Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([Si](OC)(OC)[O:8]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[Si](OCC)(OCC)OCC)C.C[Si](OCC)(OCC)OCC.CO[Si]([CH2:45][CH2:46][CH2:47][CH:48]1[CH2:53][C:52](=[O:54])[O:51][C:49]1=[O:50])(OC)OC.C(O[Si](OCC)(OCC)CCCNC(=O)CCCO)C.Cl.C(OCC(O)C)C.[OH-].[C:84]1([S+:90]([C:97]2[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=2)[C:91]2[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=2)[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1>O.C(O)C.CC(C)=O>[C:52]([O-:51])(=[O:54])[CH2:53][CH2:48][C:49]([O-:50])=[O:8].[C:97]1([S+:90]([C:84]2[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=2)[C:91]2[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=2)[CH:98]=[CH:99][CH:100]=[CH:101][CH:102]=1.[C:1]1([S+:90]([C:52]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:53]=2)[C:84]2[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO[Si](CCCC1CC(=O)OC1=O)(OC)OC
Reactant: CO[Si](OC)(OC)c1ccccc1
Agent: CCOCC(C)O
Agent: CCO[Si](C)(OCC)OCC
Agent: CCO[Si](CCCNC(=O)CCCO)(OCC)OCC
Solvent: CC(C)=O
Solvent: CCO
Solvent: O
Product: O=C([O-])CCC(=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4.73 g of phenyltrimethoxysilane, 69.54 g of tetraethoxysilane, 16.92 g of methyltriethoxysilane, 0.14 g of trimethoxysilylpropyl succinic anhydride, 7.33 g of N-(3-triethoxysilylpropyl)-4-hydroxybutyramide, and 150 g of acetone were charged into a 500 ml flask to be dissolved and the resultant mixed solution was warmed while stirring the mixed solution with a magnetic stirrer to reflux. Next, 31.78 g of a 0.01 M hydrochloric acid aqueous solution was added to the mixed solution. The reaction was carried out for 240 minutes and then the resultant reaction solution was cooled down to room temperature. Then, 200 g of propylene glycol monoethyl ether was added to the reaction solution, and ethanol, water and hydrochloric acid being reaction by-products were distilled off under reduced pressure to obtain a hydrolysis-condensation product. To the hydrolysis-condensation product, 1.34 g of a 10% by weight triphenylsulfonium hydroxide aqueous solution was added to obtain a triphenylsulfonium succinic acid salt-containing Si polymer. The obtained polymer corresponded to a polymer having five types of unit structures of Formula (3-32). The molecular weight Mw of the obtained polymer measured by GPC was found to be 1,500 in terms of polystyrene.
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:28](=[O:29])[N:6]2[CH:7]([C:12]([O:14][CH:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C:8](=C)[CH2:9][S:10][C@H:5]12)[CH3:3].C(Cl)Cl.[O:33]=[O+][O-].CSC>O=O>[OH:1][CH:2]([CH:4]1[C:28](=[O:29])[N:6]2[C:7]([C:12]([O:14][CH:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])=[C:8]([OH:33])[CH2:9][S:10][C@H:5]12)[CH3:3]
Reactant: O=[O+][O-]
Reactant: C=C1CS[C@@H]2C(C(C)O)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Agent: O=O
Solvent: ClCCl
Solvent: CSC
Product: CC(O)C1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Reaction time: 0.33 h

Procedure:
Benzhydryl 7-(1-hydroxyethyl)-3-methylene-cepham-4-carboxylate (4.6 g.) is dissolved in 500 ml. of CH2Cl2, cooled to -78° and treated with a stream of ozone in oxygen until a blue color persists in the reaction mixture. After 1 minute at -78° the reaction mixture is treated with 5 ml. of dimethyl sulfide and the reaction mixture is allowed to stand at -78° for 20 min. followed by 1 hour at 25° C. The solvent is removed under reduced pressure to give the crude benzhydryl 7-(1-hydroxyethyl)-3-hydroxy-3-cephem-4carboxylate.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Cl)cc1
Reactant: NCc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(NCc2ccccc2)cc1
Yield: 77.8 %

