Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=CC(N2CCC[C@H](C(N3CCN(C)CC3)=O)C2)=CC=1OC.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([N:36]2[CH2:41][CH2:40][CH:39]([N:42]([CH3:44])[CH3:43])[CH2:38][CH2:37]2)[CH:30]=[CH:31][C:32]=1[N+:33]([O-])=O>>[NH2:33][C:32]1[CH:31]=[CH:30][C:29]([N:36]2[CH2:41][CH2:40][CH:39]([N:42]([CH3:43])[CH3:44])[CH2:38][CH2:37]2)=[CH:28][C:27]=1[O:26][CH3:25]
Reactant: COc1cc(N2CCC(N(C)C)CC2)ccc1[N+](=O)[O-]
Agent: COc1cc(N2CCC[C@H](C(=O)N3CCN(C)CC3)C2)ccc1N
Product: COc1cc(N2CCC(N(C)C)CC2)ccc1N

Procedure:
[1-(4-Amino-3-methoxy-phenyl)-piperidin-4-yl]-dimethyl-amine was prepared in an analogous fashion to [(S)-1-(4-Amino-3-methoxy-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone of Example 460c replacing [(S)-1-(3-Methoxy-4-nitro-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone with [1-(3-Methoxy-4-nitro-phenyl)-piperidine-4-yl]dimethyl-amine (280 mg, 100%). LC/MS (E/I+) 249 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[N:6][CH:7]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([NH:16][S:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:10])=[O:9])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Product: CC(C)(C)NS(=O)(=O)c1cncc(Br)c1
Yield: 105.7 %

Procedure:
Prepared by general procedure III from 5-bromo-pyridine-3-sulfonyl chloride (Example B.2 step 2) (500 mg, 2 mmol) and tert-butylamine (1.03 mL, 10 mmol) to give the title compound as a white solid (620 mg, 108%). MS (ISP) 293.0 [(M+H)+], 295.2 [(M+2+H)+]. mp 110° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:25][CH:24]([CH:26]=[CH2:27])[O:23][C:10]2([CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:29]([O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=O)=[CH:35][C:34]=1[CH3:42])([CH3:31])[CH3:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(O)C.CN(C=O)C>[CH2:1]([N:8]1[CH2:25][CH:24]([CH:26]=[CH2:27])[O:23][C:10]2([CH2:11][CH2:12][N:13]([C:37]([C:36]3[CH:40]=[CH:41][C:33]([O:32][CH:29]([CH3:30])[CH3:31])=[C:34]([CH3:42])[CH:35]=3)=[O:39])[CH2:14][CH2:15]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC1CN(Cc2ccccc2)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Reactant: Cc1cc(C(=O)O)ccc1OC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CC1CN(Cc2ccccc2)CC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)O1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To tert-butyl 8-benzyl-10-vinyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (600 mg, 1.61 mmol) in ethanol (1 mL) was added HCl (4.028 mL of 4 M in dioxane, 16.11 mmol) and the reaction mixture was stirred for 30 minutes. The reaction mixture was concentrated in vacuo, then DMF (4 mL), 4-isopropoxy-3-methyl-benzoic acid (313 mg, 1.61 mmol) and HATU (613 mg, 1.61 mmol) were added and the reaction mixture was stirred for 10 minutes. Triethylamine (898 μL, 6.44 mmol) was added and the reaction mixture was stirred for 16 hours, The reaction mixture was concentrated in vacuo, diluted with DCM (5 mL), washed with 1 N aq. NaOH (2 mL) and brine (2 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% EtOAc/hexanes eluent to give (8-benzyl-10-vinyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone (715 mg, 99%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.35-7.22 (m, 5H), 7.20-7.14 (m, 2H), 6.79 (d, J=8.2 Hz, 1H), 5.83-5.74 (m, 1H), 5.34-5.26 (m, 1H), 5.15 (d, J=10.6 Hz, 1H), 4.59-4.50 (m, 1H), 4.33-4.14 (m, 2H), 3.59-3.14 (m, 7H), 2.79 (d, J=11.0 Hz, 1H), 2.56 (d, J=11.1 Hz, 1H), 2.19 (s, 3H), 1.91-1.80 (m, 2H), 1.69-1.39 (m, 2H), 1.34 (d, J=6.0 Hz, 6H); ESI-MS m/z calc. 448.6. found 449.5 (M+1)+; Retention time: 1.48 minutes (3 min run).
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:5]=1[C:6]([OH:8])=[O:7].[C:14](Cl)(Cl)=[O:15].C1(C)C=CC=CC=1>O>[Cl:13][C:9]1[C:5]2[C:6](=[O:8])[O:7][C:14](=[O:15])[NH:3][C:4]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: O=C(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Reaction time: 1 h
Yield: 91 %

