Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][N:5]=[N:4]1.S(C1C=CC(C)=CC=1)(O[CH2:12][C@@H:13]1[CH2:27][C@H:26]2[C@@H:16]([CH2:17][C:18]3[C:28]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]2=4)[NH:20][CH:19]=3)[N:15]([CH3:29])[CH2:14]1)(=O)=O>CN(C)C=O>[CH3:29][N:15]1[C@H:16]2[C@@H:26]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:28]=3[C:18]([CH2:17]2)=[CH:19][NH:20]4)[CH2:27][C@@H:13]([CH2:12][N:3]2[CH:7]=[N:6][N:5]=[N:4]2)[CH2:14]1
Reactant: c1nnn[nH]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C[C@H](Cn2cnnn2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
1.7 g of 50% sodium hydride in an oil was added in small portions to a mixture of 5.1 g of tetrazole and 30 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 3.0 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 11 hours. The solvent was distilled off under reduced pressure, and the residue was purified by alumina column chromatography (eluted with acetone). The product was recrystallized from acetone to obtain 0.7 g of the titled compound as colorless needles having a melting point of 206°-209° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]#[N:27])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[NH:30][N:29]=[N:28][N:27]=3)[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2oc(CCCCCC#N)nc2-c2ccc(Cl)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2oc(CCCCCc3nnn[nH]3)nc2-c2ccc(Cl)cc2)cc1
Yield: 44.9 %

Procedure:
4 g of 6-[4-(4-chlorophenyl)-5-(4-methoxyphenyl)-2-oxazolyl]hexanenitrile, twice 2 g of sodium azide and twice 1.7 g of ammonium chloride in 50 cm3 of dimethylformamide are heated according to Example 5. The product of the reaction is purified by chromatography on a column 2 cm in diameter containing 40 g of silica gel (50 to 200μ). The column is eluted, collecting 25 cm3 fractions, first with 0.2 liter of diisopropyl ether and then with 0.3 liter of ethyl acetate. The ethyl acetate eluates are concentrated to dryness and the solid residue is crystallised in 40 cm3 of ethanol. 2 g (45%) of 5-{5-[4-(4-chlorophenyl)-5-(4-methoxyphenyl)-2-oxazolyl]pentyl}tetrazole, white crystals, melting point 160° C., are obtained.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=[CH:7][CH:8]=1.[CH2:22]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:23][CH2:24][C:25]#[CH:26]>CCCCCCC>[C:27]1([CH2:22][CH2:23][CH2:24][C:25]#[C:26][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:4]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc(C(F)(F)F)c2)cc1
Reactant: C#CCCCc1ccccc1
Solvent: CCCCCCC
Product: FC(F)(F)c1cccc(C#CCCCc2ccccc2)c1

Procedure:
This product was prepared from toluene-4-sulfonic acid 3-trifluoromethyl-phenyl ester and pent-4-ynyl-benzene following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane; yield (140 mg, 97%); 1H NMR δ (CDCl3): 7.66 (s, 1H), 7.61-7.7.49 (m, 2H), 7.46-7.36 (m, 1H), 7.35-7.16 (m, 5H), 2.79 (t, J=7.15 Hz, 2H), 2.43 (t, J=7.20 Hz, 2H), 1.93 (p, J=7.11 Hz, 2H); LCMS m/z: 288.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[CH3:6][NH:7][C:8](=[O:21])[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1CO)=[N:10][O:11][CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[CH3:6][NH:7][C:8](=[O:21])[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:1][Br:5])=[N:10][O:11][CH3:12]
Reactant: BrC(Br)(Br)Br
Reactant: CNC(=O)C(=NOC)c1ccccc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)C(=NOC)c1ccccc1CBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.7 %

Procedure:
Carbon tetrabromide (0.33 g) was added to a solution of N-methyl-2-(2-hydroxymethylphenyl)-2-methoxyiminoacetamide (0.11 g) and triphenylphosphine (0.26 g) in tetrahydrofuran (10 ml) at 0° C. The reaction mixture was stirred at 0° C. for 1½ hours and then at room temperature for 1 hour. The reaction mixture was then poured into water and extracted three times with ethyl acetate. The combined extracts were washed with brine and dried over magnesium sulphate. The solution was then concentrated under reduced pressure to leave a gum. Column chromatography (eluting with diethyl ether on silica gel) gave the N-methyl-2-(2-bromomethylphenyl)-2-methoxyimino-acetamide as a gum (80 mg, 57%). 1H NMR (CDCl3) δ2.95(d,3H), 4.0(s,3H), 4.35(s,2H), 6.8(brs,1H), 7.1-7.5(m,4H) ppm.
Reaction SMILES: [C:1]([C:3](=[C:9](SC)[S:10][CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[NH2:14][NH2:15]>CC(O)C>[NH2:2][C:1]1[NH:15][N:14]=[C:9]([S:10][CH3:11])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: NN
Reactant: CCOC(=O)C(C#N)=C(SC)SC
Solvent: CC(C)O
Product: CCOC(=O)c1c(SC)n[nH]c1N
Temperature: 25 °C
Yield: 59 %