Procedure:
According to the general procedure A, 4-chlorobenzonitrile (69 mg, 0.50 mmol) reacted with benzylamine (54 mg, 0.50 mmol) using 1 mol % of Pd(dba)2, 2 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (58 mg, 0.60 mmol) in toluene at 50° C. for 24 h to give the title compound (81 mg, 76%) as a solid: 1H-NMR (300 MHz, CDCl3): δ 7.41 (d, 2H, J=8.7 Hz), 7.36 (m, 5H), 6.61 (d, 2H, J=8.4 Hz), 4.73 (bs, 1H), 4.39 (d, 2H, J=5.4 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 151.05, 137.76, 133.67, 128.82, 127.64, 127.26, 120.36, 112.36, 98.99, 47.42. GC/MS(E): m/z 208 (M+), 209.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[Cl:17][C:18]1[CH:19]=[C:20]([OH:31])[CH:21]=[N:22][C:23]=1[O:24][C@@H:25]([CH3:30])[C:26]([F:29])([F:28])[F:27].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[C:3]([O:31][C:20]2[CH:21]=[N:22][C:23]([O:24][C@@H:25]([CH3:30])[C:26]([F:29])([F:28])[F:27])=[C:18]([Cl:17])[CH:19]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: C[C@H](Oc1ncc(O)cc1Cl)C(F)(F)F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@H](Oc1ncc(Oc2cc(F)c(C(=O)OC(C)(C)C)cc2Cl)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.6 %

Procedure:
tert-Butyl 5-chloro-2,4-difluorobenzoate (Preparation 59, 8.3 g, 33.4 mmol) was added to a solution of 5-chloro-6-[(1S)-2,2,2-trifluoro-1-methylethoxy]pyridin-3-ol (Preparation 231, 16.2 g, 66.8 mmol) and potassium carbonate (27.8 g, 200 mmol) in dimethyl sulfoxide (100 mL). The reaction mixture was stirred at room temperature for 18 hours then quenched with an aqueous solution of sodium hydroxide (1 M, 100 mL). A white precipitate formed and was collected by filtration to give the title compound as a white solid (9.2 g).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[C:11]([C:21]3[CH2:26][CH2:25][C:24]4([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[CH2:23][CH:22]=3)[CH:10]=2)[CH2:5][CH2:4]1.[CH3:32][O:33][CH2:34][CH2:35]Br.C(=O)([O-])[O-].[K+].[K+].C(#N)C>[Cl-].[Na+].O.C(OCC)(=O)C>[CH3:32][O:33][CH2:34][CH2:35][N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([N:6]3[CH2:7][CH2:8][CH:3]([O:2][CH3:1])[CH2:4][CH2:5]3)=[CH:10][C:11]=2[C:21]2[CH2:26][CH2:25][C:24]3([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:23][CH:22]=2)[CH2:16][CH2:17]1
Reactant: COCCBr
Reactant: COC1CCN(c2ccc(N3CCNCC3)c(C3=CCC4(CCCCC4)CC3)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COCCN1CCN(c2ccc(N3CCC(OC)CC3)cc2C2=CCC3(CCCCC3)CC2)CC1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 1-[4-(4-methoxypiperidin-1-yl)-2-spiro[5.5]undec-2-en-3-yl-phenyl]piperazine (20 mg, 0.0472 mmol) produced in Example (39e), 2-bromoethyl methyl ether (0.0049 mL, 0.0519 mmol), potassium carbonate (11.1 mg, 0.0803 mmol) and acetonitrile (1 mL) was stirred for 5 hours at an external temperature of 80° C. Ethyl acetate and brine were added to the reaction mixture and extraction was performed three times with ethyl acetate. The separated organic layers were concentrated. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 1-(2-methoxyethyl)-4-[4-(4-methoxypiperidin-1-yl)-2-spiro[5.5]undec-2-en-3-ylphenyl]piperazine.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[C:9](#[N:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C1(C)C=CC=CC=1>C(O)(C)C>[OH:3][NH:2][C:9](=[NH:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: NO
Reactant: CCCCCC#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCCCCC(=N)NO
Reaction time: 0.21 h