Procedure:
A solution of potassium hydroxide (1.68 g, 30 mmol) and 2-amino-6-chlorobenzoic acid (3.43 g, 20 mmol) in water (25 mL) at 0° C. was treated dropwise with 20% phosgene in toluene (16.8 mL, 32 mmol) resulting in a precipitate. The mixture was stirred for 1 hour and the solid was collected by filtration, washed with water and dried to give the title compound (3.6 g, 91%). 1H NMR (300 MHz, DMSO-d6) δ 7.11 (d, J=7.35 Hz, 1H), 7.31 (d, J=6.99 Hz, 1H), 7.66 (t, J=8.09 Hz, 1H), 11.83 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:6]([OH:7])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].O([CH2:28][C:29]([F:32])([F:31])[F:30])S(C(F)(F)F)(=O)=O>CN(C=O)C.C(Cl)Cl>[CH3:10][O:9][C:8]1[CH:11]=[CH:12][C:4]([C:3]([O:2][CH3:1])=[O:13])=[CH:5][C:6]=1[O:7][CH2:28][C:29]([F:32])([F:31])[F:30]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.5 %

Procedure:
To a mixture of isovanillic acid methyl ester (33.0 g, 0.18 mol) and potassium carbonate (41.4 g, 0.30 mol) in DMF (100 ml) was added a solution of trifluoroethyl triflate [Burdon et al Tetrahedron 21, 1 (1965)] (65.0 g, 0.28 mol) in CH2Cl2. The mixture was stirred at room temperature for 18 h then evaporated to 50 ml, the mixture partitioned between ether and H2O, the organic layer washed with H2O and saturated brine, then dried over MgSO4 and evaporated. The resulting solid was triturated with hexane to give the subtitle compound as an off-white solid (42.55 g, 90%). Rf 0.47 (CH2Cl2). MS m/z 265 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH:15](OCC)=[O:16].[H-].[Na+]>COCCOC>[CH:15]([CH:9]([CH2:8][C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:16]
Reactant: CCOC=O
Reactant: CCOC(=O)CCc1ccc(C)nc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1ccc(C)nc1

Procedure:
Ethyl 3-(6-methyl-3-pyridyl)propionate was reacted at 0° with ethyl formate and sodium hydride in 1,2-dimethoxyethane to give ethyl 2-formyl-3-(6-methyl-3-pyridyl)propionate, m.p. 142°-144°, which was heated under reflux with dried nitroguanidine and sodium methoxide in methanol to give 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone, m.p. 215°-6° (decomp). p (ii) Reaction of 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone with 5-aminopentanol in refluxing pyridine gives 2-(5-hydroxypentylamino)-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone which can be converted into 2-[5-(O-isoureido)pentylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone by the procedure of Example 5(iii).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:3]=12.C([N-]C(C)C)(C)C.[Li+].CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.[I:49]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]([I:49])=[CH:10][C:3]=12
Reactant: II
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Br)ccnc32)cc1
Agent: CC(C)[N-]C(C)C
Agent: O=S([O-])([O-])=S
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3c(Br)ccnc32)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of Example 36A (25 g, 71.2 mmol) in tetrahydrofuran (600 mL) at −78° C. was added slowly 2M lithium diisopropylamide in heptane/tetrahydrofuran/ethyl benzene (39.1 mL, 78 mmol) and the mixture was stirred at −78° C. for 1 hour. A solution of iodine (19.87 g, 78 mmol) in tetrahydrofuran (100 mL) was added slowly and the reaction was allowed to warm gradually to room temperature. The reaction mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium thiosulfate and water were added and the mixture was extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[CH3:12].Cl>CO.C(Cl)Cl.[Fe]>[Br:1][C:2]1[C:3]([CH3:12])=[C:4]([NH2:9])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1c(N)cc(F)cc1Br
Reaction time: 16 h
Yield: 28.1 %

