Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.C(N(CC)C(C)C)(C)C.[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCCl>[C:17]1([S:23][C@@H:2]2[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]2[OH:7])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Sc1ccccc1
Reactant: C1CCC2OC2C1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CCCC[C@H]1Sc1ccccc1
Reaction time: 16 h

Procedure:
A room temperature solution of cyclohexene oxide (9.81 g, 100 mmol) and N,N-diisopropylethylamine (2.60 g, 20.0 mmol) in 1,2-dichloroethane (200 mL) was treated with thiophenol (11 g, 100 mmol), stirred for 16 hours, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][C@H:21]3[CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:28][C:29]([O:31]C)=[O:30])[C:22]3=[O:33])=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:34])=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Na+]>C1COCC1>[NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([NH:20][C@H:21]3[CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:28][C:29]([OH:31])=[O:30])[C:22]3=[O:33])=[O:19])[CH2:16][CH2:17]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:34])=[CH:7][CH:8]=2)[N:3]=1
Reactant: COC(=O)CN1CCCC[C@H](NC(=O)N2CCN(c3cc(N)nc4cc(Cl)ccc34)CC2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(CC(=O)O)C3=O)CC2)c2ccc(Cl)cc2n1
Reaction time: 0.5 h
Yield: 5.2 %

Procedure:
To a stirred solution of (3S)-[[[4-(2-amino-7-chloro-4-quinolinyl)-1-piperazinyl]carbonyl]amino]hexahydro-2-oxo-1H-azepine-1-acetic acid, methyl ester (300 mg, 0.613 mmol) in THF (3.0 mL) was added 2N NaOH solution (3 mL) at rt. After 30 min, THF was evaporated in vacuo, and the resulting residue was acidified to pH 4–5. The reaction mixture was extracted with ethyl acetate, washed with brine, and dried over Na2SO4. The product (15 mg) was obtained after concentration in vacuo. LC-MS: 475 (M++1). 1H NMR (CD3OD) δ 7.82 (d, 1H), 7.50 (s, 1H), 7.38 (d, 1H), 6.25 (s, 1H), 4.58 (d, 1H), 4.10 (m, 2H), 3.80 (m, 1H), 3.65 (m, 4H), 3.30 (m, 5H), 1.60–1.96 (m, 6H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH2:16][C:17]1[C:22]([C:23]([OH:25])=[O:24])=[C:21]([OH:26])[C:20]([Br:27])=[CH:19][CH:18]=1.[C:28](O)([CH3:31])([CH3:30])[CH3:29]>CN(C1C=CN=CC=1)C.C1COCC1>[NH2:16][C:17]1[C:22]([C:23]([O:25][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:24])=[C:21]([OH:26])[C:20]([Br:27])=[CH:19][CH:18]=1
Reactant: Nc1ccc(Br)c(O)c1C(=O)O
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(N)ccc(Br)c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dicyclohexylcarbodiimide (4.14 g) was added to a stirred solution of 6-amino-3-bromo-2-hydroxybenzoic acid (Intermediate 63, 3.88 g) and DMAP (0.102 g) in tert-butanol (20 mL) and THF (150 mL). The mixture was stirred at room temperature for 4 hours. The resultant white precipitate was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 2.5-15% to give tert-butyl 6-amino-3-bromo-2-hydroxybenzoate (1.16 g) as a yellow solid.
Reaction SMILES: [Si]([N:8]1[CH2:11][CH2:10][C:9]1=[O:12])(C(C)(C)C)(C)C.C([N-]C(C)C)(C)C.[Li+].[CH2:21]([O:24][C:25]([N:27]1[CH2:31][C@@H:30]([S:32][C:33]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:29][C@H:28]1[CH2:52]I)=[O:26])[CH:22]=[CH2:23]>>[CH2:21]([O:24][C:25]([N:27]1[CH2:31][C@@H:30]([S:32][C:33]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:29][C@H:28]1[CH2:52][CH:10]1[CH2:11][NH:8][C:9]1=[O:12])=[O:26])[CH:22]=[CH2:23]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CI
Reactant: CC(C)(C)[Si](C)(C)N1CCC1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC1CNC1=O
Yield: 24.5 %