Procedure:
To a solution of 0.107 g (15.4 mmol) of hydroxylamine hydrochloride in 11 mL of isopropyl alcohol, 1.90 g (22.64 mmol) of sodium bicarbonate was added. The resulting mixture was stirred at 25° C. to 30° C. for 10-15 min. 1.0 g (10.2 mmol) of hexanenitrile was added and stirred at 80° C. to 85° C. for 3-4 h. After the reaction period, the reaction mixtures was cooled to 25° C. to 30° C., filtered and washed with 2 mL of isopropyl alcohol. The filtrate was collected and distilled out completely to obtain a crude residue. The residue with chased with 5 mL of toluene, to yield the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[CH:11]OCC)[C:6](OCC)=[O:7])[CH3:2].[CH3:16][NH:17][NH2:18]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:11]=[N:18][N:17]([CH3:16])[C:6]=1[OH:7])=[O:15])[CH3:2]
Reactant: CNN
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cnn(C)c1O
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 216 g (1 mol) of diethylethoxymethylenemalonate in 216 g of ethanol, there was added 46 g (1 mol) of methylhydrazine at 10° C. Then, at room temperature, the mixture was stirred and further refluxed for one hour, and thereafter the reaction mixture was left to stand. The precipitated crystals were filtered and dried to obtain 148 g of the title compound melting at 134°-135° C.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]2[C:9](=[O:17])[C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:15](=[O:16])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[OH:3][CH:1]([C:4]1[S:8][C:7]2[C:9](=[O:17])[C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:15](=[O:16])[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CC(=O)c1cc2c(s1)C(=O)c1ccsc1C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cc2c(s1)C(=O)c1ccsc1C2=O
Reaction time: 2 h
Yield: 93 %

Procedure:
To a suspension of 9 (3.0 g, 11.2 mmol) in MeOH (200 mL) was added NaBH4 (1.5 g, 39.7 mmol) and stirring continued for 2 h. After acidification with dilute HCl, the solution was extracted with CHCl3. The organic fraction was washed with water, dried, and condensed. The residue was purified by column chromatography (silica gel, CHCl3) to give 10 as a yellow solid (mp 166-168° C.) in a 93% yield. IR (KBr) 1650, 1680 (C═O), 3200-3600 (OH) cm−1; 1H NMR (DMSO-d6) δ 1.48 (d, J=6.3 Hz, 3H, CH3), 5.02-5.07 (m, 1H, CH), 6.10 (d, J=4.8 Hz, 1H, OH), 7.45 (s, 1, H-3), 7.62 (d, J=5.1 Hz, 1H, H-7), 8.15 (d, J=5.1 Hz, 1H, H-6); 13C NMR (DMSO-d6): δ 25.3 (C-2-CH3), 64.6 (C-2-CH), 120.7 (C-3), 126.1 (C-7), 135.5 (C-6), 163.0 (C-2), 174.0, 174.4 (C-4, C-8); MS m/z 264 (M+); Anal. (C12H8O3S2) C, H.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=O)=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.CCN=C=NCCCN(C)C.[CH2:33]([CH2:35][NH2:36])[OH:34]>CN(C=O)C.ClCCl>[Cl:21][C:10]1[CH:9]=[C:8]([NH:7][CH2:6][C:3]2[O:4][CH:5]=[CH:1][CH:2]=2)[C:13]([C:14]([NH:36][CH2:35][CH2:33][OH:34])=[O:16])=[CH:12][C:11]=1[S:17](=[O:19])(=[O:18])[NH2:20]
Reactant: NCCO
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1cc(C(=O)NCCO)c(NCc2ccco2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.6 %

