Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.[OH-].[Na+]>CC(C)=O>[C:13]([C:4]1[CH:3]=[C:2]([NH:1][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[CH:7]=[C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])[C:5]=1[OH:12])([CH3:16])([CH3:15])[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1

Procedure:
To a solution of 11.05 grams (0.05 mole) of 4-amino-2,6-di-tert-butylphenol in 50 ml of acetone was added with mixing 9.5 grams (0.05 mole) of p-toluenesulfonyl chloride. After the slight exotherm subsided, 10 ml of 5N sodium hydroxide solution was added. During this addition, an oil separated which eventually solidified. An additional 50 ml of water was added, and the product was separated by filtration. The crude product weighed 12.88 grams and melted at 160°-180° C. After recrystallization from methanol/water and ethanol/water, the melting point was 180°-182° C. (Compound 1)
Reaction SMILES: C[O:2][P:3]([CH2:7][CH:8]=[CH:9][CH2:10][CH:11]([CH2:15][C:16]([CH3:33])=[CH:17][CH2:18][C:19]1[C:20]([OH:32])=[C:21]2[C:25](=[C:26]([CH3:30])[C:27]=1[O:28][CH3:29])[CH2:24][O:23][C:22]2=[O:31])[C:12]([OH:14])=[O:13])([O:5]C)=[O:4].N1C(C)=CC=CC=1C.C[Si](Br)(C)C>C(#N)C>[OH:5][P:3]([CH2:7][CH:8]=[CH:9][CH2:10][CH:11]([CH2:15][C:16]([CH3:33])=[CH:17][CH2:18][C:19]1[C:20]([OH:32])=[C:21]2[C:25](=[C:26]([CH3:30])[C:27]=1[O:28][CH3:29])[CH2:24][O:23][C:22]2=[O:31])[C:12]([OH:14])=[O:13])([OH:4])=[O:2]
Reactant: COc1c(C)c2c(c(O)c1CC=C(C)CC(CC=CCP(=O)(OC)OC)C(=O)O)C(=O)OC2
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: COc1c(C)c2c(c(O)c1CC=C(C)CC(CC=CCP(=O)(O)O)C(=O)O)C(=O)OC2
Reaction time: 0.75 h
Yield: 60.1 %

Procedure:
To a solution of 2-[4-(dimethoxy-phosphoryl)-but-2-enyl]-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-4-methyl-hex-4-enoic acid (25 mg, 0.052 mmol) in acetonitrile (2 mL) was added 2,6-lutidine (60 μL, 0.52 mmol) and TMSBr (67 μL, 0.52 mmol). The reaction was allowed to proceed for 45 minutes when it was completed as judged by LCMS. The reaction mixture was concentrated under reduced pressure and quenched with an aqueous NaOH solution (1 mL). The product was purified by RP HPLC (using a C18 column with a gradient of H2O, 0.1% TFA-acetonitrile, 0.1% TFA) to provide 14.2 mg (60%) of the product as a solid. 1H NMR (300 MHz, CD3OD) δ 1.81 (s, 3H), 2.081-2.31 (m, 4H), 2.16 (s, 3H), 2.45 (d, 1H, J=22 Hz), 2.47 (d, 1H, J=22 Hz), 2.55-2.63 (m, 1H), 3.38 (d, 2H, J=7 Hz), 3.77 (s, 3H), 5.25 (s, 2H), 5.20-5.36 (m, 1H), 5.36-5.56 (m, 2H) ppm; 31P (121.4 MHz, CD3OD) δ 25.4 ppm; MS (m/z) 453 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[C:11]1(Cl)[CH2:16][O:15][CH2:14][CH2:13][O:12]1>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:1]2[CH2:14][CH2:13][O:12][CH2:11][C:16]2=[O:15])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)cc1
Reactant: ClC1(Cl)COCCO1
Product: N#Cc1ccc(N2CCOCC2=O)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 959 mg (8.12 mmol) of 4-aminobenzonitrile and 1.12 g of a mixture of 2-chlorodioxene and 2,2-dichlorodioxane (molar ratio 89:11) is heated at 80° C. with stirring for 18 hours. On cooling to room temperature, the product crystallises: 1.9 g of 2-(2-chloroethoxy)-N-(4-cyanophenyl)acetamide as yellowish crystals. 1H-NMR (d 6-DMSO): δ=3.82 (m; 4H), 4.19 (s; 2H), 7.78 (d, J=8 Hz, 2H), 7.85 (d, J=8 Hz, 2H), 10.22 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=2)[CH2:29][CH2:28]1>C(Cl)Cl.CO>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([NH:40][C:23]([C:20]3[CH:21]=[CH:22][C:13]([C:3]4[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=4[Cl:1])=[C:14]4[C:19]=3[N:18]=[CH:17][CH:16]=[CH:15]4)=[O:24])=[N:38][CH:39]=2)[CH2:29][CH2:28]1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncccc23)c1Cl
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3ncccc23)c1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (Step 159.1), 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography), and stirring the reaction mixture for 20 h at rt. Title compound: ESI-MS: 566.1 [M+H]+; TLC: Rf=0.22 (DCM/MeOH, 9:1).
Reaction SMILES: [C:1]([C:3]1[C:4]2[NH:11][CH:10]=[N:9][C:5]=2[CH:6]=[N:7][CH:8]=1)#[CH:2].I[C:13]1[CH:14]=[C:15]([CH:37]=[CH:38][C:39]=1[CH3:40])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[C:21]([C:33]([F:36])([F:35])[F:34])[CH:20]=1)=[O:17]>>[NH:11]1[C:4]2[C:3]([C:1]#[C:2][C:38]3[CH:37]=[C:15]([CH:14]=[CH:13][C:39]=3[CH3:40])[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[C:21]([C:33]([F:36])([F:35])[F:34])[CH:20]=3)=[O:17])=[CH:8][N:7]=[CH:6][C:5]=2[N:9]=[CH:10]1
Reactant: C#Cc1cncc2nc[nH]c12
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cncc2nc[nH]c12

