Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([OH:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[F:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:23]2[CH2:22][CH2:21][C:20]([C:17]3[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=3)([OH:26])[CH2:25][CH2:24]2)=[CH:7][CH:8]=1
Reactant: Fc1ccc(OCCCCl)cc1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OC1(c2ccc(Cl)cc2)CCN(CCCOc2ccc(F)cc2)CC1

Procedure:
A mixture of 2.83 g of 1-chloro-3-(p-fluorophenoxy)-propane, 3.18 g of 4-(p-chlorophenyl)-4-hydroxypiperidine, 0.8 g of sodium carbonate and 60 ml of dimethylformamide is heated at a temperature of 80° - 90°C for 10 hours. After cooling, the reaction mixture is poured into water. The precipitate is collected by filtration and dried to give 1-[3-(p-fluorophenoxy)-propyl]-4-(p-chlorophenyl)-4-hydroxypiperidine, M.P. 134 - 135°C. Recrystallization from benzene gives the purified product, M.P. 136° - 137°C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[N:15]=[C:14]3[N:16](COCC[Si](C)(C)C)[N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][CH2:26][C:27]5[CH:31]=[CH:30][S:29][CH:28]=5)[N:20]=4)[C:13]3=[CH:12][N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCl>[N:1]1([CH2:7][CH2:8][NH:9][C:10]2[N:15]=[C:14]3[NH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][CH2:26][C:27]5[CH:31]=[CH:30][S:29][CH:28]=5)[N:20]=4)[C:13]3=[CH:12][N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(NCc3ccsc3)n2)c2cnc(NCCN3CCOCC3)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(NCc2ccsc2)nc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of crude (2-morpholin-4-yl-ethyl)-[3-{6-[(thiophen-3-ylmethyl)-amino]-pyridin-2-yl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-amine (149 mg, crude) in dichloromethane (2 mL) was added CF3COOH (2 mL). This mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. A saturated aqueous solution of NaHCO3 was added to the residue, and then extracted with ethyl acetate (3×15 mL). The combined organic phase was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was washed with dichloromethane (2 mL) to give (2-morpholin-4-yl-ethyl)-(3-{6-[(thiophen-3-ylmethyl)-amino]-pyridin-2-yl}-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-amine as a white solid. (Yield 46 mg, 18% over two steps).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12]1.CN1CCOCC1>CCO.[Pd]>[OH:1][C:2]1[C:7]([NH:8][C:16]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:17])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccnc1O
Reactant: O=C(Cl)C1CCCC1
Agent: [Pd]
Solvent: CN1CCOCC1
Solvent: CCO
Product: O=C(Nc1cccnc1O)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
A sample of 10% Pd on C (0.40 g) was added to a solution of 2-hydroxy-3-nitropyridine (3.52 g, 25.0 mmol, 1 equiv) in EtOH. The reaction mixture was stirred at room temperature under H2 atmosphere (balloon) overnight and then was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was dissolved in CH3CN (100 mL), cooled to 0° C., and cyclopentanecarbonyl chloride (25 mmol, 3.04 mL, 1 equiv) and NMM (2.75 mL, 25 mmol, 1 equiv) were added sequentially. The resulting mixture was stirred at 0° C. for 20 min, then was partitioned between water (400 mL) and 10% CH3OH in CH2Cl2 (2×400 mL). The organic layers were dried over Na2SO4, concentrated, and the resulting residue recrystallized from CH2Cl2/hexanes to afford the title intermediate as a off-white solid (3.36 g, 65%); mp=242-243° C.; IR (cm−1) 3263, 1644, 1605, 1521, 1199; 1H NMR (DMSO-d6) δ 1.51-1.57 (m, 2H), 1.60-1.72 (m, 4H), 1.79-1.88 (m, 2H), 2.98-3.08 (m, 1H), 6.20 (t, 1H, J=6.9), 7.08 (d, 1H, J=6.6), 8.23 (d, 1H, J=7.5), 9.02 (s, br. 1H), 11.95 (s, br. 1H); Anal. C11H14N2O2: C, H, N.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([O:19]C)=[O:18])=[CH:12][C:11]=3[CH:21]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([OH:19])=[O:18])=[CH:12][C:11]=3[CH:21]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(C)s3)ccc2OCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
In THF (10.5 ml) and methanol (5.2 ml) was dissolved methyl 7-(5-methyl-2-thienyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (525 mg), and to the mixture was added 1N sodium hydroxide (10.5 ml). The mixture was stirred at room temperature for 2 hours. Under reduced pressure, the organic solvent was removed, and to the residue was added ethyl acetate. The mixture was extracted with water, and to the aqueous layer was added 6N hydrochloric acid to make the solution pH 4-5, which was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed to give 7-(5-methyl-2-thienyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (410 mg).
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1>>[F:1][C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]2=[CH:13][CH:14]=1
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Reactant: [F-]
Agent: [K+]
Product: O=C1OC(=O)c2cc(F)ccc21
Temperature: 220 °C