Procedure:
A solution of ethyl 2-cyano-3,3-bis(methylthio)acrylate (2.2 g, 10.1 mmol) and hydrazine (0.325 mL, 10.1 mmol) in 2-propanol (20 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (1:1) to give ethyl 5-amino-3-(methylthio)-1H-pyrazole-4-carboxylate (1.2 g, 59%) as a solid. m/z (APCI-pos) M+1=202.0.
Reaction SMILES: C(O[CH:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)(=O)C.[CH3:19][N:20]([CH3:27])[CH:21]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]1>C1C=CC=CC=1>[CH:7]1[C:6]2[CH:5]([N:23]3[CH2:24][CH2:25][CH2:26][CH:21]([N:20]([CH3:27])[CH3:19])[CH2:22]3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Reactant: CN(C)C1CCCNC1
Solvent: c1ccccc1
Product: CN(C)C1CCCN(C2c3ccccc3Oc3ccccc32)C1

Procedure:
A solution of 9.92 g. (41.3 mmoles) of 9-acetoxyxanthene and 5.9 g. (46.1 mmoles) of 3-dimethylaminopiperidine in 200 ml. of benzene was refluxed for 18 hours. The mixture was then washed with aqueous sodium bicarbonate solution, dried, and evaporated. Chromatography on alumina (chloroform eluant) afforded 1-(9-xanthenyl)-3-dimethylaminopiperidine, as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]5[C:32](=[O:33])[C:31]6[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=6)[N:25]=[CH:24]5)[C:18]=4[CH3:34])=[CH:15][N:14]=[C:13]([C:35]([NH2:37])=[O:36])[C:9]=3[NH:10]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.CO>[OH:3][CH:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N:23]5[C:32](=[O:33])[C:31]6[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=6)[N:25]=[CH:24]5)[C:18]=4[CH3:34])=[CH:15][N:14]=[C:13]([C:35]([NH2:37])=[O:36])[C:9]=3[NH:10]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(-n4cnc5ccccc5c4=O)c3C)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(C(C)O)ccc4c23)cccc1-n1cnc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 23.9 %

