Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[OH-].[Na+]>C(O)C>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]=1[CH2:11][NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:24])=[O:2])=[CH:5][N:6]=1
Reactant: COC(=O)c1ccc(NCc2c(-c3ccccc3)noc2C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)O)cn1
Temperature: 80 °C
Yield: 91.1 %

Procedure:
To a suspension of 6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinic acid methyl ester (1.86 g, 5.50 mmol) in ethanol (100 mL) was added aqueous sodium hydroxide (1 N, 17 mL, 17 mmol) and the resulting suspension was heated to 80° C. for 0.5 h. After the solution was cooled to ambient temperature the solvent was distilled off and the residue was diluted with water (50 mL) and washed with tert-butylmethylether (50 mL). The organic layers were extracted with aqueous sodium hydroxide (1 N, 20 mL) and the combined aqueous layers were acified with aqueous hydrochloric acid (25%) to pH=3 and were extracted with a mixture of ethyl acetate and methanol (4:1, 30 mL). Drying over sodium sulfate and concentration afforded the title compound (1.55 g, 91%) which was obtained as a white solid. MS: m/e=310.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11](S(C)(=O)=O)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2].OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]2[CH2:63][CH2:62][N:61]([C:64](=[O:73])[CH2:65][N:66]3[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]3)[CH2:60][CH2:59]2)=[CH:54][CH:53]=1>CC(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[C:8]2[CH:13]=[N:12][C:11]([NH:51][C:52]3[CH:57]=[CH:56][C:55]([CH:58]4[CH2:63][CH2:62][N:61]([C:64](=[O:73])[CH2:65][N:66]5[CH2:67][CH2:68][N:69]([CH3:72])[CH2:70][CH2:71]5)[CH2:60][CH2:59]4)=[CH:54][CH:53]=3)=[N:10][C:9]=2[N:18]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[CH2:25][CH2:24][CH2:23]3)[CH:19]=1)=[O:5])[CH3:2]
Reactant: CN1CCN(CC(=O)N2CCC(c3ccc(N)cc3)CC2)CC1
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3ccc(C4CCN(C(=O)CN5CCN(C)CC5)CC4)cc3)ncc2c1=O
Temperature: 90 °C
Reaction time: 3 h
Yield: 16.8 %

Procedure:
(4-Piperidin-4-yl-phenyl)-carbamic acid tert-butyl ester (0.20 g, 0.72 mmol), (4-methyl-piperazin-1-yl)-acetic acid (0.11 g, 0.72 mmol), HOBt (0.10 g, 0.72 mmol), DCI (0.14 g, 0.72 mmol), and DIEA (0.10 g, 0.72 mmol) were all combined in DMF (5 mL). After 16 h, water (10 mL) and CH2Cl2 (10 mL) were added. The organic layer was washed with water (3×10 mL), dried (MgSO4) and concentrated. Chromatography (0-15% EtOAc/hexanes gradient) provided 0.24 g (83%) of (4-{1-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenyl)-carbamic acid tert-butyl ester. (4-{1-[2-(4-Methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenyl)-carbamic acid tert-butyl ester (0.72 mmol) was diluted in CH2Cl2 (3 mL) and TFA (3 mL) was added. After 1 h, the reaction mixture was concentrated. Water (2 mL) was added and the solution was frozen and lyophilized overnight to provide (0.16 g) (72%) of 1-[4-(4-Amino-phenyl)-piperidin-1-yl]-2-(4-methyl-piperazin-1-yl)-ethanone. 8-Indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (32.5 mg, 0.079 mmol) and 1-[4-(4-Amino-phenyl)-piperidin-1-yl]-2-(4-methyl-piperazin-1-yl)-ethanone tri-TFA salt (52 mg g, 0.079 mmol) were combined in i-PrOH (1 mL) and TEA (25 mg, 0.25 mmol) was added and the mixture was heated to 90° C. After 3 h, the reaction mixture was concentrated and purified by preparative HPLC (30 mL/min 5-100% MeCN/H2O gradient over 10 min) and lyophilized to provide 8.6 mg of 8-indan-5-yl-2-(4-{1-[2-(4-methyl-piperazin-1-yl)-acetyl]-piperidin-4-yl}-phenylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.23 (s, 1H), 8.39 (s, 1H), 7.40-7.42 (m, 2H), 7.17-7.26 (m, 3H), 7.06-7.09 (m, 2H), 4.30 (q, 2H, J=7.1 Hz), 3.07 (br s, 1H), 2.87-2.93 (m, 6H), 2.48-2.67 (m, 7H), 2.28 (br s, 3H), 2.05-2.12 (m, 2H), 1.72-1.82 (m, 2H), 1.49 (br s, 2H), 1.31 (t, 3H, J=7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][C:11]([C:22]([N:24]3[CH2:28][C:27](=[O:29])[NH:26][CH2:25]3)=[O:23])=[CH:12][C:13]=2[C:14]2[CH:15]=[C:16]([C:20]#[N:21])[CH:17]=[CH:18][CH:19]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C2SC(C(O)=O)=CC=2C2C=CC(F)=C(C#N)C=2)C=C([F:37])C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][C:11]([C:22]([N:24]3[CH2:28][C:27](=[O:29])[NH:26][CH2:25]3)=[O:23])=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([F:37])=[C:16]([C:20]#[N:21])[CH:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: N#Cc1cc(-c2cc(C(=O)O)sc2-c2cc(F)cc(Cl)c2)ccc1F
Reactant: N#Cc1cccc(-c2cc(C(=O)N3CNC(=O)C3)sc2-c2cc(F)cc(Cl)c2)c1
Product: N#Cc1cc(-c2cc(C(=O)N3CNC(=O)C3)sc2-c2cc(F)cc(Cl)c2)ccc1F

