Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:13]([O:24][CH3:25])[CH:12]=3)=[CH:9][N:8]([C@H:26]3[CH2:31][CH2:30][C@H:29]([N:32]4[CH2:37][CH2:36][NH:35][CH2:34][CH:33]4[CH3:38])[CH2:28][CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[OH-:39].[NH4+:40]>O1CCOCC1>[C:18]([OH:39])(=[O:17])[CH3:23].[CH3:25][O:24][C:13]1[CH:12]=[C:11]([C:10]2[C:3]3[C:2]([NH2:40])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([C@H:26]3[CH2:27][CH2:28][C@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:34])[CH2:38][CH2:33]4)[CH2:30][CH2:31]3)[CH:9]=2)[CH:16]=[CH:15][C:14]=1[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: [NH4+]
Reactant: COc1cc(-c2cn([C@H]3CC[C@H](N4CCNCC4C)CC3)c3ncnc(Cl)c23)ccc1Oc1ccccc1
Reactant: [OH-]
Solvent: C1COCCO1
Product: CC(=O)O
Product: COc1cc(-c2cn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1Oc1ccccc1
Temperature: 120 °C

Procedure:
A mixture of trans-4-chloro-5-(3-methoxy-4-phenoxyphenyl)-7-[4-(methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidine (220 mg, 0.414 mmol) in 1,4-dioxane (20 mL) and 30% aqueous ammonium hydroxide (20 mL) was heated at 120° C. in a sealed tube for 18 hours then cooled, concentrated under reduced pressure and purified by preparative RP-HPLC to give trans-5-(3-methoxy-4-phenoxyphenyl)-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine acetate (122 mg, 58%): 1H NMR (DMSO-d6, 400 MHz) δ 8.14(s, 1H), 7.49(s, 1H), 7.32(t, 2H), 7.22(s, 1H), 7.10(d, 1H), 7.05(m, 2H), 6.92(d, 2H), 6.2(bs, 2H), 4.56(m, 1H), 3.79 (s, 3H), 2.2-2.6(m, 9H), 2.15(s, 3H), 1.8-2.05(m, 6H), 1.90(s, 6H), 1.45(m, 2H); MS MH-513.4; RP-HPLC (Hypersil HS, 5 μm, 100 A 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 ml/min) tr 14.77 min.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.Cl.[NH2:17][CH2:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[CH:28]=[CH:29][O:30][C:23]=12)=[O:20].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C)C=O>[F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5]([NH:17][CH2:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[CH:28]=[CH:29][O:30][C:23]=12)=[O:20])=[O:6]
Reactant: NCC(=O)Nc1ccnc2ccoc12
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(/C=C/C(F)(F)F)NCC(=O)Nc1ccnc2ccoc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (15.4 mg, 0.11 mmol) was dissolved in DCM (0.75 ml containing one drop of dimethyl formamide), oxalyl chloride was added (14 mg, 0.11 mmol) and the solution was stirred at room temperature for 15 minutes. This solution was added to a solution of 2-amino-N-furo[3,2-b]pyridin-7-yl-acetamide hydrochloride (25.3 mg, 0.11 mmol) and diisopropylethylamine (44 μl, 0.25 mmol) dissolved in dimethylformamide (1 ml) and the resulting mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 6.9 mg (0.022 mmol, 20%).
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:19][O:20][C:21](=[O:30])[C:22]1C=[CH:26][C:25]([CH3:28])=[C:24](Cl)[CH:23]=1.[Br:31]N1C(=O)CCC1=O.[C:39]([Cl:43])(Cl)(Cl)Cl>>[CH3:19][O:20][C:21](=[O:30])[C:22]1[CH:23]=[CH:24][C:25]([CH2:28][Br:31])=[CH:26][C:39]=1[Cl:43]
Reactant: COC(=O)c1ccc(C)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Reactant: ClC(Cl)(Cl)Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: COC(=O)c1ccc(CBr)cc1Cl
Temperature: 25 °C

Procedure:
Add benzoyl peroxide (308 mg, 1.27 mmol) to a mixture of methyl-3-chloro-4-metylbenzoate (4.7 g, 25.5 mmol) and N-bromosuccinimide (4.98 g, 28.00 mmol) in anhydrous carbon tetrachloride (100 mL). Reflux the reaction mixture for 4 hrs and cool to room temperature. Filter the reaction mixture and concentrate the filtrate to provide the title compound as a crude oil (7.6 g, 28.8 mmol). MS (m/z): 264 (M+1).
