Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][N:5]=[C:4]([CH3:10])[C:3]=1[OH:11].Cl.I[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18]>>[OH:9][CH2:8][C:7]1[C:2]([CH3:1])=[C:3]([O:11][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])[C:4]([CH3:10])=[N:5][CH:6]=1
Reactant: Cc1ncc(CO)c(C)c1O
Reactant: N#Cc1cccc(I)c1
Agent: Cl
Product: Cc1ncc(CO)c(C)c1Oc1cccc(C#N)c1
Yield: 6.7 %

Procedure:
The coupling of 4-deoxypyridoxine hydrochloride (5.6 g, 29.5 mmol) and 3-iodobenzonitrile (10.0 g, 43.0 mmol), as described in Example 81, gave 3-(5-hydroxymethyl-2,4-dimethyl-pyridin-3-yloxy)-benzonitrile (93) (0.5 g, 7.5% yield).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH2:3][OH:4].C(N(CC)CC)C.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Si:22]([O:4][CH2:3][C@@H:2]([NH2:1])[CH2:5][S:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N[C@H](CO)CSCc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@@H](N)CSCc1ccc(F)cc1
Reaction time: 8 h
Yield: 104.8 %

Procedure:
2(R)-Amino-3-(4-fluorobenzylsulfanyl)propan-1-ol (16.15 g), 4-dimethylamino-pyridine (554 mg), and triethylamine (16.7 mL) were weighed into a 1000 mL round bottom flask fitted with a stir bar, 250 mL addition funnel, septum, and nitrogen inlet. Methylene chloride (150 mL) was added to give a clear pale amber solution. A solution of tert-butyldimethylsilyl chloride (12.54 g) in CH2Cl2 (100 mL) was added dropwise over 40 min. After stirring overnight, the reaction mixture was poured into water and the organic phase was separated, dried over anhydrous MgSO4 and removed the solvent on rotavap to give 2-(tert-butyldimethylsilanyloxy)-1(R)-(4-fluoro-benzylsulfanylmethyl)ethylamine (25.92 g) as a clear yellow oil.
Reaction SMILES: [N+]([O-])([O:3][CH:4]([C:6]1[CH:11]=[C:10]([NH:12][C:13]([CH3:15])=[O:14])[C:9]([F:16])=[CH:8][C:7]=1[Cl:17])[CH3:5])=O.C[O-].[Na+].[CH2:22](OCC)C>CO>[Cl:17][C:7]1[C:6]([CH:4]([O:3][CH3:22])[CH3:5])=[CH:11][C:10]([NH:12][C:13](=[O:14])[CH3:15])=[C:9]([F:16])[CH:8]=1
Reactant: CCOCC
Reactant: CC(=O)Nc1cc(C(C)O[N+](=O)[O-])c(Cl)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(C)c1cc(NC(C)=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a clear, colorless solution of 0.4 g (0.0015 mole) of 1-(2-chloro-4-fluoro-5-methylcarbonylaminophenyl)ethyl nitrate in 15 ml of absolute methanol was added dropwise 0.31 g (0.0015 mole) of a 25 weight percent solution of sodium methoxide in methanol. The reaction mixture turned pale yellow immediately and was stirred at room temperature for 2.5 hours. An additional 0.31 g (0.0015 mole) of the sodium methoxide solution was added, and stirring at room temperature continued for 18 hours. The mixture was heated at reflux for 2.5 hours and then was allowed to cool to room temperature. To the mixture was added 100 ml of diethyl ether, and this mixture was washed with water. The diethyl ether solution was dried, filtered, and the solvent was evaporated under reduced pressure, yielding 0.28 g of N-[4-chloro-2-fluoro-5-(1-methoxyethyl)-phenyl]acetamide. The nmr and ir spectra were consistent with the proposed structure. This reaction was repeated to provide sufficient starting material for Step G.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[H-].[Na+].[CH3:13][CH:14]([CH3:26])[C:15]([O:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16]>>[CH3:13][CH:14]([CH3:26])[C:15]([O:17][N:18]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[S:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:9])=[O:8])=[O:16]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)C(=O)ONC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: CC(C)C(=O)ON(C(=O)OC(C)(C)C)S(=O)(=O)c1cccnc1

