Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=O)=[CH:15][CH:14]=1.[Cl:23][C:24]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:25]=1C(OC)=O>C1COCC1>[Cl:23][C:24]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:25]=1[C:20](=[O:22])[CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: COC(=O)c1ccc(F)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)c2ccc(F)cc2Cl)cc1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
230 ml of a 2M solution of NaHMDS in THF are introduced into 250 ml of THF under nitrogen. The solution is cooled to −60° C. and then 30.5 g of (4-methoxyphenyl)acetic acid in 120 ml of THF are added at this temperature. After 1 h 30 min at −60° C., 33 g of methyl 2-chloro-4-fluorobenzoate are added and the mixture is stirred at −60° C. for 45 min and then allowed to return to 0° C. The reaction medium is poured onto 500 ml of ice-cold 2N HCl and extracted with ether and the extract is washed with water and then with a saturated aqueous sodium chloride solution. After drying, concentrating to dryness and then crystallizing from pentane, 27.4 g of the expected compound are obtained.
Reaction SMILES: [CH:1]1([C:6]#[N:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:18](=[N:20]/[S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])\[CH3:19]>C1COCC1>[C:6]([C:1]1([C@H:18]([NH:20][S@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[CH3:19])[CH2:5][CH2:4][CH2:3][CH2:2]1)#[N:7]
Reactant: N#CC1CCCC1
Reactant: C/C=N/[S@@](=O)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](N[S@@](=O)C(C)(C)C)C1(C#N)CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
In a flask, cyclopentanecarbonitrile (3.53 g, 37.1 mmol) was dissolved in THF (40 mL) and cooled at −78° C. LiHMDS (1.0 M in THF, 41 mL, 41 mmol) was added and the mixture stirred for 30 min at −78° C. A solution of (S)-2-methyl-propane-2-sulfinic acid (E)-ethylideneamide (crude from step 1, 1.82 g, 12.4 mmol) in THF (10 mL) was slowly added. The mixture was stirred at −78° C. for 2 h then allowed to warm to room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography (50-100% EtOAc/heptane) to afford 1.96 g (65%) of (S)-2-methyl-propane-2-sulfinic acid [(R)-1-(1-cyano-cyclopentyl)-ethyl]-amide as a white solid.
Reaction SMILES: Cl.C([N:9]([CH2:23][C@@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)[OH:25])[CH:10]1[CH2:16][CH2:15][CH2:14][C:13]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:12]=2[CH2:11]1)C1C=CC=CC=1.ClC1C=CC=CC=1>[Pd].CO>[ClH:32].[CH3:22][O:21][C:19]1[CH:18]=[CH:17][C:13]2[CH2:14][CH2:15][CH2:16][CH:10]([NH:9][CH2:23][C@@H:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[OH:25])[CH2:11][C:12]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CC(N(Cc1ccccc1)C[C@H](O)c1cccc(Cl)c1)CCC2
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: Clc1ccccc1
Product: COc1ccc2c(c1)CC(NC[C@H](O)c1cccc(Cl)c1)CCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 173 %

Procedure:
A mixture of (1R)-2-[N-benzyl-N-(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-1-(3-chlorophenyl)ethanol hydrochloride (0.20 g), chlorobenzene (0.86 ml) and 10% palladium on carbon (0.01 g) in methanol (4 ml) was stirred at room temperature under hydrogen atmosphere for 1.5 hours. The catalyst was filtered off and washed with methanol. The filtrate was evaporated in vacuo, and the residue was powdered from diisopropyl ether to afford (1R)-2-[(3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-1-(3-chlorophenyl)ethanol hydrochloride (0.14 g)
Reaction SMILES: C[C@]12CC[C@H]3[C@@H](CCC4[C@]3(CO)CCCC=4)[C@@H]1CC[C@@H]2O.[C:22]([O:26][C@H:27]1[CH2:32][CH2:31][C@H:30]2[C@H:33]3[C@H:48]([CH2:49][CH2:50][C@:28]12[CH3:29])[C@:41]1([CH2:42][O:43][C:44](=[O:47])[CH2:45][CH3:46])[C:36](=[CH:37][CH2:38][CH2:39][C@@H:40]1C)[CH2:35][CH2:34]3)(=[O:25])[CH2:23][CH3:24]>>[C:22]([O:26][C@H:27]1[CH2:32][CH2:31][C@H:30]2[C@H:33]3[C@H:48]([CH2:49][CH2:50][C@:28]12[CH3:29])[C@:41]1([CH2:42][O:43][C:44](=[O:47])[CH2:45][CH3:46])[C:36](=[CH:37][CH2:38][CH2:39][CH2:40]1)[CH2:35][CH2:34]3)(=[O:25])[CH2:23][CH3:24]
Reactant: CCC(=O)OC[C@@]12C(=CCC[C@@H]1C)CC[C@H]1[C@@H]3CC[C@H](OC(=O)CC)[C@@]3(C)CC[C@@H]12
Agent: C[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@]43CO)[C@@H]1CC[C@@H]2O
Product: CCC(=O)OC[C@]12CCCC=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(=O)CC)CC[C@@H]12