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 1 starting with 82.3 mg (0.22 mmol) of the compound from Example 22A. 35.0 mg (35% of theory) of the title compound are obtained.
Reaction SMILES: [OH-].[Na+].Cl.[NH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13]>O>[CH2:9]([O:8][C:6]([CH2:5][NH:4][CH2:13][CH2:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])[CH3:10]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)CCNCC(=O)OCC
Temperature: 25 °C

Procedure:
A 4.7 M aqueous solution of sodium hydroxide (50 mL) is added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) is added and the mixture is stirred at room temperature until completion of the reaction is ascertained by TLC. After 19 h the solution is partitioned with dichloromethane (3×100 mL). The organic layer is dried with anhydrous sodium sulfate, filtered and evaporated. The residue is distilled to afford AA (28.8 g, 61%).
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH:6]([CH3:10])[CH2:7][CH2:8][N:9]=1.[NH2:11][C:12]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][C:13]=1[C:14](O)=[O:15]>CN(C=O)C.O>[CH3:10][CH:6]1[CH2:7][CH2:8][N:9]2[C:3](=[N:11][C:12]3[C:13]([C:14]2=[O:15])=[CH:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[CH:20]=3)[CH2:4][CH2:5]1
Reactant: Nc1cc(C(=O)O)ccc1C(=O)O
Reactant: COC1=NCCC(C)CC1
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCc2nc3cc(C(=O)O)ccc3c(=O)n2CC1
Temperature: 25 °C
Yield: 2.2 %