Procedure:
To furosemide (1.013 g, 3.0627 mmol) in DMF (3 mL) was added EDAC (608.3 mg, 3.173 mmol) in dichloromethane (3 mL) and then ethanolamine (185 μL, 3.065 mmol). The reaction solution was stirred at ambient temperature for 3 hours, and concentrated to dryness under high vacuum. The crude product was treated with water, and the resultant gum collected and chromatographed on silica gel eluting with methanol:dichloromethane (1:20) to give the title compound (476 mg, 42% yield). Mp 183-185° C. 1H NMR (300 MHz, CD3OD) δ8.17 (s, 1H), 7.45 (m, 1H), 6.94 (s, 1H), 6.37-6.36 (m, 1 H), 6.32-6.31 (m, 1H), 4.44 (s, 2H), 3.70-3.66 (m, 2H), 3.32-3.29 (m, 2H). 13C NMR (75 MHz, CD3OD) δ 170.4, 153.0, 152.7, 143.6, 136.7, 131.3, 127.5, 114.8, 114.4, 111.4, 108.5, 61.5, 43.2, 40.7. LRMS (APIMS) m/z 374(MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][C:3]=1[CH3:12].[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([NH:13][CH:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]2)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1F
Reaction time: 38 h
Yield: 64 %

Procedure:
1,4-Difluoro-2-methyl-5-nitrobenzene (1.5 mol, 260 mg) in dimethylformamide (10 mL) was treated under argon at room temperature with 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (1.5 mmol, 300.5 mg, 1 eq) and diisopropylethylamine (1.5 mmol, 260 μL, 1 eq) then stirred at 70 (→80) ° C. for 38 h. The mixture was concentrated under vacuum, treated with water and extracted twice with ether. Organics were combined, dried on MgSO4 and concentrated under vacuum to give a red-brown residue which was chromatographed (0-25% ethyl acetate/petrol ether 6 CV) to give the title compound as a red solid (0.96 mmol, 340 mg, 64% yield). M+H=298.07, main fragment (molecule has lost its tert-butyl group).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O>>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:12]1[N:13]([CH:18]([CH3:19])[CH3:20])[N:14]=[C:15]2[C:11]=1[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]2
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: OB(O)c1ccccc1Cl
Product: CC(C)n1nc2c(c1-c1ccccc1Cl)CCNCC2
Yield: 49.9 %

Procedure:
The title compound (90 mg) was prepared according to Example 189 using 266 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 292 mg of 2-chlorophenylboronic acid. MS (ESI): exact mass calculated for C16H20ClN3, 289.13; found, m/z 290.4 [M+H]+, 292.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.65-7.63 (m, 1H), 7.58-7.49 (m, 2H), 7.41-7.39 (m, 1H), 4.66 (br s, 2H), 4.16 (m, 1H), 4.00-3.44 (m, 2H), 3.0-2.6 (m, 2H), 1.47-1.38 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[O:27]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[CH2:37][CH2:38][NH2:39])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:18])[NH:39][CH2:38][CH2:37][C:36]3[CH:40]=[CH:41][CH:42]=[C:34]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:35]=3)=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: NCCc1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4cccc(Oc5ccccc5)c4)cc3)c(Cl)cc21
Reaction time: 24 h
Yield: 91.2 %

