Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C([N:19]1[CH2:26][C:25]2([CH2:27][CH2:28][CH:29]=[CH2:30])[CH:21]([CH2:22][O:23][C:24]2=[O:31])[CH2:20]1)C1C=CC=CC=1>ClCCl>[CH2:5]([O:4][C:2]([N:19]1[CH2:26][C:25]2([CH2:27][CH2:28][CH:29]=[CH2:30])[CH:21]([CH2:22][O:23][C:24]2=[O:31])[CH2:20]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=CCCC12CN(Cc3ccccc3)CC1COC2=O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: C=CCCC12CN(C(=O)OCc3ccccc3)CC1COC2=O
Temperature: 25 °C
Reaction time: 120 h
Yield: 89.1 %

Procedure:
Benzyl chloroformate (1.72 mL, 12.0 mmol) was added to a solution of 7-benzyl-1-(3-buten-1-yl)-3-oxa-7-azabicyclo[3.3.0]octan-2-one (1.09 g, 4.02 mmol) in dichloromethane (13.4 mL) in a nitrogen atmosphere, and the mixture was stirred at room temperature for five days. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→90:10→84:16→80:20→75:25→66:34→50:50) to give 1.13 g of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([O:8][C:9]1[CH:10]=[N:11][C:12]([O:15]CC2C=CC=CC=2)=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]>C(O)C>[CH2:1]([O:3][C:4](=[O:23])[C:5]([O:8][C:9]1[CH:10]=[N:11][C:12]([OH:15])=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)nc1
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(O)nc1
Reaction time: 0.75 h
Yield: 94 %

Procedure:
To a solution of 0.29 g (0.92 mmol) 2-(6-benzyloxy-pyridin-3-yloxy)-2-methyl-propionic acid ethyl ester in 3 mL ethanol 29 mg 10% palladium on charcoal was added. The suspension was hydrogenated at 1.5 bar for 0.75 h. The catalyst was filtered off over Dicalite Speed Plus, washed with ethanol and the filtrate evaporated to dryness to give the desired compound as a light brown solid (94%). MS (Turbo Spray): m/z=226.1 [M+H].
Reaction SMILES: CN(C)C=O.[C:6]([C:8]1[C:13]([C:14]#[N:15])=[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=[CH:10][C:9]=1[OH:21])#[N:7].C(=O)([O-])[O-].[K+].[K+].[CH2:28]([C:31]12[CH2:38][CH2:37][C:34]([CH2:39]Br)([CH2:35][CH2:36]1)[CH2:33][CH2:32]2)[CH2:29][CH3:30]>O>[C:6]([C:8]1[C:13]([C:14]#[N:15])=[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=[CH:10][C:9]=1[O:21][CH2:39][C:34]12[CH2:35][CH2:36][C:31]([CH2:28][CH2:29][CH3:30])([CH2:38][CH2:37]1)[CH2:32][CH2:33]2)#[N:7]
Reactant: CCCC12CCC(CBr)(CC1)CC2
Reactant: CCCCCc1ccc(O)c(C#N)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCc1ccc(OCC23CCC(CCC)(CC2)CC3)c(C#N)c1C#N
Temperature: 80 °C
Reaction time: 48 h

Procedure:
50 ml of dimethylformamide were added to 0.04 mole of 2,3-dicyano-4-pentylphenol, 0.2 mole of potassium carbonate and 0.04 mole of 4-propyl-1-bicyclo(2,2,2)-octylmethyl bromide. The mixture was stirred at 80° C. for 48 hours. The mixture was then cooled to room temperature and poured into 200 ml of water and the organic phase was extracted. The organic extract was washed with water and dried over magnesium sulfate. After the solvent had been evaporated off, the crude product was recrystallized several times. The pure product has a high melting point of 133.1° C. and a negative DCA.
Reaction SMILES: C([Li])(CC)C.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:22])=[C:11]([CH:21]=1)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[CH:32][C:33]([F:36])([F:35])[F:34])=[CH:27][CH:26]=1>C1COCC1>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:22][CH:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[C:33]([F:35])([F:34])[F:36])=[C:11]([CH:21]=1)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19]
Reactant: Cc1ccc(Cl)cc1CNC(=O)OC(C)(C)C
Reactant: COc1ccc(N=CC(F)(F)F)cc1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1ccc(NC(Cc2ccc(Cl)cc2CNC(=O)OC(C)(C)C)C(F)(F)F)cc1
Temperature: 25 °C
Yield: 41.5 %

