F:23])=[O:15]
Reactant: CN
Reactant: Nc1c(C(=O)NCC2(C(F)(F)F)CO2)cnn1-c1ccc(F)cc1
Solvent: C1CCOC1
Product: CNCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Temperature: 21 °C
Reaction time: 15 h
Yield: 56.8 %

Procedure:
To a solution of 5-amino-1-(4-fluorophenyl)-N-{[2-(trifluoromethyl)-2-oxiranyl]methyl}-1H-pyrazole-4-carboxamide (750 mg, 2.18 mmol) in anhydrous tetrahydrofuran (10 ml) was added methylamine (2M in tetrahydrofuran, 4 ml, 8 mmol) and stirred at 21° C. for 15 hours. It was evaporated to give a foam which was triturated with diethyl ether (ca. 5 ml). The resulting solid was filtered off and washed with a little diethyl ether and then petroleum ether)(40-60° to give the title compound (465 mg).
Reaction SMILES: [CH2:1]([CH:3]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][CH:7]=1)[CH3:2].Br[C:19]1[CH:20]=[C:21]([CH:24]=[C:25](Br)[CH:26]=1)[CH:22]=[O:23]>O1CCCC1.C(N(CC)CC)C.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.[Cu]I>[CH2:1]([CH:3]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:19]2[CH:20]=[C:21]([CH:24]=[C:25]([C:13]#[C:12][C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:7][CH:8]=3)[CH:26]=2)[CH:22]=[O:23])=[CH:10][CH:11]=1)[CH3:2]
Reactant: C#Cc1ccc(OCC(CC)CCCC)cc1
Reactant: O=Cc1cc(Br)cc(Br)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC(CC)COc1ccc(C#Cc2cc(C#Cc3ccc(OCC(CC)CCCC)cc3)cc(C=O)c2)cc1
Temperature: 70 °C
Reaction time: 23 h
Yield: 79.3 %

Procedure:
Nitrogen was bubbled through a solution of 1-(2-Ethylhexyloxy)-4-ethynylbenzene (4) (1.69 g, 7.34 mmol) and 3,5-dibromobenzaldehyde (5) (692 mg, 2.62 mmol) in tetrahydrofuran (33 mL) and triethylamine (50 mL) for 5 min. Tetrakis(triphenylphosphine)palladium(0) (218 mg, 0.189 mmol) and copper(I) iodide (65 mg, 0.34 mmol) were added and nitrogen bubbled through the solution for a further 5 min, before stirring at 70° C. for 23 h. Once cool, the solvent was removed and the residue purified by column chromatography over silica with dichloromethane-light petroleum (1:2 to 1:1) as eluent to leave 3,5-bis[4-(2-ethylhexyloxy)phenylethynyl]benzaldehyde (6) (1.17 g, 79%) as a pale brown oil. (Found: C, 83.3; H, 8.2; C39H46O3 requires C, 83.2; H, 8.2%); νmax(film)/cm−1 2211 (C≡C) and 1704 (C═O); δH(400 MHz, CDCl3) 0.93-0.99 (12 H, m, CH3), 1.28-1.56 (16 H, m, CHCH2CH2CH2CH3 and CHCH2CH3), 1.75 (2 H, m, OCH2CH), 3.87 (4 H, d, J 6, OCH2CH), 6.90 (4 H, AA′BB′), 7.48 (4 H, AA′BB′), 7.87 (1 H, dd, J 1.5, 4-H), 7.92 (2 H, d, J 1.5, 2, 6-H) and 10.00 (1 H, s, CHO); δc(100.6 MHz, CDCl3) 11.1, 14.1, 23.1, 23.8, 29.0, 30.4, 39.3, 70.6, 86.0, 91.7, 114.1, 114.6, 125.2, 131.3, 133.5, 136.6, 139.1, 159.9 and 191.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[C:21]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:22]([CH:30]=[CH:31][CH:32]=2)[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:5]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:7]=1.O.[CH2:39]1[O:47][C:46]2[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][C:41]=2[O:40]1.C(=O)([O-])[O-].[K+].[K+]>CCO.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>[O:40]1[C:41]2[CH:42]=[CH:43][C:44]([C:2]3[CH:3]=[C:4]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]4[C:21]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:22]([CH:30]=[CH:31][CH:32]=4)[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:5]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:7]=3)=[CH:45][C:46]=2[O:47][CH2:39]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: CN(C)C(=O)c1cc(Br)cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)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: [K+]
Solvent: CCO
Solvent: O
Product: CN(C)C(=O)c1cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3c(c2)OCO3)c1
Temperature: 78 °C

