Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([CH:14]2[CH2:18][NH:17][CH:16]([C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])[CH2:23][CH2:22]3)=[O:20])[CH2:15]2)[N:13]=1.[F:35][C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH:39]=O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[N:11][N:12]([C@@H:14]2[CH2:18][N:17]([CH2:39][C:38]3[CH:41]=[CH:42][CH:43]=[C:36]([F:35])[CH:37]=3)[C@H:16]([C:19]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[C:29]#[N:30])[CH2:25][CH2:26]3)=[O:20])[CH2:15]2)[N:13]=1
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(n3nnc(-c4ccc(F)cc4F)n3)CN2)CC1
Reactant: O=Cc1cccc(F)c1
Product: N#Cc1ccccc1N1CCN(C(=O)[C@@H]2C[C@H](n3nnc(-c4ccc(F)cc4F)n3)CN2Cc2cccc(F)c2)CC1
Yield: 13.3 %

Procedure:
As described for Example 1e, 2-(4-{4-[5-(2,4-difluoro-phenyl)-tetrazol-2-yl]-pyrrolidine-2-carbonyl}-piperazin-1-yl)-benzonitrile (60 mg, 0.13 mmol) was converted, using 3-fluoro-benzaldehyde (17 mg, 0.14 mmol) instead of benzaldehyde, to the title compound (9.9 mg, 13.3%) as light yellow oil. MS m/e=573.1 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH3:12])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>N1C=CC=CC=1>[C:7]([O:6][C:4](=[O:5])[CH2:3][CH:2]([O:1][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20])[CH2:11][CH3:12])([CH3:8])([CH3:10])[CH3:9]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(O)CC(=O)OC(C)(C)C
Solvent: c1ccncc1
Product: CCC(CC(=O)OC(C)(C)C)OS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 7.9 %

Procedure:
A solution of t-butyl 3-hydroxypentanoate (5.22 g, 0.3 mol) in dry pyridine (10 ml) was treated with p-toluenesulfonyl chloride (6.3 g, 0.33 mol) dissolved in dry pyridine (15 ml). The resulting solution was stirred at room temperature for 24 h and poured into ice-water (300 ml). The oily layer was separated and dissolved in ether (140 ml). This solution was washed with water (3×150 ml) and dried over anhydrous MgSO4. Evaporation of the ether under reduced pressure gave an oil (7.75 g, 78.7%). ir (neat) νmax : 1725 (C=O of ester) and 1178 cm-1 (sulfonate); 1Hmr (CDCl3) δ: 0.80 (3H, t), 1.38-1.78 (2H, m), 1.42 (9H, s), 2.32-2.62 (2H, m), 2.38 (3H, s), 4.82 (H, m), 7.25 (2H, d) and 7.70 ppm (2H, d). Anal. calcd for C15H24O5S: C 56.94, H 7.65; found: C 58.39, H 7.54.
Reaction SMILES: [CH2:1]([C:4]1[N:5]=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:7][C:8]=1[CH2:9][CH3:10])[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH:24]O.[OH-].[Na+]>CCOC(C)=O.O.C1COCC1>[C:11]([C:6]1[O:7][C:8]([CH2:9][CH3:10])=[C:4]([CH2:1][CH2:2][CH2:3][OH:24])[N:5]=1)([CH3:13])([CH3:12])[CH3:14]
Reactant: OO
Reactant: C=CCc1nc(C(C)(C)C)oc1CC
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1oc(C(C)(C)C)nc1CCCO
Reaction time: 3 h