Procedure:
The title compound can be synthesized from 7-ethynyl-1H-imidazo[4,5-c]pyridine and 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for Example 1. 7-ethynyl-1H-imidazo[4,5-c]pyridine is prepared from 7-bromo-1H-imidazo[4,5-c]pyridine and ethynyltrimethylsilane according to the 2 steps procedure described in Example 1.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][N:6]=[CH:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:11][C:12]=1[CH3:13])C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:13][C:12]1[N:11]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]2[C:8]=1[CH:7]=[N:6][NH:5][C:4]2=[O:3]
Reactant: CCOC(=O)NN=Cc1nc(-c2ccccc2)[nH]c1C
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1nc(-c2ccccc2)n2c(=O)[nH]ncc12

Procedure:
An 8.33 gm. portion of 3-[(5-methyl-2-phenyl-4-imidazolyl)methylene]carbazic acid ethyl ester in 60 ml. of diphenyl ether is heated in an oil bath at 215°-230° C. for 20 minutes. The reaction mixture is diluted to 400 ml. with petroleum ether. The precipitate is collected and recrystallized from 350 ml. of benzene giving the desired product, m.p. 182°-184.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][CH2:16][O:17][CH2:18][C:19]([OH:21])=O)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:22])[CH:4]=1.[ClH:23].Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][C:32]2([OH:38])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:26]=1.C(=O)(O)[O-].[Na+].Cl.CCOCC.N1C=CC=C(C2(O)CCNCC2)C=1.N1C=CC(C2(O)CCNCC2)=CC=1.S1C=CC=C1C1(O)CCNCC1.N1CCCCC1=O>C(Cl)Cl.C(N(CC)CC)C>[ClH:23].[OH:38][C:32]1([CH2:31][C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)[CH2:37][CH2:36][N:35]([C:19](=[O:21])[CH2:18][O:17][CH2:16][CH2:15][N:13]([CH3:14])[S:10]([C:6]2[C:5]([CH3:22])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=2[CH3:9])(=[O:11])=[O:12])[CH2:34][CH2:33]1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)O)c(C)c1
Reactant: OC1(Cc2cccnc2)CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C1CCCCN1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)N2CCC(O)(Cc3cccnc3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-Carbonyldiimidazole (77 mg, 0.475 mmol) was added to a solution of 2-(2-(4-methoxy-N,2,6-trimethylphenylsulfonamido)-ethoxy)acetic acid (acid unit S2) (150 mg, 0.453 mmol) in methylene chloride (7 ml), and the mixture was stirred for 1 h at room temperature. A solution of 4-(pyridin-3-ylmethyl)piperidin-4-ol dihydrochloride (120 mg, 0.453 mmol) dissolved in methylene chloride (3 ml) and triethylamine (0.18 ml) was then added, and the reaction mixture was stirred overnight at room temperature. Saturated sodium bicarbonate solution (10 ml) was then added to the reaction mixture, and the aqueous phase was then extracted with methylene chloride (20 ml). The combined organic phases were extracted with saturated sodium chloride solution (10 ml), dried with sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography with ether/methylene chloride/methanol (10:10:1) and 25% strength ammonia solution. N-(2-(2-(4-Hydroxy-4-(pyridin-3-ylmethyl)piperidin-1-yl)-2-oxoethoxy)ethyl)-4-methoxy-N,2,6-trimethylphenylsulfonamide (140 mg) was dissolved in methyl ethyl ketone (1 ml), and HCl in ether (3 eq.) was added slowly, whereupon a white solid precipitated. After addition of diethyl ether, stirring was carried out for 1 h, while cooling with ice. The solid was filtered off, washed with diethyl ether and dried. Yield: 120 mg (48%). The amine units used in Examples 279 and 280 can be prepared analogously to the synthesis processes described above for amine units A2, A3, A4 and A7 with addition of a corresponding Li organyl or Grignard radical to the corresponding piperidone derivative.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:25])[C:13]([C:22](O)=[O:23])=[C:14]4[CH2:21][CH2:20][CH2:19][CH2:18][N:15]43)=[CH:10][C:9]=2[F:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC(OCC(C)C)=O.[BH4-].[Na+].[Cl-].[NH4+]>C(N(CC)CC)C.C1COCC1>[CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:25])[C:13]([CH2:22][OH:23])=[C:14]4[CH2:21][CH2:20][CH2:19][CH2:18][N:15]43)=[CH:10][C:9]=2[F:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1c2n(c3cc(NC4CCCCC4)c(F)cc3c1=O)CCCC2
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1c(CO)c2n(c3cc(NC4CCCCC4)c(F)cc13)CCCC2
Yield: 50.5 %