Procedure:
To a cloudy solution of 7-acetyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (45 mg, 0.092 mmol) in tetrahydrofuran (4 mL) and methanol (12 mL) at 0° C. was added sodium borohydride (17.46 mg, 0.462 mmol) in one portion. The mixture was stirred at room temperature for 20 min and then the reaction was quenched with ice cold water (15 mL). The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with brine (25 mL) and dried over anhydrous MgSO4. The organic solution was concentrated under vacuum, and the residue was purified by reverse phase HPLC. The correct fraction was concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with dichloromethane (3×35 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (10.9 mg, 0.022 mmol, 23.5% yield) as a white solid. LCMS (M+H)+=490.1. 1H NMR (500 MHz, DMSO-d6) (recognizable peaks for the major atropisomer) δ: 11.78 (s, 1H), 8.44 (s, 1H), 8.30 (s, 1H), 8.28 (dd, J1=8.0 Hz, J2=1.4 Hz, 1H), 8.25 (s, 1H), 8.24 (s, 1H), 7.30 (m, 1H), 7.12 (m, 1H), 5.25 (s, 1H), 4.85 (m, 1H), 1.82 (s, 3H),
Reaction SMILES: [C:1]1([O:11][CH2:12][C:13]([NH:15][C@H:16]([C:20]([NH:22][CH:23]([CH:32]([OH:35])[CH2:33][F:34])[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]1([O:11][CH2:12][C:13]([NH:15][C@H:16]([C:20]([NH:22][CH:23]([C:32](=[O:35])[CH2:33][F:34])[CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)[C@H](NC(=O)COc1cccc2ccccc12)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)COc1cccc2ccccc12)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CF
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
To a solution of (3RS,4RS)-3-[N-((1-naphthyloxy)acetyl)valinyl]amino-5-fluoro-4-hydroxypentanoic acid, tert-butyl ester (0.163 g, 0.315 mmol) and N-methylmorpholine N-oxide (0.144 g, 0.98 mmol) in CH2Cl2 (5.0 mL) at room temperature was added activated 4 Å molecular sieves. After stirring at room temperature for 20 min, the mixture was treated with tetra(n-propyl)ammonium perruthenate (0.011 g). After stirring at room temperature for 3.5 hrs, the mixture through Celite and evaporated to dryness. The residue was purified by flash chromatography on silica gel eluting with EtOAc-hexane (3:4) to give the title compound (0.124 g, 40%) as a pale yellow oil. TLC(MeOH-CH2Cl2; 1:9) Rf=0.71. 1H NMR (CDCl3): δ 8.27–8.23 (m, 1H), 7.86–7.83 (m, 1H), 7.59–7.51 (m, 3H), 7.42–7.36 (m, 1H), 7.23–7.19 (m, 1H), 7.05–6.95 (m, 1H), 6.84 (d, 1H, J=7.7 Hz), 5.26–4.97 (m, 2H), 4.93–4.89 (m, 1H), 4.76 (s, 2H), 4.45–4.35 (m, 1H), 3.05–2.76 (m, 2H), 1.42 (d, 9H, J=4.1 Hz), 1.02–0.87 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:19](COC)[S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)(=[O:22])=[O:21])[C:5]([C:8](=[O:18])[C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2[F:17])=[N:6][CH:7]=1.Cl>O.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=2)(=[O:22])=[O:21])[C:5]([C:8](=[O:18])[C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2[F:17])=[N:6][CH:7]=1
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1c(F)cccc1OC)S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(F)c1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1cccc(C(F)(F)F)c1

Procedure:
N-[5-Chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (180 mg, 0.313 mmol) was magnetically stirred in water (1.0 mL) and 4N HCl in dioxane (2.5 mL) and heated at 85° C. for 7 h. The reaction was subsequently concentrated and the residue was neutralized (pH 7) with aqueous sodium bicarbonate and extracted with EtOAc (3×80 mL). The extracts were dried (MgSO4), filtered, and chromatographed on silica gel using EtOAc-hexane (gradient, 0:100 to 50:50) to provide N-[5-chloro-2-(2-fluoro-6-methoxy-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide: MS m/z 489.1 (M+H); 511.0 (M+Na).
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[C:12]([O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=1)([CH3:15])([CH3:14])[CH3:13].[NH2:26][C@H:27]1[C@H:33]([OH:34])[CH2:32][CH2:31][CH2:30][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:28]1>ClCCl.CN(C)C1C=CN=CC=1.CCCCCCC>[C:12]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([NH:26][C@H:27]2[C@H:33]([OH:34])[CH2:32][CH2:31][CH2:30][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:28]2)=[O:23])=[CH:24][CH:25]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)Oc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)[C@H](N)C1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](O)[C@H](NC(=O)c2ccc(OC(C)(C)C)cc2)C1
Reaction time: 2 h

Procedure:
12.91 g of p-toluenesulphonyl chloride dissolved in 15 ml of dichloromethane were added at room temperature in the course of 15 minutes to 1.94 g of 4-(tert-butoxy)-benzoic acid and 2.63 g of 4-dimethylaminopyridine in 20 ml of dichloromethane. The reaction mixture was stirred for 2 hours and added in the course of 1 hour to 2.30 g of tert-butyl (3R,4R)-3-amino-4-hydroxy-azepan-1-carboxylate dissolved in 10 ml of dichloromethane. After stirring for 1 hour the reaction mixture was washed with 20 ml of 1N NaOH, 20 ml of 1N HCl and 20 ml of water. All aqueous phases were washed in succession with 10 ml of dichloromethane. The combined organic phases were dried over sodium sulphate, filtered and the solvent was evaporated. The foam-like residue obtained was dissolved in 80 ml of hot heptane and crystallized at room temperature overnight. The crystals were washed with 10 ml of heptane and dried to yield 3.23 g of tert-butyl (3R,4R)-3-(4-tert-butoxy-benzoylamino)-4-hydroxy-azepan-1-carboxylate, m.p. 134-135° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].O[N:21]=[C:22]([C:24]1[CH:32]=[C:31]([CH3:33])[C:27]2[NH:28][CH:29]=[N:30][C:26]=2[CH:25]=1)[NH2:23]>CCOCC>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:12][N:21]=[C:22]([C:24]3[CH:32]=[C:31]([CH3:33])[C:27]4[NH:28][CH:29]=[N:30][C:26]=4[CH:25]=3)[N:23]=2)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: Cc1cc(C(N)=NO)cc2nc[nH]c12
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Solvent: CCOCC
Product: COCc1cc(-c2nc(-c3cc(C)c4[nH]cnc4c3)no2)ccc1-c1ccccc1C