Procedure:
A mixture of 20 parts of anhydrous potassium fluoride, 20 parts of 4-chlorophthalic anhydride and 2 parts of Carbowax® m-peg 2000 catalyst was charged to a reaction vessel and heated at 220° C. for about 18 hours. The product was removed by distillation, then recrystallized from a chloroform-hexane solution to yield 8.13 parts of 4-fluorophthalic anhydride having a melting point of 76°-78° C. Following the procedure of Example 3B, the fluorophthalic anhydride is reacted with ammonia to yield the ammonium salts of a mixed 4- and 5-fluorophthalamic acid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[C:7]([C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=O)=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:24][NH2:25]>>[F:1][C:2]1[CH:9]=[C:8]2[C:7]([C:11]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)=[N:24][NH:25]2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(C(=O)c2ccc3ccccc3c2)c(F)cc1F
Reactant: NN
Solvent: O
Product: N#Cc1cc2c(-c3ccc4ccccc4c3)n[nH]c2cc1F

Procedure:
A total of 2.1 g of 2,4-difluoro-5-(naphthalene-2-carbonyl)-benzonitrile was allowed to react with hydrazine monohydrate by the procedure of Production Example II-10-c and thereby yielded 1.6 g of the title compound as a colorless powder.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][NH:7][C:8]1[N:13]=[CH:12][C:11]([C:14]2[NH:22][C:21]3[C:20](=[O:23])[N:19]([CH2:24][CH2:25][CH3:26])[C:18](=[O:27])[N:17]([CH2:28][CH2:29][CH3:30])[C:16]=3[CH:15]=2)=[CH:10][CH:9]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>C1COCC1>[F:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:40])[N:7]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[NH:22][C:21]4[C:20](=[O:23])[N:19]([CH2:24][CH2:25][CH3:26])[C:18](=[O:27])[N:17]([CH2:28][CH2:29][CH3:30])[C:16]=4[CH:15]=3)=[CH:12][N:13]=2)[CH2:6][CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)=[CH:34][CH:33]=1
Reactant: CCCn1c(=O)c2[nH]c(-c3ccc(NCC4CCCO4)nc3)cc2n(CCC)c1=O
Reactant: O=C=Nc1ccc(F)cc1
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(-c3ccc(N(CC4CCCO4)C(=O)Nc4ccc(F)cc4)nc3)cc2n(CCC)c1=O
Temperature: 94 °C
Reaction time: 72 h
Yield: 45 %