Procedure:
The same procedure as in Reference Example 22-1 was carried out by using N-tert-butyldimethylsilyl-2-oxoazetidine (650 mg, 3.5 mmol), lithium diisopropylamide (2.1M tetrahydrofuran solution, 3.34 ml, 7.0 mmol), and (2S,4S)-N-allyloxycarbonyl-2-iodomethyl-4-tritylthiopyrrolidine (1 g, 1.75 mmol) to obtain (2R,4S)-N-allyloxycarbonyl-2-(2-oxoazetidin-3-ylmethyl)-4-tritylthiopyrrolidine (220 mg, yield: 24%).
Reaction SMILES: [Cl:1][C:2]1[C:14]([OH:15])=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[N:12]2[Cl:16])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:23](I)[CH3:24]>CC(C)=O>[Cl:1][C:2]1[C:14]([O:15][CH2:23][CH3:24])=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[N:12]2[Cl:16])=[CH:4][CH:3]=1
Reactant: CCI
Reactant: Oc1c(Cl)ccc2c3ccncc3n(Cl)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1c(Cl)ccc2c3ccncc3n(Cl)c12
Temperature: 25 °C
Reaction time: 72 h
Yield: 20.3 %

Procedure:
A mixture of the product of example 38 (35 mg, 0.14 mmol), K2CO3 (100 mg), and ethyl iodide (0.014 ml, 0.17 mmol) in acetone (5 ml) was stirred in a closed reaction tube at RT for 3 days. After concentrating the reaction, the residue was partitioned in ethyl acetate and water. The organic layer was dried (MgSO4) and concentrated to give crude product. The crude product was chromatographed (5% methanol in chloroform) on silica gel to give 8 mg of 7,9-dichloro-8-ethoxy-β-carboline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[CH2:11]([O:18][C:19]1[CH:39]=[CH:38][C:22]([C:23]([CH:25]2[C:34]3[C:29](=[CH:30][C:31]([O:35][CH3:36])=[CH:32][CH:33]=3)[CH2:28][CH2:27][C:26]2=O)=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:26]2[CH2:27][CH2:28][C:29]3[C:34]([C:25]=2[C:23](=[O:24])[C:22]2[CH:38]=[CH:39][C:19]([O:18][CH2:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:20][CH:21]=2)=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)=[CH:5][CH:4]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: COc1ccc2c(c1)CCC(=O)C2C(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C2=C(C(=O)c3ccc(OCc4ccccc4)cc3)c3ccc(OC)cc3CC2)cc1
Temperature: 45 °C

Procedure:
To a solution of about 50 grams (0.24 mole) of p-methoxyphenylmagnesium bromide in tetrahydrofuran (THF) were added at room temperature 30.2 grams (0.08 mole) of 1-(p-benzyloxybenzoyl)-6-methoxy-2-tetralone dissolved in THF. Upon completion of the addition, the entire mixture was warmed to 45° C. Analysis of a sample of the mixture by thin-layer chromatography (TLC) showed the absence of starting material. The mixture then was poured into aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The ethyl acetate extract was washed, dried, and evaporated. The resulting residue was dissolved in benzene, and a catalytic amount of p-toluene- sulfonic acid was added. The mixture was stirred at room temperature until a TLC of the mixture indicated the absence of any carbinol intermediate. The mixture then was washed with water, dried, and concentrated. The residue was chromatographed over one kg. of alumina using 6 l. of benzene. The product was eluted with a mixture of 2 percent ethyl acetate in benzene. The product, 3-(4-methoxyphenyl)-4-(4-benzyloxybenzoyl)-7-methoxy-1,2-dihydronaphthalene was obtained as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:23][C:24]1[CH:30]=[C:29]([F:31])[C:27]([NH2:28])=[C:26]([F:32])[CH:25]=1.[H-].[Na+]>CN(C=O)C>[Cl:23][C:24]1[CH:30]=[C:29]([F:31])[C:27]([NH:28][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[C:26]([F:32])[CH:25]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Nc1c(F)cc(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(F)cc(Cl)cc3F)ncnc2cc1OCC1CCN(C)CC1
Yield: 61.2 %

