Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21])([CH3:18])([CH3:17])[CH3:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)(C)c1ccccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C(C)(C)C)CC1
Reaction time: 16 h
Yield: 83.9 %

Procedure:
A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1 g, 0.00502 mole) in dry 1,2-dichloroethane (10 mL) was stirred under an atmosphere of nitrogen for 10 minutes. 2-Tert-butylaniline (0.974 g, 0.00652 mole), acetic acid (0.301 g, 0.005 mole) and sodium triacetoxyborohydride (1.596 g, 0.00753 mole) were then added portionwise and stirring was continued at ambient temperature for 16 hours. The reaction mixture was basified with sodium bicarbonate solution and the product was extracted with dichloromethane. The dichloromethane layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting transparent viscous liquid was purified by column chromatography using neutral aluminium oxide (1-2% ethyl acetate in hexane) to afford 1.4 g (83%) of 4-(2-tert-butyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3): δ 7.25 (m, 1H), 7.15 (t, 1H), 6.8-6.6 (m, 2H), 4.0 (dd, 2H), 3.9-3.8 (dd, 2H), 3.6 (bs, 1H), 3.1 (t, 2H), 2.2-2.2 (dd, 2H), 1.5-1.4 (d, 18H). A solution of 4-(2-tert-butyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.35 g, 0.00406 mole) in ethyl acetate.HCl (10 mL) was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was washed with ether and dried to afford 0.9 g (72%) of (2-tert-butyl-phenyl)-piperidin-4-yl-amine dihydrochloride. LCMS: 233.19 (M+1)+, 86.32%, 1H NMR (DMSO-d6): δ 9.1 (d, 2H), 7.2 (d, 1H), 7.1 (s, 3H), 6.8 (d, 1H), 6.6 (t, 1H), 3.7 (m, 1H), 3.4 (m, 3H), 3.0 (q, 3H), 2.6 (t, 1H), 2.2 (d, 2H), 1.7 (m, 2H), 1.4 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH2:21])[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](Cl)(=[O:25])[CH3:24].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH:21][C:23](=[O:25])[CH3:24])[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc2c(cc(N)c3nnc(C)n32)n1Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)Nc1cc2c(cc(C)n2Cc2ccccc2)n2c(C)nnc12
Reaction time: 3.5 h

Procedure:
To a suspension of 6-benzyl-1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-4-amine (32.0 mg, 0.110 mmol, from Step 3) in tetrahydrofuran (1 mL) was added acetyl chloride (15.1 μL, 0.213 mmol, Aldrich) and N,N-diisopropylethylamine (76 μL, 0.44 mmol). After 3.5 hours, the product was purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield: (19 mg, 52%).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][CH:28]([CH3:34])[CH2:29][CH2:30][C:31](O)=[O:32]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:31](=[O:32])[CH2:30][CH2:29][CH:28]([CH3:34])[CH3:27])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: CC(C)CCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: CC(C)CCC(=O)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (72 mg, 68%), MS (ISP) m/z=425.3 [(M+H)+], mp 179° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-methyl-pentanoic acid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20]2[N:23]([C:26](=[O:48])[CH:27]([NH:34][C:35](=[O:47])[CH:36]([N:38](C(OC(C)(C)C)=O)[CH3:39])[CH3:37])[CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:24][CH2:25][CH:19]12)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[CH2:8]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20]2[N:23]([C:26](=[O:48])[CH:27]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[NH:34][C:35](=[O:47])[CH:36]([NH:38][CH3:39])[CH3:37])[CH2:24][CH2:25][CH:19]12)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C(=O)NC(C(=O)N1CCC2C1CCN2C(=O)OCc1ccccc1)C1CCCCC1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(C)C(=O)NC(C(=O)N1CCC2C1CCN2C(=O)OCc1ccccc1)C1CCCCC1
Reaction time: 1.5 h