Procedure:
A solution of (E)-7-methoxy-4-methyl-3,4,5,6-tetrahydro-2H-azepine (1.1 g) and 2-aminoterephthalic acid (1.4 g, 7.7 mmol) in DMF (30 mL) was stirred at 100° C. for 4 h. After it was cooled to room temperature, the reaction was diluted with water (80 mL) and extracted with ethyl acetate (2×60 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by silica gel chromatography to give 47 mg of desired product.
Reaction SMILES: C([O:4][P:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([C:19]2[NH:23][C:22]3[CH:24]=[C:25]([Cl:40])[C:26]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[CH:30][CH:29]=4)=[CH:27][C:21]=3[N:20]=2)=[O:18])[CH:12]=1)(=[O:10])[O:6]C(C)C)(C)C.C[Si](N[Si](C)(C)C)(C)C.Br[Si](C)(C)C>C(Cl)Cl>[C:31]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:30]=[CH:29][C:28]([C:26]2[C:25]([Cl:40])=[CH:24][C:22]3[NH:23][C:19]([C:17]([C:13]4[CH:12]=[C:11]([P:5](=[O:4])([OH:10])[OH:6])[CH:16]=[CH:15][CH:14]=4)=[O:18])=[N:20][C:21]=3[CH:27]=2)=[CH:33][CH:32]=1
Reactant: CC(C)OP(=O)(OC(C)C)c1cccc(C(=O)c2nc3cc(-c4ccc(-c5ccccc5)cc4)c(Cl)cc3[nH]2)c1
Agent: C[Si](C)(C)Br
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: ClCCl
Product: O=C(c1cccc(P(=O)(O)O)c1)c1nc2cc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of compound 14-3 (56 mg, 0.098 mmol) in 2 mL of CH2Cl2 was added hexamethyldisilizane (0.3 mL), followed by bromo trimethylsilane (0.13 mL, 0.98 mmol). The reaction was allowed to stir for 18 h at ambient temperature. The organic solvent was removed in vacuo, followed by the addition of H2O (2 mL). The crude product was sonicated and yielded a yellow suspension. The product was collected by vacuum filtration and washed three times with CH2Cl2 and two times with MeOH. The product was then dried in vacuo to give the title compound 14-4 as a yellow solid. 1H NMR δ 7.37-7.42 (1H, m), 7.47-7.57 (5H, m), 7.73-7.77 (5H, m), 7.95 (2H, t), 8.60 (2H, t); LC-MS: m/e 489(M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[C:6](=[O:16])[NH:5]2.[CH3:17][C:18]1(OC)[CH2:22][CH2:21][C:20]([CH3:25])(OC)O1>>[CH3:17][C:18]1[N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[C:6](=[O:16])[NH:5]3)[C:20]([CH3:25])=[CH:21][CH:22]=1
Reactant: COC1(C)CCC(C)(OC)O1
Reactant: Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Product: Cc1ccc(C)n1-c1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-]

Procedure:
13.5 mmol of 6-amino-7-nitro-2,3(1H,4H)-quinoxalinedione were reacted with 13.5 mmol of 2,5-dimethyl-2,5-dimethoxytetrahydrofuran by the method of Example 5d.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([CH:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:25][OH:26])=[O:23])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:33]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][N:19]([C:22]([CH:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:25][O:26][S:35]([CH3:34])(=[O:37])=[O:36])=[O:23])[CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:33]=1
Reactant: O=C(C(CO)c1ccccc1)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC(C(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1)c1ccccc1

Procedure:
Dissolve 0.40 g (0.9 m mole) of 8-chloro-11-[1-(2-hydroxy-1-phenylethylcarbonyl)-4-piperidylidene]-6,11-dihydro-5H-benzo[5,6]-cyclohepta-[1,2-b]pyridine (Example 41 of Table 2) in 10 mL of pyridine and stir under nitrogen. Add 0.15 g (1.3 m mole) of methanesulfonyl chloride and stir for 20 hours. Concentrate under vacuo and triturate the residue with ether. Purify the resulting solid by silica gel chromatography using 2% MeOH saturated with amonia, and 98% CH2 Cl2 as the solvent. The product is obtained as a white solid, mp=110.7°-111.6° C.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].Cl.Cl[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccn(CCN2CCOCC2)n1