Procedure:
Using an analogous procedure to that described in Example 4, 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (246 mg, 0.764 mmol), (prepared as described for the starting material in Example 2c), was reacted with 4-chloro-2,6-difluoroaniline (250 mg, 1.53 mmol), (see WO 97/30035 Example 15), in DMF (9 ml) and in the presence of sodium hydride (60%, 76.5 mg, 1.9 mmol) to give 4-(4-chloro-2,6-difluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (210 mg, 61%).
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[CH:9]=[C:10]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[C:18]([CH2:24][OH:25])[CH:17]=3)[CH:11]=[CH:12][CH:13]=2)OCC[O:4]1)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.CC(C)=O>[OH:25][CH2:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:10]2[CH:9]=[C:8]([C:3](=[O:4])[CH2:1][CH3:2])[CH:13]=[CH:12][CH:11]=2)[CH:21]=[CH:20][C:19]=1[CH2:22][OH:23]
Reactant: CCC1(c2cccc(CCc3ccc(CO)c(CO)c3)c2)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CCC(=O)c1cccc(CCc2ccc(CO)c(CO)c2)c1
Reaction time: 5 h

Procedure:
6.4 g (18.7 mmol) of (4-{2-[3-(2-ethyl-[1,3]dioxolan-2-yl)phenyl]ethyl}2-hydroxymethyl-phenyl)methanol are dissolved in a mixture of 40 ml of water and 40 ml of acetone. 650 mg of paratoluene-sulfonic acid are added, and the medium is stirred for 5 hours. After the usual treatment, the desired product is pure without purification, and obtained in the form of colorless oil (m=5.57 g; Y=100%).
Reaction SMILES: [H-].[Na+].CS(C)=O.[C:7]([O:11][C:12](=[O:51])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[C:41]=2[Cl:50])[CH2:25][CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:15]=1)([CH3:10])([CH3:9])[CH3:8].[CH3:52][O:53][C:54](=[O:57])[CH2:55]Br>CN(C=O)C>[CH3:52][O:53][C:54](=[O:57])[CH2:55][N:13]([C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:51])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:48])([F:49])[F:47])[C:41]=2[Cl:50])[CH2:25][CH:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:15]=1
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)Nc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COC(=O)CN(C(=O)OC(C)(C)C)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of sodium hydride (18.8 mg, 0.47 mmol, 60% in mineral oil) in anhydrous DMF (10 mL) at 0° C. and DMSO (10 ml) was added dropwise a solution of (3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-carbamic acid tert-butyl ester (150 mg, 0.235 mmol) in DMF (5 ml). The solution was stirred at 0° C. for 20 minutes and was then treated with bromo-acetic acid methyl ester (72 mg 0.47 mmol). The resulting solution was warmed to room temperature and stirred for 6 hours. The reaction mixture was poured into ice water (30 ml). The mixture was extracted with EtOAC (3×) and the combine organic layers were washed with saturated aqueous sodium bicarbonate (2×), brine (×), dried over sodium sulphate, and filtered. The ethyl acetate filtrate was concentrated to afford the title compound as an oil. MS(ES) m/e 711.2 (M+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]2[CH2:15][CH:16]([CH2:18][NH2:19])[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>>[CH2:35]([O:34][C:32](=[O:33])[NH:19][CH2:18][CH:16]1[CH2:15][C:14]2[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:20])([F:1])[F:21])=[CH:10][CH:11]=[CH:12][C:13]=2[O:17]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2c(cccc2-c2ccccc2C(F)(F)F)O1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2c(cccc2-c2ccccc2C(F)(F)F)O1)OCc1ccccc1
Yield: 90.8 %