Procedure:
N-[(tert-Butoxy)carbonyl]pyridine-3-sulfonamido 2-methylpropanoate (78) is synthesised from 3-pyridine sulfonyl chloride, sodium hydride and [(tert-butoxy)carbonyl]amino 2-methylpropanoate according to Scheme 2. (0.6 g, 37%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.21 (1H, d, 1.6 Hz), 8.89 (1H, dd, 4.7, 1.3 Hz), 8.34 (1H, dd, 7.4, 1.4 Hz), 7.53 (1H, dd, 8.2, 4.9 Hz), 2.84 (1H, sept, 7.0 Hz), 1.42 (9H, s), 1.32 (6H, d, 6.9 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14](OS(C)(=O)=O)[C@H:13]2[O:21][CH2:22][C:23]([O:26][CH3:27])([O:24][CH3:25])[C@@H:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-:28].[Li+]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([Cl:28])[C@H:13]2[O:21][CH2:22][C:23]([O:26][CH3:27])([O:24][CH3:25])[C@@H:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1(OC)CO[C@H]2[C@@H]1N(C(=O)OCc1ccccc1)C[C@H]2OS(C)(=O)=O
Reactant: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COC1(OC)CO[C@H]2[C@@H]1N(C(=O)OCc1ccccc1)C[C@@H]2Cl
Temperature: 120 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
To a stirred solution of compound 12e (550 mg, 1.37 mmol) in DMF (30 mL) was added lithium chloride (721 mg, 13.7 mmol). After stirring for 120 minutes at 120° C. the reaction was concentrated in vacuo. The residue was diluted with CH2Cl2 (50 mL) washed with water (1×20 mL), dried with MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (5-66% isohexane:EtOAc) to give the title compound (330 mg, 72%) as a yellow oil. MS M+H 342, 344.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[O:15][C@H:16]3[C@@:25]45[CH2:35][CH2:36][C@:22]6([CH2:23][C@@H:24]4[C@:29]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[O:28][CH2:27][O:26]5)[C@@:17]43[CH2:18][CH2:19][N:20]([CH2:38]C3CC3)[C@@H:21]6[CH2:37][C:12]([C:13]=24)=[CH:11][CH:10]=1)C1C=CC=CC=1.CI.C(Br)C1C=CC=CC=1.C([C@]1(C)[C@@H]2[C@@]3(CC[C@]4(C2)[C@@]25C6C(=CC=C(O)C=6O[C@@H]32)C[C@H]4N(CC2CC2)CC5)OCO1)(C)(C)C>>[C:31]([C@:29]1([CH3:30])[C@@H:24]2[C@@:25]3([CH2:35][CH2:36][C@@:22]4([CH2:23]2)[C@@:17]25[C:13]6[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH3:1])[C:14]=6[O:15][C@@H:16]32)[CH2:37][C@H:21]4[N:20]([CH3:38])[CH2:19][CH2:18]5)[O:26][CH2:27][O:28]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)[C@@]1(C)OCO[C@]23CC[C@@]4(C[C@@H]21)[C@H]1Cc2ccc(OCc5ccccc5)c5c2[C@@]4(CCN1CC1CC1)[C@H]3O5
Agent: BrCc1ccccc1
Agent: CC(C)(C)[C@@]1(C)OCO[C@]23CC[C@@]4(C[C@@H]21)[C@H]1Cc2ccc(O)c5c2[C@@]4(CCN1CC1CC1)[C@H]3O5
Solvent: CI
Product: COc1ccc2c3c1O[C@H]1[C@@]45CC[C@]6(C[C@@H]4[C@@](C)(C(C)(C)C)OCO5)[C@@H](C2)N(C)CC[C@]316
Yield: 81.3 %

Procedure:
The title compound 23 was synthesized similar to the procedure described in Example 5 for preparing compound 7 using methyl iodide rather than benzyl bromide and compound 22 rather than compound 3. After column chromatography, 168 mg (81.3% yield) of compound 23 was isolated in a purity of >99% as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][O:5][C:6]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:7]=1[C:8]#[N:9].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC>[NH2:9][CH2:8][C:7]1[CH:10]=[CH:11][C:12]([C:14]([F:15])([F:16])[F:17])=[CH:13][C:6]=1[O:5][CH2:4][CH2:3][N:2]([CH3:18])[CH3:1]
Reactant: CN(C)CCOc1cc(C(F)(F)F)ccc1C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CN(C)CCOc1cc(C(F)(F)F)ccc1CN
Temperature: 0 °C
Yield: 67.7 %