Procedure:
9b (30 mg) was suspended in THF (2 ml) in a pressure tube, 4-fluorophenyl isocyanate (300 mg) was added and the mixture was stirred at 94° C. for 3 days. After cooling to room temperature, the mixture was evaporated to almost dry and the solid was filtered, washed with ether and purified by column (14 g silica gel, RT Scientific) (CH2Cl2:MeOH=100:0 to 98:2) to give the product (11b) (18 mg). HPLC condition: MeOH 40%-95% gradient in 10 minutes then MeOH 95%. Retention Time=11.60 min. 1H NMR (DMSO, d6): 0.83-0.95 (m, 6H), 1.53-2.00 (m, 8H), 3.60-4.20 (m, 9H), 6.85 (s, 1H), 7.15 (t, 2H, J=8.7 Hz), 7.51 (m, 3H), 8.30 (dd, 1H, J1=8.7 Hz, J2=2.4 Hz), 8.94 (d, 1H, J=2.4 Hz), 10.69 (s, 1H), 12.50 (s, 1H). MS: m/z 549 (M+H)+.
Reaction SMILES: Br[CH:2]1[C:10]2[N:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:8]=[C:7]([CH3:17])[C:6]=2[C:5](=[O:18])[CH2:4][C:3]1([CH3:20])[CH3:19].C[C:22](C)=[O:23]>CO.[N+]([O-])([O-])=O.[Ag+]>[CH3:22][O:23][CH:2]1[C:10]2[N:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[N:8]=[C:7]([CH3:17])[C:6]=2[C:5](=[O:18])[CH2:4][C:3]1([CH3:20])[CH3:19]
Reactant: Cc1nn(-c2ccccn2)c2c1C(=O)CC(C)(C)C2Br
Reactant: CC(C)=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CO
Product: COC1c2c(c(C)nn2-c2ccccn2)C(=O)CC1(C)C
Reaction time: 48 h
Yield: 25 %

Procedure:
A solution of 0.1N silver nitrate in methanol (12 ml, 1.2 mmol) was added to a solution of 7-bromo-1-(2-pyridyl)-3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydroindazole (0.2 g, 0.6 mmol), prepared as described in example 4, in acetone (12 ml). After stirring for about 48 hours, 6 ml of a 0.1N silver nitrate solution in methanol were added. The reaction mixture was stirred for further 72 hours and then filtered. The solvent was evaporated and the residue was chromatographed on silica gel (cyclohexane:ethyl acetate=90:10) to yield the title compound as a colourless solid (0.044 g, 25%): m.p. 86-89° C.
Reaction SMILES: [I:1]I.[CH3:3][C@:4]12[CH2:21][CH2:20][C@H:19]3[C@@H:9]([CH2:10][CH2:11][C:12]4[C@:17]3([CH3:18])[CH2:16][CH2:15][C:14](=[O:22])[CH:13]=4)[C@@H:8]1[CH2:7][CH2:6][C:5]2=[O:23]>C(O)(=O)C>[I:1][CH:15]1[CH2:16][C@@:17]2([CH3:18])[C:12]([CH2:11][CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:4]2([CH3:3])[C@H:8]3[CH2:7][CH2:6][C:5]2=[O:23])=[CH:13][C:14]1=[O:22]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: II
Solvent: CC(=O)O
Product: C[C@]12CC(I)C(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Yield: 109.1 %

Procedure:
2.79 g (11 mmol) of iodine is added to 2.86 g (10 mmol) of androst-4-ene-3,17-dione and 0.875 g (11 mmol) of CuO in 30 ml of glacial acetic acid with stirring at room temperature. The reaction mixture is stirred under nitrogen atmosphere for 24 hours at 60° C. Under reduced pressure, acetic acid is distilled off and the residue is mixed with 50 ml of water. The water phase is extracted 3 times with 50 ml of ethyl acetate each, the combined ethyl acetate phases are washed with sodium thiosulfate solution and dried on sodium sulfate. After concentration by evaporation of the solution, 4.5 g of crude product is obtained. After recrystallization from ethyl acetate, 2.9 g of 2-iodo-androst-4-ene-3,17-dione (70% of theory) of melting point 92° C. is obtained.
Reaction SMILES: [H][H].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-])=O)=[N:11]2)=[CH:6][CH:5]=1>[Pt].C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[NH2:23])=[N:11]2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccccc1COc1ccn(-c2ccc(Cl)cc2)n1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1ccccc1COc1ccn(-c2ccc(Cl)cc2)n1
Reaction time: 20 h
Yield: 86.4 %