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.[NH2:18][C:19]1[N:20]=[CH:21][NH:22][C:23]=1C#N>C(O)(=O)C>[F:16][C:13]([F:14])([F:15])[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[N:20]3[CH:21]=[N:22][C:23]([C:19]#[N:18])=[C:17]3[N:2]=[CH:3][CH:4]=2)[CH:8]=1
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: N#Cc1[nH]cnc1N
Solvent: CC(=O)O
Product: N#Cc1ncn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-3'-(trifluoromethyl)acrylophenone and 0.01 mole of 4-amino-5-imidazolecarbonitrile in 30 ml. of glacial acetic acid is refluxed for 6 hours. The solvent is removed under reduced pressure and worked up as for Example 29 to give the product as crystals, m.p. 168°-169° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)([CH2:13][OH:14])[CH2:11]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1COCC1.C(OCC)C>[CH2:1]([O:8][CH2:9][C:10]1([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)[CH2:13][O:14][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC(CO)(COCc1ccccc1)c1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Brc1ccc(C2(COCc3ccccc3)COC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
To a solution of 2-Benzyloxymethyl-2-(4-bromo-phenyl)-propane-1,3-diol (475 mg, 1.35 mmol) in THF (5 mL) at 0° C. was added nBuLi (0.54 mL, 2.5M in hexanes, 1.35 mmol). The reaction mixture was stirred for 30 minutes at 0° C., at which point a solution of p-toluenesulfonyl chloride (258 mg, 1.35 mmol) in THF (5 mL) was added via syringe. The reaction mixture was stirred for 1 hour at 0° C. and nBuLi (0.54 mL, 2.5M in hexanes, 1.35 mmol) was added. The reaction mixture was stirred at 60° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl ether (100 mL) and washed with water (50 mL). The aqueous layer was extracted with ethyl ether (2×50 mL). The combined organics were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 477 mg cloudy beige oil. The crude oil was purified by flash chromatography (12 g silica, 0-50% ethyl acetate/heptane, 26 column volumes). Product fractions were combined and concentrated in vacuo to afford the title compound as a colorless oil (258 mg, 57% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1.C[Si]([N-:20][Si](C)(C)C)(C)C.[Li+].[Br:26][C:27]1[CH:43]=[CH:42][CH:41]=C[C:28]=1[O:29][C:30]1[CH:39]=[CH:38][C:33]([C:34](OC)=[O:35])=[CH:32][CH:31]=1>C1COCC1>[Br:26][C:27]1[C:28]([O:29][C:30]2[CH:39]=[CH:38][C:33]([C:34]([C:8]3[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)=[O:35])=[CH:32][CH:31]=2)=[N:20][CH:41]=[CH:42][CH:43]=1
Reactant: COC(=O)c1ccc(Oc2ccccc2Br)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: c1ccc2c(c1)ncn2C1CCCCO1
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1ccc(Oc2ncccc2Br)cc1)c1nc2ccccc2n1C1CCCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole (39.5 g, 195 mmol) in anhydrous THF (300 ml) was cooled to 0° C. and treated with lithium bis(trimethylsilyl)amide (212 ml, 212 mmol) added dropwise over a 30 mins period. The reaction was allowed to stir for 1 hour and then methyl 4-(2-bromophenoxy)benzoate (50.00 g, 163 mmol), dissolved in 100 ml of anhydrous THF was added slowly to the reaction. The reaction was stirred for 1 hour at 0° C. and allowed to warm up to RT. After 1 hour, the reaction was cooled down to 0° C. and quenched with water (50 ml) dropwise. The reaction was diluted with 400 ml of Ethyl acetate and 400 ml of water. The layers were separated. The aqueous layer was extracted 2× (100 ml) with ethyl acetate. All the organic layers were combined, washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and reduced to a smaller volume. The solid that precipitated out was filtered off, washed well with ether and dried to give product as solid. The mother liquor was concentrated and purified by column chromatography on silica gel using a gradient of 10 to 60% EtOAc in hexanes to give another batch of product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][CH2:21][NH2:22])=[CH:12]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:8][C:6]1[C:5]([C:9]#[N:10])=[CH:4][N:3]=[C:2]([NH:22][CH2:21][CH2:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][CH:12]=2)[N:7]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: N#Cc1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1cnc(NCCc2c[nH]c3ccccc23)nc1Cl
Temperature: 50 °C
Reaction time: 3 h
Yield: 38.4 %

Procedure:
A mixture of 2,4-dichloro-pyrimidine-5-carbonitrile (2.0 g, 11.5 mmol), 2-(1H-indol-3-yl)-ethylamine (1.83 g, 11.4 mmol), and DIEA (1.94 g, 15.0 mmol) in THF (50 mL) was stirred at 50° C. for 3 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was diluted with ethyl acetate (150 mL). The organic layer was washed with saturated aqueous ammonium chloride, brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuum to give the crude product, which was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to afford the title compound as a brown solid (1.3 g, 4.38 mmol, 38% yield). MS (ESI) m/z 298.1 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:4][CH2:3]1.[CH2:17]([I:20])[CH:18]=[CH2:19]>>[I-:20].[CH2:17]([N+:2]1([CH3:1])[CH2:3][CH2:4][N:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:6][CH2:7]1)[CH:18]=[CH2:19]