Procedure:
Substituting 4-androstene-17β,19-diol for the 1α-methyl-4-androstene-17β,19-diol above results in the formation of 4-androstene-17β,19-diol dipropionate.
Reaction SMILES: [CH2:1]([C:8]1([C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CC(C)=O.[Cl-].[Na+].O>[CH2:1]([C:8]1([C:18]#[C:19][Si:20]([CH3:22])([CH3:21])[CH3:23])[CH2:17][CH2:16][C:11](=[O:12])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#CC1(Cc2ccccc2)CCC2(CC1)OCCO2
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C[Si](C)(C)C#CC1(Cc2ccccc2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.6 %

Procedure:
A sample of 29 (243.1 mg, 0.74 mmol) was dissolved in acetone (2.89 mL) to give a translucent, yellow solution. To the solution was added a solution of 10% aqueous hydrochloric acid solution (1.15 mL) and the reaction mixture was stirred at room temperature for 5 hours. The mixture was then diluted with brine (25 mL) and the aqueous layer was extracted with methylene chloride/ethyl ether (1:2, 3×20 mL). The organic layers were combined and washed with saturated aqueous sodium bicarbonate solution (2×20 mL) and brine (1×20 mL), then dried over magnesium sulfate, filtered, and concentrated in vacuo to give the crude 30 as pale yellow crystals (195 mg). The crystals were combined with the crude product of a previous reaction (62.5 mg) and were purified by flash column chromatography [hexanes-ethyl acetate (5:1)] to give 30 as white crystals (197.1 mg, 0.69 mmol, 74%). Note, an impure fraction was collected and saved for future purification. 1H NMR (CDCl3) δ 7.31-7.24 (5H, m), 2.81 (2H, s), 2.74 (2H, td, J=6, 14.5 Hz), 2.30 (2H, dt, J=2, 15 Hz), 2.00 (2H, dt, J=3, 14 Hz), 1.68 (2H, dt, J=4, 13.5 Hz), 0.17 (9H, s); 13C NMR (CDCl3) δ 211.7, 137.1, 130.8, 128.0, 126.9, 109.0, 47.6, 38.6, 38.0, 37.2, 0.29. MS (ESI+) m/z 285.1 [M+H]+, HRMS (ESI+) calcd for C18H24OSi+H 285.1675. found 285.1661.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5](N)=[N:4][CH:3]=1.N([O-])=O.[Na+].[CH3:17][OH:18].C(Cl)(Cl)Cl>S(=O)(=O)(O)O>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:18][CH3:17])=[N:4][CH:3]=1
Reactant: CO
Reactant: COC(=O)c1nc(Br)cnc1N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1nc(Br)cnc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 100 ml of concentrated sulfuric acid is dissolved 17.00 g of methyl 6-bromo-3-amino-2-pyrazinecarboxylate obtained according to the method described in literature [J. Am. Chem. Soc., 2798-2800 (1949)]. At an ice-cooled temperature, 10.11 g of sodium nitrite is added to the suspension, which is stirred for 30 minutes. The reaction mixture is poured into 920 mL of methanol, and heated under reflux for 5 hours. The reaction mixture is cooled and then concentrated under reduced pressure. The residue thus obtained is added to a mixture of 500 mL of ice water and 600 mL of chloroform and separated into layers. The organic layer is washed successively with saturated aqueous solution of sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. Then, the solvent is distilled off under reduced pressure to obtain 6.30 g of methyl 6-bromo-3-methoxy-2-pyrazinecarboxylate.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:19])[C@H:10]([NH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](OCC)(=O)C.S(OC)(OC)(=O)=O.[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([NH:8][C:9](=[O:19])[C@H:10]([NH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][O:12][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)N[C@H](CO)C(=O)NCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CCOC(=O)N[C@H](COC)C(=O)NCc1ccccc1
Yield: 70.96 %