Procedure:
At 20-25° C. and a hydrogen pressure of 20 bar, a mixture of 30 g (90 mmol) of 2-[1-(4-chlorophenyl)pyrazol-3-yl]oxymethylnitrobenzene and 2 g of platinum on activated carbon (5%) in 200 ml of ethyl acetate was hydrogenated with stirring for approximately 20 hours. The mixture was filtered through Al2O3 and the solvent was removed from the filtrate by distillation, giving 23.3 g of the aniline as yellow crystals of m.p. 81-83° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([CH3:14])[CH:6]=[CH:5]2.[Se](=O)=[O:16]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([CH:14]=[O:16])[CH:6]=[CH:5]2
Reactant: O=[Se]=O
Reactant: COc1cc2nc(C)ccc2cc1F
Solvent: C1COCCO1
Solvent: O
Product: COc1cc2nc(C=O)ccc2cc1F
Yield: 73.4 %

Procedure:
To 6-fluoro-7-methoxy-2-methylquinoline (1.4 g, 7.3 mmol) in dioxane/water (10 ml/l mL) at ambient temperature was added selenium dioxide (0.97 g, 8.8 mmol) and the reaction was heated to reflux for 2-3 hours. After cooling, the reaction was filtered and the solids were washed with DCM. The filtrate was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 6-fluoro-7-methoxyquinoline-2-carbaldehyde (1.1 g, 73% yield) as a tan solid.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1OC)NC(=O)N[C:6]2=[O:16].N1C=CC(=O)NC1=O.C[Si](C)(C)CCO[CH2:30][Cl:31]>>[CH2:6]([O:16][CH2:30][Cl:31])[C:5]1[CH:4]=[CH:3][CH:12]=[CH:11][CH:10]=1
Reactant: COc1cc2[nH]c(=O)[nH]c(=O)c2cc1OC
Reactant: C[Si](C)(C)CCOCCl
Agent: O=c1cc[nH]c(=O)[nH]1
Product: ClCOCc1ccccc1

Procedure:
In a similar manner to the procedures described in Reference Example 3, reactions were carried out using 6,7-dimethoxyquinazoline-2,4-dione, instead of pyrimidine-2,4-dione, and using 2-(trimethylsilyl)ethoxymethyl chloride, instead of benzyloxymethyl chloride, to give the title compound (yield 93%) as a white powder.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:29][C:30]1[S:31][C:32](B2OC(C)(C)C(C)(C)O2)=[C:33]([CH3:35])[N:34]=1>C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:32]3[S:31][C:30]([CH3:29])=[N:34][C:33]=3[CH3:35])[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: Cc1nc(C)c(B2OC(C)(C)C(C)(C)O2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3sc(C)nc3C)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 90 °C