Procedure:
TFA (5 mL) was added to a solution containing crude 116 (0.9 g) in DCM (20 mL) at 0° C. After 90 min, another portion of TFA (2 mL) was added. After 75 min, the reaction mixture was carefully quenched by the addition of saturated aqueous NaHCO3. The mixture was then diluted with EtOAc and water and the layers were separated. The organic phase was washed three times with aqueous NaHCO3 then once with brine. The combined aqueous washes were back-extracted with EtOAc and the combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by reverse-phase HPLC [2″ Dynamax C18; Method: 10-55% ACN/water containing 0.1% HOAc over 30 min; Flow: 40 mL/min]. The product-containing fractions were pooled, frozen, and lyophilized to afford 410 mg (53% from 115) of 117 as a white-colored solid. 1H NMR (300 MHz, d6-DMSO), mixture of carbamate rotomers: δ7.67 (d, J=8.7 Hz, 1H), 7.34-7.28 (m, 5H), 5.17-5.05 (m, 2H), 4.52 (m, 2H), 4.34 (m, 1H), 4.00 (m, 1H), 3.75 (m, 1H), 3.33 (m, 1H), 3.14-3.01 (m, 2H), 2.35 (br s, 3H), 2.30 (m, 1H), 1.90 (m, 1H), 1.69-1.60 (m, 5H), 1.27 (d, J=6.9 Hz, 3H), 1.18-0.94 (m, 5H) ppm. 13C NMR (75 MHz, d6-DMSO), mixture of carbamate rotomers: δ174.7, 174.4 172.9, 170.1, 170.0, 154.1, 154.0, 137.5, 129.1, 128.5, 128.2, 128.1, 66.7, 66.6, 63.0, 61.9, 61.6, 60.9, 59.5, 55.2, 54.7, 46.7, 46.1, 45.6, 41.5, 34.5, 32.3, 31.2, 30.7, 30.1, 29.6, 29.5, 28.9, 28.7, 26.4, 26.2, 26.1, 26.0, 22.0, 19.5, 19.4 ppm. Mass spectrum, m/z [471.0] (M+H)+.
Reaction SMILES: [C:1]([CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]2[O:14][CH2:15][O:16][C:9]=12)C(O)=O)#[N:2].CN(C)C(=O)C>O>[C:1]([CH2:3][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]2[O:14][CH2:15][O:16][C:9]=12)#[N:2]
Reactant: N#CC(Cc1cccc2c1OCO2)C(=O)O
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#CCCc1cccc2c1OCO2
Temperature: 150 °C
Yield: 87 %

Procedure:
60.6 g of acid prepared in Stage B are mixed with 115 ml of N,N-dimethylacetamide and the mixture is heated at 150° C. for approximately 2 hours and then allowed to cool, taken up in water and extracted with diethyl ether. The ethereal phases are washed with a sodium hydrogen carbonate solution and then with water and dried to yield the desired compound in the form of an oil.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].Cl.[Br:7][C:8]1[CH:16]=[C:15]([O:17][CH3:18])[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[OH:19]>O.C(OCC)C>[Br:7][C:8]1[CH:16]=[C:15]([O:17][CH3:18])[C:11]([C:12]([OH:14])=[O:13])=[C:10]([N+:1]([O-:4])=[O:2])[C:9]=1[OH:19]
Reactant: O=[N+]([O-])[O-]
Reactant: COc1cc(Br)c(O)cc1C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COc1cc(Br)c(O)c([N+](=O)[O-])c1C(=O)O
Temperature: 0 °C
Reaction time: 7 h

Procedure:
Sodium nitrate (361 mg, 4.25 mmol) was dissolved in water (4 mL) and LaNO3 *6H2O (18 mg, 0.04 mmol) and HCl (12M, 4 mL) were added. The solution was cooled to 0° C. and a slurry of 4-bromo-3-hydroxy-6-methoxybenzoic acid in diethyl ether (20 mL) was added to the reaction mixture in portions during 10 min. After slowly raising the temperature to room temperature the mixture was stirred for 7 h. Extraction between H2O (20 ml) and CH2Cl2 (3×30 mL), drying the organic phase with MgSO4, filtration and evaporation under reduced pressure gave a mixture of products. Purification by silica gel chromatography (HOAc-EtOAc-toluene 1:2:8) gave the title compound (0.6 g). 1H NMR (CD3OD): δ 7.57 (s, 1 H), 3.85 (s, 3 H). MS (EI, 70 eV): m/z (rel.int.) 291/293 (M+, 21/19).
Reaction SMILES: [CH3:1][C@H:2]([N:13]=[N+]=[N-])[CH2:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:5]=1[F:12]>CCOC(C)=O.[Pd]>[CH3:1][C@H:2]([NH2:13])[CH2:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[C:5]=1[F:12]
Reactant: C[C@@H](Cc1cc(F)cc(F)c1F)N=[N+]=[N-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@H](N)Cc1cc(F)cc(F)c1F
Yield: 58.1 %