Procedure:
To a 50 ml THF suspension of 1.02 g of 9-(cyclohexylamino)-8-fluoro-6-oxo-2,3,4,6-tetrahydro-1H-pyrido[1,2-a]quinoline-5-carboxylic acid were added 0.5 ml of triethylamine and 0.4 ml of isobutyl chloroformate under ice-cooling, followed by stirring under ice-cooling for 1 hour. Aqueous solution (4 ml) of 431 mg of sodium borohydride was added dropwise thereto at −78° C., followed by stirring at −15° C. for 15 minutes and under ice-cooling for 30 minute. Aqueous saturated ammonium chloride was added thereto, followed by extraction with ethyl acetate and subsequent drying over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 495 mg of 9-(cyclohexylamino)-8-fluoro-5-(hydroxymethyl)-1,2,3,4-tetrahydro-6H-pyrido[1,2-a]quinolin-6-one.
Reaction SMILES: [CH2:1]([C@H:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C@H:9]([OH:18])[CH2:10][NH:11][O:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.CN(C)C1C=CN=CC=1>[CH2:1]([C@H:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C@H:9]([OH:18])[CH2:10][N:11]([O:12][CH:13]([CH2:14][CH3:15])[CH2:16][CH3:17])[S:35]([C:32]1[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:34][CH:33]=1)(=[O:37])=[O:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(CC)ONC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.3 %

Procedure:
A mixture of tert-butyl (1S,2R)-1-benzyl-3-[(1-ethylpropoxy)amino]-2-hydroxypropylcarbamate (100 mg, 0.273 mmol), 4-methoxyphenylsulphonyl chloride (57 mg, 0.273 mmol), and diisoproylethylamine (0.0476 mL, 0.273 mmol) in anhydrous tetrahydrofuran (2 mL) was stirred under Argon for 16 hours at ambient temperature. A catalytic quantity of 4-dimethylaminopyridine (˜1 mg) was added and the reaction was heated at reflux for approximately two hours. After cooling, the reaction was evaporated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with aqueous potassium carbonate (5% w/v), aqueous hydrochloric acid (1N) and brine. The organic layer was then dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 500 NM) eluting with 95:5 methylene chloride:methanol. The product band was removed, eluted with 4:1 methylene chloride:methanol, filtered, and evaporated in vacuo. The residue was purified again on a preparative TLC plate (20×20 cm, 500 μM) eluting with 95:5 methylene chloride:ethyl acetate. The product band was removed, eluted with 4:1 methylene chloride:methanol, filtered, and evaporated in vacuo to provide tert-butyl (1S,2R)-1-benzyl-3-{(1-ethylpropoxy)[(4-methoxyphenyl)sulfonyl]amino}-2-hydroxypropylcarbamate (103 mg, 70%) as a foam. H1-NMR (chloroform-D3): 0.95 (m, 6H), 1.38 (s, 9H), 1.64 (m, 4H), 3.01 (m, 5H), 3.83 (m, 2H), 3.93 (s, 3H), 4.20 (m, 1H), 4.61 (m, 1H), 7.03 (d, 2H), 7.29 (m, 5H), 7.80 (d, 2H). MS(ESI): 559(M+Na).
Reaction SMILES: C([O:5][C:6](=[O:48])[C@H:7]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:8][C:9](=[O:40])[CH2:10][N:11]([C:21](=[O:39])[C@H:22]([CH3:38])[NH:23][C@@H:24]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)(C)(C)C.[BrH:49].CCOCC>C(O)(=O)C>[BrH:49].[CH2:36]([O:35][C:33]([C@H:24]([NH:23][C@H:22]([C:21]([N:11]([CH:12]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20]1)[CH2:10][C:9]([NH:8][C@H:7]([C:6]([OH:48])=[O:5])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:40])=[O:39])[CH3:38])[CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:34])[CH3:37]
Reactant: CCOC(=O)[C@@H](CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)[C@@H](CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)N[C@@H](Cc1ccccc1)C(=O)O)C1Cc2ccccc2C1