Reactant: CN1CCN(c2nc3ccccc3o2)CC1
Reactant: C=CCI
Product: C=CC[N+]1(C)CCN(c2nc3ccccc3o2)CC1
Product: [I-]

Procedure:
A 1.09 g portion of 2-(4-methyl-1-piperazinyl)-benzoxazole and 0.69 ml of allyl iodide were treated in the same manner as in Example 2 to obtain 1.88 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C([N:10](CC)CC)C.[CH3:15][C:16]1[CH:29]=[C:28]2[C:19]([S:20][C:21]3[CH:22]=[C:23]([C:31](Cl)=[O:32])[CH:24]=[CH:25][C:26]=3[C:27]2=[O:30])=[CH:18][CH:17]=1>C(Cl)Cl.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:25]2[C:26]3[C:27](=[O:30])[C:28]4[C:19](=[CH:18][CH:17]=[C:16]([CH3:15])[CH:29]=4)[S:20][C:21]=3[CH:22]=[C:23]([C:31]([NH2:10])=[O:32])[CH:24]=2)[CH2:4][CH2:3]1
Reactant: CCN(CC)CC
Reactant: Cc1ccc2sc3cc(C(=O)Cl)ccc3c(=O)c2c1
Reactant: CN1CCNCC1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc2sc3cc(C(N)=O)cc(N4CCN(C)CC4)c3c(=O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
A solution of 3.0 g (31 mmoles) of 4-methyl piperazine and 3.1 g (31 mmoles) of triethyl amine in 40 cc of CH2Cl2 is poured drop by drop in the CH2Cl2 solution containing 7.47 g (25.9 mmoles) of 7-methyl-9-oxo-thioxanthene-3-carbonyl chloride. After approximately 1 hour at room temperature under stirring, the mixture is poured in water, the organic phase is separated and washed again with water. The organic phase is then separated, dehydrated and dried after purification on a flash column (SiO2— eluent: CH2Cl2:AcOEt 9:1) obtaining 4.63 g (50.8%) of a yellow solid, with the following spectral properties:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:27][O:28][C:29](=[O:38])[CH:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][CH:30]([C:29]([O:28][CH3:27])=[O:38])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Reactant: COC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1ccc(Cl)cc1OC1CN(C(=O)OC(C)(C)C)C1)c1ccccc1
Reaction time: 15 h
Yield: 96.5 %

Procedure:
To 3-(5-Chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (1.1 g, 3.7 mmol) in DMF (18 mL) was added Cs2CO3 (1.5 g, 4.4 mmol) and bromophenylacetic acid methyl ester (0.92 g, 0.63 mL, 4.0 mmol). After 15 h, H2O was added and the mixture extracted with EtOAc (2×). The combined organics were washed with brine and dried. Silica gel chromatography (5-25% EtOAc in hexanes) gave 1.6 g (96%) of the title compound. 1H NMR (CDCl3): 7.55-7.33 (m, 2H), 7.43-7.36 (m, 3H), 6.85 (d, J=1.2, 2H), 6.51 (t, J=1.2 Hz, 1H), 5.58 (s, 1H), 4.91-4.85 (m, 1H), 4.31-4.26 (m, 2H), 3.98-3.93 (m, 2H), 3.89-3.74 (m, 3H), 1.46 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1.C([Li])(CC)C.[I:18]I>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[I:18]
Reactant: COC(=O)Nc1cccc(F)c1
Reactant: II
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COC(=O)Nc1cccc(F)c1I

Procedure:
The starting material (3-fluoro-2-iodo-phenyl)-carbamic acid methyl ester was prepared from (3-fluoro-phenyl)-carbamic acid methyl ester by double deprotonation with sec.butyllithium in tetrahydrofuran at −78° C. followed by reaction with iodine. m.p.:80-82° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH2:10][OH:11])[CH:3]=[CH:2]1>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=[O:11])[CH:3]=[CH:2]1
Reactant: OCc1cccc2cc[nH]c12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Indole-7 carboxyldehyde (K-44). Methyl 7-indolecarboxylate was prepared according to literature procedure {Batcho B. and Leimgruber, K., Org. Syn. Vol IIV, page 34-40). To a solution of methyl 7-indolecarboxylate (13 g, 74.2 mmol) in anhydrous THF (250 mL) was added LiAlH4 (10.9 g, 0.288 mol) in portions, and reaction mixture was heated to reflux for 2 h. After cooling to room temperature, the excess hydride was quenched by addition of water (12mL), 15% NaOH (12 mL) and water (26 mL). The solids were removed by filtration through a pad of Celite and filtrate was evaporated in vacuo to yield (1H-indol-7-yl)-methanol (10.7 g, 98%). 1HNMR (CDCl3). To a solution of the alcohol, (1H-indol-7-yl)-methanol (8.0 g, 54.3 mmol) in 400 mL of methylene chloride was added activated manganese (IV) oxide (85%, 41.0 g, 0.40 mol), and stirred at ambient temperature for 72 h. After additional of 200 mL of methylene chloride and 400 mL of methanol to the reaction mixture, the whole mixture was filtered through a pad of silica gel to remove solid materials. The filtrate was concentrated to afford a crude product, which was purified by a column chromatography on silica gel to yield 1H-indole-7-carbaldehyde, K-44 (6.55 g, 83%).