Procedure:
1-Methylethyl((cis)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (for a preparation see Example 61) (100 mg, 0.271 mmol) were dissolved in ethanol (1 mL) and Toluene (1 mL), mixed with potassium carbonate (74.9 mg, 0.542 mmol), 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboroian-2-yl)-1,3-thiazole (78 mg, 0.325 mmol, available from Maybridge), followed by tetrakis(triphenylphosphine)palladium(0) (15.65 mg, 0.014 mmol) and refluxed under nitrogen at 90° C. for 18.5 hours reaction time. The reaction mixture was partitioned between distilled water (40 mL) and EtOAc (40 mL). The organic and aqueous layers were run off and the latter extracted twice more using EtOAc (2×40 mL). Organic fractions were combined, dried (brine (80 mL) and sodium sulfate), filtered and evaporated to dryness to give a pale white solid (0.123 g). This was purified on a 25+M Biotage silica column, eluting with cyclohexane:EtOAc (1:0 to 1:3). Product-containing fractions were evaporated to dryness to give a clear, colourless solid which was repurified on a 12+M column using the same solvent system. Analysis of the product still showed contamination and it was further purified using MDAP. Product-containing fractions were evaporated to dryness to give a clear, colourless solid (41 mg). LCMS (Method C): Rt=0.76, MH+=402
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@H:9]([OH:28])[CH2:10][N:11]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])(C)(C)C.N(CCO)(CCO)CCO.[H][H].[OH-].[Na+]>C(O)(C)C.[C].[Pd]>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([N:11]([CH2:10][C@@H:9]([OH:28])[C@@H:8]([NH2:7])[CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: [H][H]
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: OCCN(CCO)CCO
Solvent: CC(C)O
Product: CC(C)CN(C[C@@H](O)[C@@H](N)Cc1ccccc1)S(=O)(=O)c1ccc(N)cc1
Temperature: 42.5 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
(1S,2R)-{1-benzyl-2-hydroxy-3-[isobutyl-(4-nitro-benzenesulfonyl)-amino]-propyl}-carbamic acid tert-butyl ester (3, 100 g), 10% palladium carbon (10 gm) and triethanolamine (2 gm) were suspended in isopropyl alcohol. The reaction was heated to 40-45° C. and maintained under 4-6 kg/cm2 of hydrogen pressure for 3 hours. After completion of reaction, the mass was filtered and hydrochloric acid (70 mL) was added to the filtered mass. The solution was heated to reflux and maintained for 2-3 hours. After completion of reaction the mass was cooled to 25-35° C., the reaction mass pH was adjusted to 6.0-7.0 with 20% sodium hydroxide solution and distilled out isopropyl alcohol under vacuum at below 55° C. Ethanol (200 mL) and water (400 mL) was added to the distillate, the mass pH was adjusted to 9.0-10.0 with 20% sodium hydroxide solution at 25-35° C. and maintained the stirring for 2 hours at 25-35° C. The mass was cooled to 0-5° C., filtered and wash with water. The wet product was taken into ethanol (350 mL), maintained the stirring for 30 minutes at reflux temperature. The mass was cooled to 2-4° C., stirred for 2 hours, filtered and washed with ethanol (50 mL). The wet product was dried under normal drying to get title compound 1 (Yield 60 g).
Reaction SMILES: [C:1]12([C:11]3[C:12]([OH:30])=[CH:13][C:14]4[CH2:15][CH2:16][C@@H:17]5[C@@H:26]([C:27]=4[CH:28]=3)[CH2:25][CH2:24][C@@:22]3([CH3:23])[C@H:18]5[CH2:19][CH2:20][C:21]3=[O:29])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(O)C.[BH4-].[Na+]>CO>[C:1]12([C:11]3[C:12]([OH:30])=[CH:13][C:14]4[CH2:15][CH2:16][C@@H:17]5[C@@H:26]([C:27]=4[CH:28]=3)[CH2:25][CH2:24][C@@:22]3([CH3:23])[C@H:18]5[CH2:19][CH2:20][C@@H:21]3[OH:29])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: C[C@]12CC[C@@H]3c4cc(C56CC7CC(CC(C7)C5)C6)c(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: C[C@]12CC[C@@H]3c4cc(C56CC7CC(CC(C7)C5)C6)c(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reaction time: 2 h
Yield: 59.5 %