Procedure:
N-[1(R)-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-(2-indanyl)glycyl-L-phenylalanine tert-butyl ester (0.2 g) is dissolved in 0.5 ml of acetic acid and shaken with 1 ml of 30% hydrogen bromide in acetic acid for 10 minutes, followed by addition of 50 ml of ether and 50 ml of petroleum ether. The supernatant is decanted off and petroleum ether is added to the residue. The solid substance is collected by filtration and dried to give 0.18 g of N-[1(R)-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-N-(2-indanyl)glycyl-L-phenylalanine hydrobromide as powder.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]([N:13]([CH:36]3[CH2:38][CH2:37]3)[C:14]([C@H:16]3[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18][N:17]3C(OC(C)(C)C)=O)=[O:15])[CH3:12])=[CH:8][CH:9]=2)[N:4]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH:3]=1.N1C(C)=CC=CC=1C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(=O)([O-])O.[Na+]>ClCCl.CO>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]([N:13]([CH:36]3[CH2:38][CH2:37]3)[C:14]([C@H:16]3[CH2:21][NH:20][CH2:19][CH2:18][NH:17]3)=[O:15])[CH3:12])=[CH:8][CH:9]=2)[N:4]([CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH:3]=1
Reactant: COCCCn1cc(Cl)c2ccc([C@@H](C)N(C(=O)[C@H]3CN(C(=O)OC(C)(C)C)CCN3C(=O)OC(C)(C)C)C3CC3)cc21
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COCCCn1cc(Cl)c2ccc([C@@H](C)N(C(=O)[C@H]3CNCCN3)C3CC3)cc21
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a solution of di-tert-butyl (2R)-2-{[{(1R)-1-[3-chloro-1-(3-methoxypropyl)-1H-indol-6-yl]ethyl}(cyclopropyl)amino]carbonyl}piperazine-1,4-dicarboxylate (44.0 mg) and 2,6-lutidine (0.050 mL) in dichloromethane (1.0 mL) was added trimethylsilyltriflate (0.051 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Then, thereto were added aqueous saturated sodium hydrogen carbonate solution and methanol (2.0 mL) under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (eluent: ethyl acetate→ethyl acetate/methanol=5/1) to give (2R)-N-{(1R)-1-[3-chloro-1-(3-methoxypropyl)-1H-indol-6-yl]ethyl}-N-cyclopropylpiperazine-2-carboxamide [Ex(2-1)] (25.4 mg) and as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].Cl[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28].C(N(CC)CC)C>C(O)C>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])=[C:20]([N+:27]([O-:29])=[O:28])[CH:21]=1)#[N:24]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCCC1Cc1c[nH]c2ccc(Nc3ccc(C#N)cc3[N+](=O)[O-])cc12
Yield: 80 %

Procedure:
(R)-5-Amino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and 4-chloro-3-nitrobenzonitrile were used. Triethylamine was used as base, absolute ethanol was used as solvent, and the reaction was heated at reflux for 4 hours. Column chromatography afforded the title compound (80%) as a red solid: mp, 170.0°-171.0° C.; 13C NMR (CDCl3) δ 147.3,137.1, 135.4, 132.0, 131.4, 128.6, 128.0, 125.3, 120.6, 117.9, 117.1, 116.3, 113.1, 111.9, 99.1, 68.1, 57.3, 40.6, 31.2, 28.1, 21.9. Anal. calcd for C21H21N5O2.0.05 CH2Cl2 : C, 66.59; H, 5.60; N, 18.44. Found: C, 66.56; H, 5.26; N, 18.42.
Reaction SMILES: Cl[C:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[O:4][N:3]=1.[CH3:9][S-:10].[Na+].O>CN(C=O)C>[CH3:9][S:10][C:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[O:4][N:3]=1
Reactant: C[S-]
Reactant: CC1(C)CC(Cl)=NO1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSC1=NOC(C)(C)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.8 %