Procedure:
To a solution of (1S)-1-methyl-2-(2,3,5-trifluorophenyl)ethyl azide (930 mg, 4.32 mmol) in 100 mL of EtOAc was added Pd/C (300 mg of 10% Pd) and the mixture was hydrogenated under hydrogen balloon for 1 h. The catalyst was removed by filtration through celite, then passed through silica gel plug eluting first with EtOAc (40 mL), then MeOH/EtOAc/NH4OH 20:75:5 (120 mL). The fraction with product was evaporated to give (1S)-1-methyl-2-(2,3,5-trifluorophenyl)ethylamine (475 mg, 58%) as pale yellow oil. ESI-MS: m/z (MH+) 190.1. 1H NMR (300 MHz, CDCl3): δ 7.04 (m, 1H), 6.83 (m, 1H), 4.06 (s, 2H), 3.42 (m, 1H), 2.92 (m, 2H), 1.29 (d, J=6.21 Hz, 3H).
Reaction SMILES: [O-:1][CH2:2][CH2:3][CH2:4][CH3:5].[Li+].[CH2:7](O)[CH2:8][CH2:9][CH3:10].[Li].[CH2:13]([Li])CCC>CCOCC.CCCCCC>[CH3:13][C:3](=[CH:4][CH2:5][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:2][OH:1]
Reactant: [Li]CCCC
Reactant: CCCC[O-]
Reactant: CCCCO
Agent: [Li+]
Agent: [Li]
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCCCC=C(C)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To 85.6 mg (1.1 mmol) of lithium butoxide prepared from n-butanol and lithium metal, there was added 10 ml of ether under an argon atmosphere and stirred at room temperature. The resulting mixture was cooled to -20° C., and a hexane solution of n-butyllithium (1.2 mmol) was added thereto and stirred. An ether solution of 3-methyl-3,4-epoxybutene-1 (89.9 mg; 1.1 mmol) was added dropwise thereto at -20° C., and after the addition was completed, stirring was effected at -20° C. for 1 hour and at 0° C. for 1 hour, followed by the usual work up to give 2-methyl-2-octen-1-ol in a yield of 74%. The Z/E ratio was 93.1/6.9.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([NH2:16])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]1(=O)[O:24][C:22](=[O:23])[CH2:21][CH2:20]1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>CC(C)=O.CN(C)C=O>[CH:1]1([O:7][N:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH:11]([N:16]3[C:22](=[O:23])[CH2:21][CH2:20][C:19]3=[O:24])[CH2:12][C:13]2([CH3:14])[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCC(=O)O1
Reactant: CC1(C)CC(N)CC(C)(C)N1OC1CCCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)CC(N2C(=O)CCC2=O)CC(C)(C)N1OC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2.64 g of 1-cyclohexyloxy-4-amino-2,2,6,6-tetramethylpiperidine in 10 ml of acetone is added to a solution of 1.0 g of succinic anhydride in 25 ml of acetone. After stirring the reaction mixture at room temperature for 8 hours and removal of the solvent under reduced pressure, 3.54 g of the intermediate amide acid are obtained. A solution of the above (3.0 g), 0.1 g of sodium acetate and 3.1 ml of acetic anhydride in 10 ml of dimethylformamide is heated at 90° C. for 3 hours to effect cyclization to the desired imide. The removal of solvents under reduced pressure followed by purification utilizing SiO2 flash chromatography [heptane:ethyl acetate (60:40)] and crystallization from ethyl acetate-heptane provide the desired succinimide as a white crystalline solid m.p. 133°-36° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:30][O:29][C:27]([CH:24]1[CH2:25][CH2:26][N:21]([CH2:2][C:3]2[N:4]=[C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[S:6][CH:7]=2)[CH2:22][CH2:23]1)=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(CCl)cs2)CC1
Reactant: COC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(Cc2csc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 50.2 %