Procedure:
0.693 g of 4-allyl-2-tert-butyl-5-ethyl-oxazole (3.585 mmol) was dissolved under an argon atmosphere in 10 ml of abs. THF and treated at 0° with 3 eq. of 9-BBN (0.5 M, hexane). After 3 h at ambient temperature, when TLC indicated the absence of starting material, 20.9 ml of 30% H2O2 and 10. 3 ml of 3N NaOH was added dropwise, but simultaneously. After cessation of the strongly exothermic reaction, the mixture was diluted with AcOEt and water, the layers separated, the aqueous phase reextracted with AcOEt, and the combined organic phases washed with water. Drying over sodium sulfate and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=1/1) afforded 0.400 g of 3-(2-tert-butyl-5-ethyl-oxazol-4-yl)-propan-1-ol as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][N:32]([C:6](=[O:7])[C:5]4[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=4[C:11]([F:14])([F:13])[F:12])[CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3ccc(F)cc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 4-fluoro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (83.5% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 7.97, 7.46-7.42, 7.39-7.29, 6.97, 4.07-4.01, 3.89-3.67, 3.58-3.51, 3.36-3.32, 1.53-147, 0.76-0.69, 0.48-0.42, 0.10-0.06. 13C NMR (75 MHz, CDCl3) δ 166.7, 163.9, 162.8, 160.6, 159.9, 145.4, 129.6, 129.5, 127.0, 119.7, 119.4, 114.8, 114.7, 114.4, 114.38, 112.5, 44.4, 44.5, 44.3, 41.3, 39.6, 34.4, 8.6, 4.1. MS (ES+) m/z 466.1 (M+1).
Reaction SMILES: O1CCCC1.[S:6]1[CH2:11][CH2:10][CH2:9][S:8][CH2:7]1.C([Li])CCC.[C:17]([C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][CH2:28][C:29]2=[O:34])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCCCCC>[C:17]([C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][CH2:28][C:29]2([CH:7]1[S:8][CH2:9][CH2:10][CH2:11][S:6]1)[OH:34])(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C1CSCSC1
Reactant: O=C1CCc2c1cccc2C(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1ccccc1)c1cccc2c1CCC2(O)C1SCCCS1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
In 100 ml. of dry tetrahydrofuran is dissolved 3.6 g. of 1,3-dithian and while the solution is chilled to -30° C. in nitrogen gas streams and stirred, 10 ml. of a 20% solution of n-butyl lithium in hexane is added dropwise over a period of about 15 minutes. After the dropwise addition has been completed, the solution is stirred at that temperature for 2 hours and, then, at -5° C. for 30 minutes. The solution is chilled again to -20° C and, under stirring, a solution of 7.1 g. of 4-benzoylindan-1-one in 75 ml. of dry tetrahydrofuran is added dropwise. After the dropwise addition has been completed, the mixture is stirred at that temperature for 1 hour, after which it is allowed to stand at 0° C. overnight. Then, the solvent is distilled off under reduced pressure. To the residue is added 15 ml. of dilute hydrochloric acid, followed by extraction with ether. The extract is washed with water and aqueous sodium chloride and, then, dried. The solvent is distilled off under reduced pressure and the residue is purified by column chromatography on silica gel (500 g. silica gel, eluted with a 20:1 mixture of benzene and ethyl acetate). The described procedure gives 2-(4-benzoyl-1-hydroxy-1-indanyl)-1,3-dithian as an oily product. The infrared absorption spectrum (neat) of this product is in good agreement with the assumed structure, absorbing at 1660 cm-1 (ketone) and 3450 cm-1 (hydroxyl).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7](B(O)O)[N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.[OH:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26](Br)[CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C=O)C>C(OCC)(=O)C.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>[C:14]([O:13][C:11]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[CH:6]=[C:7]1[C:26]1[CH:25]=[N:24][CH:23]=[C:22]([OH:21])[CH:27]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: Oc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccc(Cl)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1c(-c2cncc(O)c2)cc2ccc(Cl)cc21
Temperature: 110 °C