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (51.6 mg, 0.137 mmol), in 1:1 DCM:DMF (0.1 M) was sequentially treated with 3-phenoxyphenethylamine (32.1 mg, 0.151 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31.5 mg, 0.164 mmol), and 1-hydroxy-7-azabenzotriazole (5.59 mg, 0.0411 mmol) at ambient temperature. After 24 hours the reaction was applied directly to a silica gel column and eluted with a gradient (15% to 60%) of ethyl acetate-hexanes to provide the title compound (71.6 mg, 0.125 mmol, 91.4% yield) as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:19]([CH2:20][CH2:21][C@:3]12[CH3:4])[C@:16]1([CH2:17][OH:18])[C@H:11]([CH2:12][C:13](=[O:23])[CH2:14][C@@H:15]1[CH3:22])[CH2:10][CH2:9]3.[CH3:24][Si:25]([CH3:28])([CH3:27])Cl.N1C=CC=CC=1>C1C=CC=CC=1>[CH3:22][C@@H:15]1[C@@:16]2([CH2:17][O:18][Si:25]([CH3:28])([CH3:27])[CH3:24])[C@@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:19]2[CH2:20][CH2:21][C@@:3]2([CH3:4])[C@H:5]3[CH2:6][CH2:7][C@@H:2]2[O:1][Si:25]([CH3:28])([CH3:27])[CH3:24])[CH2:12][C:13](=[O:23])[CH2:14]1
Reactant: C[Si](C)(C)Cl
Reactant: C[C@H]1CC(=O)C[C@@H]2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: C[C@H]1CC(=O)C[C@@H]2CC[C@H]3[C@@H]4CC[C@H](O[Si](C)(C)C)[C@@]4(C)CC[C@@H]3[C@]21CO[Si](C)(C)C

Procedure:
A mixture of 17β,19-dihydroxy-1α-methyl-5α-androstan-3-one, trimethylchlorosilane and pyridine in benzene is heated to its reflux temperature for a period of about 14 hours. The reaction mixture is vacuum filtered, the organic layer is washed with water, dried over magnesium sulfate and concentrated in vacuum. Crystallization of the residue from hexane yields 1α-methyl-17β,19-di(trimethylsiloxy)-5α-androstan-3-one.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:15])[C:4]=1[C:16]([O:18][CH3:19])=[O:17].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>ClCCl>[CH3:8][N:7]1[C:3]([CH2:2][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:4]([C:16]([O:18][CH3:19])=[O:17])[C:5](=[O:15])[N:6]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C1CCNC1
Reactant: COC(=O)c1c(CBr)n(C)n(-c2ccccc2)c1=O
Solvent: ClCCl
Product: COC(=O)c1c(CN2CCCC2)n(C)n(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.2 %

Procedure:
Methyl 5-(bromomethyl)-1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate (1.266 g, 3.9 mmol) was dissolved in dichlormethane (30 ml) and pyrrolidine (0.40 ml, 4.8 mmol) was added via syringe. The reaction was stirred under nitrogen at room temperature. After about 20 minutes, more pyrrolidine (0.090 ml, 1.1 mmol) was added, and stirring was continued for 3.5 hours. The reaction was concentrated and purified on silica gel (dichlormethane, MeOH, 2 N ammonia in MeOH) to give the desired methyl 1-methyl-3-oxo-2-phenyl-5-(pyrrolidin-1-ylmethyl)-2,3-dihydro-1H-pyrazole-4-carboxylate (1.182 g, 70% purity by HPLC, 2.62 mmol, 67% yield). MS (ESI pos. ion) m/z: 316 (MH+). Calc'd exact mass for C17H21N3O3: 315.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=C(C=CC=1)CBr.[N+:28]([C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34]Br)([O-:30])=[O:29]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[C:31]([N+:28]([O-:30])=[O:29])[CH:32]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cc1cccc(CBr)c1
Product: CCOC(=O)C1(Cc2cccc([N+](=O)[O-])c2)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
The title compound was prepared using the protocol described in Example 61, Step A substituting methyl N-tert-butoxycarbonyl-piperidine-4-carboxylate with ethyl N-tert-butoxycarbonyl-piperidine-4-carboxylate (Example 30, Step A), and 3-methylbenzyl bromide with 3-nitrobenzyl bromide.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:4]=1.[F:15][C:16]1[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([F:25])[C:17]=1[C:18]#[N:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]=[C:3]([CH2:2][O:24][C:23]3[C:16]([F:15])=[C:17]([C:20]([F:25])=[CH:21][CH:22]=3)[C:18]#[N:19])[S:7][N:6]=2)=[CH:9][CH:10]=1
Reactant: N#Cc1c(F)ccc(O)c1F
Reactant: Clc1ccc(-c2nsc(CBr)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)ccc(OCc2nc(-c3ccc(Cl)cc3)ns2)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.4 %