Procedure:
The nitrile 26b (2.15 g, 8.33 mmol) solubilized in Et2O (20 mL) was added in small portion to a mixture of LiAlH4 (0.63 g, 2 mol eq) in Et2O (25 mL) stirred at 0° C. Then the mixture was stirred at room temperature overnight. The excess of LiAlH4 was decomposed by water addition at 0° C., the solid formed was filtered, washed with Et2O and the filtrate was separated. The organic phase was anhydrified over Na2SO4 and evaporated to dryness to obtain 27b as yellow oil (1.48 g, 5.64 mmol, 67% Yield) used without further purifications.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:10](Cl)(=[O:12])[CH3:11].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:12])[CH3:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)CCO2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCO2
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
2,3-Dihydrobenzofuran (10 g, 83.2 mmol) was dissolved in dichloromethane (400 mL). The resultant mixture was added sequentially with acetyl chloride (11.8 mL, 167 mmol) and aluminum chloride (33.3 g, 250 mmol) at −10° C., and stirred at −10° C. for 0.5 hour. The reaction solution was added with 5% aqueous solution of hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. 1-(2,3-Dihydrobenzofuran-5-yl)ethanone (13.4 g, yield 99%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:11]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[CH2:31]([O:33][C:34](=[O:38])[CH2:35][CH2:36][NH2:37])[CH3:32].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:11]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:37][CH2:36][CH2:35][C:34]([O:33][CH2:31][CH3:32])=[O:38])=[O:26])=[CH:28][CH:29]=1)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1c(C(COc2ccccc2)Nc2ccc(C(=O)O)cc2)oc2ccccc12
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(NC(COc2ccccc2)c2oc3ccccc3c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.2 %

Procedure:
To a mixture of 4-{[1-(3-methyl-1-benzofuran-2-yl)-2-phenoxyethyl]amino}benzoic acid (100 mg) synthesized above, β-alanine ethyl ester hydrochloride (59.4 mg), 1-hydroxybenzotriazole monohydrate (59.3 mg), triethylamine (72 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (74.2 mg), and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (45% ethyl acetate/hexane) to give the title object compound (63.0 mg, 50%) as a pale-yellow oil.
Reaction SMILES: CC(C)(C(=O)[N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][N:9]([C:14]1[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=1)[CH2:10]2)C#N.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C=CC=CC=1C(O)=O>CN(C=O)C>[CH2:12]1[C:11]2([CH2:10][N:9]([C:14]3[C:15]4[CH:22]=[CH:21][NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:8][CH2:7][NH:6]2)[CH2:13]1
Reactant: CC(C)(C#N)C(=O)N1C2CCC1CN(c1ncnc3[nH]ccc13)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1ccccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: c1nc(N2CCNC3(CC3)C2)c2cc[nH]c2n1
Reaction time: 16 h

Procedure:
(intermediate 2) (0.05 mmol) was dissolved in dry DMF (0.3 mL). Triethylamine (0.18 mmol) and HATU (0.09 mmol) was added followed by 2-pyridincarboxylic acid (0.07 mmol). The reaction mixture was left at rt for 16 hours. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH2:10][CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:10][CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]
Reactant: Sc1ccccc1Cl
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(CSc1ccccc1Cl)OCC
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of 2-chlorobenzenethiol (5.0 g, 34.5 mmol) in acetone (35 mL) was added 2-bromo-1,1-diethoxyethane (7.15 g, 36.3 mmol) followed by potassium carbonate (9.55 g, 69.1 mmol). The mixture was heated at reflux for 3 h. then cooled to rt, filtered and the filtrate evaporated under reduced pressure to yield the crude product. This material was purified by chromatography over silica gel eluting with ethyl acetate in hexanes (0→2%) to afford pure 1-chloro-2-(2,2-diethoxyethylsulfanyl)benzene (7.3, 80%). 1H NMR (400 MHz, CDCl3) δ=1.20 (t J=7.07 Hz, 6H), 3.15 (d, J=5.56 Hz, 2H), 3.51-3.61 (m, 2H), 3.63-3.74 (m, 2H), 4.69 (t, J=5.56 Hz, 1H), 7.12 (td, J=7.58, 1.52 Hz, 1H), 7.20 (td, J=7.58, 1.52 Hz, 1H), 7.36 (dd J=−7.83, 1.52 Hz, 1H), 7.39 (dd, J=8.08, 1.52 Hz, 1H); MS (ES+): m/z 187.17 [M-74].
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([OH:11])=[CH:6][C:5]=2[C:4]2[CH2:12][CH2:13][C:14](=[N:15][CH2:16][C:17]#[CH:18])[C:3]1=2.N12CCCN=C1CCCCC2.[CH3:30][N:31]=[C:32]=[O:33]>C(Cl)Cl>[CH3:30][NH:31][C:32](=[O:33])[O:11][C:7]1[CH:8]=[CH:9][C:10]2[N:2]([CH3:1])[C:3]3[C:14](=[N:15][CH2:16][C:17]#[CH:18])[CH2:13][CH2:12][C:4]=3[C:5]=2[CH:6]=1
Reactant: CN=C=O
Reactant: C#CCN=C1CCc2c1n(C)c1ccc(O)cc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C#CCN=C1CCc2c1n(C)c1ccc(OC(=O)NC)cc21
Reaction time: 1 h
Yield: 29 %

