Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:45])[N:20]([CH2:39][CH:40]2[CH2:44][CH2:43][CH2:42][O:41]2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:45])[N:20]([CH2:39][CH:40]2[CH2:44][CH2:43][CH2:42][O:41]2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(CC2CCCO2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC2CCCO2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
A mixture of hydroxylammonium chloride (0.82 g), sodium hydrogen carbonate (1.16 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-2-methyl-6-oxo-1-(tetrahydrofuran-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.61 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.32 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.61 g, 89%).
Reaction SMILES: C[C:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[C:5](C)[NH:4][N:3]=1.[Br:17]C12CC3CC(CC(CO)(C3)C1)C2.[C:30]12([CH2:40]O)[CH2:39][CH:34]3[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]3)[CH2:31]1)[CH2:37]2>>[Br:17][C:5]1[CH:6]=[CH:2][N:3]([CH2:40][C:30]23[CH2:39][CH:34]4[CH2:35][CH:36]([CH2:38][CH:32]([CH2:33]4)[CH2:31]2)[CH2:37]3)[N:4]=1
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: OCC12CC3CC(CC(Br)(C3)C1)C2
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Product: Brc1ccn(CC23CC4CC(CC(C4)C2)C3)n1

Procedure:
The title compound was prepared by substituting pyrazole for 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 3-bromo-1-adamantanemethanol for 1-adamantanemethanol in EXAMPLE 2A.
Reaction SMILES: [CH:1]([C:4]1[S:5][C:6]([C:9](OCC)=[O:10])=[CH:7][N:8]=1)([CH3:3])[CH3:2].CO>C(Cl)(Cl)Cl>[OH:10][CH2:9][C:6]1[S:5][C:4]([CH:1]([CH3:3])[CH3:2])=[N:8][CH:7]=1
Reactant: CCOC(=O)c1cnc(C(C)C)s1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)c1ncc(CO)s1
Yield: 25 %

Procedure:
Using the procedure of Example 5B, but replacing ethyl 2-isopropyl-4-thiazolecarboxylate with ethyl 2-isopropylthiazole-5-carboxylate provided, after silica gel chromatography using 3% methanol in chloroform, the desired compound, Rf 0.3, (5% methanol in chloroform) in 25% yield. 1H NMR (d6 -DMSO) δ 1.30 (d, J=7 Hz, 6H), 3.22 (heptet, J=7 Hz, 1H), 4.61 (dd, J=6, 1 Hz, 2H), 5.45 (t, J=6 Hz, 1H), 7.48 (br s,1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:23])[CH2:18][CH2:17]3)[CH:11]=2)[N:6]=1)=O.[NH3:30]>C1(C)C=CC=CC=1>[C:3]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][CH2:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:23])[CH2:20][CH2:21]3)[CH:11]=2)[N:6]=1)(=[O:2])[NH2:30]
Reactant: COC(=O)c1nc(-c2ccnc(N3CCN(C(=O)OCC(C)(C)C)CC3)c2)no1
Reactant: N
Solvent: Cc1ccccc1
Product: CC(C)(C)COC(=O)N1CCN(c2cc(-c3noc(C(N)=O)n3)ccn2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2,2-Dimethylpropyl 4-{4-[5-(methoxycarbonyl)-1,2,4-oxadiazol-3-yl]pyridin-2-yl}-1-piperazinecarboxylate (86.5 mg) obtained in Example 31 was dissolved in toluene (1 mL), and aqueous ammonia (0.3 mL) was added thereto and stirred at room temperature for 4 hours. Then, the solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (chloroform/methanol=97/3) to obtain 40 mg of the entitled compound as a colorless solid.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][O:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O.Cl.[NH2:25][CH2:26][C:27]([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[O:36][CH3:37])=[O:28].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:13][O:14][C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][C:20](=[O:22])[NH:25][CH2:26][C:27]([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=1[O:36][CH3:37])=[O:28]
Reactant: COC(=O)CCCCC(=O)O
Reactant: COc1ccc(Cl)cc1C(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCCCC(=O)NCC(=O)c1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 65.6 %