Procedure:
A microwave flask is charged with 6-chloro-1-Boc-indole-2-boronic acid (1.91 g, 6.46 mmol), 3-hydroxy-5-bromopyridine (0.750 g, 4.31 mmol), potassium phosphate (1.83 g, 8.62 mmol) and DMF (15 mL). The flask is evacuated and filled with nitrogen thrice and Pd(PPh3)4 (0.250 g, 0.215 mmol) is added. The flask is evacuated and filled with nitrogen thrice again, and heated to 110° C. under microwave irradiation for 45 min. Pd(PPh3)4 (0.100 g, 0.086 mmol) is added and the vial is heated again to 110° C. under microwave irradiation for 45 min. The mixture is then diluted with ethyl acetate and washed with water thrice. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica gel flash chromatography (dichloromethane-methanol, 19:1) to afford 6-chloro-2-(5-hydroxy-pyridin-3-yl)-indole-1-carboxylic acid tert-butyl ester as a solid. MS (ESI) m/z 345.06 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][C@H:9]([NH:17]C(=O)[C@@H](O)C3C=CC=CC=3)[CH2:8]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O>C(O)C.CCOC(C)=O.[OH-].[Na+].O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][C@H:9]([NH2:17])[CH2:8]2)=[CH:28][CH:29]=1
Reactant: O=C(N[C@H]1Cc2ccccc2N(Cc2ccc(F)cc2)C1)[C@@H](O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: N[C@H]1Cc2ccccc2N(Cc2ccc(F)cc2)C1
Temperature: 85 °C
Reaction time: 24 h

Procedure:
To a solution of (S)—N—((S)-1-(4-fluorobenzyl)-1,2,3,4-tetrahydroquinolin-3-yl)-2-hydroxy-2-phenylacetamide (350 mg, 0.90 mmol) in absolute ethanol (20 mL) was added concentrated sulfuric acid (2 mL). The reaction mixture was stirred at 85° C. for 24 hours. The mixture was diluted with EtOAc (100 mL), 6 M NaOH aqueous solution (20 mL) and water (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (100 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by flash chromatography using a gradient (0-10% MeOH in EtOAc). The desired product (S)-1-(4-fluorobenzyl)-1,2,3,4-tetrahydroquinolin-3-amine was obtained as yellow oil (169 mg, 73% yield). 1H NMR (DMSO-d6) 400 MHz δ 7.32-7.25 (m, 2H), 7.18-7.10 (m, 2H), 6.91-6.85 (m, 2H), 6.50-6.42 (m, 2H), 4.49 (d, J=16.8 Hz, 1H for AB system), 4.42 (d, J=16.8 Hz, 1H for AB system), 3.36-3.28 (m, 2H), 3.18-3.10 (m, 1H), 3.01 (dd, J=11.0, 8.6 Hz, 1H), 2.84 (dd, J=15.7, 2.7 Hz, 1H), 1.70 (br. s, 2H). LCMS m/e 258 (M+H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:25]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:23]=[CH:22][C:21]=1[C:34]1[CH:42]=[C:41]2[C:37]([C:38]([NH:51][C:52](=[O:56])[CH2:53][CH2:54][CH3:55])=[N:39][N:40]2COCC[Si](C)(C)C)=[CH:36][CH:35]=1.C(OCC)(=O)C>O1CCCC1>[Cl:19][C:20]1[CH:25]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:23]=[CH:22][C:21]=1[C:34]1[CH:42]=[C:41]2[C:37]([C:38]([NH:51][C:52](=[O:56])[CH2:53][CH2:54][CH3:55])=[N:39][NH:40]2)=[CH:36][CH:35]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OCc4ccccc4)cc3Cl)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OCc4ccccc4)cc3Cl)ccc12
Yield: 60.5 %

Procedure:
14.2 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1.3 g of N-[6-[2-chloro-4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 60 cm3 of tetrahydrofuran, and the mixture is refluxed for 18 hours; after cooling, 75 cm3 of ethyl acetate are added and the organic phase is washed successively with 50 cm3 of saturated sodium hydrogen carbonate solution and with 50 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.) to give 1.8 g of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (60/40 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) and the residue is taken up in 10 cm3 of diisopropyl ether, filtered off, washed with 2×10 cm3 of diisopropyl ether and dried under reduced pressure (90 Pa; 45° C.) to give 600 mg of N-[6-[2-chloro-4-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide in the form of white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8](O)[CH2:9][N:10]([CH2:17][CH2:18]O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH2:33]([NH2:36])[CH:34]=[CH2:35].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:9][N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:17][CH2:18][N:36]2[CH2:33][CH:34]=[CH2:35])=[CH:4][CH:3]=1
Reactant: OCCN(C[C@H](O)c1ccc(Cl)cc1)c1ccccc1
Reactant: C=CCN
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CCN1CCN(c2ccccc2)C[C@H]1c1ccc(Cl)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 19.9 %