Procedure:
To a solution of 193.0 g (1.07 M) of 3-chloro-5,5-dimethyl-2-isoxazoline dissolved in 500 ml of DMF was dropwise added, with ice-cooling, 1.0 kg (content=15%, 2.14 M) of an aqueous sodium methanethiolate solution. The mixture was stirred at room temperature for 12 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic phase was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 115.0 g (yield: 74.1%) of 3-methylthio-5,5-dimethyl-2-isoxazoline. This residue (141.2 mmoles) was dissolved in 1 liter of chloroform. Thereto was added, with ice-cooling, 392.0 g (1.59 M) of m-chloroperbenzoic acid (purity: 70%), followed by stirring at that temperature for 1 hour and at room temperature for 12 hours to give rise to a reaction. After the completion of the reaction, the precipitated m-chloroperbenzoic acid was removed by filtration. The filtrate was washed with an aqueous sodium hydrogensulfite solution, water, an aqueous sodium hydrogencarbonate solution and an aqueous sodium chloride solution in this order, and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was washed with diisopropyl ether to obtain 77.6 g (yield: 59.1%) of 3-methylsulfonyl-5,5-dimethyl-2-isoxazoline as a white powder (melting point: 82 to 84° C.).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([NH:11][NH:12][C:13]([C:15]2[S:16][C:17]([CH2:26][CH3:27])=[C:18]3[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][CH2:20][C:19]=23)=O)=[O:10])[CH:6]=[C:5]([CH3:28])[N:4]=1)[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1.CC(=O)OCC>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[O:10][C:13]([C:15]3[S:16][C:17]([CH2:26][CH3:27])=[C:18]4[CH2:23][C:22]([CH3:25])([CH3:24])[CH2:21][CH2:20][C:19]=34)=[N:12][N:11]=2)[CH:6]=[C:5]([CH3:28])[N:4]=1)[CH3:2]
Reactant: CCc1cc(C(=O)NNC(=O)c2sc(CC)c3c2CCC(C)(C)C3)cc(C)n1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cc(-c2nnc(-c3sc(CC)c4c3CCC(C)(C)C4)o2)cc(C)n1
Temperature: 110 °C
Yield: 28.9 %

Procedure:
A mixture of crude 3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophene-1-carboxylic acid N′-(2-ethyl-6-methyl-pyridine-4-carbonyl)-hydrazide (289 mg, ca. 0.48 mmol) and Burgess Reagent (367 mg, 1.6 mmol) in THF (5 mL) is heated at 110° C. for 3 min in a microwave oven. The mixture is diluted with EA (50 mL) and extracted with 1M aq. NaOH (2×10 mL). The organic phase is dried (MgSO4), filtered and evaporated. The residue is purified by HPLC to give 2-ethyl-4-[5-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-[1,3,4]oxadiazol-2-yl]-6-methyl-pyridine (53 mg); LC-MS: tR=0.96 min, [M+1]=382.26.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18]C)=[CH:15][CH:16]=3)[C:11](=[O:20])[C:10]([CH3:22])([CH3:21])[CH2:9]2)=[CH:4][CH:3]=1>C(O)(=O)C.Br>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:20])[C:10]([CH3:22])([CH3:21])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)C(=O)C(C)(C)CC2c1ccc(Cl)cc1
Agent: Br
Solvent: CC(=O)O
Product: CC1(C)CC(c2ccc(Cl)cc2)c2ccc(O)cc2C1=O

Procedure:
A solution of 4-(4-chlorophenyl)-7-methoxy-2,2-dimethyl-1-tetralone (16.1 g) in acetic acid (75 ml) and hydrobromic acid (48%, 75 ml) was heated under reflux for 16 hr. The solution was concentrated in vacuo, water was added and the mixture extracted with ethyl acetate. The extracts were washed well with water and sodium bicarbonate solution, dried (MgSO4) and the solvent removed to give 4-(4-chlorophenyl)-7-hydroxy-2,2-dimethyl-1-tetralone as a white solid which was used without purification (14.7 g, 91%).