Procedure:
To a solution of 5-bromomethyl-3-(4-chlorophenyl)-[1,2,4]thiadiazole (0.24 g, 0.82 mmol) in DMF (7 ml) was added 2,6-difluoro-3-hydroxybenzonitrile (0.12 g, 0.74 mmol) and potassium carbonate (0.39 g, 2.90 mmol). The reaction mixture was stirred at 25° C. for 2 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), the reaction mixture was evaporated to dryness under vacuum, added 50 ml water and extracted with ethyl acetate (3×40 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified over silica gel (100-200 M, 15% EtOAc-Hexane) to get the desired product (0.30 g, 73%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[O:16]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1
Reactant: OCc1ccc(Oc2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(OCc2ccc(Oc3ccccc3)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
To a solution of ice-cooled ethyl 3-(3-fluoro-4-hydroxyphenyl)propanoate (0.19 g, 0.88 mmol), (4-phenoxyphenyl)methanol (0.12 g, 0.58 mmol) and triphenylphosphine (0.23 g, 0.88 mmol) in tetrahydrofuran (5 mL) was added dropwise diethyl azodicarboxylate (a 40% solution in toluene, 0.40 mL, 0.88 mmol), and the mixture was stirred at room temperature for 4 hours. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was washed with water, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=8:2) to give the title compound (0.16 g, yield 71%) as an oily matter.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([N+]([O-])=O)=[CH:4][C:3]=1[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:22].NC1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C([N+]([O-])=O)=CC=1C(Cl)=O.C(O)CCCC.C(=O)([O-])[O-].[K+].[K+].[CH3:64][C:65]1[CH:70]=[CH:69][C:68]([SH:71])=[CH:67][CH:66]=1>O.CN1CCCC1=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([S:71][C:68]2[CH:69]=[CH:70][C:65]([CH3:64])=[CH:66][CH:67]=2)=[CH:4][C:3]=1[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:22]
Reactant: Cc1ccc(S)cc1
Reactant: CCCCCOC(=O)c1cc([N+](=O)[O-])c2c(c1N)C(=O)c1ccccc1C2=O
Agent: Nc1c(C(=O)Cl)cc([N+](=O)[O-])c2c1C(=O)c1ccccc1C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCO
Solvent: CN1CCCC1=O
Product: CCCCCOC(=O)c1cc(Sc2ccc(C)cc2)c2c(c1N)C(=O)c1ccccc1C2=O
Reaction time: 1.5 h
Yield: 72.4 %

Procedure:
7.7 g of pentyl 1-amino-4-nitroanthraquinone-2-carboxylate, prepared from 1-amino-4-nitroanthraquinone-2-carboxylic acid chloride and n-pentanol, 2.7 g of anhydrous potassium carbonate and 2.7 g of 4-methylthiophenol are introduced into 50 cc of N-methylpyrrolidone, and the mixture is heated to 125°-130° C. in the course of 1 hour and is stirred at this temperature until, after about 1.5 hours, complete reaction has been achieved. The reaction mixture is allowed to cool and is diluted at 40° C. with 20 cc of water. When the mixture has cooled completely, the dyestuff which has been precipitated is filtered off with suction and washed with a mixture of N-methylpyrrolidone and water and then with hot water. After drying at 60° C., 6.7 g of n-pentyl 1-amino-4-(4-methylphenylmercapto)-anthraquinone-2-carboxylate are obtained, corresponding to a yield of 72% of theory. The dyestuff can be purified by recrystallisation from dimethylformamide.