Procedure:
To (R)-1-(4-chlorophenyl)-2-[(2-hydroxyethyl)(phenyl)amino]-1-ethanol (1.68 g, 4.94 mmol) produced in Example 11, ethyl acetate (10 mL) and triethylamine (1.75 g, 3.5 equivalents) were added. The mixture was cooled to 5° C. Methanesulfonyl chloride (1.81 g, 3.2 equivalents) was added dropwise thereto, and then allylamine (1.69 g, 6.0 equivalents) was added dropwise thereto. The mixture was stirred at 5° C. for 1 hour and then at 25° C. for 2 hours. The reaction mixture was transferred in an autoclave, and stirred at 50° C. for 18 hours. The mixture was cooled to room temperature, and then 10 wt % aqueous solution of sodium carbonate (8.38 g) was added to the mixture. After the organic layer and aqueous layer were separated, the organic layer was washed twice with distilled water (10 mL). The obtained organic layer was concentrated to give 1.11 g of a concentrate as yellow oil (chemical purity: 30.2 area %). The concentrate was purified by column chromatography (gel: silica gel, solvent: ethyl acetate/hexane=1/9), and the obtained fractions were concentrated and dried under vacuum, to obtain 307 mg of the title compound as colorless oil (yield: 19%, chemical purity: 98.1 area %). The retention time in the chemical purity analysis method was 56.6 min.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=O.[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([NH2:25])[CH:19]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]2[N:24]=[C:4]([C:3]3[C:2]([NH2:1])=[N:9][CH:8]=[C:7]([C:10]4[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=4)[CH:6]=3)[NH:25][C:20]=2[CH:19]=1
Reactant: Nc1ncc(-c2ccc(F)cc2)cc1C=O
Reactant: Nc1ccc(F)cc1N
Product: Nc1ncc(-c2ccc(F)cc2)cc1-c1nc2ccc(F)cc2[nH]1

Procedure:
Using the procedure of step (b) in Example 15, utilizing 2-amino-5-(4-fluorophenyl)nicotinaldehyde and 4-fluoro-o-phenylenediamine gave 3-(6-fluoro-1H-benzimidazol-2-yl)-5-(4-fluorophenyl)-pyridin-2-amine.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:11][C:6]1[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=1[CH2:8][CH2:9][CH3:10])[CH3:21]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CBr
Product: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1O

Procedure:
1-(2,4-Dihydroxy-3-propyl-phenyl)-ethanone was treated with ethyl 2-bromoacetate and processed as described in the synthesis of example 20a. Yield, 80%, white solid; mp, 61-62° C.; MS (EI): 280 (M+), 265, 251 (100%), 193; analysis: C15H20O5 requires C, 64.27; H, 7.19; found: C, 64.56; H, 7.39%.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:5]2[N:6]=[C:7]([NH2:16])[CH:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:4]2[N:3]=1.[C:18]([C:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)([CH3:22])[CH3:21])#[N:19].C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[C:18]([C:20]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([NH:16][C:7]2[CH:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:4]3[N:3]=[C:2]([CH3:1])[CH:17]=[C:5]3[N:6]=2)=[O:28])=[CH:30][CH:31]=1)([CH3:22])[CH3:21])#[N:19]
Reactant: CC(C)(C#N)c1ccc(C(=O)Cl)cc1
Reactant: Cc1cc2nc(N)cc(-c3ccccc3)n2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)C#N)cc3)cc(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
In a 50 ml pear flask was added 2-methyl-7-phenylpyrazolo[1,5-a]pyrimidin-5-amine (10A, 450 mg, 2.0 mmol) in pyridine (10 ml). To this mixture was added 4-(2-cyanopropan-2-yl)benzoyl chloride (550 mg, 2.6 mmol) and the mixture was stirred at room temperature for 2 h. Saturated NaHCO3 was then added and pyridine was removed in vacuo. The residue was partitioned between saturated NaHCO3 and ethyl acetate, and the aqueous layer was extracted one more time with ethyl acetate. Combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2, 15-25% EtOAc/hexanes) to give the titled compound (380 mg, 48%). 1H NMR (DMSO-d6) δ: 11.35 (s, 1H), 8.10-8.16 (m, 2H), 8.04-8.09 (m, 2H), 7.96 (s, 1H), 7.67-7.73 (m, 2H), 7.60-7.66 (m, 3H), 6.41 (s, 1H), 2.41 (s, 3H), 1.74 (s, 6H); ESI-MS: m/z 396.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(#N)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:9])[CH:4]=1)[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(Cl)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.2 %