Procedure:
To a stirred solution of 4-methyl-3-(2-propynyl)imino-1,2,3,4-tetrahydrocyclopent[b]indol-7-ol (3.4 g) in CH2Cl2 (15.0 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (326 mg) followed by the dropwise addition of methyl isocyanate (0.8 g) in CH2Cl2 (5.0 ml). The reaction was monitored via TLC and after 1.0 hour, the solution was concentrated and the crude product was purified via flash chromatography eluting with hexane/acetone (2:1). The product which precipitated out of the pure fractions was collected to give 4-methyl-3-(2-propynyl)imino-1,2,3,4-tetrahydrocyclopent[b]indol-7-yl methylcarbamate (1.2 grams) and the fractions were concentrated to give an additional 0.9 gram.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][O-:11].[Na+].O>CO>[Br:1][C:2]1[C:3]([O:11][CH3:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: C[O-]
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(Cl)ncc1Br
Temperature: 23 °C
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (17.82 g, 78.2 mmol) in methanol (100 mL) stirred at 0° C. was added solid sodium methoxide (4.22 g, 78 mmol) portionwise during 5 minutes. The reaction mixture was stirred at 23° C. overnight. To the organic phase was added water (25 mL) and the methanol was removed. Then it was extracted with dichloromethane. The organic phase was dried over sodium sulphate and evaporated in vacuo to give the title compound as a white solid (17.2 g, 67.6 mmol, 86 yield). LC/MS [M+H]+=223/225.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=[O:30])[NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([O:27][CH3:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:16]=3[F:29])[N:14]=2)[CH:5]=[C:4]([F:31])[C:3]=1/[CH:32]=[C:33](\[O:38][CH3:39])/[C:34]([O:36]C)=[O:35].Cl>C1COCC1.CO.[OH-].[Na+]>[F:1][C:2]1[CH:7]=[C:6]([C:8](=[O:30])[NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([O:27][CH3:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:16]=3[F:29])[N:14]=2)[CH:5]=[C:4]([F:31])[C:3]=1/[CH:32]=[C:33](\[O:38][CH3:39])/[C:34]([OH:36])=[O:35]
Reactant: CCCCCC(OC)c1cccc(-c2csc(NC(=O)c3cc(F)c(/C=C(\OC)C(=O)OC)c(F)c3)n2)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCC(OC)c1cccc(-c2csc(NC(=O)c3cc(F)c(/C=C(\OC)C(=O)O)c(F)c3)n2)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl (Z)-3-(2,6-difluoro-4-{4-[2-fluoro-3-(1-methyloxyhexyl)phenyl]thiazol-2-ylcarbamoyl}phenyl)-2-methyloxyacrylate (630 mg) was dissolved in a mixture of THF (2 mL), methanol (2 mL), and 2N sodium hydroxide aqueous solution (2 mL), and the mixture was stirred at room temperature for 3 h. The reaction mixture was acidified with hydrochloric acid, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, and brine, dried over magnesium sulfate, evaporated. The obtained residue was recrystallized from ethyl acetate to obtain the compound (B533) 590 mg.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:38]/[O:39][C:40]([CH3:49])([CH3:48])[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][NH:24][CH2:25][C@H:26]([OH:37])[CH2:27][O:28][CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:55](N2C=NC=C2)=[O:56])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:38]/[O:39][C:40]([CH3:49])([CH3:48])[C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])/[C:15](=[O:16])[NH:17][C@H:18]2[C@@H:19]([CH2:23][N:24]3[CH2:25][C@@H:26]([CH2:27][O:28][CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:36])[CH3:35])[O:37][C:55]3=[O:56])[NH:20][C:21]2=[O:22])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CNC[C@H](O)COCOCC[Si](C)(C)C)cs1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CN2C[C@@H](COCOCC[Si](C)(C)C)OC2=O)cs1
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a solution of tert-butyl 2-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-((S)-9-hydroxy-2,2-dimethyl-5,7-dioxa-11-aza-2-siladodecan-12-yl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)-2-methylpropanoate (155 mg, 0.21 mmol) in DCM (10 mL) at 0° C. was added CDI (62 mg, 0.38 mmol). After stirring at <15° C. for 2 h, the reaction mixture was concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 3-5%) to afford the title compound (130 mg, 81%). LCMS: m/z=755.3 (M−1).
Reaction SMILES: [C:1]([OH:18])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].S(Cl)([Cl:21])=O>>[C:1]([Cl:21])(=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)Cl