Procedure:
Into an 8-dram vial, 3-Nitro-1H-pyrazole (0.50 g, 4.4 mmol), 4-(2-chloroethyl)-morpholine hydrochloride (1.23 g, 6.63 mmol), Potassium carbonate (1.83 g, 13.3 mmol), and Acetonitrile (30 mL, 600 mmol) were added. The reaction mixture was heated. The reaction was poured over ice. The reaction was partitioned with water and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with DCM and methanol as eluant (1 to 3% methanol). The collected fractions afforded 4-[2-(3-Nitro-pyrazol-1-yl)-ethyl]-morpholine a yellow solid (0.75 g, 75%).
Reaction SMILES: [Br:1][C:2]1[N:3]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[N:31]=[N:32][N:33](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:34]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([CH2:11][N:12]1[C:16]([CH:17]=[O:18])=[C:15]([Cl:19])[N:14]=[C:13]1[CH2:20][CH2:21][CH2:22][CH3:23])[CH:7]=[CH:6]2.Cl.[OH-].[Na+]>CO>[Br:1][C:2]1[N:3]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]2[NH:34][N:33]=[N:32][N:31]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([CH2:11][N:12]1[C:16]([CH:17]=[O:18])=[C:15]([Cl:19])[N:14]=[C:13]1[CH2:20][CH2:21][CH2:22][CH3:23])[CH:7]=[CH:6]2
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nn(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)c(Br)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nn(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Temperature: 10 °C
Yield: 32.6 %

Procedure:
Methanol (2 ml) was added to 1-{[3-bromo-2-[2-(2-(triphenylmethyl)-2H-tetrazol-5-yl)phenyl]-2H-indazol-5-yl]methyl}-2-butyl-4-chloro-1H-imidazole-5-carbaldehyde (0.200 g, 0.256 mmol) as obtained in Example 11, and the mixture was stirred at 10°C. Thereto was added 2N hydrochloric acid (0.23 ml), and the mixture was stirred at room temperature for 2 hours. Then, 2N hydrochloric acid (0.23 ml) and methanol (2.5 ml) were added thereto, and the mixture was stirred for 3 hours, after which conc. hydrochloric acid (2 ml) was added thereto and the mixture was stirred for 15.5 hours. 10N Aqueous sodium hydroxide was added to adjust its pH to 13, and the methanol was distilled away in an evaporator. The resultant solid was filtered, and the cake was washed twice with 1N sodium hydroxide (2.5 ml). The filtrate was washed with ether (5 ml), and conc. hydrochloric acid was dropwise added while stirring so as to adjust its pH to 4-5. The resultant solid was filtered off and washed twice with ion-exchanged water (5 ml). Drying in vacuo at 37° C. gave 45 mg of 1-{[3-bromo-2-[2-(1H-tetrazol-5-yl)phenyl]-2H-indazol-5-yl]methyl}-2-butyl-4-chloro-1H-imidazole-5-carbaldehyde.
Reaction SMILES: [C:1]([Mg]Cl)#[CH:2].[O:5]1[CH:11]2[CH:6]1[CH2:7][N:8]([C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10]2>C1COCC1.OS(O)(=O)=O>[C:12]([N:8]1[CH2:9][CH2:10][CH:11]([OH:5])[CH:6]([C:1]#[CH:2])[CH2:7]1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(c1ccccc1)N1CCC2OC2C1
Reactant: C#C[Mg]Cl
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: C#CC1CN(C(=O)c2ccccc2)CCC1O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
To a solution of ethynyl magnesium chloride in THF (5 mmole) at 0° C., is added dropwise a solution of 40 (5.8 mmole) in THF. The mixture is allowed to stir at 0-10° C. for 1 hour, then at room temperature for an additional hour and then heated with gentle reflux for 30 mm. The reaction mixture is added to ice-water and the formed precipitate, Mg(OH)2, is dissolved in 30% H2SO4. The product formed is extracted repeatedly with methylene chloride. Standard work-up and flash chromatography affords 54.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8](C=O)=[C:7]([O:13][CH3:14])[CH:6]=1.[OH:15]O>OS(O)(=O)=O.CO.O>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([OH:15])=[C:7]([O:13][CH3:14])[CH:6]=1
Reactant: OO
Reactant: COc1cc(OCCO)ccc1C=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COc1cc(OCCO)ccc1O

