Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10]([C:11](=O)[N:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10]([C:11](=[S:29])[N:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCc1nc(=O)c2ccccc2n1-c1ccccc1
Solvent: Cc1ccccc1
Product: CCc1nc(=S)c2ccccc2n1-c1ccccc1
Reaction time: 1 h

Procedure:
1.50 g (5.99 mmol) 2-ethyl-1-phenyl-1H-quinazolin-4-one and 2.42 g (5.99 mmol) Lawesson's reagent (C14H14O2P2S4, Fluka) were suspended in 40 ml toluene and boiled for 1 h. After evaporation the crude mixture was purified by column chromatography on silica gel, eluent dichloromethane/acetone 95/5.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=O.[NH2:23][CH:24]1[N:28]=[C:27]2[CH2:29][CH2:30][S:31][CH:32]=[C:26]2[S:25]1>C1(C)C(C)=CC=CC=1>[N:28]1[CH:24]([NH:23][C:3]([C:5]2[N:6]([CH3:22])[S:7](=[O:20])(=[O:21])[C:8]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][C:9]=3[C:10]=2[OH:11])=[O:2])[S:25][C:26]2[C:27]=1[CH2:29][CH2:30][S:31][CH:32]=2
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Reactant: NC1N=C2CCSC=C2S1
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)NC2N=C3CCSC=C3S2)=C(O)c2ccc3ccccc3c2S1(=O)=O
Yield: 67 %