Procedure:
To a solution of crude 1-bromo-5-fluoro-2-methyl-3-nitro-benzene (5.96 g) in MeOH (90 mL) was added concentrated hydrochloric acid (11.7 mL) and iron (6.1 g) and the reaction mixture was heated to reflux. After 16 h, the mixture was cooled, diluted with DCM, washed with sodium carbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to yield 3-bromo-5-fluoro-2-methyl-phenylamine (1.46 g).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([OH:53])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2].[CH3:57][O:58][CH:59]([O:62][CH3:63])[CH2:60]Br>[Ag]=O>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:54])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([N:50]=[N+:51]=[N-:52])[CH:46]([O:53][CH2:60][CH:59]([O:62][CH3:63])[O:58][CH3:57])[CH2:45]2)[CH:7]([CH3:55])[CH2:6][CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: COC(CBr)OC
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(O)C3)C(C)CCC1=O)C(C)CC2OC
Agent: O=[Ag]
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N=[N+]=[N-])C(OCC(OC)OC)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 70 °C

Procedure:
A suspension of 17-ethyl-1-hydroxy-12-[2'-(4"-azido-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (25 mg, Example 42) and silver oxide (25 mg) in 2 ml of bromoacetaldehyde dimethyl acetal is heated at 70° C. for 4 days. The solids are removed by filtration, washed with ethyl acetate, and concentrated in vacuo. The resulting oil is purified by preparative tlc on silica gel to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:14])OC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.O>C1(C)C(C)=CC=CC=1.CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]([NH:15][CH2:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:14])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NCc1cccnc1
Reactant: COC(=O)Nc1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C(NCc1cccnc1)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 88.2 %

Procedure:
A mixture of 5.88 g (0.03 mole) of methyl N-(4-nitrophenyl)-carbamate, 2.70 g (0.025 mole) of 3-aminomethyl-pyridine, 9.6 ml of Gemanin CS 302D (a mixture of N,N-dimethyl-C10-18 alkylamines sold by the firm Hoechst AG) and 50 ml of xylene is filled into a flask equipped with a 20 cm Vigreux column and a Dean-Stark trap, and the mixture is boiled for 2 hours. During this period 6 ml of a mixture of water, methanol and xylene accumulate in the trap. The mixture is filtered when hot, the crystalline end-product is washed twice with 5 ml of hot xylene, each, and then with a few amount of acetone and dried. 6.0 g (88.2%) of N-(4-nitrophenyl)-N'-(3-pyridylmethyl)-urea are obtained; m.p.: 223°-225° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17](O)=[O:18].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O.N>CN(C=O)C.CO.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:17]([C@@H:12]2[CH2:13][CH2:14][CH2:15][CH2:16][N:11]2[CH3:10])=[O:18])=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: CN1CCCC[C@H]1C(=O)O
Agent: N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CN1CCCC[C@H]1C(=O)NNc1ccc(F)cn1
Reaction time: 8 h
Yield: 66.9 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (250 mg, 1.96 mmol) in DMF (20.0 mL) was added (S)-1-methyl-piperidine-2-carboxylic acid (281 mg, 1.96 mmol), EDC (416 mg, 2.16 mmol) and HOBt.H2O (25.0 mg, 0.20 mmol). The reaction was stirred overnight then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was taken up in MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound (331 mg, 67%). LCMS (Method 1): Rt 0.35 min, m/z 253.2 [MH+].
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[CH2:14]([O:21][C:22]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(NCc1ccc(C(=O)O)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.3 %