Procedure:
A solution of 4-(2-hydroxyethoxy)-2-methoxybenzaldehyde (465.6 mg, 2.373 mmol) and 30 wt % hydrogen peroxide (0.313 mL, 3.04 mmol) in conc. H2SO4 (0.0475 mL) and MeOH (4.75 mL) was stirred overnight at 25° C. under N2. After this time the mixture was diluted with water (20 mL) and extracted with CH2Cl2 (3×30 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 55% EtOAc in hexanes over 2394 mL, gradient to 100% EtOAc over 999 mL) to afford 4-(2-hydroxyethoxy)-2-methoxyphenol, as a colorless oil. Rf=0.30 (50% EtOAc/hexanes). LCMS calc.=207.1; found=206.9 (M+Na)+. 1H NMR (500 MHz, CHCl3): δ 6.77 (d, J=8.6 Hz, 1 H); 6.47 (d, J=2.8 Hz, 1 H); 6.34 (dd, J=8.7, 2.8 Hz, 1 H); 5.82 (s, 1 H); 3.98 (t, J=4.6 Hz, 2 H); 3.90 (t, J=4.5 Hz, 2 H); 3.76 (s, 3 H); 2.96 (s, 1 H).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:14]([NH:16][C@@H:17]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:18][CH2:19][CH2:20][CH3:21])=[O:15])[CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[CH:11]2)=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:1][C@@H:2]([C:14]([NH:16][C@@H:17]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[CH2:18][CH2:19][CH2:20][CH3:21])=[O:15])[CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[CH:11]2)=[CH:6][CH:5]=1
Reactant: CCCC[C@@H](NC(=O)[C@@H](Cc1ccc2ccccc2c1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC[C@@H](NC(=O)[C@H](N)Cc1ccc2ccccc2c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 98.4 %

Procedure:
To a solution of Boc-DNal-DNle-OBzl (233 mg) in dichloromethane (2 ml) was added TFA (5 ml) and the mixture was stirred at room temperature for 13 h. The mixture was concentrated in vacuo. The residue was dissolved in dichloromethane, washed with sat. aq. NaHCO3, water and brine successively, dried over MgSO4 and evaporated in vacuo to give the product (185 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([NH:14][C:15]2[C:20]([CH:21]([CH3:23])[CH3:22])=[CH:19][C:18]([OH:24])=[CH:17][C:16]=2[CH:25]([CH3:27])[CH3:26])=[O:13])[CH2:7][CH2:6]1.[CH2:28]([O:30][CH2:31][CH2:32]Br)[CH3:29].[F-].[K+]>CN(C=O)C>[CH:21]([C:20]1[CH:19]=[C:18]([O:24][CH2:29][CH2:28][O:30][CH2:31][CH3:32])[CH:17]=[C:16]([CH:25]([CH3:27])[CH3:26])[C:15]=1[NH:14][C:12](=[O:13])[CH2:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][OH:1])[CH2:10][CH2:9]1)([CH3:23])[CH3:22]
Reactant: CCOCCBr
Reactant: CC(C)c1cc(O)cc(C(C)C)c1NC(=O)CN1CCN(CCCO)CC1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCCOc1cc(C(C)C)c(NC(=O)CN2CCN(CCCO)CC2)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 78 %

Procedure:
To a solution of this acetamide (500 mg, 1.32 mmol) solution in DMF (12 ml) were added 2-bromoethyl ethyl ether (7 ml) and potassium fluoride 40 wt. % on alumina (40 wt. %, 1.96 g, 13.2 mmol), and the mixture was stirred at room temperature for 5 days. After the catalyst was filtered off, the filtrate was diluted with water and extracted with ethylacetate. The organic layer was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was evaporated therefrom. The resulting residue was purified by a silica gel column chromatography (developing solvent; chloroform:methanol=30:1) to provide 448 mg (yield 78%) of N-[2,6-diisopropyl-4-(2-ethoxyethyloxy)phenyl]-2-[4-(3-hydroxypropyl)piperazin-1-yl]acetamide as colorless powdery crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[CH3:8].S(Cl)([Cl:16])=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([Cl:16])=[O:13])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(CCC(=O)O)cc1C
Solvent: ClCCl
Product: Cc1ccc(CCC(=O)Cl)cc1C