Procedure:
N-(5,6-Dihydro-7H-thiopyrano[4,3-d]thiazol-2-yl)-4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous toExample 22 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 2-amino-5,6-dihydro-7H-thiopyrano[4,3-d]thiazole. yield: 67% of theory: m.p. 255° C (decomp.; from xylene).
Reaction SMILES: CN(C)C=O.[Cl:6][CH:7]1[CH2:12][NH:11][CH:10]([OH:13])[CH:9]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][C:36](Cl)=[O:37]>C(OCC)(=O)C.O>[Cl:6][C:7]1[CH:12]=[N:11][C:10]2[O:13][CH2:35][C:36](=[O:37])[N:14]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:9]=2[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CC(Cl)CNC2O)CC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)COc3ncc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an N,N-dimethylformamide suspension (60 ml) of tert-butyl 4-[(5-chloro-2-hydroxypiperidin-3-yl)amino]piperidine-1-carboxylate (3.00 g) and potassium carbonate (3.79 g) was added chloroacetyl chloride (1.09 ml), followed by stirring at room temperature for 30 minutes, and at 140° C. for 4 hours. After the reaction solution was brought back to room temperature, water and ethyl acetate were added, and the solution was separated. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl 4-(7-chloro-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)piperidine-1-carboxylate (1.33 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15](C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].I[C:38]1[C:39](=[O:56])[C:40]2[C:41]([O:48][C:49]=1[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[N:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=2>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:38]3[C:39](=[O:56])[C:40]4[C:41]([O:48][C:49]=3[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[N:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=4)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: COc1ccc2c(=O)c(I)c(-c3ccccc3)oc2n1
Product: COc1ccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc2n1
Yield: 76 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 3-iodo-7-methoxy-2-phenyl-pyrano[2,3-b]pyridin-4-one was reacted to give the title compound (57 mg, 76%) as a colourless gum. LCMS (Method A): RT=4.88 min, [M+H]+=499.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:45][C:46]([NH2:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([NH:49][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([CH2:21][N:10]2[C:11](=[O:20])[N:12]([CH2:13][CH:14]([OH:19])[C:15]([F:18])([F:16])[F:17])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:9]2)=[CH:23][CH:24]=1)([CH3:48])([CH3:47])[CH3:45]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(CC(O)C(F)(F)F)c2=O)cc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1ccc(Cn2nc(-c3ccc(Cl)cc3)n(CC(O)C(F)(F)F)c2=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
An amount of 50 mg (0.11 mmol) of the compound from Example 28A was introduced in 1 ml of DMF and admixed with 18 mg (0.14 mmol) of HOBt and with 28 mg (0.15 mmol) of EDC. After 10 minutes of stirring at RT, 13 μl (0.12 mmol) of 2-methylpropan-2-amine were added and the mixture was stirred at room temperature for 16 h. Subsequently the reaction solution was admixed with about 3 ml of water and extracted with twice 5 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography [Method 8]. This gave 31 mg (55% of theory) of the target compound.
Reaction SMILES: [C:1]([N:5]1[CH2:31][CH2:30][CH2:29][CH2:28][C:8]2[C:9]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([NH2:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:3])[CH3:2].C[Si]([N:37]=[N+:38]=[N-])(C)C.N(OC(C)(C)C)=O>C(#N)C.O>[C:1]([N:5]1[CH2:31][CH2:30][CH2:29][CH2:28][C:8]2[C:9]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([N:20]=[N+:37]=[N-:38])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(cc1N)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: O
Product: COc1cc2c(cc1N=[N+]=[N-])-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To a solution of 1.75 g of 20b in 40 ml of acetonitrile was added dropwise at 0° C. 0.54 g of trimethylsilyl azide, followed by 0.6 gr of tertbutyl nitrite. The reaction was stirred for ½ hr at ambient temperature, and then diluted with water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The remainder was chromatographed on silicagel (using a gradient of heptane/ethyl acetate as eluent), to provide 1.14 g of 20c. LCMS-ESI: [M+1] 476.17.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1)=[O:4].[Li+].[CH3:18][CH:19]([N-]C(C)C)[CH3:20].C(Br)C=C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH2:20][CH:19]=[CH2:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester 2 (see Example 1, Step 1) (4.58 g, 20 mmol) was dissolved in THF (100 mL) and cooled down to −78° C. in a dry ice-acetone bath. LDA (12 mL, 2.0 M, 24 mmol) was then added dropwise. The mixture was stirred at −78° C. for 1 hr. Allyl bromide (5.3 mL, 61 mmol) was added in neat. The reaction was allowed to warm to rt naturally and stirred for 24 hrs. It was then quenched with sat. NH4Cl solution, extracted with ethyl acetate 2×150 mL. The organic layer washed with brine, dried (MgSO4) and concentrated. The crude was purified on silica gel column using 4:1 hexanes/ethyl acetate to get the title compound (3.6 g) as a yellow oil. MS (292, MNa).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[NH2:9][OH:10].Cl.N1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]([CH:7]=[N:9][OH:10])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1ccc(C=O)s1
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: Cc1ccc(C=NO)s1
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
1.20 kg (9.51 moles) of 5-methyl-2-thiophenecarboxaldehyde and 727 g (10.46 moles) of NH2OH.HCl were placed in a reaction vessel and cooled to 10° C. Then, 0.85 L (10.46 moles) of pyridine was dropwise added thereto for 1 hour (an exothermic reaction: 10° C.→43° C). After 10 minutes, 7 L of benzene was added thereto and heated to remove the obtained water by Dean-Stark apparatus (initial internal temperature: 80° C.). After 165 mL of water was collected for 8 hours, (theoretical quantity: 171 mL), the product was cooled to obtain 5-methyl-2-thiophenecarboxaldehyde oxime. At this time, if stirring was stopped, two-phases were formed. After 0.85 L (10.46 moles) of pyridine was completely added at 15° C., 1.26 kg (12.36 moles) of Ac2O was dropwise added thereto for 25 minutes, with maintaining a temperature less than 15° C. The reaction mixture was stirred for 1 hour at room temperature, and completion of the acetylation reaction was confirmed by HPLC (2 phases).
Reaction SMILES: [C:1](O)(=[O:8])[C:2]1C=CC=CC=1.[CH3:10][C:11]([CH2:15]CC=C(C)CCCC(C)CCCC(C)CCCC(C)C)=[CH:12][CH:13]=[O:14].[CH:36]1C=CC=C[CH:37]=1>>[CH2:1]([O:8][CH:13]([O:14][CH2:36][CH3:37])[CH:12]=[C:11]([CH3:10])[CH3:15])[CH3:2]
Reactant: c1ccccc1
Reactant: CC(=CC=O)CCC=C(C)CCCC(C)CCCC(C)CCCC(C)C
Reactant: O=C(O)c1ccccc1
Product: CCOC(C=C(C)C)OCC