Procedure:
To a solution of 4-(aminomethyl)benzoic acid (25 g) in a 2N aqueous solution of sodium hydroxide (100 ml), a solution of benzyloxycarbonyl chloride (33.8 g) in tetrahydrofuran (50 ml) was added drop by drop under ice cooling conditions, followed by stirring at room temperature for 2 hours. The resulting precipitate was collected by filtration, washed with water, 1N hydrochloric acid and ether and dried under reduced pressure to yield the title compound (10.5 g, yield 22%) as a colorless powder.
Reaction SMILES: C([O:9][CH2:10][C@H:11]1[O:16][C:15]([CH3:18])([CH3:17])[O:14][C@@H:13]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:9][CH2:10][C@H:11]1[O:16][C:15]([CH3:17])([CH3:18])[O:14][C@@H:13]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COC(=O)c2ccccc2)OC(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Reaction time: 2 h

Procedure:
To a solution of (4R-cis)-6-[(benzoyloxy)methyl]-2,2-dimethyl-1,3-dioxane-4-acetic acid, 1,1-dimethylethyl ester prepared in step (a) above (30.00 g, 82.4 mmole) in methanol (275 ml) was added granular anhydrous potassium carbonate (5.68 g, 41.2 mmole) in one portion. The resulting heterogeneous solution was stirred vigorously for 2 hours to complete the hydrolysis. The progress of the reaction was followed by TLC analysis. (TLC: Rf =0.31 for the benzoyloxy starting material, Rf =0.17 for the title compound (silica gel, Ether:Hexane, 1:1, visualized by Ce(SO4)2 spray).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:11]1([C:17]#[C:18][C:2]2[CH:3]=[N:4][C:5]3[N:6]([N:8]=[CH:9][CH:10]=3)[CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1cnc2ccnn2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C(#Cc1cnc2ccnn2c1)c1ccccc1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Bis-(triphenylphosphine)-palladium (II) dichloride (27 mg, 0.04 mmol) was dissolved in 1 ml of THF. 6-Bromo-pyrazolo[1,5-a]pyrimidine (150 mg, 0.76 mmol) and phenylacetylene (130 μl, 1.21 mmol) were added at room temperature. Triethylamine (310 μl, 2.3 mmol), triphenylphosphine (6 mg, 0.023 mmol) and copper (I) iodide (4 mg, 0.023 mmol) were added and the mixture was stirred for 2 hours at 65° C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with heptane:ethyl acetate 100:0->50:50. The desired compound was obtained as a yellow solid (150 mg, 90% yield), MS: m/e=220.3 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH:30]1[CH2:44][CH2:43][CH2:42][C@H:31]1[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>C(OCC)(=O)C.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([N:30]1[CH2:44][CH2:43][CH2:42][C@H:31]1[C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])=[O:13])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.6 %

Procedure:
A solution of t-butoxycarbonyl-L-alanine (2.48 g., 13.1 mmole) in 23 ml. of dry chloroform at -15° (ice-salt bath) is treated with N-methylmorpholine (1.47 ml., 13.1 mmole) followed by isobutyl chloroformate (1.8 ml., 13.1 mmole) to give a precipitate. After 15 minutes, L-proline, phenylmethyl ester, hydrochloride salt (3.18 g., 13.1 mmole) and N-methylmorpholine (1.47 ml., 13.1 mmole) are added. Gas evolution ensues and the mixture is kept below -10° for one hour, then allowed to warm to room temperature, and stirred overnight under argon. The mixture is diluted with ethyl acetate, filtered, and the filtrate evaporated to dryness. The residue is taken up in ethyl acetate and washed successively with 5% potassium bisulfate, saturated sodium bicarbonate, saturated sodium chloride, dried (Na2SO4) and evaporated. The residue is purified by flash chromatography on silica gel (210 g.) eluting with ethyl acetate/hexane (1:2) to give t-butoxycarbonyl-L-alanyl-L-proline, phenylmethyl ester (4.37 g.) as a colorless oil; Rf (ethyl acetate/hexane, 1:1) is 0.47.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.[Cl:22][CH2:23][CH2:24]Cl>O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:24][CH2:23][Cl:22])=[CH:6][CH:5]=1
Reactant: ClCCCl
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(OCCCl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-hydroxybenzoic acid methyl ester (1.52 g, 10 mmol), anhydrous potassium carbonate (1.38 g, 10 mmol), 10 ml of dimethylsulfoxide, and 20 ml of 1,2-dichloroethane are combined and heated to reflux. HPLC shows the reaction is at equilibrium at about 1 hour. Therefore, another equivalent of potassium carbonate is added. After the second addition of potassium carbonate, the ratio of product to bis alkylated biproduct is greatly enhanced. The reaction mixture is cooled to room temperature and diluted with 30 ml of water. The mixture is stirred then the layers separated. The organic layer is back extracted with 20 ml of brine and then filtered through sodium sulfate. The filtrate is concentrated in vacuo at about 60° C. to a yellow green oil which solidifies on cooling. This crude product is redissolved in 12 ml of hot methanol and water is added (total of 6 ml) dropwise until crystals appear. The crystallization is allowed to continue for one hour with cooling. The precipitate is filtered and rinsed with 12 ml of 1:1 methanol:water. The filter cake is dried in vacuo at about room temperature to give 2.00 g of product. (93.5%). HPLC.
Reaction SMILES: C[O:2][C:3]([C:5]1([OH:28])[CH2:10][C@@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[C:8](=[CH2:19])[C@H:7]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:6]1)=O.C1COCC1>>[Si:12]([O:11][C@H:9]1[C:8](=[CH2:19])[C@H:7]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:6][C:5]([CH2:3][OH:2])([OH:28])[CH2:10]1)([C:15]([CH3:17])([CH3:18])[CH3:16])([CH3:14])[CH3:13]
Reactant: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(O)(C(=O)OC)C[C@H]1O[Si](C)(C)C(C)(C)C
Solvent: C1CCOC1
Product: C=C1[C@H](O[Si](C)(C)C(C)(C)C)CC(O)(CO)C[C@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 6 h