Procedure:
sec-Butyl-lithium (1.3 M in cyclohexane, 21.72 mL) was added to a stirred solution of tert-butyl 5-chloro-2-methylbenzylcarbamate (3.61 g, 14.12 mmol) in THF (30 mL) at −78° C. under nitrogen to give a deep red solution. After 10 min N-(4-methoxyphenyl)-N-(2,2,2-trifluoroethylidene)amine (3.01 g, 14.12 mmol) was added and after a further 5 min the solution was quenched with excess saturated aqueous NH4Cl and warmed to ambient temperature. The solution was partitioned between EtOAc and brine. The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash column chromatography on silica (eluting with 5% methylene chloride, 5-20% ethyl acetate/hexanes gradient) to give tert-butyl 5-chloro-2-{2-[(4-methoxyphenyl)amino]-3,3,3-trifluoropropyl}benzylcarbamate (2.69 g) as a gum; 1H NMR (CDCl3 400 MHz) δ 1.47 (s, 9H), 2.90 (dd, J=10.7 and 14.7 Hz, 1H), 3.16 (dd, J=3.4 and 14.7 Hz, 1H), 3.62 (br d, J=8.2 Hz, 1H), 3.71 (s, 3H), 4.03 (br m, 1H), 4.29 (dd, J=5.6 and 14.7 Hz, 1H), 4.34 (br dd, 1H), 4.87 (br s, 1H), 6.47 (d, J=8.9 Hz, 2H), 6.69 (d, J=8.9 Hz, 2H), 7.14 (d, J=8.2 Hz, 1H), 7.19 (dd, J=8.2 and 2.0 Hz, 1H), 7.23 (s, 1H).
Reaction SMILES: Cl[CH2:2][C@@H:3]1[CH2:7][O:6]C(C)(C)[O:4]1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:27]3[C:26](=[O:28])[NH:25][CH:24]=[N:23][C:22]=3[N:21]([CH3:29])[C:20](=[O:30])[C:19]=2[CH3:31])=[C:13]([F:32])[CH:12]=1.Cl>>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:27]3[C:26](=[O:28])[N:25]([CH2:2][C@@H:3]([OH:4])[CH2:7][OH:6])[CH:24]=[N:23][C:22]=3[N:21]([CH3:29])[C:20](=[O:30])[C:19]=2[CH3:31])=[C:13]([F:32])[CH:12]=1
Reactant: CC1(C)OC[C@@H](CCl)O1
Reactant: Cc1c(Nc2ccc(Br)cc2F)c2c(=O)[nH]cnc2n(C)c1=O
Agent: Cl
Product: Cc1c(Nc2ccc(Br)cc2F)c2c(=O)n(C[C@@H](O)CO)cnc2n(C)c1=O