Procedure:
To a solution of 4-[3-[7-(3-bromo-5-dimethylcarbamoyl-phenyl)-hept-6-ynyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (100 mg, 0.17 mmol) in EtOH (4 mL)/H2O (1 mL) were added 3,4-methylenedioxyphenylboronic acid (58 mg, 0.35 mmol), potassium carbonate (100 mg, 0.7 mmol) and Pd(PPh3)4 (5 mg, 0.004 mmol). The mixture was heated at 78° C. for 5 h and then cooled to room temperature. The reaction mixture was filtered using a syringe filter 0.45 μm and the filtrate concentrated under reduced pressure. The crude oil was then purified by preparative HPLC using acetonitrile/water gradient. HRMS calcd for C36H39NO8 [M+H]+ 614.2749, observed 614.2748
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1([CH:12]([OH:22])[C:13](=[O:21])[NH:14][C:15]2[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])(C)C.Cl.C(Cl)(OCC1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=O.C([O-])(O)=O.[Na+]>O1CCOCC1.O.C(Cl)Cl>[OH:22][CH:12]([C:8]1([NH:7][C:6](=[O:23])[O:5][CH2:1][CH:4]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:35]=3[C:36]3[C:41]2=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:9][CH2:10][CH2:11]1)[C:13]([NH:14][C:15]1[CH:19]=[CH:18][N:17]([CH3:20])[N:16]=1)=[O:21]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: Cn1ccc(NC(=O)C(O)C2(NC(=O)OC(C)(C)C)CCC2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1ccc(NC(=O)C(O)C2(NC(=O)OCC3c4ccccc4-c4ccccc43)CCC2)n1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
{1-[Hydroxy-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-methyl]-cyclobutyl}-carbamic acid tert-butyl ester (209 mg, 0.64 mmol) was treated with HCl (4M in dioxane, 5 mL) overnight and then concentrated. The resulting hydrochloride salt was added to a solution of Fmoc-Cl (232 mg, 0.89 mmol) in dioxane:water 2:3, whereafter NaHCO3 (181 mg, 2.24 mmol) was added. The reaction mixture was stirred at room temperature and after for 40 min the solution was diluted with DCM and extracted. The organic phase was washed with brine, dried (NaSO4) and concentrated. Purification by flash column chromatography (EtOAc/iso-Hexane, 4:6-6:4) gave the title compound as a white solid (257 mg, 90%). MS m/z 446.9 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=2)=[N:5][C:4]=1[S:25][CH3:26])#[N:2].[Cl:27][S:28](O)(=[O:30])=[O:29]>C(Cl)(Cl)Cl>[C:1]([C:3]1[C:8](=[O:9])[N:7]([C:10]2[CH:11]=[CH:12][C:13]([S:28]([Cl:27])(=[O:30])=[O:29])=[CH:14][CH:15]=2)[C:6]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH3:24])=[CH:20][CH:21]=2)=[N:5][C:4]=1[S:25][CH3:26])#[N:2]
Reactant: CCOc1ccc(-c2nc(SC)c(C#N)c(=O)n2-c2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(-c2nc(SC)c(C#N)c(=O)n2-c2ccc(S(=O)(=O)Cl)cc2)cc1
Yield: 64.1 %