Procedure:
To a 500 mL three-neck round bottom flask, 7.2 g (0.027 mol) (R)-N-benzyl-2-(ethoxycarbonylamino)-3-hydroxypropionamide, 300 mL ethyl acetate, 27.2 g (0.216 mol) dimethyl sulfate, and 2.0 g tetrabutylammonium bromide were added in sequence. At a normal temperature, 24.8 g 50% potassium hydroxide (0.2214 mol) solution was added. After the reaction was completed, 100 mL water was added, and the mixture was stirred for several minutes, and stood for layering. An organic layer was separated, and washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was evaporated, to obtain a transparent oily substance, which was triturated with n-hexane, suction-filtered, washed, and dried, to obtain a white solid of 5.37 g (0.01916 mol). The molar yield was 70.96%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:32]=[CH:31][CH:30]=[C:27]([C:28]#[N:29])[CH:26]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC/C=C/c3cccc(C#N)c3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C/C=C/c1cccc(C#N)c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 70 °C
Reaction time: 9 h

Procedure:
To a solution of 3-[3-[N-[4-(1-t-butoxycarbonylpiperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzonitrile (1.00 g) in N,N-dimethylformamide (20 ml) were added potassium carbonate (0.96 g) and ethyl bromoacetate (0.62 ml). The mixture was stirred at 70° C. for 9 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=2/1 as an eluant to give the desired compound (1.31 g, yield quantitative) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8](Br)[C:7]([O:11][CH2:12][O:13][CH3:14])=[CH:6][C:5]=1[O:15][CH2:16][O:17][CH3:18].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]([O:11][CH2:12][O:13][CH3:14])=[CH:6][C:5]=1[O:15][CH2:16][O:17][CH3:18])=[O:19]
Reactant: COCOc1cc(OCOC)c(C(=O)OC)cc1Br
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: COCOc1cc(OCOC)c(-c2ccccc2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.3 %

Procedure:
A Schlenk tube was charged with 5-bromo-2,4-bis-methoxymethoxy-benzoic acid methyl ester (3) (503 mg, 1.5 mmol), phenylboronic acid (272 mg, 2.3 mmol), Pd(OAc)2 (22 mg, 0.1 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (82 mg, 0.2 mmol), K3PO4H2O (4.70 g, 34.0 mmol). The reaction tube was evacuated and backfilled with N2 (×3). Toluene (10 mL, anhydrous and sure seal bottle from Aldrich) was added. The reaction was stirred at room temperature for 10 min and heated at 105° C. (preheated oil bath) for 24 h. The reaction mixture was allowed to cool to room temperature and diluted with EtOAc (50 mL) and water (70 mL). The aqueous phase was extracted with EtOAc (40 mL×3) and the combined organic layers were washed with water and brine and dried over MgSO4. The purification of the concentrated crude product by column chromatography (25% EtOAc in Hexane) afforded the title product as colorless oil (460 mg, 93%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[C:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)#[N:14].C(=O)([O-])[O-].[Na+].[Na+].O>C(#N)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>[OH:12][CH2:11][CH2:10][CH2:9][S:8][C:4]1[CH:5]=[CH:6][C:7]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:13]#[N:14])=[CH:2][CH:3]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: OCCCSc1cccc(Br)c1
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: [Na+]
Solvent: CC#N
Solvent: O
Product: N#Cc1ccccc1-c1ccc(SCCCO)cc1
Temperature: 80 °C
Reaction time: 7 h
Yield: 71.2 %