Procedure:
Palmitic acid (1 mole) is heated with thionyl chloride (20 mole) at 75° C. for 2 hours. The thionyl chloride is removed by distillation at atmospheric pressure and the palmitoyl chloride is then separated by distillation under reduced pressure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[CH3:28])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[CH3:29][S:30]([NH:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)(=[O:32])=[O:31]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([C:37]3[CH:38]=[CH:39][C:34]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:35][CH:36]=3)=[CH:7][CH:6]=2)[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[C:22]([CH3:28])[CH:23]=1
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Reactant: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1

Procedure:
The title compound was prepared in analogy to example 166, from (+)-5-{3-(4-bromo-phenyl)-3-(4-chloro-2-methyl-phenyl)-1-[(E)-hydroxyimino]-propyl}-1-methyl-1H-pyridin-2-one (example 415) and 4-(methanesulfonylamino)phenylboronic acid (CAS RN 380430-57-9). The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of dichloromethane:methanol (100:0 to 90:10). Light brown foam. MS (ESI+): m/z=550.2 ([M+H]+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[N:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[C:17]=3[NH:16][C:15]2=[O:27])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3[CH:19]=[N:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[C:17]=3[NH:16][C:15]2=[O:27])[CH2:12][CH2:13]1
Reactant: O=c1[nH]c2c3ccccc3ncc2n1C1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=c1[nH]c2c3ccccc3ncc2n1C1CCNCC1

Procedure:
A mixture of 44.0 g (0.123 mol) 3-(1-benzylpiperidin-4-yl)-1,3-dihydroimidazo[4,5-c]quinolin-2-one and 10.0 g palladium (Pd/C 10%) in 500 mL methanol was hydrogenated for 16 h at 50 C in a hydrogen atmosphere of 50 psi. After filtration of the reaction mixture the solvent was eliminated in vacuo. The product was precipitated out by the addition of isopropanol. It was filtered off and dried.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[CH2:34][NH2:35])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>CC#N.C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[C:27]3[C:28](=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[CH2:34][NH:35][C:1]2=[O:2])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Cl)cc2CN)CC1
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)NCc3cc(Cl)ccc32)CC1
Temperature: 50 °C
Yield: 55.9 %

Procedure:
1,1′-Carbonyldiimidazole (0.51 g, 3.15 mmol) was added to a solution of 4-(2-aminomethyl-4-chloro-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.79 g, 2.25 mmol) in CH3CN (10 mL) over 3 h with stirring at 50° C. The reaction mixture was then cooled to room temperature and stirred for additional 2 h. The reaction mixture was dissolved in CH2Cl2 (100 mL), washed with water (2×10 mL), brine (1×10 mL). The organic layer was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica, 30-50% EtOAc/hexanes) to obtain 0.46 g (63%) of the desired product. TLC (silica, 50% EtOAc/hexanes): Rf=0.5. MS (electrospray): exact mass calculated for C18H24ClN3O3, 365.15. m/z found, 388.1 [M++Na]. 1H NMR (CDCl3, 400 MHz): 7.18 (dd, J=6.26 Hz, 2.54 Hz, 1H), 7.05 (d, J=2.15 Hz, 1H), 6.94 (d, J=9.00 Hz, 1H), 6.29 (s, 1H), 4.32-4.18 (m, 4H), 4.13-4.02 (m, 1H), 2.88-2.71 (m, 2H), 2.64-2.50 (m, 2H), 1.82-1.73 (m, 2H), 1.49 (s, 9H).