Procedure:
Treatment of (±)-1-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine (2.21 g, 6.7 mmol) with diisopropylethylamine (1.3 g, 10.05 mmol) followed by benzyl chloroformate (1.25 g, 7.37 mmol) generally according to the procedure described for Intermediate 12 provided 2.6 g (91%) of (±)-benzyl({4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)carbamate as a colorless oil. Anal. calcd. for C24H20F3NO3: C, 67.44; H, 4.72; N, 3.28. Found: C, 67.5; H, 4.7; N, 3.13. Chiral HPLC separation of (±)-benzyl ({4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)carbamate (Chiralcel OJ, ethanol:hexane 1:1) provided two fractions. Fraction 1 (Rt=5.701 min, Chiralcel OJ, ethanol:hexane 1:1); Fraction 2 (Rt=7.122 min, Chiralcel OJ, ethanol:hexane 1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([I:11])[CH:3]=1.C[O:13][C:14](=[O:32])[CH2:15][C@@H:16]1[C:20]2=[CH:21][C:22]3[C:23]([CH:29]([CH3:31])[CH3:30])=[CH:24][C:25]([F:28])=[CH:26][C:27]=3[N:19]2[CH2:18][CH2:17]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:21]2[C:22]3[C:23]([CH:29]([CH3:30])[CH3:31])=[CH:24][C:25]([F:28])=[CH:26][C:27]=3[N:19]3[CH2:18][CH2:17][C@H:16]([CH2:15][C:14]([OH:32])=[O:13])[C:20]=23)=[O:7])=[C:4]([I:11])[CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1I
Reactant: COC(=O)C[C@H]1CCn2c1cc1c(C(C)C)cc(F)cc12
Product: CC(C)c1cc(F)cc2c1c(C(=O)c1ccc(Cl)cc1I)c1n2CC[C@@H]1CC(=O)O

Procedure:
Starting from 4-chloro-2-iodobenzoyl chloride (542 mg, 1.8 mmol) and methyl[(1R)-6-fluoro-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (Example 44A, Step 1, 173 mg, 0.6 mmol), the title compound was synthesized following the procedures described in Step 1 of Example 61 and Step 10 of Example 7.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[CH:13]=[C:12]2[C:14]([C:17]([C:19](Cl)=[O:20])=[O:18])=[CH:15][NH:16][C:11]2=[CH:10][CH:9]=1.[C:22]([NH:30][CH2:31][CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][NH:34]1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:22]([NH:30][CH2:31][CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][N:34]1[C:19](=[O:20])[C:17]([C:14]1[C:12]2[C:11](=[CH:10][CH:9]=[CH:8][CH:13]=2)[NH:16][CH:15]=1)=[O:18])(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(Cl)C(=O)c1c[nH]c2ccccc12
Reactant: O=C(NCCC1CCCN1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCC1CCCN1C(=O)C(=O)c1c[nH]c2ccccc12)c1ccccc1
Reaction time: 10 h