Procedure:
3-(3-Bromophenylsulfanyl)propane-1-ol (0.49 g) was suspended in acetonitrile (8.5 mL), 4-cyanophenylboronic acid (0.34 g), sodium carbonate (0.42 g), water (1.7 mL) and tetrakis(triphenylphosphine)palladium(0) (0.12 g) were added, and the resulting mixture was stirred at 80° C. for 7 hours. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate (35 mL) and water (10 mL). The organic layer was washed successively with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1) to give the title compound (0.38 g).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:10]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:9]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:8]([C:36]2[CH:41]=[C:40]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH3:51])=[CH:45][CH:44]=3)[C:39]([Cl:52])=[CH:38][C:37]=2[O:53]CC=C)[O:7]1)(=[O:3])[CH3:2].[BH4-].[Na+]>O1CCCC1.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:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:10]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@@H:9]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:8]([C:36]2[CH:41]=[C:40]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH2:50][CH3:51])=[CH:45][CH:44]=3)[C:39]([Cl:52])=[CH:38][C:37]=2[OH:53])[O:7]1)(=[O:3])[CH3:2]
Reactant: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
To a solution of ((2R,3R,4R,5S,6S)-6-(2-(allyloxy)-4-chloro-5-(4-ethoxybenzyl)phenyl)-3,4,5-tris(benzyloxy)tetrahydro-2H-pyran-2-yl)methyl acetate (20, 2.51 g, 3.23 mmol) in tetrahydrofuran (40 mL) were added sodium borohydride (984 mg, 0.026 mol) and tetrakis(triphenylphosphine)palladium (373 mg, 0.323 mmol). The reaction mixture was stirred at room temperature for 5 h. The mixture was diluted with ethyl acetate and quenched with saturated sodium hydrogen carbonate, extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. Flash chromatography on a Biotage® apparatus (silica gel, 10 to 35% tetrahydrofuran in hexanes gradient) gave the title compound (45, 2.19 g, 2.97 mmol, 92%) as colorless oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:9][N:8]=[C:7]([OH:10])[CH:6]=1)=[O:4].[OH-].[Na+]>CO>[OH:10][C:7]1[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[O:9][N:8]=1
Reactant: COC(=O)c1cc(O)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(O)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-hydroxy-isoxazole-5-carboxylic acid methyl ester (286 mg, 2.0 mmol) in methanol (7 mL) is added 1N NaOH (4.0 mL, 4.0 mmol) and the mixture is stirred at room temperature for 18 hrs. The solvent is removed under reduced pressure and 4.0 mL of 1N HCl is added to the residue. The resulting solution is lyophilized to give the product which is used as is in subsequent reactions.
Reaction SMILES: Cl.[CH3:2][N:3]1[N:7]=[N:6][C:5]([CH2:8][NH2:9])=[N:4]1.Cl.[Cl:11][C:12]1[CH:13]=[C:14]([CH:36]=[CH:37][C:38]=1[Cl:39])[CH2:15][N:16]1[CH2:21][CH2:20][O:19][C@@H:18]([CH2:22][NH:23][C:24](=O)[O:25]C2C=CC([N+]([O-])=O)=CC=2)[CH2:17]1.C(N(CC)C(C)C)(C)C.CO>CN(C)C=O>[Cl:11][C:12]1[CH:13]=[C:14]([CH:36]=[CH:37][C:38]=1[Cl:39])[CH2:15][N:16]1[CH2:21][CH2:20][O:19][C@@H:18]([CH2:22][NH:23][C:24]([NH:9][CH2:8][C:5]2[N:6]=[N:7][N:3]([CH3:2])[N:4]=2)=[O:25])[CH2:17]1
Reactant: O=C(NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cn1nnc(CN)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cn1nnc(CNC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)n1
Reaction time: 20 h
Yield: 86.6 %