Procedure:
A solution of tert-butyl 4(4-chloromethylthiazol-2-yl)piperazine-1-carboxyate (860 mg, 2.7 mmol) and methyl piperidine-4-carboxylate (539 mg, 3 mmol) in DMF was treated with potassium carbonate (414 mg, 3 mmol). The mixture was stirred at 70° C. for 18 hours and then concentrated under vacuum. Product was purified from the residue by flash chromatography on silica gel to provide tert-butyl 4-[4-(4-methoxycarbonylpiperidin-1-ylmethyl)thiazol-2-yl]piperazine-1-carboxylate (575 mg, 50% yield). HNMR (dmso-d6): 6.58 (1H, s), 3.59 (2H, s), 3.42 (4H, m), 3.34 (4H, m), 3.32 (3H, s), 2.78 (2H, m), 2.28 (1H, m), 2.02 (2H, m), 1.77 (2H, m), 1.57 (2H, m), 1.41 (3H, s).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][NH:11][CH2:10]3)=[CH:5][CH:4]=1.C(N(CC)CC)C.Br[CH2:25][CH2:26][CH2:27][OH:28].[Na+].[I-]>O1CCCC1.C(OCC)(=O)C>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][N:11]([CH2:25][CH2:26][CH2:27][OH:28])[CH2:10]3)=[CH:7][CH:8]=1
Reactant: OCCCBr
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: OCCCN1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C

Procedure:
To a solution of (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (151 mg, prepared following the procedure reported in WO 2005080382) in dry tetrahydrofuran (3.3 mL), triethylamine (0.112 mL), 3-bromo-1-propanol (0.073 mL) and NaI were added and the resulting mixture was heated at reflux for 4 hours. After cooling at room temperature it was diluted with ethyl acetate (20 mL), washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by a silica SPE cartridge (10 g) eluting with dichloromethane/methanol from 99/1 to 97/3 to give the title compound as a colourless oil (144 mg).
Reaction SMILES: [C:1]1([S:7][CH2:8][F:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C1C(=O)N(Br)C(=[O:15])C1>O>[C:1]1([S:7]([CH2:8][F:9])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: FCSc1ccccc1
Solvent: O
Solvent: CO
Product: O=S(CF)c1ccccc1
Yield: 89.5 %