Procedure:
The title compound was prepared according to the procedure used for Example 9 synthesis by reaction of (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane with compound 9F, followed by hydrolysis with 1N HCl. 1H NMR (400 MHz, MeOD) δ ppm 1.71 (s, 3H) 3.44-3.51 (m, 1H) 3.59 (d, J=5.31 Hz, 2H) 3.74 (s, 3H) 3.76-3.82 (m, 1H) 3.91-4.01 (m, 1H) 4.41 (dd, J=13.64, 3.28 Hz, 1H) 6.77 (t, J=8.59 Hz, 1H) 7.26 (d, J=9.09 Hz, 1H) 7.39 (d, J=2.02 Hz, 1H) 8.38 (s, 1H)) [M+H] calc'd for C18H18BrFN4O4, 454. found, 454.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][C:6]([C:15](O)=[O:16])=[CH:5][C:4]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Cl)(=O)C(Cl)=O.[CH2:30]([C:32]1[O:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[CH:36]=1)[CH3:31].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH2:30]([C:32]1[O:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[C:36]=1[C:15]([C:6]1[CH:7]=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]([O:2][CH3:1])=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=1)=[O:16])[CH3:31]
Reactant: CCc1cc2ccccc2o1
Reactant: COc1c(-c2ccccc2)cc(C(=O)O)cc1-c1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCc1oc2ccccc2c1C(=O)c1cc(-c2ccccc2)c(OC)c(-c2ccccc2)c1
Yield: 73 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 2′-methoxy-[1,1′;3′,1″]terphenyl-5′-carboxylic acid (1.031 g, 3.388 mmol), oxalyl chloride (0.325 mL, 3.727 mmol), commercial 2-ethylbenzofuran (0.4953 g, 3.388 mmol) and tin (IV) chloride (0.436 mL, 3.727 mmol) in CH2Cl2. Purification on Biotage KP-Sil eluting with 3% EtOAct pet. ether gave 1.070 g, (73%) of the title compound. 1H NMR (DMSO-d6) δ1.24 (t, 3 H), 2.90 (quartet, 2 H), 3.21 (s, 3 H), 7.30-7.67 (m, 14 H), 7.75 (s, 2 H).
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>O1CCCC1>[CH2:30]([O:29][C:27]([O:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:28])[CH3:31]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C1=C(O)C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)OC1=C(C(=O)OCC)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2.48 g of ethyl 3-hydroxy-1,4-dihydro1,4-dioxo-2-naphthoate and 1.5 ml of triethylamine in 10 ml of dry tetrahydrofuran was added dropwise 1 ml of ethyl chloroformate at 5° C. or below, and the mixture was stirred at room temperature for 2 hours. The resulting solid was removed by filtration, and the filtrate was evaporated to dryness to give crude ethyl 3-ethoxycarbonyloxy-1,4-dihydro-1,4-dioxo-2-naphthoate.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[NH:27][CH2:26]4)[CH2:19][CH2:18]3)[C:11]=2[O:10][CH2:9][CH2:8]1.[C:34](O)(=O)C(O)=O.C(O)(=O)C(O)=O.O1C2C=CC=C(N3CCN(CCC4C5C(=CC=CC=5)NC4)CC3)C=2OCC1.[H-].[Na+].IC.C(OCC)(=O)C>O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]([CH3:34])[CH2:26]4)[CH2:19][CH2:18]3)[C:11]=2[O:10][CH2:9][CH2:8]1
Reactant: c1ccc2c(c1)NCC2CCN1CCN(c2cccc3c2OCCO3)CC1
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: CN1CC(CCN2CCN(c3cccc4c3OCCO4)CC2)c2ccccc21
Reaction time: 1 h

Procedure:
A solution of 4a (1.5 g) in dry tetrahydrofuran (50 mL) was added dropwise to a suspension of sodium hydride (60% in mineral oil, 0.21 g) in tetrahydrofuran (25 mL) at room temperature. After stirring for 30 min a solution of iodomethane (0.75 g) in dry tetrahydrofuran (25 mL) was added dropwise. Stirring for 1 hour followed by standard work-up with ethyl acetate gave an oil which was purified by flash chromatography (eluent: heptane/ethyl acetate/triethylamine 15:3:2). The resulting oil was converted to the title oxalate salt (0.3 g) from acetone by addition of oxalic acid. Mp 155-65° C. 1H NMR (DMSO-d6) 1.75-1.85 (m, 1H); 2.05-2.15 (m, 1H); 2.70 (s, 3H); 2.90-3.25 (m, 12H); 3.40 (t, 1H); 4.15-4.30 (m, 4H); 6.45-6.55 (m, 3H); 6.65 (t, 1H); 6.75 (t, 1H); 7.05 (t, 1H); 7.10 (d, 1H). MS m/z (%): 380 (MH+, 4%), 178 (4%), 132 (53%).
Reaction SMILES: [ClH:1].C([O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:15]([CH3:17])[CH3:16])[C:10]([CH3:18])=[C:9]2[C:19]([NH:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:24][CH2:23]1)=[O:20])(=O)C.[OH-].[Na+]>CO.O>[ClH:1].[OH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:15]([CH3:16])[CH3:17])[C:10]([CH3:18])=[C:9]2[C:19]([NH:21][CH:22]1[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:27]1)=[O:20]
Reactant: CC(=O)Oc1ccc2c(c1)c(C(=O)NC1CCN(CCc3ccccc3)CC1)c(C)n2C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)NC2CCN(CCc3ccccc3)CC2)c2cc(O)ccc2n1C(C)C
Reaction time: 0.17 h