Procedure:
Tri-ethylamine (1 ml) was added into a solution of indole-3-glyoxyloyl chloride, intermediate 9 (50 mg, purchased from Lancaster) and intermediate 10 2-(N-benzoylaminoethyl)-pyrrolidine (49 mg, Wang, et al, Tetrahedron Lett. 1999, 40, 6745-6747) in THF (5 ml). After the reaction was stirred for 10 hours, the solvents were removed under vacuum to afford a residue which was purified using Shimadzu automated preparative HPLC System to give 2-(N-benzoylaminoethyl)-1-[(indol-3-yl)-2-oxoacetyl]-pyrrolidine (20 mg). Start %=0
Reaction SMILES: [Si:1]([CH:18]([OH:25])[C@H:19]1[O:23][C:22](=[O:24])[CH2:21][CH2:20]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.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Si](Cl)(C)(C)C.[C:41]1([Se:47]Br)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1.CCOCC>[Si:1]([CH:18]([OH:25])[C@H:19]1[O:23][C:22](=[O:24])[C@H:21]([Se:47][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([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
Reactant: Br[Se]c1ccccc1
Reactant: CC(C)(C)[Si](c1ccccc1)(c1ccccc1)C(O)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](c1ccccc1)(c1ccccc1)C(O)[C@@H]1C[C@@H]([Se]c2ccccc2)C(=O)O1
Temperature: -78 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
To a solution of 4 (5 g, 14.1 mmol) in anhydrous THF (50 mL) at −78° C. was added lithium bis(trimethylsilyl)amide (1 M solution in THF, 15.8 mL, 15.8 mmol) over a period of 10 min. After stirring at −78° C. for 1 h, Me3SiCl (1.918 g, 17.65 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature. After being stirred at room temperature for 30 min, the mixture was cooled to −78° C., and a solution of PhSeBr (5 g, 21.19 mmol) in anhydrous THF (25 mL) was added rapidly. The mixture was diluted with ether (50 mL), washed with water until the color of organic layer changed from dark brown to light yellow, dried (Na2SO4), filtered, and evaporated. The resulting oily residue [containing 3R(α, 5) and 3S(β) isomers; TLC: hexane/EtOAc, 10:1; Rf=0.42 and 0.28, respectively] was purified by flash chromatography on silica gel eluting with hexane/EtOAc (99:1 to 95:5) to give the title compound 5 as a light yellow oil (4.22 g, 59%). 1H NMR (CDCl3) δ 7.69-7.60 (m, 6H, arom.), 7.46-7.30 (m, 9H, arom.), 4.37-4.34 (m, 1H, H-5), 4.12-4.08 (m, 1H, H-3), 3.86-3.82 (dd, J=3 & 11 Hz, 1H, CH2OH), 3.62-3.59 (dd, J=3 & 11 Hz, 1H, CH2OH), 2.73-2.67 (m, 1H, H-4), 2.32-2.28 (m, 1H, H-4), 1.02 (s, 9H, t-Bu).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:18]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)P(OC1C=CC=CC=1)(=O)OC1C=CC=CC=1.CC(C)([O-])C.[K+]>O1CCOCC1.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:10]#[C:18][C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: O=P(Oc1ccccc1)(Oc1ccccc1)C(Cl)c1ccncc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C#Cc2ccncc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.3 %

Procedure:
To a suspension of 3-cyclopentyloxy-4-methoxybenzaldehyde (6.07 g, 27.6 mmol) and diphenyl 1-chloro-1-(4-pyridyl)methanephosphonate (J. Org. Chem., 1992, 57, 1622) (9.03 g, 52.1 mmol) in dioxane (150 mL) there was added in portions potassium tert-butoxide (7.03 g, 62.8 mmol). The mixture was stirred at room temperature for 1 h and then refluxed. After 3.5 h, there was added another 7 g of potassium tert-butoxide and refluxing was continued for 18 h. After cooling, the mixture was diluted with water (1 L) and extracted 3 times with EtOAc. The extracts were washed 3 times with water, dried and evaporated and the residue was chromatographed on silica gel (EtOAc/hexane 1:2) to afford the title acetylene (4.72 g, 64%) as a cream-colored solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2C2CCCCO2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.[Li]CCCC.[CH3:28][C:29]([CH3:31])=[O:30]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:29]([OH:30])([CH3:31])[CH3:28])[NH:8]2)=[C:4]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[N:3]=1
Reactant: CC(C)=O
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2[nH]1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
4-(2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (2.76 gm) was cooled in THF to −78° C. A 2.5 M solution of n-BuLi in THF (1.5 eq) was added dropwise over 20 minutes. The reaction was stirred at −78° C. for 30 mins, after which acetone (1.56 mL) was added and the reaction was stirred over 2 hours, slowly warming to 0° C. The reaction mixture was then quenched with water and extracted with ethyl acetate. The crude product 2-(2-chloro-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-8-yl)propan-2-ol was concentrated and brought up in MeOH. The THP group was then removed via General Procedure D. The reaction mixture was concentrated and the crude solid was brought up in water, filtered and collected and dried overnight to give 2.23 gm of 2-(2-chloro-6-morpholino-9H-purin-8-yl)propan-2-ol as a light yellow solid.
Reaction SMILES: [OH-].[Na+].FC(F)(F)C(O)=O.C[O:11][C:12](=[O:45])[CH2:13][CH2:14][CH2:15][N:16]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42](=[O:44])[NH2:43])[C:17](=[O:35])[C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][NH:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[CH:21]=[C:20]([Cl:34])[CH:19]=1.Cl>O1CCOCC1>[C:42]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[N:16]([C:17](=[O:35])[C:18]1[CH:23]=[C:22]([O:24][CH2:25][CH2:26][NH:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[CH:21]=[C:20]([Cl:34])[CH:19]=1)[CH2:15][CH2:14][CH2:13][C:12]([OH:45])=[O:11])(=[O:44])[NH2:43]
Reactant: COC(=O)CCCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)c1ccccc1C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: NC(=O)c1ccccc1N(CCCC(=O)O)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Yield: 100.6 %