Procedure:
Dissolve 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (8.0362 g, 41.92 mmol), 4-(dimethylamino)pryidine (1.0525 g, 8.62 mmol) and adipic acid monomethyl ester (6.71 g, 41.90 mmol) in 100 mL of CH2Cl2 and allow it to stir at room temperature for 45 minutes. Add crude 2-amino-1-(5-chloro-2-methoxy-phenyl)-ethanone hydrochloride (10.99 g, 46.55 mmol) and triethylamine (9.42 g, 93.1 mmol) to the reaction mixture and allow it to stir at ambient temperature for 21 hours. Dilute the reaction with 200 mL of CH2Cl2 and wash it with 1 N HCl (2×), saturated aqueous NaHCO3 (2×) and brine (1×). Dry the organic layer with MgSO4. Filter off the drying agent and concentrate in vacuo to afford 9.39 g of the crude titled product: mass spectrum: m/z=342.1 (M+H).
Reaction SMILES: [O:1]([C@H:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>ClCCl.O>[OH:58][C:51]1[C:50]([CH2:49][NH:48][C:14](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([C@@H:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH3:9])=[CH:18][CH:17]=2)=[C:55]([CH3:56])[CH:54]=[C:53]([CH3:57])[N:52]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: C[C@H](Oc1ccccc1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc([C@H](C)Oc3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
To a solution of (S)-4-(1-phenoxyethyl)benzoic acid (121 mg, 0.5 mmol) in dichloromethane (20 mL) was added 1H-benzo[d][1,2,3]triazol-1-ol (135 mg, 1 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (190 mg, 1 mmol) and triethylamine (252 mg, 2.5 mmol), and stirred at room temperature for 0.5 hour, 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (152 mg, 1 mmol) was added and stirred for 4 hours. To the reaction mixture was added water (20 mL), extracted with dichloromethane (20 mL) two times, combined and concentrated the organic layers, the residue was purified by chromatography with dichloromethane/methanol=20:1 to afford (S)—N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-phenoxyethyl)benzamide (Compound I-31) (150 mg, 80%). LRMS (M+H+) m/z: calcd for 376.18. found 376. HPLC Purity (214 nm): 96%. 1H NMR (300 MHz, DMSO-d6): δ 11.45 (s, 1H), 8.30 (t, J=5.1 Hz, 1H), 7.79 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.1 Hz, 2H), 7.18 (t, J=7.2 Hz, 2H), 6.88-6.81 (m, 3H), 5.84 (s, 1H), 5.52 (q, J=6.3 Hz, 1H), 4.27 (d, J=4.8 Hz, 2H), 2.15 (s, 3H), 2.10 (s, 3H), 1.54 (d, J=6.6 Hz, 3H).
Reaction SMILES: [Na].Br[C:3]1[N:4]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH3:18])[N:6]=2.[CH3:25][OH:26]>>[CH2:17]([O:16][CH2:15][CH2:14][O:13][C:7]1[N:6]=[C:5]2[C:10]([N:11]=[C:3]([O:26][CH3:25])[N:4]2[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[C:9]([NH2:12])[N:8]=1)[CH3:18]
Reactant: CCOCCOc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Reactant: CO
Agent: [Na]
Product: CCOCCOc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Reaction time: 0.17 h
Yield: 78.4 %

Procedure:
Sodium (1.25 g, 54.4 mmol) was dissolved in methanol (40 ml). After 10 min, 8-bromo-2-{[2-(ethyloxy)ethyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (7 g, 18 mmol) was added with stirring. The mixture was heated to reflux for 2 h. The solvent was removed. The residue on a silica column using DCM: MeOH 100:1 as eluent to give the product as a yellow solid (4.78 g, 78.4%).
Reaction SMILES: [C:1]([CH:4]([OH:22])[C@H:5]1[O:9][C@@H:8]([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[N:19]=[N+:20]=[N-:21])(=[O:3])[CH3:2].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[C:1]([CH:4]([OH:22])[C@H:5]1[O:9][C@@H:8]([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[N:13]([C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:11]2=[O:12])[CH2:7][C@@H:6]1[N:19]=[N+:20]=[N-:21])(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)C(O)[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Solvent: c1ccncc1
Product: CC(=O)C(O)[C@H]1O[C@@H](n2cc(C)c(=O)n(C(=O)c3ccccc3)c2=O)C[C@@H]1N=[N+]=[N-]
Reaction time: 8 h

Procedure:
5'-Acetyl-3'-azido-3'-deoxythymidine (0.75 g, 2.4 mMol) was dissolved in pyridine (5 mL) and benzoyl chloride (1.4 mL, 12 mMol, 5 eq.) was added at room temperature. The reaction was stirred overnight then poured onto ice water (250 mL). The pH of the aqueous solution was adjusted to 1. The product was extracted with chloroform. The organic phase was washed with water, dried with MgSO4 and filtered. The chloroform was removed and the oily product was flash chromatographed on silica gel eluted with chloroform. The product was collected as an oil.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]#N)[CH:7]=[CH:8][CH:9]=1.I[CH3:14].C[N:16]([CH:18]=O)C>C(OCC)C>[Br:3][C:4]1[CH:5]=[C:6]([C:10]([CH3:11])([CH3:14])[C:18]#[N:16])[CH:7]=[CH:8][CH:9]=1
Reactant: N#CCc1cccc(Br)c1
Reactant: CI
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C#N)c1cccc(Br)c1
Temperature: 25 °C

Procedure:
257 mg 95% sodium hydride were stirred at room temperature in 25 ml dry DMF under an atmosphere of nitrogen. A solution of 1 g 3-bromophenylacetonitrile and 1.593 g iodomethane in 10 ml dry diethyl ether was added slowly below 30° C. The mixture was stirred over night at room temperature and then quenched by addition of a small amount of water. The solvents were evaporated under vacuum and the residue was purified by chromatography on silica in a heptane/ethyl acetate gradient.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:18][CH2:19][CH:20]1[O:24][CH2:23][CH2:22][O:21]1.O>C(#N)C.C(OCC)(=O)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:18][CH2:19][CH:20]2[O:24][CH2:23][CH2:22][O:21]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: NCC1OCCO1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)nc1NCC1OCCO1
Reaction time: 2 h

Procedure:
To a solution of 0.50 g of 2,6-dichloro-3-nitropyridine in 5 mL of acetonitrile, 0.43 g of potassium carbonate was added, thereto was added a solution of 0.24 mL of 2-aminomethyl-1,3-dioxolan in 3 mL of acetonitrile under cooling with ice, and the mixture was stirred for 2 hours under cooling with ice. Thereto was further added 80 μL of 2-aminomethyl-1,3-dioxolan, and the mixture was stirred for 2 hours under cooling with ice. Water and ethyl acetate were added thereto under cooling with ice, the organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using an eluent of hexane:ethyl acetate=20:1 to obtain 0.44 g of 6-chloro-N-(1,3-dioxolan-2-ylmethyl)-3-nitropyridin-2-amine as a yellow solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH2:11](I)[CH3:12].[OH-].[C:15]([OH:24])(=[O:23])[CH:16]([CH:18]([C:20]([OH:22])=[O:21])[OH:19])[OH:17]>C(#N)C>[C:20]([CH:18]([CH:16]([C:15]([O-:24])=[O:23])[OH:17])[OH:19])([O-:22])=[O:21].[CH2:11]([N+:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH3:12].[CH2:11]([N+:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH3:12]
Reactant: c1ccc2cnccc2c1
Reactant: CCI
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: [OH-]
Solvent: CC#N
Product: CC[n+]1ccc2ccccc2c1
Product: O=C([O-])C(O)C(O)C(=O)[O-]

Procedure:
Isoquinoline is reacted with ethyl iodide in acetonitrile; the halide intermediate is converted to the hydroxide with Rexyn 201, and then reacted with tartaric acid.
Reaction SMILES: Br[CH:2]([CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([SH:19])=[CH:15][CH:14]=1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([S:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1)[CH:8]([CH3:10])[CH3:9])[CH3:7]
Reactant: COc1ccc(S)cc1
Reactant: CCOC(=O)C(Br)C(C)C
Product: CCOC(=O)C(Sc1ccc(OC)cc1)C(C)C
Yield: 99 %

Procedure:
2-(4-Methoxy-phenylsulfanyl)-3-methyl-butyric acid ethyl ester was prepared according to the general method of Example 1. Starting from ethyl 2-bromo-3-methyl-butanoate (20.9 g, 100 mmol) and 4-methoxybenzenethiol (14.0 g, 100 mmol), 30 g of the product was isolated Yield 99%; Light yellow oil; MS: 271 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.O=[C:16]([CH3:24])[CH2:17][C:18]([O:20][CH2:21][CH2:22][CH3:23])=[O:19].[NH2:25][C:26]([CH3:37])=[CH:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)=[O:29].C(O)(=O)C>CC(O)C>[CH3:24][C:16]1[NH:25][C:26]([CH3:37])=[C:27]([C:28](=[O:29])[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:17]=1[C:18]([O:20][CH2:21][CH2:22][CH3:23])=[O:19]
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: CCCOC(=O)CC(C)=O
Reactant: CC(N)=CC(=O)c1ccc(F)cc1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CCCOC(=O)C1=C(C)NC(C)=C(C(=O)c2ccc(F)cc2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
110 mg (0.54 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 78 mg (0.54 mmol) of n-propyl 3-oxobutanoate, 97 mg (0.54 mmol) of 3-amino-1-(4-fluorophenyl)but-2-en-1-one and 6 μl (0.05 mmol) of acetic acid in 10 ml of 2-propanol and heated under reflux under argon for 30 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 228 mg (87% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C>[CH2:19]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)Cc1ccccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccccc1OCc1ccccc1
Temperature: 25 °C
Yield: 83 %

Procedure:
Methyl (2-hydroxyphenyl)acetate (21.0 g) was dissolved in DMF (200 ml), and potassium carbonate (19.35 g) was added in one portion. Benzyl bromide (23.94 g) in DMF (50 ml) was added dropwise to this mixture, with stirring, at room temperature. After eighteen hours the mixture was poured into water (500 ml) and extracted with ether (2×400 ml). The extracts were washed with water (3×150 ml) and brine (100 ml), dried and filtered through silica gel (50 g; Merck 60), then concentrated under reduced pressure to afford a yellow oil. Distillation at 160° C. and 0.05 mmHg afforded methyl 2-benzyloxyphenylacetate as a clear, colourless oil (26.99 g; 83% yield), infrared max. (film): 1730 cm-1 ; 1H nmr (90 MHz): delta 3.60 (3H,s), 3.75 (2H,s), 4.10 (2H, s), 6.80-7.40 (9H,m)ppm.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][CH2:17]Cl.O>CC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:15][O:16][CH3:17])[CH:3]=1
Reactant: COCCl
Reactant: Oc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COCOc1cccc(I)c1
Temperature: 25 °C
Reaction time: 65 h
Yield: 102.5 %

Procedure:
To a solution of m-iodophenol (3.00 g, 13.6 mmol) in acetone (30 ml) were added potassium carbonate (2.30 g, 16.6 mmol) and chloromethyl methyl ether (1.20 g, 14.9 mmol) under ice cooling and the mixture was stirred for 65 hours at room temperature. To the reaction mixture were further added potassium carbonate (0.600 g, 4.30 mmol) and chloromethyl methyl ether (0.300 g, 3.70 mmol), and the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, and dried over magnesium sulfate. The solvent was removed under reduced pressure to give the subject compound (3.68 g, 102%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][N:6]1[CH:10]=[CH:9][C:8](/[CH:11]=[C:12]2\[CH2:13][N:14]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:16][CH:17]\2O)=[CH:7]1)=[O:4].[C:38]([OH:41])(=[S:40])[CH3:39].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.O>C1(C)C=CC=CC=1.CO>[C:38]([S:40][CH:17]1[CH2:16][CH2:15][N:14]([C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:13]/[C:12]/1=[CH:11]\[C:8]1[CH:9]=[CH:10][N:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH:7]=1)(=[O:41])[CH3:39]
Reactant: CC(O)=S
Reactant: COC(=O)Cn1ccc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)c1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: COC(=O)Cn1ccc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2SC(C)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of (E)-3-{[1-(methoxycarbonylmethyl)pyrrol-3-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (12.1 g) in toluene (100 ml) were added thioacetic acid (3.5 ml) and N,N-dimethylformamide dineopentyl acetal (13.7 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:3) as the eluent. The amorphous solid obtained was dissolved in methanol (100 ml), and the resulting mixture was stirred at 50° C. for 2 days. The reaction mixture was concentrated in vacuo to afford the title compound (12.8 g, yield: 95%) as a pale yellow amorphous solid.
Reaction SMILES: FC1C=CC(NC(=O)NC2C=CC(C3C=C4C(=CC=3)C(=O)N([C@@H](C(C)C)C(O)=O)C4)=CC=2)=CC=1.[C:35]([C:37]1[CH:38]=[C:39]([NH:43][C:44](=[O:70])[NH:45][C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:53]=[C:54]4[C:58](=[CH:59][CH:60]=3)[C:57](=[O:61])[N:56]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[CH2:55]4)=[CH:48][CH:47]=2)[CH:40]=[CH:41][CH:42]=1)#[N:36]>>[C:35]([C:37]1[CH:38]=[C:39]([NH:43][C:44](=[O:70])[NH:45][C:46]2[CH:47]=[CH:48][C:49]([C:52]3[CH:53]=[C:54]4[C:58](=[CH:59][CH:60]=3)[C:57](=[O:61])[N:56]([C@@H:62]([CH:67]([CH3:68])[CH3:69])[C:63]([OH:65])=[O:64])[CH2:55]4)=[CH:50][CH:51]=2)[CH:40]=[CH:41][CH:42]=1)#[N:36]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C#N)c4)cc3)ccc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C#N)c4)cc3)ccc2C1=O
Yield: 86 %

Procedure:
The compound of example 255 was prepared analogous to compound of example 225 by hydrolysis of compound of example 254.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH:18]1[CH2:26][CH:27]=O>O1CCCC1>[CH2:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:17][CH:18]1[CH2:26]/[CH:27]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=CCC1Cc2ccccc2C1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/CC1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
3.90 g of 63% sodium hydride was suspended in 60 ml of tetrahydrofuran, and 22.8 g of ethyl diethylphosphonoacetate dissolved in 100 ml of tetrahydrofuran was added dropwise to the suspension under water cooling. The mixture was stirred at the same temperature for 30 minutes. 13.58 g of 2-indanacetaldehyde dissolved in 100 ml of tetrahydrofuran was added dropwise to said mixture. The resulting mixture was stirred at the same temperature for 1 hour and further stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. After the ethyl acetate layer was washed and dried, the solvent was removed. The residue was purified by silica gel column chromatography (hexane-ethyl acetate (20:1)) to obtain 19.22 g of ethyl 2-indanecrotonate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH2:14][CH2:15][C@@H:16]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([Cl:34])[CH:27]=1)[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].CCN(CC)CC>C(Cl)Cl>[Cl:34][C:28]1[CH:27]=[C:26]([NH:25][C@H:16]([CH2:15][NH:14][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH:31]=[CH:30][C:29]=1[C:32]#[N:33]
Reactant: CC(C)(C)OC(=O)C[C@@H](CN)Nc1ccc(C#N)c(Cl)c1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])Nc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-nitrobenzenesulfonyl chloride (14.15 g, 64 mmol) in CH2Cl2 (50 mL) was added dropwise over 20 min to an ice cold solution of 1,1-dimethylethyl (3S)-4-amino-3-[(3-chloro-4-cyanophenyl)amino]butanoate (19.8 g, 64 mmol) and Et3N (6.5 g, 64 mmol) in CH2Cl2 (150 mL) and the reaction was stirred at room temperature for 30 min. The reaction was washed with H2O and cold 0.1 N HCl. The organic layer was dried over CaCl2, filtered, and concentrated. The crude product was used directly in the next step.