Procedure:
To a solution of a total amount of the hydrochloride in 80 ml of methanol was added a solution of 2 g of sodium hydroxide in 10 ml of water, and the mixture was stirred for 10 minutes. After the methanol was concentrated, water was added to the residue to separate oil. To the oil was added 3 ml of glacial acetic acid and ethyl acetate, and the mixture was shaken well. The organic layer was washed with water and an aqueous solution of sodium hydrogencarbonate and the precipitated crystals were filtered. The crystals were dissolved in acetone containing ethanol and treated with concentrated hydrochloric acid to precipitate the corresponding hydrochloride. The crystalline hydrochloride was filtered and recrystallized from aqueous ethanol to give 5-hydroxy-1-isopropyl-2-methyl-N-(1-(2-phenylethyl)-4-piperidyl)indole-3-carboxamide hydrochloride, melting at 271°-276° C. with decomposition.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:10])[CH:8]=2)[CH:3]=[N:2]1.CN(C=O)C.N1C=CN=C1.[CH3:21][C:22]([Si:25](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:24])[CH3:23]>C(OCC)(=O)C.O>[Si:25]([O:10][C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[N:2][NH:1]2)=[CH:5][CH:6]=1)([C:22]([CH3:24])([CH3:23])[CH3:21])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Oc1ccc2cn[nH]c2c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](Oc1ccc2cn[nH]c2c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Indazol-6-ol (4.029 g) which can be prepared according to the method described in Reference example 35, etc. was dissolved dehydrated DMF (60 mL; manufactured by Kanto Chemical Co., Inc.), and added with imidazole (4.49 g; manufactured by Tokyo Chemical Industry, Co., Ltd.) and TBDPSCl (17.1 mL; manufactured by Tokyo Chemical Industry, Co., Ltd.). The mixture was stirred overnight at room temperature. The reaction solution was added to water and extraction was carried out three times with ethyl acetate. The organic layer was washed three times with water and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (“COLUMN-A”; n-hexane:ethyl acetate=92:8→71:29) to obtain the title compound (9.214 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[C:5]2I.CN(C=O)C.C([Sn](CCCC)(CCCC)[C:29]1[N:34]=[C:33]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[CH:32]=[CH:31][CH:30]=1)CCC.O>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.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[C:5]2[C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)[N:34]=1
Reactant: CC(C)(C)OC(=O)n1cc(I)c2cc(Br)ccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(N2CCOCC2)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1cc(-c2cccc(N3CCOCC3)n2)c2cc(Br)ccc21
Temperature: 100 °C
Yield: 53.1 %