Procedure:
(i) To a stirred solution of the ester 3 (90 mg, 0.21 mmol) in anhydrous THF (8 mL) lithium aluminum hydride (60 mg, 1.6 mmol) was added at 0° C. under argon. The cooling bath was removed after 1 h and the stirring was continued at 6° C. for 12 h and at room temperature for 6 h. The excess of the reagent was decomposed with saturated aq. Na2SO4, and the mixture was extracted with ethyl acetate and ether, dried (MgSO4) and evaporated. Flash chromatography of the residue with hexane/ethyl acetate (9:1) afforded unreacted substrate (12 mg) and a pure, crystalline diol 4 (35 mg, 48% based on recovered ester 3): 1H NMR (CDCl3 +D2O) δ 0.079, 0.091, 0.100, and 0.121 (each 3H, each s, 4×SiCH3), 0.895 and 0.927 (9H and 9H, each s, 2×Si-t-Bu), 1.339 (1H, t, J~12 Hz), 1.510 (1H, dd, J=14.3, 2.7 Hz), 2.10 (2H, m), 3.29 and 3.40 (1H and 1H, each d, J=11.0 Hz), 4.66 (1H, t, J~2.8 Hz), 4.78 (1H, m), 4.92 (1H, t, J=1.7 Hz), 5.13 (1H, t, J=2.0 Hz); MS m/z (relative intensity) no M+, 345 (M+-t-Bu, 8), 327 (M+-t-Bu-H2O, 22), 213 (28), 195 (11), 73 (100).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.I[CH3:12].[H-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:12])=[CH:4][CH:3]=1
Reactant: CI
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.8 %

Procedure:
5.00 g of 6-bromoindole was added to 25 ml of N,N-dimethylformamide. To the mixture was added 4.37 g of iodomethane in the presence of 1.12 g of sodium hydride (purity: 60%). The resulting mixture was stirred for 1 hour at room temperature to obtain 5.67 g of 6-bromo-1-methylindole. 2.10 g of this compound was dissolved in 21 ml of diethyl ether. Into the solution was dropwise added 7.0 ml of a 1.5M n-hexane solution of n-butyllithium at -45° to -40° C. in a nitrogen atmosphere. The resulting mixture was stirred for 1 hour at room temperature. To the reaction mixture was added 1.46 g of N,N-dimethylformamide at -30° to -20° C. The mixture was stirred for 30 minutes at the same temperature. The temperature of the reaction mixture was elevated to room temperature. 30 ml of water and 10 ml of ethyl acetate were added thereto. The mixture was adjusted to pH 8.0 with dilute hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: n-hexane/ethyl acetate=10/1) to obtain 1.09 g of light brown solid 6-formyl-1-methylindole.