Procedure:
2M Aqueous sodium hydroxide (0.200 ml) was added to a stirred solution of 4-((2-carbamoyl-phenyl)-{3-chloro-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoyl}-amino)-butyric acid methyl ester trifluoroacetate (0.030 g) in 1,4-dioxan (1 ml). 2M Aqueous hydrochloric acid (0.2 ml) was added after 16 h. The reaction mixture was evaporated in vacuo and the residue was subjected to preparative hplc to give the title compound (0.024 g) as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[CH3:5].[H-].[Na+].[Cl:14][C:15]1[CH:22]=[C:21](F)[CH:20]=[CH:19][C:16]=1[CH:17]=[O:18]>CN(C)C=O.C(OCC)(=O)C>[Cl:14][C:15]1[CH:22]=[C:21]([O:1][CH2:2][CH2:3][N:4]([CH3:5])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)[CH:20]=[CH:19][C:16]=1[CH:17]=[O:18]
Reactant: CN(CCO)c1ccccn1
Reactant: O=Cc1ccc(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(CCOc1ccc(C=O)c(Cl)c1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
To a solution of 2-[N-(2-hydroxyethyl)-N-methylamino]pyridine (3.87 g) in dry N,N-dimethylformamide (39 ml) was added sodium hydride (60% in oil, 1.12 g), and the reaction mixture was stirred at room temperature for 30 min. 2-Chloro-4-fluorobenzaldehyde (4.43 g) was added to the reaction mixture and the mixture was stirred for 3 days. The mixture was diluted with ethyl acetate and washed with water. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give the objective compound (3.30 g) as a pale-yellow oil.
Reaction SMILES: Br[CH:2]([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=1)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:18]1([NH:24][C:25]([NH2:27])=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[C:18]1([NH:24][C:25]2[S:26][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=3)[N:27]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(Br)C(=O)c1cccc(C#N)c1
Reactant: NC(=S)Nc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1sc(Nc2ccccc2)nc1-c1cccc(C#N)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 49.3 %

Procedure:
To a solution of ethyl 2-bromo-3-(3-cyanophenyl)-3-oxopropionate (0.60 g, 2.03 mmol) in 20 mL of absolute ethanol was added N-phenylthiourea (0.31 g, 2.03 mmol). The resulting mixture was stirred at 80° C. for 3 h. The reaction was allowed to cool and the solvent was evaporated in vacuo. The residue was taken up in ethyl acetate, washed with saturated aq NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo to yield a solid. Trituration with hexanes/ethyl ether left the title compound as an off-white solid (0.35 g, 49%). MS(NH3—CI) 350 (M+H)+.