Procedure:
To a solution of 4-chloro-3-fluoro-phenol (0.50 g, 3.34 mmol) in acetonitrile (8 ml) were added caesium carbonate (1.31 g, 4.01 mmol) and ethyl bromoacetate (0.40 ml, 3.51 mmol). The resulting suspension was stirred at room temperature for 1 hour and was then poured onto ice/aq. ammonium chloride solution (50 ml) and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2: heptane/ethyl acetate=gradient 100:0-70:30) to yield a colourless oil (0.81 g, 100%); 1H NMR (300 MHz, CDCl3): 7.30 (1H, d), 6.73 (1H, dd), 6.66 (1H, dd), 4.59 (2H, s), 4.28 (2H, q), 1.30 (3H, t).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH:13]=[C:14]2[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:6]1)(=O)C.[OH-].[Na+]>CO>[N:26]1[CH:27]=[CH:28][CH:29]=[C:24]([C:14]2[C@:15]3([CH2:17][CH2:18][C@H:19]4[C@@H:10]([CH2:9][CH2:8][C@@H:7]5[C@:20]4([CH3:23])[CH2:21][CH2:22][C@@H:5]([OH:4])[CH2:6]5)[C@@H:11]3[CH2:12][CH:13]=2)[CH3:16])[CH:25]=1
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(c4cccnc4)=CC[C@@H]32)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Temperature: 80 °C
Yield: 78.1 %

Procedure:
The method followed that described in Example 2, but using 3α-acetoxy-17-(3 -pyridyl)-5α-androst-16-ene (2.33 g, 5.9 mmol), methanol (40 ml), aqueous sodium hydroxide (10% w/v, 8 ml), and the mixture was heated at 80° C. for 20 min. Chromatography, on elution with toluene-methanol (40:1 ), afforded the title compound (1.62 g, 78%) which crystallised from toluene, m.p. 198°-199° C.; 1H-NMR(CDCl3) inter alia. δ0.84(3H,s,19-CH3), 1.00(3H,s,18-CH3), 4.06(1H,m,3β-H), 5.97(1H,m,16-H), 7.21(1H,m,Py 5-H), 7.64(1H,m,Py 4-H), 8.45(1H,m,Py 6-H), 8.61(1H,m,Py 2-H). Anal. Calcd: C, 82.00; H,9.46; N,3.99. Found: C,81.78; H,9.47; N.3.96%.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:17]=3)[NH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>C1COCC1>[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:20][CH2:21][N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)[CH:17]=3)[NH:12][N:11]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4ccccc4)c3c2)cc1
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1n[nH]c2ccc(OCCN3CCCC3)cc12
Yield: 21.8 %

Procedure:
A solution of toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl ester (0.347 g, 0.734 mmol) and pyrrolidine (1.0 mL, 12 mmol) in THF (8 mL) was stirred at 70° C. in a sealed tube for 6 hours. After cooling somewhat, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 7.5% methanol in chloroform. After drying at 55° C. in vacuo, 3-benzenesulfonyl-5-(2-pyrrolidin-1-yl-ethoxy)-1H-indazole as a pale yellow solid (0.0595 g, 21.8%) was obtained. This was dissolved in methanol and chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacuo at 75° C. for 16.5 hours to yield the hydrochloride as a yellow foam (0.0598 g). Mass Spectrum (+EI, [M+H]+) m/z 372.