Procedure:
0.1 Part of the reaction product, 1.74 parts of benzene, and 0.00018 part of benzoic acid were charged into a sealed tube, and reacted at 250°C. for 10 minutes. The product was subjected to gas chromatography analysis. It was thus confirmed that 3,7,11,15,19-pentamethyl-2,6-eicosadienal was obtained at the selectivity of 69.5% to the originally fed β-methyl-crotonaldehyde diethylacetal. The analytical value of the resulting acetal and aldehyde is shown in Table 16.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:23])[CH:5]=[C:6]([Cl:22])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([OH:21])[CH:12]=1)[OH:10].[C:24]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[Cl:22][C:6]1[CH:5]=[N+:4]([O-:23])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH3:24])[CH:12]=1)[OH:10]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(O)c2)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(O)Cc2c(Cl)c[n+]([O-])cc2Cl)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
(S)-3,5-dichloro-4-(2-(4-(difluoromethoxy)-3-hydroxyphenyl)-2-hydroxyethyl)-pyridine 1-oxide (2 g, 5.46 mmol) was dissolved in DMF (16 mL) then K2CO3 (2 g, 14.47 mmol) and iodomethane (1.72 g, 12.12 mmol) were added and the mixture was stirred at r.t. for 4 hours. The mixture was poured into 200 mL of water, filtered, washed with water and dried under vacuum at 40° C. 1.98 g of whitish solid was obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1([NH2:20])[CH2:19][CH2:18]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:20][C:17]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)[CH2:19][CH2:18]1)=[O:7]
Reactant: O=C(O)c1cccc(I)c1
Reactant: NC1(c2ccccn2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=C(NC1(c2ccccn2)CC1)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Iodobenzoic acid (2.7 g, 11.1 mmol, 1 eq), 1-(pyridin-2-yl)cyclopropanamine (1.5 g, 11.1 mmol, 1 eq), EDCI.HCl (3.2 g, 16.7 mmol, 1.5 eq), HOBT (2.2 g, 16.7 mmol, 1.5 eq) and DIPEA (6 ml, 33.5 mmol, 3 eq) were dissolved in DCM and the resulting mixture was stirred at room temperature for 18 hours. Water was added to the mixture and the product was extracted with DCM. The organic layer was concentrated and the product crystallized using dichloromethane and hexane. Yield: 2.3 g (57%). 1HNMR (400 MHz, DMSO-d6): δ 1.26 (m, 2H), 1.54 (m, 2H), 7.13 (t, J=4.04 Hz, 1H), 7.29 (m, 2H), 7.69 (t, J=8.06 Hz, 1H), 7.92 (d, J=3.05 Hz, 2H), 8.29 (s, 1H), 8.45 (d, J=4.56 Hz, 1H), 9.33 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[C:8]([CH3:11])[CH:7]=[C:6]([CH3:12])[C:3]=1[CH:4]=[O:5].C1(=[O:19])CCCCC1>C(O)(=O)C.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[CH3:1][C:2]1[C:9]([CH3:10])=[C:8]([CH3:11])[CH:7]=[C:6]([CH3:12])[C:3]=1[C:4]([OH:19])=[O:5]
Reactant: Cc1cc(C)c(C=O)c(C)c1C
Reactant: O=C1CCCCC1
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1cc(C)c(C(=O)O)c(C)c1C
Yield: 58.4 %

Procedure:
To a flask equipped with an oxygen inlet, stirrer and condenser were added 2,3,4,6-tetramethylbenzaldehyde (8.10 g, 50 mmol), 20 mL (0.194 mol) of cyclohexanone and 4 mg of cobalt (II) acetate dissolved in several drops of acetic acid. Oxygen was bubbled in while the solution was rapidly stirred. After 21/2 hr at room temperature and 4 hr at 50° the solution was poured into a separatory funnel and extracted with 100 mL, then 50 mL, of 3% aqueous sodium bicarbonate solution. The combined aqueous extracts were rinsed with 50 mL of cyclohexane, then acidified to a pH of 2 with concentrated hydrochloric acid and the precipitated product was collected by filtration, washed with water and air dried. A total of 5.2 g (58% yield) of fluffy white 2,3,4,6-tetramethylbenzoic acid was obtained: mp 164°-167°.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[CH2:8]Cl>CO>[F:3][C:4]([F:18])([F:17])[C:5]1[CH:6]=[C:7]([CH2:8][NH:2][CH3:1])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1
Reactant: CN
Reactant: FC(F)(F)c1cc(CCl)cc(C(F)(F)F)c1
Solvent: CO
Product: CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Yield: 40.9 %