Procedure:
To a mixture of Pd(PPh3)4 (255.0 mg, 220.6 μmol), tert-butyl 5-bromo-3-iodo-1H-indole-1-carboxylate (1000 mg, 2369 μmol) and CuI (546.2 mg, 2868 μmol) was added DMF (12 mL) followed by 4-(6-(tributylstannyl)pyridin-2-yl)morpholine (1000 mg, 2206 μmol). The mixture was heated at 100° C. for 20 min. After cooled to RT, the reaction was added H2O (5 mL) and DCM (5 mL). The organic layer was separated. The aqueous layer was extracted with DCM (10 mL×2). The organic layers were combined, dried with sodium sulfate, filtered and evaporated to dryness. The brown crude oil was purified with silica gel chromatography (eluting with 100% DCM) to give tert-butyl 5-bromo-3-(6-morpholinopyridin-2-yl)-1H-indole-1-carboxylate (537.3 mg, 53.13%) as a white solid. MS (ESI, pos. ion) m/z: 458 (M+1). 1H NMR (400 MHz, DMSO-d6) ppm 1.66 (s, 9H), 3.50-3.62 (m, 4H), 3.74-3.83 (m, 4H), 6.80 (d, J=8.4 Hz, 1H), 7.33 (d, J=7.4 Hz, 1H), 7.54 (dd, J=8.9, 2.1 Hz, 1H), 7.64 (dd, J=8.4, 7.6 Hz, 1H), 8.06 (d, J=9.0 Hz, 1H), 8.29 (s, 1H), 8.68 (d, J=2.2 Hz, 1H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]1[C:13](=[O:14])[N:12]([O:15][C:16](ON2C(=O)CCC2=O)=[O:17])[C:10](=[O:11])[CH2:9]1>C(#N)C>[O:11]=[C:10]1[CH2:9][CH2:8][C:13](=[O:14])[N:12]1[O:15][C:16](=[O:17])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccccn1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CC#N
Product: O=C(Nc1ccccn1)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
A solution of 2-aminopyridine (2.0 g, 21.3 mmol) in acetonitrile (20 mL) was added to a stirred suspension of N,N-disuccinimidyl carbonate (5.4 g, 21.3 mmol) in acetonitrile (150 mL). The mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was dissolved in methylene chloride (120 mL). The methylene chloride solution was washed with sat. NaHCO3 (40 mL), water (2×40 mL), brine (40 mL) and dried (MgSO4). Solvent was removed, and the residue was slurried with ether (30 mL) to give pyridin-2-yl-carbamic acid 2,5-dioxo-pyrrolidin-1-yl ester (2.5 g).
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:14]=[CH:13][C:6]([C:7]([CH2:9][C:10](=O)[CH3:11])=[O:8])=[CH:5][N:4]=1.[ClH:15].S(Cl)([Cl:18])=O>C1(C)C=CC=CC=1>[ClH:18].[CH3:2][C:3]1[CH:14]=[CH:13][C:6]([CH:7]([OH:8])[CH2:9][CH:10]([Cl:15])[CH3:11])=[CH:5][N:4]=1
Reactant: CC(=O)CC(=O)c1ccc(C)nc1
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: [Na]
Solvent: Cc1ccccc1
Product: Cc1ccc(C(O)CC(C)Cl)cn1

Procedure:
A suspension of the sodium salt of 6-methyl-nicotinoyl-acetone in anhydrous toluene is saturated with hydrogen chloride and then reacted with thionyl chloride in a known manner. Reduction of the reaction product gives 1-(2-methyl-5-pyridyl)-3-chloro-butan-1-ol hydrochloride which is used without additional purification
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)[CH:2]=1.[CH3:17][C:18]1[N:19]=[C:20]([NH2:23])[S:21][CH:22]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:17][C:18]1[N:19]=[C:20]([NH:23][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[C:8]([O:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:9]=2)[S:21][CH:22]=1
Reactant: Cc1csc(N)n1
Reactant: O=C(O)c1cccc(Oc2cccnc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1csc(NC(=O)c2cccc(Oc3cccnc3)c2)n1
Yield: 24.4 %

Procedure:
Compound 2 (0.1 g, 0.5 mmol, 1 eq), 4-methylthiazol-2-amine (111 mg, 0.972 mmol, 2.10 eq), 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (371 g, 0.972 mmol, 2.10 eq), and DIEA (170 μL, 0.972 mmol, 2.10 eq) were dissolved in CH2Cl2 (5 mL) and DMF (1 mL) and stirred rt for 48 h. The reaction was diluted with CH2Cl2 and washed with water (1×). The organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 38 mg (26%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=2.1 Hz, 1H), 8.49 (d, J=4.6 Hz, 1H), 7.94-7.90 (m, 1H), 7.76 (t, J=2.0 Hz, 1H), 7.69 (ddd, J=8.5, 2.7, 1.1 Hz, 1H), 7.62-7.57 (m, 2H), 7.38 (dd, J=8.0, 2.1 Hz, 1H), 6.81 (s, 1H), 2.29 (s, 3H); [M+1]+: 312.1.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][OH:7].[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][O:7][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][O:15]1
Reactant: CC(CO)(CCCBr)c1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: CC(CCCBr)(COC1CCCCO1)c1ccccc1
Yield: 94.9 %