Procedure:
Title compound was prepared following general procedure 2 starting from Intermediate 14 (308 mg; 1.2 mmol) and Intermediate 3 (228 mg; 1.2 mmol). The reaction mixture was diluted with Et2O, washed with water and brine and evaporated under vacuum. Purification by silica column chromatography (EtOAc/c-Hex, 30/70 to 70/30) afforded the title compound as a pink powder. 1H NMR (DMSO-d6) δ 12.92 (br s, 0.5H), 12.71 (br s, 0.5H), 8.38 (d, J=6.0 Hz, 1H), 8.34 (d, J=1.3 Hz, 1H), 8.26-8.12 (m, 2H), 7.80 (d, J=6.8 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.39-7.25 (m, 3H), 7.16 (d, J=7.0 Hz, 1H), 4.27-4.14 (m, 2H), 3.26 (s, 3H), 2.65 (s, 1.5H), 2.62 (s, 1.5H), 2.05 (s, 3H). LC/MS (method B): 409.3 (M−H)−; 411.3 (M+H)+. HPLC (Method A) Rt 4.11 min (Purity: 100.0%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:31]=[CH:30][C:21]([CH:22]=[C:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]2[CH:31]=[CH:30][C:21]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:20][CH:19]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Yield: 99.1 %

Procedure:
A solution of 0.5 g (1.14 mmole) 5-(4-[2-(4-tert-butyloxycarbonylaminophenyl)ethoxy]benzylidene)thiazolidine-2,4-dione in ethyl acetate was hydrogenated in the presence of 5% palladium on charcoal at room temperature and atmospheric pressure until hydrogen uptake ceased. The solution was filtered through celite, the filter pad was washed with ethyl acetate and the filtrate was evaporated to give 0.5 g (yield 99%) of 5-(-[4-[2-(4-tert-butyloxycarbonylaminophenyl)ethoxy]phenyl]methyl)thiazolidine-2,4-dione.
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+].[Na+].Cl[C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]([N+:24]([O-:26])=[O:25])=[C:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:9]=1>O.C(O)C>[CH2:17]([O:16][C:14]([C:13]1[C:8]([S:1]([OH:4])(=[O:3])=[O:2])=[N:9][C:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:11]([N+:24]([O-:26])=[O:25])[C:12]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:15])[CH3:18]
Reactant: O=S([O-])[O-]
Reactant: CCOC(=O)c1c(Cl)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(S(=O)(=O)O)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Yield: 59.9 %