Procedure:
Fluoromethyl phenyl sulphide (85 g, 351.63 mmol) was added to a mixture of methanol (250 ml) and water (50 mL) The resulting mixture was cooled to a temperature between 0° C. and 5° C. NBS (75.10 g, 1.2 eq) was added in small portions maintaining the same temperature range. The reaction mixture was stirred until the reaction was complete, and then, was quenched with Na2SO3 solution (10%, 150 mL). The pH of the reaction mixture was adjusted to a value between 7 and 8 with NaHCO3 saturated solution. The mixture was concentrated under vacuum at a temperature between 20° C. and 25° C. The residue was extracted with dichloromethane (200 mL, 300 mL). The combined organic layer was washed with water (2×300 mL) and concentrated to 1/3 of the volume. Heptane (50 mL) was added and the resulting mixture was concentrated again. The crude product was purified by flash chromatography (Ethyl Acetate/Hexane 30:70) to give 49.8 g (89.6%) of the desired product as colourless oil at rt, which is a white solid at −20° C.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([F:24])[CH2:20][CH2:19]3)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:25]1[C:26](=[O:55])[N:27](COCC[Si](C)(C)C)[CH:28]=[C:29]([NH:31][C:32]([C:34]2[CH:35]=[N:36][N:37]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)[CH:38]=2)=[O:33])[CH:30]=1)=O)(C)(C)C.C(OC(C1(C2C(=O)N(COCC[Si](C)(C)C)C=C(NC(C3C=NN(CC4C=CC(C)=CC=4)C=3)=O)C=2)C=C2C(C=CC(CN3CCC(F)CC3)=C2)=N1)=O)(C)(C)C.NCCN.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C.O1CCCC1>[F:24][CH:21]1[CH2:22][CH2:23][N:18]([CH2:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][C:9]([C:25]2[C:26](=[O:55])[NH:27][CH:28]=[C:29]([NH:31][C:32]([C:34]4[CH:35]=[N:36][N:37]([CH2:39][C:40]5[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=5)[CH:38]=4)=[O:33])[CH:30]=2)=[CH:10]3)[CH2:19][CH2:20]1
Reactant: Cc1ccc(Cn2cc(C(=O)Nc3cc(-c4cc5cc(CN6CCC(F)CC6)ccc5n4C(=O)OC(C)(C)C)c(=O)n(COCC[Si](C)(C)C)c3)cn2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(Cn2cc(C(=O)Nc3cc(C4(C(=O)OC(C)(C)C)C=c5cc(CN6CCC(F)CC6)ccc5=N4)c(=O)n(COCC[Si](C)(C)C)c3)cn2)cc1
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: NCCN
Product: Cc1ccc(Cn2cc(C(=O)Nc3c[nH]c(=O)c(-c4cc5cc(CN6CCC(F)CC6)ccc5[nH]4)c3)cn2)cc1
Temperature: 120 °C

Procedure:
A 2-5 mL microwave vial was charged with intermediate (8g), 5-(4-fluoro-piperidin-1-ylmethyl)-2-[5-{[1-(4-methyl-benzyl)-1H-pyrazole-4-carbonyl]amino}-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]-indolecarboxylic acid tert-butyl ester (96 mg, 0.125 mmol), tetrahydrofuran (3 mL), 1,2-diaminoethane (38 mg, 42 ul, 0.63 mmol) and finally tetrabutylammonium fluoride solution 1.0M in tetrahydrofuran (0.63 mL, 0.63 mmol). The vial was heated under microwave irradiation at 120° C. for 20 mins. After cooling, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with water (4×20 mL) and brine (4×20 mL). The organics were dried (Na2SO4) and concentrated in vacuo. The resultant yellow solid was purified via trituration using acetonitrile, to afford the title compound as a yellow solid, 42 mg, 63%.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][N:21]([CH2:52][CH3:53])[C:22](=O)[CH2:23][C@@H:24]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](=[O:43])(=[O:42])[NH2:41])=[CH:36][C:35]=1[S:44]([C:47]([F:50])([F:49])[F:48])(=[O:46])=[O:45])[CH2:25][S:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1.N.CO>[Si:1]([O:18][CH2:19][CH2:20][N:21]([CH2:52][CH3:53])[CH2:22][CH2:23][C@@H:24]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH2:41])(=[O:42])=[O:43])=[CH:36][C:35]=1[S:44]([C:47]([F:49])([F:50])[F:48])(=[O:45])=[O:46])[CH2:25][S:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Agent: B
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
(R)—N-(2-(tert-Butyldiphenylsilyloxy)ethyl)-N-ethyl-4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)butanamide (INTERMEDIATE 24, 0.59 g, 0.73 mmol) was dissolved in THF (4.6 ml), under a nitrogen atmosphere, and a solution of borane-THF complex (1M in THF; 2.2 ml, 2.2 mmol) was added and the resulting solution was stirred at ambient temperature overnight. An additional solution of borane-THF complex (1M in THF; 2.2 ml, 2.2 mmol) was added. The resulting mixture was stirred at ambient for further 6 hrs. The mixture was diluted with NH3 in MeOH (7N, 20 ml) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (75 ml), washed with water (40 ml), and dried (Na2SO4). Evaporation of the volatiles under reduced pressure afforded a concentrate, which was purified by column chromatography (ISCO, 40 g silica gel column, eluting with 0→100% EtOAc/hexanes) to provide the title compound (280 mg, yield: 48%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][CH2:10][CH2:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[CH3:13])=[C:4]([CH3:22])[N:3]=1.B(Br)(Br)Br.[OH-].[NH4+]>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][CH2:10][CH2:11][CH:12]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)[CH3:13])=[C:4]([CH3:22])[N:3]=1
Reactant: COc1ccc(C(C)CCCc2c(C)nc(N)nc2N)cc1
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1nc(N)nc(N)c1CCCC(C)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 100.7 %