Procedure:
According to the method described for the synthesis of 207d, 206b (20.0 g, 77.8 mmol) was treated with 3,4-dihydro-2H-pyran (8.2 g, 96.5 mmol) and p-toluenesulfonic acid hydrate (0.57 g, 3.0 mmol) in CH2Cl2 (350 mL) to afford 207b (25.2 g, 95%) as an oil, which was used without further purification. 1H NMR (CDCl3): 7.26-7.08 (m, 5H), 4.45 (m, 1H), 3.72 (m, 1H), 3.58 (m, 1H), 3.35-3.05 (m, 2H), 3.28 (t, 2H, J=6.6), 1.95-1.39 (m, 10H), 1.25 (s, 3H). 13C NMR (CDCl3): δ 145.38, 128.15, 126.51, 126.03, 99.06, 98.92, 76.20, 61.91, 61.80, 41.82, 41.74, 37.58, 37.43, 34.65, 30.61, 27.88, 25.58, 23.03, 22.90, 19.39, 19.32. HRMS (LSIMS, nba): Calcd for C17H26O2Br (MH+): 341.1116, found: 341.1127.
Reaction SMILES: FC(F)(F)S([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])(=O)=O.[CH3:14][C:15]1[NH:20][C:19](=O)[C:18]([N+:22]([O-:24])=[O:23])=[C:17]([N:25]2[CH2:30][CH2:29][CH:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)[N:16]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][C:15]1[N:16]=[C:17]([N:25]2[CH2:30][CH2:29][CH:28]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:27][CH2:26]2)[C:18]([N+:22]([O-:24])=[O:23])=[C:19]([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])[N:20]=1
Reactant: Cc1nc(N2CCC(c3ccccc3)CC2)c([N+](=O)[O-])c(=O)[nH]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1nc(OCC(F)(F)F)c([N+](=O)[O-])c(N2CCC(c3ccccc3)CC2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 30.5 %

Procedure:
0.591 g (2.55 mmol) of 2,2,2-trifluoroethyl trifluoromethanesulfonate were added slowly at room temperature to a suspension of 0.200 g (0.636 mmol) of the 2-methyl-5-nitro-6-(4-phenyl-piperidin-1-yl)-3H-pyrimidin-4-one (example 5) and 0.135 g (1.27 mmol) of sodium carbonate in 5.0 ml of acetone. After stirring of the reaction mixture for 2 hours, 0.136 g (0.99 mmol) of potassium carbonate were added and stirring continued for 18 hours. Additional 0.296 g (1.27 mmol) of 2,2,2-trifluoroethyl trifluoromethanesulfonate were added and stirring continued for 4 hours. The reaction mixture was then poured into 50 ml of an ice/water mixture and extracted 3 times with 50 ml of dichloromethane. The combined dichloromethane phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue formed was chromatographed on silica gel with a 9:1 to 1:1 v/v gradient of hexane and ethylacetate as the eluent giving 0.077 g (0.194 mmol, 30.5% of theory) of the 2-methyl-5-nitro-4-(4-phenyl-piperidin-1-yl)-6-(2,2,2-trifluoro-ethoxy)-pyrimidine as a light yellow solid; m.p. 114-117° C.; MS: [M+H]+=397; and 0.166 g (0.419 mmol, 65.8% of theory) of the 2-methyl-5-nitro-6-(4-phenyl-piperidin-1-yl)-3-(2,2,2-trifluoro-ethyl)-3H-pyrimidin-4-one as yellowish solid;
Reaction SMILES: [C:1]([NH:5][C:6]([NH:8][C:9]1[C:10]([CH3:30])=[C:11]([CH:28]=[O:29])[C:12]2[O:16][CH2:15][C@H:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[C:13]=2[C:26]=1[CH3:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.CCCCCC>C(Cl)(Cl)Cl>[C:1]([NH:5][C:6]([NH:8][C:9]1[C:10]([CH3:30])=[C:11]([CH2:28][OH:29])[C:12]2[O:16][CH2:15][C@H:14]([C:17]3[CH:18]=[CH:19][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=3)[C:13]=2[C:26]=1[CH3:27])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1c(C=O)c2c(c(C)c1NC(=O)NC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: Cc1c(CO)c2c(c(C)c1NC(=O)NC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Yield: 97 %

Procedure:
Using (−)-N-(tert-butyl)-N′-((3R)-7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)urea obtained in Example 48, the title compound was synthesized in the same manner as in Example 21. Yield: 97%. Melting point: 187-188° C. (ethyl acetate-hexane). [α]D20=+34.0° (c=0.43, chloroform).