Procedure:
Methylamine (3 g, 40% aqueous solution) was dissolved in 30 mL of MeOH. The reaction mixture was heated at 50° C. under stirring. 3,5-Bis(trifluoromethyl)-benzyl chloride (2 g, 7.6 mmol) dissolved in 10 mL of MeOH, was added. The solution was left stirring at this temperature for 5 h. The solution was concentrated carefully to remove MeOH as much as possible, then an aqueous solution of NaOH 1M was added and the aqueous layer was extracted with DCM. The two phases were separated; the organic phase was filtered through a phase separator and removed carefully in vacuo obtaining the title compound (0.8 g) as a yellow oil. UPLC-MS: m/z (ES+): 258.01 [M+H]+ Rt=0.60. 1H NMR (400 MHz, CDCl3) δ ppm 7.83 (s, 2H), 7.79 (s, 1H), 3.91 (s, 2H), 3.30 (m, 1H), 2.50 (s, 3H); UPLC-MS: Rt=1.30; m/z (ES+): 586 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[O:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@@H:7]1[CH2:18]OS(C)(=O)=O.[CH3:30][NH2:31]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[O:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C@@H:7]1[CH2:18][NH:31][CH3:30]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2cc(F)cc([N+](=O)[O-])c2)[C@H]1COS(C)(=O)=O
Reactant: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC[C@@H]1[C@@H](Oc2cc(F)cc([N+](=O)[O-])c2)CCN1C(=O)OC(C)(C)C
Temperature: 55 °C

Procedure:
To a solution of (2R,3S)-tert-butyl 3-(3-fluoro-5-nitrophenoxy)-2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate (1.0 equiv) in THF (0.4 M) was added 40% aq. methylamine (90 equiv). The resulting solution was heated to 55° C. overnight. The reaction mixture was cooled to room temperature and diluted with EtOAc (20 volume equivalents) and washed twice with sat. aq. NaHCO3 and once with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound as a dark oil with 147% mass balance; the material was used without further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].[F:15][C:16]1[C:17]([CH3:25])=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.[F-].[Cs+].O>O1CCOCC1.CC(OC)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:15][C:16]1[C:17]([CH3:25])=[C:18]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[CH2:12][O:13][CH3:14])[CH:19]=[CH:20][CH:21]=1
Reactant: COCc1cc(C(=O)OC)ccc1Br
Reactant: Cc1c(F)cccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: O
Solvent: COC(C)(C)C
Product: COCc1cc(C(=O)OC)ccc1-c1cccc(F)c1C
Temperature: 100 °C