Procedure:
Intermediate 30 (0.041 g) was added to a stirred solution of Intermediate 29 (0.110 g) in N,N-dimethylformamide (2 ml) at 22° C., and N,N-diisopropylethylamine (0.052 ml) was added. After stirring for 20 h, the mixture was applied in two equal portions to ion exchange cartridges (10 g Isolute SCX pre conditioned with methanol). Elution with methanol (3 column volumes) followed by 10% 0.880 ammonia in methanol (2 column volumes) and evaporation of the first basic fractions in vacuo gave the crude product. Purification by Biotage flash chromatography on silica gel (8 g cartridge), eluting with 100:8:1 dichloromethane/ethanol/0.880 ammonia, gave the title compound as a white solid, (0.0828 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][C:20](=O)[CH2:21][CH3:22]>>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)[CH2:20][CH2:21][CH2:22][CH2:8][CH2:5][CH2:6][CH2:7][CH2:2][CH:3]=[CH2:4]
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CCC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCCCCCCCCCOc1ccc(CC(=O)OC)cc1

Procedure:
A solution of methyl (4-hydroxyphenyl)ethanoate (7.50 g, 45 mmol)1-bromoudec-10-ene (10 g, 43 mmol) and potassium carbonate (7.50 g, 54 mmol) in butanone (250 ml) was heated under reflux (12 h). The solvent was removed in vacuo to yield a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:6]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].[C:24]([Si](C)(C)C)#[C:25][CH2:26][CH3:27].N#N>CCOC(C)=O.O.[Cu]I.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].CC(N(C)C)=O>[C:24]([C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:6]=[CH:5]2)#[C:25][CH2:26][CH3:27]
Reactant: Fc1cc(Br)cc2cnn(C3CCCCO3)c12
Reactant: CCC#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCC#Cc1cc(F)c2c(cnn2C2CCCCO2)c1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 52.2 %

Procedure:
Nitrogen was bubbled into a solution of 5-bromo-7-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (7.5 g, 25.33 mmol) and DMA (100 mL). After 5 min, CuI (241 mg, 1.27 mmol), Pd(OAc)2 (284 mg, 1.27 mmol), dppf (704 mg, 1.27 mmol), K2CO3 (4.89 g, 35.46 mmol), and but-1-yn-1-yltrimethylsilane (4.46 g, 35.46 mmol) were added sequentially with continued N2 bubbling. The resulting mixture was heated at 80° C. for 10 h under N2. The reaction mixture was diluted with EtOAc (250 mL) and H2O (200 mL) and filtered. The organic layer of the filtrate was separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (3×50 mL), dried over anhydrous Na2SO4, concentrated, and purified by silica gel chromatography (1:30 EtOAc/petroleum ether) to give the pure product as a yellow solid (3.6 g) and an impure product (2 g; further purified to give additional 1.47 g). 1H NMR (300 MHz, DMSO-d6): δ 8.19 (d, 1H), 7.68 (d, 1H), 7.26 (dd, 1H), 5.79 (dd, 1H), 3.92-3.87 (m, 1H), 3.69-3.60 (m, 1H), 2.47-2.34 (m, 1H), 2.43 (q, 2H), 2.07-2.02 (m, 2H), 1.76-1.69 (m, 1H), 1.57-1.50 (m, 2H), 1.17 (t, 3H); LCMS: 273 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[CH:19]=[C:20](Cl)[CH:21]=C=O.[CH2:25]([NH2:28])[CH2:26][CH3:27]>C(OCC)(=O)C>[CH2:25]([NH:28][C:12](=[O:13])[C:11]1[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:19]=[C:20]([C:9](=[O:18])[NH:8][CH2:5][CH2:4][CH3:3])[CH3:21])[CH:4]=1)=[O:18])[CH2:26][CH3:27]
Reactant: O=C=CC(Cl)=Cc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl
Reactant: CCCN
Solvent: CCOC(C)=O
Product: CCCNC(=O)C(C)=Cc1cc(NC(=O)C2=C(C(=O)NCCC)CCCC2)ccc1Cl
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of 10.9 g of N-[4-chloro-3-(2-chloro-carbonylprop-1-en-1-yl)-phenyl]-3,4,5,6-tetrahydrophthalimide in 200 ml of ethyl acetate was added dropwise to a solution of 5.9 g of n-propylamine in about 150 ml of ethyl acetate while cooling with ice. The mixture was stirred for 3 hours at about 20° C., after which the solid formed was separated off, washed twice with 5% by weight aqueous hydrochloric acid and then once with petroleum ether and then dried under reduced pressure at 40° C. The crude product was recrystallized from ethyl acetate. Mp.: 130°131° C.