Procedure:
A stirred mixture of 5.2 grams (0.017 mole) of 2,4-diamino-5-[4-(4-methoxyphenyl)pentyl]-6-methylpyrimidine in 200 mL of methylene chloride was cooled to about 0° C., and 52 mL (0.052 mole) of boron tribromide (1M in methylene chloride) was added dropwise during a 20 minute period while maintaining the reaction mixture temperature between -5° C. and +5° C. Upon completion of addition, the reaction was allowed to warm to ambient temperature as it stirred for about 18 hours. After this time the reaction mixture was poured into about 200 grams of ice. The mixture was made slightly basic with concentrated ammonium hydroxide and was stirred until the ice melted. A solid precipitate was collected by filtration and dried at 60° C., yielding 4.9 grams of 2,4-diamino-5-[4-(4-hydroxyphenyl)pentyl]-6-methylpyrimidine, mp 197°-201° C., dec. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:24][C:23]2[C:25](=[O:26])[C:18](=[CH:19][C:20]([C:22]=2OC)=[O:21])[NH:17][C:15](=[O:16])[C:14]([CH3:29])=[CH:13][CH:12]=[CH:11][C@H:10]([O:30][CH3:31])[C@@H:9]([O:32][C:33]([NH2:35])=[O:34])[C:8]([CH3:36])=[CH:7][C@H:6]([CH3:37])[C@@H:5]([OH:38])[C@@H:4]([O:39][CH3:40])[CH2:3]1.[NH3:41]>CO.C(Cl)Cl>[CH3:1][C@@H:2]1[CH2:24][C:23]2[C:25](=[O:26])[C:18](=[CH:19][C:20]([C:22]=2[NH2:41])=[O:21])[NH:17][C:15](=[O:16])[C:14]([CH3:29])=[CH:13][CH:12]=[CH:11][C@H:10]([O:30][CH3:31])[C@@H:9]([O:32][C:33]([NH2:35])=[O:34])[C:8]([CH3:36])=[CH:7][C@H:6]([CH3:37])[C@@H:5]([OH:38])[C@@H:4]([O:39][CH3:40])[CH2:3]1
Reactant: N
Reactant: COC1=C2C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)C=C(C)[C@H](OC(N)=O)[C@@H](OC)C=CC=C(C)C(=O)NC(=CC1=O)C2=O
Agent: COC1=C2C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)/C=C(\C)[C@H](OC(N)=O)[C@@H](OC)/C=C\C=C(/C)C(=O)NC(=CC1=O)C2=O
Agent: CO[C@H]1/C=C\C=C(/C)C(=O)NC2=CC(=O)C(N)=C(C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)/C=C(\C)[C@@H]1OC(N)=O)C2=O
Solvent: ClCCl
Solvent: CO
Product: CO[C@H]1C=CC=C(C)C(=O)NC2=CC(=O)C(N)=C(C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)C=C(C)[C@@H]1OC(N)=O)C2=O
Reaction time: 24 h

Procedure:
Geldanamycin (1.12 g, 2 mmol, 1 equiv) was added to anhydrous DCM (5 mL). NH3 in MeOH was added to this solution (9 mL, 100 mmol, 50 equiv) and was allowed to stir for 24 hours. At which point the reaction solution was diluted with DCM and extracted with water, followed by dilute HCl. The organic layer was collected washed with brine, dried over Na2SO4 and concentrated to yield a purple solid. This solid was recrystalized twice from acetone/heptanes to yield 0.239 of 17-amino-17-demethoxygeldanamycin.