Procedure:
A mixture of methyl 4-bromo-3-(methoxymethyl)benzoate (5.00 g, 19.3 mmol), 3-fluoro-2-methylphenylboronic acid (Combi-Blocks BB-3475, 4.46 g, 29.0 mmol), bis(triphenylphosphine)palladium(II) chloride (271 mg, 0.39 mmol) and cesium fluoride (8.79 g, 57.9 mmol) was prepared in dioxane (50 mL) and water (20 mL) under N2 atmosphere. The reaction mixture was heated at 100° C. for 1 hour. The reaction mixture was cooled at RT, diluted with MTBE (250 mL) and the layers were separated. The organic layer was washed with water (100 mL) and brine (100 mL). The aqueous layers were extracted with MTBE (150 mL). The organic layers were combined, dried (MgSO4) and concentrated under reduced pressure. After purification by flash chromatography (silica, EtOAc/n-hexane), the title compound was obtained as a colorless oil (4.85 g, 87%). HPLC (Method A), Rt: 5.0 min (purity: 99.5%). UPLC/MS, M+(ESI): 289.0.
Reaction SMILES: O1CCCC1.[B:6]([O:11]C)(OC)[O:7]C.[F:13][C:14]1[CH:15]=[C:16](Br)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.Cl>O>[F:13][C:14]1[CH:15]=[C:16]([B:6]([OH:11])[OH:7])[CH:17]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:19]=1
Reactant: COB(OC)OC
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: OB(O)c1cc(F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
In a second reaction vessel, 40 mL of tetrahydrofuran is cooled to -78° C., and 2.3 mL (0.021 mole) of trimethyl borate is added dropwise as the Grignard reagent of 3-fluoro-5-trifluoromethylphenyl bromide prepared above is transferred into the second reaction vessel using a cannula. The temperature of the reaction mixture is maintained below -60° C. during the additions. Upon completion of the additions, the reaction mixture is again cooled to -78° C., where it is stirred for about 45 minutes. After this time, the reaction mixture is allowed to warm to ambient temperature. The reaction mixture is then poured into about 200 mL of water and is made acidic with aqueous 5% hydrochloric acid. The mixture is extracted with four 100 mL portions of ethyl acetate. The combined extracts are dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 3.3 grams of 3-fluoro-5-trifluoromethylphenylboronic acid, mp 167°-168° C. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][CH2:7][CH2:8]OC1C=CC(Cl)=CC=1C=O)(C)(C)C.C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.C[Si](Cl)(C)C.[CH2:40]([N:42](CC)CC)C.C(Cl)(=O)C>>[CH3:1][Si:5]([CH3:20])([CH3:19])[O:6][C:7](=[CH2:8])[N:42]=[CH2:40]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Cl)cc1C=O
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CC(=O)Cl
Product: C=NC(=C)O[Si](C)(C)C

Procedure:
In a manner similar to the method described in example 1b, 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-benzaldehyde (5.2 g, 17 mmol) prepared in example 131a was reacted with 1,1,1,3,3,3-hexamethyldisilazane (2.4 g, 15 mmol), n-butyllithium (2.5 M, 6 mL, 15 mmol), trimethylsilyl chloride (1.6 g, 15 mmol), triethylamine (1.6 g, 20 mmol) and acetyl chloride (1.5 g, 20 mmol) to give 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene as yellow oil and used for the next step without further purification.
Reaction SMILES: [CH2:1]([C:5]1[NH:9][C:8]([CH:10]=[O:11])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.C1C(=O)N([Br:24])C(=O)C1>>[Br:24][C:7]1[N:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[NH:9][C:8]=1[CH:10]=[O:11]
Reactant: CCCCc1ncc(C=O)[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCCCc1nc(Br)c(C=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
2-Butyl-3H-imidazole-4-carbaldehyde (30.0 g, 197 mmol) was dissolved in DMF (220 mL, 2.8 mol). NBS (36.8 g, 207 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was then concentrated and taken up in EtOAc and water. The aqueous layer was extracted three times with EtOAc, and the combined organic extracts washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated. The mixture was purified by silica gel chromatography (0-50% EtOAc:hexanes) to obtain 7.8 g of the title compound as a gray solid. MS m/z: [M+H+] calcd for C8H11BrN2O, 232.09; found 233.0. 1H-NMR (DMSO): 13.3 (1H, br), 9.48 (1H, s), 2.66 (2H, t), 1.59 (2H, m), 1.25 (2H, m), 0.85 (3H, t).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][CH2:28][NH:29]2>>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15](=[O:17])[N:29]3[C:30]4[C:26](=[C:25]([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=5)[CH:33]=[CH:32][CH:31]=4)[CH2:27][CH2:28]3)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: c1ccc(-c2cccc3c2CCN3)nc1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(-c3ccccn3)cccc21
Yield: 62.8 %

Procedure:
The product is prepared by following the procedure described in example 10d using 26.7 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (example 1d, step 2d) and 25 mg of 4-pyridin-2-yl-2,3-dihydro-1H-indole in place of 4-pyridin-4-yl-2,3-dihydro-1H-indole. 26.8 mg of 6-(morpholin-4-yl)-2-{2-oxo-2-[4-(pyridin-2-yl)-2,3-dihydro-1H-indol-1-yl]ethyl}pyrimidin-4(3H)-one are obtained in the form of a purple solid, the characteristics of which are the following: