Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[C:3]([NH:5][C@H:6]([CH2:10][S:11][S:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:7]([OH:9])=[O:8])=[O:4].C(N(C(C)C)C(C)C)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([NH:1][C@@H:2]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[C:3]([NH:5][C@H:6]([CH2:10][S:11][S:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:7]([OH:9])=[O:8])=[O:4])(=[O:38])[CH3:37]
Reactant: CC(C)(C)SSC[C@@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@H](CSSC(C)(C)C)C(=O)O
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of (S)-2-((S)-2-amino-3-(1H-indol-3-yl)propanamido)-3-(tert-butyldisulfanyl)propanoic acid (H-Trp-D-Cys(StBu)-OH) (Compound SP643) (870 mg, 2.20 mmol) in methylene chloride (4.4 mL) was mixed with N-ethyldiisopropylamine (DIPEA) (1.15 mL, 6.60 mmol) and acetic anhydride (208 μL, 2.20 mmol) with stirring at room temperature, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-3-(tert-butyldisulfanyl)propanoic acid (Ac-Trp-D-Cys(StBu)-OH) (Compound SP644) (960 mg, 2.20 mmol, 100%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:20]([C:22]1[S:23][CH:24]=[CH:25][N:26]=1)=[O:21].OS(O)(=O)=O>CC(O)=O.O>[OH:21][CH:20]([C:22]1[S:23][CH:24]=[CH:25][N:26]=1)[CH:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:10]=2)[C:15]1=[O:19]
Reactant: O=Cc1nccs1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccc(OCCn3ccnc3)cc2CCC1C(O)c1nccs1
Yield: 74.6 %

Procedure:
6-(2-Imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.200 g, 0.78 mmol) was reacted with 2-formylthiazole (0.107 g, 0.94 mmol) in a mixture of HOAc (1 mL) and concentrated H2SO4 (0.100 mL) at room temperature overnight. The resulting biphasic reaction mixture was diluted with water and then extracted with EtOAc. The aqueous portion was made to pH 10 with 50% NaOH and extracted with EtOAc (3×50 mL). The pooled organic extracts were washed well with water, dried, filtered, and concentrated to afford 0.215 g (74%) of the title compound as a golden oil: APCI-MS m/e 370.2 (M+ +1).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:27][CH3:28])[N:10]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)=[CH:13][CH:12]=3)[C:6]=2[CH:5]=[C:4]([CH3:29])[N:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH2:27][CH3:28])[N:10]([C:11]3[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][NH2:19])=[CH:15][CH:16]=3)[C:6]=2[CH:5]=[C:4]([CH3:29])[N:3]=1
Reactant: CCc1nc2c(Cl)nc(C)cc2n1-c1ccc(CCNC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(Cl)nc(C)cc2n1-c1ccc(CCN)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a stirred solution of tert-butyl 2-[4-(4-chloro-2-ethyl-6-methyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethylcarbamate (step 3, 90 mg, 0.22 mmol) in dichloromethane (8.5 ml) was added trifluoroacetic acid (1.0 ml, 13.0 mmol) at 0° C., and the mixture was stirred at 0° C. for 30 min, then at room temperature for 5 h. The mixture was concentrated, and diluted with dichloromethane (50 ml), washed with saturated aqueous NaHCO3 solution (10 ml) and brine (10 ml). The organic layer was dried (MgSO4), and concentrated. Purification by PTLC eluting with ethyl acetate to afford 50 mg (73%) of the title compound as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:3]=1[O:4][CH2:5][C:6](=O)[CH3:7].Cl.[CH2:21]([O:23][NH2:24])[CH3:22].Cl>N1C=CC=CC=1>[CH2:21]([O:23][N:24]=[C:6]([CH2:5][O:4][C:3]1[C:2]([Cl:1])=[CH:12][C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])=[CH:10][C:9]=1[Cl:19])[CH3:7])[CH3:22]
Reactant: CC(=O)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: CCON
Agent: Cl
Solvent: c1ccncc1
Product: CCON=C(C)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.6 %

Procedure:
To a mixture of 0.34 g of (2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)-phenoxy)acetone and 10 ml of pyridine was added 0.11 g of O-ethylhydroxylamine hydrochloride. After stirring at room temperature for 24 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.32 g (yield, 81%) of (2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)acetone O-ethyloxime, m.p., 65.4° C.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]=[C:9]([Si](C)(C)C)[S:10][CH:11]=1.[C:16]([C:19]1[O:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[CH:23]=1)(=[O:18])[CH3:17]>C(OCC)C>[O:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[CH:23]=[C:19]1[C:16]([C:11]1[S:10][CH:9]=[N:8][C:7]=1[CH3:6])([OH:18])[CH3:17]
Reactant: Cc1csc([Si](C)(C)C)n1
Reactant: CC(=O)c1cc2ccccc2o1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1ncsc1C(C)(O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M solution in hexane, 1 equivalent) was added dropwise to a solution of 4-methyl-2-trimethylsilylthiazole (1 equivalent) in dry diethyl ether at -70° C. under an atmosphere of dry nitrogen. After 30 minutes, 2-acetylbenzofuran (1 equivalent) in diethyl ether was added. After 1 hour the mixture was allowed to warm to room temperature and was then quenched by the addition of saturated aqueous sodium hydrogen carbonate. Work up in the normal fashion and column chromatography on silica gel then afforded the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH3:13])[CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15](=[CH:17][CH2:18][CH2:19][CH:20]([CH2:22][CH:23]=[O:24])[CH3:21])[CH3:16]>>[CH2:1]([O:8][CH2:9][CH:10]([CH3:13])[CH2:11][CH:23]([OH:24])[CH2:22][CH:20]([CH3:21])[CH2:19][CH2:18][CH:17]=[C:15]([CH3:14])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=CCCC(C)CC=O
Reactant: CC(CBr)COCc1ccccc1
Product: CC(C)=CCCC(C)CC(O)CC(C)COCc1ccccc1

Procedure:
This compound was prepared starting from the rac. 3-benzyloxy-2-methyl-1-propyl bromide and racemic citronellal using the procedure described in Example 4. Rac.-1-benzyloxy-2,6,10-trimethyl-9-undecen-4-ol was obtained as a colorless oil, b.p. 145°-150° C. (bath temperature) (0.01 mm Hg.).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([CH:7]=[C:8]([Br:12])[C:9]=1[O:10][CH3:11])[CH:5]=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C>[Br:12][C:8]1[C:9]([O:10][CH3:11])=[C:2]([Br:1])[C:3]2[O:13][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5][C:4]=2[CH:7]=1
Reactant: COc1c(Br)cc(C=O)c(O)c1Br
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Br)c(OC)c(Br)c2o1
Temperature: 80 °C
Reaction time: 6 h
Yield: 79.3 %

Procedure:
16 g (51,6 mmol) of 3,5-dibromo-2-hydroxy-4-methoxybenzaldehyde (Biorg. Med. Chem. 1998, 6, 1153–1162) and 17.84 g (129 mmol) of potassium carbonate are initially introduced in DMF and 8.62 g (51.6 mmol) of ethyl bromoacetate are then added dropwise to the mixture. The latter is stirred at 80° C. for 6 hours and then poured onto ice water after having been cooled; the precipitate is filtered off with suction. The precipitate is washed with water and dried. 15.47 g (79%) of ethyl 5,7-dibromo-6-methoxy-1-benzofuran-2-carboxylate are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:4]=1[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:20]([CH3:23])([O-:22])=[O:21]>>[CH3:14][O:13][C:9]1[CH:8]=[CH:7][C:4](/[CH:5]=[CH:23]\[N+:20]([O-:22])=[O:21])=[C:3]([O:2][CH3:1])[C:10]=1[O:11][CH3:12]
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C=O)c(OC)c1OC
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ccc(/C=C\[N+](=O)[O-])c(OC)c1OC
Temperature: 50 °C

Procedure:
2,3,4-trimethoxybenzaldehyde (20 g) was dissolved in nitromethane (50 ml). Ammonium acetate (8.25 g) was added, and the reaction was heated to 50° C. for 2 hrs. The solvents were evaporated in vacuo. The orange residue was partitioned between water and DCM. The organic layer was washed with brine, dried over Na2SO4 filtered and concentrated in vacuo.
Reaction SMILES: [Br-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2-].[Na+].[CH3:26][O:27][C:28]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=O>C1COCC1.O>[CH3:2][O:3][CH:4]=[CH:30][C:29]1[CH:32]=[CH:33][CH:34]=[C:35]([O:36][CH3:37])[C:28]=1[O:27][CH3:26]
Reactant: COc1cccc(C=O)c1OC
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC=Cc1cccc(OC)c1OC
Reaction time: 0.25 h
Yield: 83 %

Procedure:
THF (15 mL) was added to a mixture of methoxymethyltriphenylphosphonium bromide and sodium amide (mfd. by Aldrich Chemical Co.; 3.0 g, 6.9 mmol) at room temperature and stirred for 15 minutes. To the resulting orange-colored suspension was added a solution of 2,3-dimethoxybenzaldehyde (997 mg, 6.00 mmol) in THF (5 mL), and stirred for 3 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by the use of a silica gel column (silica gel 50 mL; hexane/ethyl acetate=1/0 to 15/1) to obtain 2-(2,3-dimethoxyphenyl)ethenyl methyl ether (808 mg, 83%) as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=1)(=O)[CH3:2].[CH:11]1([C:14]([NH:16][NH2:17])=[O:15])[CH2:13][CH2:12]1>C(O)C>[Cl:10][C:7]1[N:6]=[CH:5][C:4]([C:1](=[N:17][NH:16][C:14]([CH:11]2[CH2:13][CH2:12]2)=[O:15])[CH3:2])=[CH:9][CH:8]=1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: NNC(=O)C1CC1
Solvent: CCO
Product: CC(=NNC(=O)C1CC1)c1ccc(Cl)nc1

Procedure:
Following the general method of procdure 53 and making non-critical variations, except the product was purified by recrystallization from absolute ethanol rather than by chromotography, 5.25 gm (0.0337 mole) of 3-acetyl-6-chloropyridine and 3.40 gm (0.034 mole) of cyclopropanecarboxylic acid hydrazide yield 6.52 gm (81%) of the title compound having a melting point of 218.1° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:27])=[C:6]([CH:26]=1)[C:7]([NH:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:13]=[C:12]([C:21]([O:23]CC)=[O:22])[CH:11]=1)=[O:8].[Li+].[OH-].Cl>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:27])=[C:6]([CH:26]=1)[C:7]([NH:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:13]=[C:12]([C:21]([OH:23])=[O:22])[CH:11]=1)=[O:8]
Reactant: CCOC(=O)c1cc(NC(=O)c2cc(Br)ccc2Cl)n(-c2ccccc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(NC(=O)c2cc(Br)ccc2Cl)n(-c2ccccc2)n1
Temperature: 40 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a suspension of ethyl 5-(5-bromo-2-chlorobenzamido)-1-phenyl-1H-pyrazole-3-carboxylate (Preparation 13, 2.81 mmol, 1.26 g) in EtOH (14 mL) was added 0.5M aqueous LiOH solution (14.04 mmol, 336 mg in 28 mL of water). The reaction was stirred at 40° C. for 3 hours before acidifying to pH=5 with 1N HCl. The resulting precipitate was filtered and dried to afford the title compound (1.13 g, 97%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:23])[CH2:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>C1(C)C=CC=CC=1.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:23])[CH2:16][C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:13][CH:14]=1
Reactant: CCCCC(=O)CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCCC(=O)CC(=O)c1ccc(O)cc1

Procedure:
1-(4-Benzyloxyphenyl)-heptane-1,3-dione (4 g; see step (a) above) was dissolved in toluene (20 ml) and Pd/C (3%; 80 mg) was added. The mixture was stirred at room temperature until hydrogen uptake ceased. After filtration of the catalyst, the solvent was evaporated leaving 2.84 g, 100%, 1-(4-hydroxyphenyl)-heptane-1,3-dione.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH3:22])[C:17]=1[C:18]([O:20][CH3:21])=[O:19]>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:12][C:13]2[S:14][CH:15]=[C:16]([CH3:22])[C:17]=2[C:18]([O:20][CH3:21])=[O:19])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(C)csc1N
Reactant: O=C(O)Cc1ccc(I)cc1
Product: COC(=O)c1c(C)csc1NC(=O)Cc1ccc(I)cc1
Yield: 87 %

Procedure:
The title compound was synthesized in 87% yield according to protocol A from 2-(4-iodophenyl)acetic acid and methyl 2-amino-4-methylthiophene-3-carboxylate. 13C NMR (CDCl3) δ 167.5, 166.6, 149.8, 138.1, 134.8, 133.1, 131.4, 113.0, 112.3, 93.2, 51.5, 43.3, 17.8; MH+ 416.0.
Reaction SMILES: CN1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=N1.[CH2:31]([NH:33][NH2:34])[CH3:32]>>[CH2:31]([N:33]1[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[CH:6]=[N:34]1)[CH3:32]
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Reactant: CCNN
Product: CCn1ncc(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting ethyl hydrazine provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.35 (bs, 2H), 8.23 (d, J=8.3 Hz, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.85 (d, J=7.4 Hz, 1H), 7.83 (s, 1H), 7.74 (m, 2H), 7.57 (t, J=7.9 Hz, 1H), 7.21 (d, J=8.7 Hz, 2H), 7.14 (d, J=9.1 Hz, 2H), 7.04 (m, 2H) 5.42 (s, 2H), 4.03 (q, J=7.5 Hz, 2H), 1.36 (t, J=7.5 Hz, 3H); MS: (M+H m/z=407.3).
Reaction SMILES: [C:1](#[N:3])[CH3:2].[CH3:4][C:5]1([C:8](OC)=[O:9])[CH2:7][CH2:6]1.[H-].[Na+]>O1CCCC1>[CH3:4][C:5]1([C:8]([CH2:2][C:1]#[N:3])=[O:9])[CH2:7][CH2:6]1
Reactant: COC(=O)C1(C)CC1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C(=O)CC#N)CC1

Procedure:
A mixture of 61.1 g of acetonitrile and 108.3 g of methyl 1-methylcyclopropanecarboxylate was added drop-by-drop over a one-hour period to a stirred, refluxing mixture of 35.8 g of sodium hydride and 650 ml of tetrahydrofuran. The resulting mixture was stirred and refluxed for a further 18 hours, then most of the solvent was evaporated in a rotary evaporator. The residue was dissolved in 1 liter of water, and the solution was acidified with hydrochloric acid and extracted with ether. The extract was dried (MgSO4) and concentrated. The residue, a liquid, was fractionally distilled to give (1-methylcyclopropylcarbonyl)acetonitrile (D) as a colorless oil which crystallized on standing, m.p.: 32°-33° C.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([C:12]#[N:13])=[CH:6][CH:5]=[CH:4][C:3]1=2.[CH:14](C1C2C=CC=C(C#N)C=2CC1)=[O:15]>>[CH:14]([CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([C:12]#[N:13])=[CH:6][CH:5]=[CH:4][C:3]1=2)=[O:15]
Reactant: N#Cc1cccc2c1CCC2C=O
Reactant: N#Cc1cccc2c1CCCC2=O
Product: N#Cc1cccc2c1CCCC2C=O

Procedure:
5-Formyl-5,6,7,8-tetrahydronaphthalene-1-carbonitrile was prepared from 5-oxo-5,6,7,8-tetrahydronaphthalene-1-carbonitrile in an analogous fashion to that described above for the synthesis of 1-formyl-2,3-dihydro-1H-indene-4-carbonitrile (Steps B and C).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[H-].[Na+].[SH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16]>>[F:10][C:7]1[CH:8]=[CH:9][C:2]2[S:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:4][C:3]=2[CH:6]=1
Reactant: COC(=O)CS
Reactant: O=Cc1cc(F)ccc1F
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2cc(F)ccc2s1

Procedure:
Using 5.0 g (35.2 mmol) of 2,5-difluorobenzaldehyde, 2.11 g (52.78 mmol) of sodium hydride (60% pure) and 4.11 g (38.7 mmol) of methyl mercaptoacetate, 1.1 g (14.3% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([SH:12])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([NH:30][CH:31]([CH2:36][CH:37]3[O:39][CH2:38]3)[C:32]([O:34]C)=[O:33])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([NH:30][CH:31]([CH2:36][CH:37]([OH:39])[CH2:38][S:12][C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[NH:11][N:10]=3)[C:32]([OH:34])=[O:33])(=[O:28])=[O:29])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: Sc1n[nH]c(-c2ccccc2)n1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3n[nH]c(-c4ccccc4)n3)C(=O)O)cc2)cc1

Procedure:
Example 42 is prepared from 5-phenyl-1H-1,2,4-triazole-3-thiol and 1d using the procedure described for compound 20.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:8][C:9]([N:11]1[C@H:12]([CH3:13])[C:14](=[O:16])[O:15][CH2:17]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H]1C(=O)OCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
In toluene (190 mL) were suspended benzyloxycarbonyl-D-alanine (19.3 g), paraformaldehyde (6.56 g) and p-toluenesulfonic acid monohydrate (0.17 g), and the mixture was heated at reflux while removing water produced. At the end of the reaction, the mixture was cooled to room temperature, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline. The toluene solution was dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. The precipitated crystals were filtered to give the title compound (17.4 g) as white crystals in a yield of 85%.
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13](=[O:20])[C:14](=[N+:18]=[N-:19])[C:15](=[O:17])[CH3:16])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:21]([OH:23])[CH3:22].O>C(N(CC)CC)C>[N+:18](=[C:14]([C:15](=[O:17])[CH3:16])[C:13](=[O:20])[CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([S:2]([O:23][CH2:21][CH3:22])(=[O:4])=[O:3])=[CH:6][CH:7]=1)=[N-:19]
Reactant: CCO
Reactant: CC(=O)C(=[N+]=[N-])C(=O)CCc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOS(=O)(=O)c1ccc(CCC(=O)C(=[N+]=[N-])C(C)=O)cc1

Procedure:
6-(4-Chlorosulfonylphenyl)-3-diazo-2,4-hexanedione (2.0 g, 6.4 mmol) obtained in Example 3, (3) was stirred in triethylamine (1.5 ml) and ethanol (5 ml) for 16 h at room temperature, then the mixture was poured into H2O and extracted thrice with chloroform. The organic extract was washed with H2O, dried over anhydrous MgSO4 and evaporated under reduced pressure. The residue was chromatographed on silica gel (Wako Gel C-200) with chloroform as eluent to give the title compound as a pale yellow viscous oil; yield: 550 mg.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[CH:51]=[C:50]([O:52][CH3:53])[CH:49]=[CH:48][C:6]=1[CH2:7][N:8]([C:43]1[S:47][N:46]=[CH:45][N:44]=1)[S:9]([C:12]1[C:41]([F:42])=[CH:40][C:15]2[N:16]([C@@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3(O)[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]3)[CH3:21])[C:17](=[O:19])[O:18][C:14]=2[CH:13]=1)(=[O:11])=[O:10].CCN(S(F)(F)[F:60])CC>C(Cl)Cl>[CH3:3][O:4][C:5]1[CH:51]=[C:50]([O:52][CH3:53])[CH:49]=[CH:48][C:6]=1[CH2:7][N:8]([C:43]1[S:47][N:46]=[CH:45][N:44]=1)[S:9]([C:12]1[C:41]([F:42])=[CH:40][C:15]2[N:16]([C@@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3([F:60])[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]3)[CH3:21])[C:17](=[O:19])[O:18][C:14]=2[CH:13]=1)(=[O:10])=[O:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)n([C@H](C)c4ccccc4C4(O)CN(C(=O)OC(C)(C)C)C4)c3cc2F)c(OC)c1
Agent: N#N
Solvent: ClCCl
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)n([C@H](C)c4ccccc4C4(F)CN(C(=O)OC(C)(C)C)C4)c3cc2F)c(OC)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In an oven-dried 2 dram vial under N2, added (R)-tert-butyl 3-(2-(1-(6-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-5-fluoro-2-oxobenzo[d]oxazol-3(2H)-yl)ethyl)phenyl)-3-hydroxyazetidine-1-carboxylate (32-3, 55.8 mg, 0.075 mmol) to DCM (376 μl) and cooled to −78° C. Added DAST (19.88 μl, 0.150 mmol) dropwise. After 30 min at −78° C., removed from bath and allowed to slowly warm to RT. After 20 min, LCMS showed complete consumption of SM to desired product. Cooled reaction to 0° C., slowly quenched with 3 mL H2O. Diluted with 5 mL DCM, separated layers, back-extracted aqueous with 1×5 mL DCM. Washed combined organics with 1×5 mL H2O, 1×5 mL brine. Dried combined organics over Na2SO4, filtered, concentrated to give 32-5 as a white solid. Carried crude material forward to subsequent step.
Reaction SMILES: [C:1]1([O:14][C:15]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]([OH:25])=[O:24])[CH2:18]2)=[O:16])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:26](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[C:1]1([O:14][C:15]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]([O:25][CH3:26])=[O:24])[CH2:18]2)=[O:16])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1CN(C(=O)Oc2cccc3c2Cc2ccccc2-3)CCO1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)C1CN(C(=O)Oc2cccc3c2Cc2ccccc2-3)CCO1
Reaction time: 6 h
Yield: 99.2 %

Procedure:
To a solution of 3.00 g of 4-fluorenyloxycarbonylmorpholine-2-carboxylic acid in 150 mL of acetone was added 1.77 g of potassium carbonate and 1.33 g of dimethyl sulfate. The mixture was heated to reflux and stirred at this temperature for 6 h, then cooled, filtered, and concentrated. The residue was dissolved in 125 mL of Et2O and washed with 50 mL each of saturated NaHCO3, water, and brine. The organic phase was dried over MgSO4 and concentrated to yield 3.10 g of the title compound, which was used without further purification. 1H NMR (500 MHz, CDCl3): δ7.76 (d, J=7.6 Hz, 2H), 7.57 (br d, J=6.6 Hz, 2H), 7.40 (t, J=7.3 Hz, 2H), 7.32 (t, J=7.6 Hz, 2H), 4.51 (br s, 2H), 4.25 (br t, J=6.2 Hz, 1H), 3.90-4.10 (m, 4H), 3.80 (s, 3H), 3.40-3.70 (m, 1H), 3.04-3.23 (m, 2H).