Procedure:
2-(1-Adamantyl)-3-hydroxyestra-1,3,5(10)-trien-17-one (250 mg, 0.62 mmol) was added to cold ethanol (25 mL) and methanol (10 mL) to give a turbid solution. Sodium borohydride (NaBH4, 140 mg) was added in one portion and the reaction was continued with stirring for 2 hours. Solvents were removed on a rotary evaporator and crushed ice was added. On standing overnight, the initially formed oil became a solid. The solid was filtered and washed with water until the filtrate was pH neutral. The solid was dried in a vacuum oven at 50° C. to give the crude product (0.25 g), which was purified by flash chromatography (silica gel eluted with 18% ethyl acetate in hexanes). The pure product (200 mg, 79.6%) was recrystallized from chloroform and hexanes to obtain crystals (150 mg), and was then characterized as follows: (i) melting point=174-175° C.; (ii) 1H NMR (CDCl3, 300 MHZ) δ0.81 (s, 3H, C18—CH3), 2.76 (m, 2H, C6—CH2), 3.73 (t, 1H, C17—H), 4.78 (s, 1H, C3—OH), 6.38 (s, 1H, C4—H), 7.16 (s, 1H, C1—H); (iii) 13C NMR (CDCl3, 300 MHZ) δ10.95, 23.02, 26.33, 27.12, 28.77, 28.98 (3×C), 30.49, 36.54, 36.71, 37.01 (3×C), 38.89, 40.68 (3×C), 43.20, 44.22, 49.96, 81.99, 116.84, 124.06, 132.06, 133.83, 135.20, 152.36.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26](O)=[O:27])=[CH:9]2.N1(O)C2C=CC=CC=2N=N1.[CH2:39]([S:46][C:47]([CH3:55])([CH:50]([O:53][CH3:54])[O:51][CH3:52])[CH2:48][NH2:49])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:39]([S:46][C:47]([CH3:55])([CH:50]([O:51][CH3:52])[O:53][CH3:54])[CH2:48][NH:49][C:26]([C:10]1[NH:11][C:12]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=2[N:15]([CH3:25])[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)(=[O:18])=[O:17])=[O:27])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Reactant: COC(OC)C(C)(CN)SCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(C)(SCc3ccccc3)C(OC)OC)cc2c1
Yield: 76.3 %

Procedure:
To a mixture of 5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylic acid (1.62 g), 1H-1,2,3-benzotriazol-1-ol (919 mg), 2-(benzylthio)-3,3-dimethoxy-2-methylpropan-1-amine (1.02 g) and N,N-dimethylformamide (30 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.53 g) at room temperature, and the mixture was added overnight at room temperature, and concentrated under reduced pressure. The residue was diluted with ethyl acetate and water. The organic layer was washed with saturated brine, dried over sodium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give the title compound (1.96 g, yield 76%) as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (4:1).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[OH:7][C:8]([CH3:41])([CH3:40])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:24]=[CH:23][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:21][CH:20]=2)[CH3:18])[CH2:12][CH2:11]1.BrC1C=NC(C[CH:50]2[C:55](Br)=[CH:54][NH:53][C:52]([CH3:57])=[N:51]2)=NC=1>CN(C)C=O>[OH:7][C:8]([CH3:40])([CH3:41])[CH2:9][C@@:10]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:15][C:14](=[O:16])[N:13]([C@H:17]([C:19]2[CH:20]=[CH:21][C:22]([C:55]3[CH:54]=[N:53][C:52]([CH3:57])=[N:51][CH:50]=3)=[CH:23][CH:24]=2)[CH3:18])[CH2:12][CH2:11]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC1=NC(Cc2ncc(Br)cn2)C(Br)=CN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ncc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
2 M aqueous Na2CO3 solution (1.67 mL) was added to a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.80 g) and 5-bromo-2-(5-bromo-2-methyl-1,4-dihydro-pyrimidin-4-ylmethyl)-pyrimidine (0.40 g) in dimethylformamide (5 mL). The resulting mixture was sparged with argon for 5 min, before [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) dichloromethane complex (82 mg) was added. The mixture was heated to 100° C. and stirred at this temperature overnight. After cooling to ambient temperature, water was added, and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel (CH2Cl2/MeOH 95:5->80:20) followed by HPLC (MeCN/H2O/NH4OH) to afford the title compound (340 mg) which was crystallized from 1:3 EtOAc/diisopropylether by scratching to yield a solid, mp 112-115° C. Yield: 0.25 g (34% of theory). Mass spectrum (ESI+): m/z=446 [M+H]+