Procedure:
A solution of 5-cyano-2-(4-ethoxyphenyl)-1-phenyl-4-(methylthio)-6-oxo-1,6-dihydropyrimidine (1 g, 2.7 mmol) in chlorosulfonic acid (6.14 g, 53 mmol) and chloroform (30 ml) was refluxed 1 hr and then poured on to ice. The chloroform layer was collected and dried over Na2SO4 and concentrated under vacuo to yield title compound (0.8 g, yield 62.9%). 1H-NMR (DMSO):δ 1.21-1.24 (t, 3H), 2.6 (s, 3H), 3.94-3.99 (q, 2H), 6.7-6.72 (d, 1H), 7.03-7.05 (q, 1H), 7.33-7.39 (m, 5H), 8.04-8.05 (1H). MS m/z:463.7 (M+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)[C:3]=1[CH:22]([CH2:38][CH2:37][CH3:41])[C:23]([O:25][CH3:26])=[O:24]
Reactant: CCc1ccc(-c2c(CC(=O)OC)c(C)nc3sc4c(c23)CCC4)cc1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(CC)cc1)CCC3
Yield: 60.6 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(4-ethylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.120 g; 0.328 mmol), LHMDS 1N in THF (0.365 mL; 0.365 mmol), 1-iodopropane (0.052 mL; 0.533 mmol) in DMF (4.7 mL) for 4 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 0.081 g (61%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[C:8]1=[O:28].[CH2:36]([O:38][CH2:39][CH2:40][N:41]1[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[N:43]=[C:42]1[NH:50][CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[CH3:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:54]2[CH2:53][CH2:52][CH:51]([NH:50][C:42]3[N:41]([CH2:40][CH2:39][O:38][CH2:36][CH3:37])[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:56][CH2:55]2)([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:8]1=[O:28]
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1ccc(CC2(CCOS(C)(=O)=O)CCN(Cc3cc(OC)c(OC)c(OC)c3)C2=O)cc1
Product: CCOCCn1c(NC2CCN(CCC3(Cc4ccc(OC)cc4)CCN(Cc4cc(OC)c(OC)c(OC)c4)C3=O)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 18.5 using 1-(3,4,5-trimethoxybenzyl)-3-(4-methoxyphenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine (0.42 g, 1.5 mmol) and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.74 g, 1.5 mmol). Purify by chromatography on silica gel eluting with 2% triethylamine/5% methanol/ethyl acetate to give the title compound: Rf=0.17 (silica gel, 2% triethylamine/10% methanol/ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][N:6]1[CH2:10][C@@H:9]([N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH3:12])[CH2:8][C@H:7]1[C:22]([OH:24])=O.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][N:6]1[CH2:10][C@@H:9]([N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH3:12])[CH2:8][C@H:7]1[C:22]([N:39]1[CH2:38][CH2:37][N:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[O:29][CH3:28])[CH2:41][CH2:40]1)=[O:24]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CN(Cc1ccc(F)cc1F)[C@H]1C[C@@H](C(=O)O)N(Cc2cccc(Cl)c2)C1
Product: COc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](N(C)Cc3ccc(F)cc3F)CN2Cc2cccc(Cl)c2)CC1
Yield: 7 %

Procedure:
As described for Example 64e, (2S,4S)-1-(3-chloro-benzyl)-4-[(2,4-difluoro-benzyl)-methyl-amino]-pyrrolidine-2-carboxylic acid (1 mmol) was converted, using 1-(2-methoxy-phenyl)-piperazine instead of 2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one, to the title compound (40 mg) in 7% yield as colorless oil. MS m/e=570.1 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([NH2:5])=[O:4].C(N(CC)CC)C.[C:35]([O:38][CH2:39]C)(=[O:37])C>ClCCl.O1CCCC1>[CH3:39][O:38][C:35]([O:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([NH2:5])=[O:4])=[O:37]
Reactant: CCOC(C)=O
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(O)C(N)=O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)OC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(N)=O
Reaction time: 1 h
Yield: 17 %

Procedure:
To a solution of 2-hydroxy-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionamide (550 mg, 1.50 mmol) obtained in Example 36 in dichloromethane-tetrahydrofuran (1:1, 50 ml) was added equivalent of methyl chlorofornate and triethylamine under ice-cooling until the reaction completed. The mixture was stirred for 1 hr, and the reaction mixture was diluted with ethyl acetate (100 ml) and washed successively with saturated brine, 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine. The mixture was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent; dichloromethane:methanol=98:2) to give the title compound (110 mg, yield 17%) as a white solid.