Procedure:
A solution of 0.28 g of sodium sulfite in 7 ml of water was added to a solution of 0.70 g of 2-chloro-3,4-diethoxycarbonyl-5-nitro-6-phenylpyridine in 7 ml of ethanol, and the mixture was heated under reflux for minutes. After the reaction mixture was concentrated, the concentrate was acidified with 1N HCl, followed by extraction with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over magnesium sulfate. After concentration to dryness under reduced pressure, the residue was recrystallized from chloroform/ether, to give 0.47 g of white crystals.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][C:11]([OH:15])([C:13]#[CH:14])[CH3:12]>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.[Cu]I>[CH3:10][C:11]([OH:15])([CH3:12])[C:13]#[C:14][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CC(C)(O)C#Cc1ccc(C=O)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
4-Bromobenzaldehyde (3.0 g, 16 mmol), Pd(PPh3)2Cl2 (110 mg, 0.170 mmol) and CuI (16 mg, 0.07 mmol) were placed in a Schienk flask. The flask was then evacuated and purged with argon (3 times) on the Schienk line. Then freshly distilled and degassed TEA (32 mL) was added, and after purging with argon, 2-methyl-3-butyn-2-ol (1.90 mL, 19.4 mmol) was added. The reaction mixture was stirred for 2 h at 40° C. (The progress of the reaction was monitored by GC-MS). T he reaction mixture was evaporated to dryness and then chromatographed (silica, CH2Cl2). Bulb-to-bulb distillation (93-95° C., 0.001 mm Hg) gave a pale yellowish oil (2.90 g, 95%). 1H NMR (CDCl3) δ 1.61 (s, 6H), 2.23 (brs, 1H), 7.52 (AB/2, J=8.1 Hz, 2H), 7.79 (AB/2, J=8.1 Hz, 2H), 9.02 (s, 1H); 13C NMR δ 31.9, 66.1, 81.9, 98.8, 129.8, 130.1, 132.7, 35.9, 192.3; IR (film)ν(cm−1) 790.4, 830.1, 906.3, 963.4, 1014.3, 1046.1, 1165.9, 1207.0, 1273.4, 1303.0, 1373.0, 1457.6, 1563.8, 1603.6, 1700.0, 2228.1, 2735.0, 2837.8, 2934.1, 2982.2, 3413.3; MS (EI+) m/z 188 (M+,35%), 173 (100%), 159 (10%); EI-MS obsd 188.0835, calcd exact mass 188.0837 (C12H12O2).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH2:7][OH:8])[CH2:3][CH2:4][OH:5].N1C=CN=C1.[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16].O>ClCCl>[C:15]([Si:19]([CH3:22])([CH3:21])[O:5][CH2:4][CH2:3][C:2]([CH3:9])([CH3:1])[CH2:6][CH2:7][OH:8])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(CCO)CCO
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(CCO)CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A mixture of 3,3-dimethyl-pentane-1,5-diol (1.5 g, 11 mmol) and imidazole (1.4 g, 20 mmol) in dichloromethane (50 mL) was added tert-butyldimethylchlorosilane (1.7 g, 11 mmol). The reaction mixture was stirred at room temperature for 2 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, concentrated to give 5-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-pentan-1-ol as a colorless oil (2.7 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]2[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:10][CH2:11][C:9]2=[O:20])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccc(C=C2CC2)cc1
Solvent: ClCCl
Product: O=C1CCC1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a solution of 1-chloro-4-(cyclopropylidenemethyl)benzene (5 g, 30 mmol) in CH2Cl2 (80 ml) was added in 5 separate portions m-chloroperbenzoic acid (5.3 g, 30 mmol) at 0° C. After stirring at 0° C. for 3 h, the reaction mixture was washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4 and concentrated. To the crude product in CH2Cl2 (40 ml) was added 10% HBF4 (11.6 ml 48% HBF4 and 46 ml H2O). After stirring at rt for 17 h, the mixture was extracted with CH2Cl2, washed with saturated NaHCO3 aq. solution and brine. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel (eluent i-hexane, KMnO4 stain) to give 2-(4-chlorophenyl)cyclobutanone (3.470 g, 64%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1([CH:24]([CH3:26])[CH3:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH3:22])[C:14]1=[O:23].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH:24]([C:13]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:36]2[CH2:35][CH2:34][N:33]([CH2:32][C:31]3[CH:39]=[C:40]([O:44][CH3:45])[C:41]([O:42][CH3:43])=[C:29]([O:28][CH3:27])[CH:30]=3)[CH2:38][CH2:37]2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([CH3:22])[C:14]1=[O:23])([CH3:26])[CH3:25]
Reactant: CC(C)C1(c2ccccc2OCCCCBr)C(=O)N(C)c2ccccc21
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Product: COc1cc(CN2CCN(CCCCOc3ccccc3C3(C(C)C)C(=O)N(C)c4ccccc43)CC2)cc(OC)c1OC

Procedure:
Preparation in analogy to Example 3(d) from 3-[2-(4-bromo butoxy)phenyl]-3-isopropyl-1-methylindolin-2-one and 3,4,5-trimethoxybenzylpiperazine
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[C:29]([CH2:30][NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=2)=[CH:28][CH:27]=[C:26]([O:41][CH3:42])[N:25]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:31]([CH2:30][C:29]1[C:24]([O:23][CH3:22])=[N:25][C:26]([O:41][CH3:42])=[CH:27][CH:28]=1)[C:32]1[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[CH:34][CH:33]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CNc2ccc(C(C)C)cc2)c(OC)n1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Product: COc1ccc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)cc2)c(OC)n1
Yield: 86.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.42 g) and [(2,6-dimethoxypyridin-3-yl)methyl](4-isopropylphenyl)amine (0.43 g) as starting materials, 5-benzyloxy-N-[(2,6-dimethoxypyridin-3-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.71 g) was obtained.