Procedure:
A 1 L three-neck round bottom flask equipped with a condenser, magnetic stir bar, thermometer, and a nitrogen inlet was charged with 3-(3,4-dimethylphenyl) propionic acid (64.0 g, 0.359 mol), dichloromethane (500 mL), and thionyl chloride (110 mL, 1.5 mol). The reaction mixture was stirred at reflux for 7 hours. Dichloromethane and excess thionyl chloride were removed by rotary evaporation under reduced pressure to yield 3-(3,4-dimethylphenyl)propionyl chloride as an amber oil (70.6 g, 100% conversion by GC).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[C:3]=1[S:23][CH3:24].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl.ClCCl>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]([F:21])([F:20])[F:22])[C:3]=1[S:23]([CH3:24])=[O:33]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CS(=O)c1c(C(F)(F)F)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reaction time: 6 h

Procedure:
A stirred solution of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylthio-3-trifluoromethylpyrazole (1.0 g) in chloroform (40 ml) was treated with m-chloroperbenzoic acid (0.42 g), portionwise at room temperature. After stirring for 6 hours, the solution was diluted with dichloromethane and washed in turn with sodium sulphite solution, sodium hydroxide solution, and water. The solution was dried over anhydrous magnesium sulphate, and evaporated in vacuo to give a yellow oil. Purification by chromatography on silica (Merck, 230-400 mesh, 0.7 kg cm-2) eluting with dichloromethane-ethylacetate (4:1) gave 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylsulphinyl-3-trifluoromethylpyrazole in the form of a white solid, m.p. 142°-145° C. with decomposition.
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[CH2:2]2.[Cu](C#N)[C:18]#N.C[Mg]Br>C1COCC1>[OH:6][C@H:5]1[C@H:1]([CH3:18])[CH2:2][N:3]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4]1
Reactant: N#C[Cu]C#N
Reactant: O=C(OCc1ccccc1)N1CC2OC2C1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Temperature: -20 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To solution of benzyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (9.6 g, 43.8 mmol) in THF (150 mL) was added copper cyanide (3.92 g, 43.8 mmol) and the resulting suspension was cooled to −20° C. with dry ice-ice-water-acetone bath. Methylmagnesium bromide (3 M in diethylether) (29.2 mL, 88 mmol) was added via syringe dropwise and the resulting mixture was stirred at this temperature for 1 h. At this time, TLC analysis of the resulting slurry (after quenching an aliquot with MeOH) indicated total comsumption of substrate to give a single, more polar component. At this time, the reaction was carefully quenched at −20° C. by a slow dropwise addition of 50 mL of sat. aq. ammonium chloride. The cooling bath was removed and the mixture was allowed to stir vigorously for 1 h while warming to rt. Solid was removed by vacuum filtration through Celite and the filter cake was rinsed with dichloromethane (80 mL×3). The resulting two layers of the filtrate were separated and the aqueous portion was extracted with dichloromethane (80 mL). The combined organic portions were washed with brine and dried over magnesium sulfate, filtered and concentrated to afford the title compound as a clear oil (9.2 g, 39.1 mmol, 89% yield). HPLC (method B) retention time=2.64 min. and LCMS (m+1)=236.2.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([OH:37])[C@@H:30]([OH:38])[C@@:29]2([CH3:39])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:40](OC(=O)C)(=[O:42])[CH3:41].N1C=CC=CC=1>C(Cl)Cl>[Si:1]([O:8][C@H:9]1[CH2:35][CH2:34][C@@:33]2([CH3:36])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:32]2[C@@H:31]([OH:37])[C@@H:30]([O:38][C:40](=[O:42])[CH3:41])[C@@:29]2([CH3:39])[C@H:15]3[CH2:16][C@@H:17]3[O:22][C@@:21]4([O:28][CH2:27][C@H:25]([CH3:26])[CH2:24][CH2:23]4)[C@@H:19]([CH3:20])[C@@H:18]32)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4[C@@H](O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@H](O)[C@H]2[C@@H](CC[C@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@@]32C)[C@@H]2C[C@@H]3O[C@]4(CC[C@@H](C)CO4)[C@@H](C)[C@@H]3[C@@]12C

Procedure:
(3β,5α,11β,12β,25R)-3-(t-butyldimethylsilyloxy)spirostan-11,12-diol was selectively acetylated with acetic anhydride, pyridine and dimethylaminopydriine in methylene chloride to give the title compound.