Reaction SMILES: NC(CS)C(O)=O.C(O)(C(F)(F)F)=O.[CH2:15]([C:19]1[CH:46]=[CH:45][C:22]([CH2:23][O:24][C:25]2[CH:33]=[CH:32][C:31]3[N:30]4[CH2:34][CH2:35][CH:36]([CH2:37][C:38]([O:40]C(C)(C)C)=[O:39])[C:29]4=[CH:28][C:27]=3[CH:26]=2)=[CH:21][C:20]=1[C:47]([F:50])([F:49])[F:48])[CH:16]([CH3:18])[CH3:17]>O>[CH2:15]([C:19]1[CH:46]=[CH:45][C:22]([CH2:23][O:24][C:25]2[CH:33]=[CH:32][C:31]3[N:30]4[CH2:34][CH2:35][CH:36]([CH2:37][C:38]([OH:40])=[O:39])[C:29]4=[CH:28][C:27]=3[CH:26]=2)=[CH:21][C:20]=1[C:47]([F:50])([F:48])[F:49])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)Cc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)OC(C)(C)C)cc1C(F)(F)F
Agent: NC(CS)C(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
A solution of 2-amino-3-mercaptopropanoic acid (0.042 g, 0.347 mmol) in TFA (600 pt, 7.79 mmol) was added to neat tert-butyl 2-(7-(4-isobutyl-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.058 g, 0.116 mmol). The reaction mixture was stirred for 1 h at room temperature and then diluted with ice and water causing a tan solid to precipitate. The aqueous mixture was decanted off of the tan solid and the solid was rinsed with water. The solid was dried under vacuum to give the title compound (37 mg). LCMS m/z=446.7 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.89 (d, J=6.6 Hz, 6H), 1.87-1.98 (m, 1H), 2.16-2.26 (m, 1H), 2.53-2.82 (m, 5H), 3.53-3.62 (m, 1H), 3.92-4.00 (m, 1H), 4.06-4.14 (m, 1H), 5.13 (s, 2H), 6.01 (s, 1H), 6.77 (dd, J=8.7, 2.4 Hz, 1H), 7.07 (d, J=2.3 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.75 (d, J=1.1 Hz, 1H).
Reaction SMILES: [N-:1]=[C:2]=[O:3].[C:4]([O-:17])(=[O:16])[CH2:5][CH2:6]CCCCCCCCC.C([Sn+2]CCCC)CCC.[C:27]([O-])(=[O:39])[CH2:28]CCCCCCCCCC.C([O-])(=O)C=C>>[C:4]([OH:17])(=[O:16])[CH:5]=[CH2:6].[NH2:1][C:2]([O:39][CH2:27][CH3:28])=[O:3]
Reactant: CCCCCCCCCCCC(=O)[O-]
Reactant: [N-]=C=O
Agent: C=CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Product: C=CC(=O)O
Product: CCOC(N)=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A quantity of 0.1 moles of isocyanate terminated prepolymer and 0.1 ml of dibutyltin laurate were charged to a 500 ml glass kettle. The mixture was heated at 70° C. and air was purged through the reaction mixture and a solution of diol (0.05 moles) was added dropwise while the mixture was stirred at 200 RPM. After a two hour reaction, hydroyethyl acrylate (0.1 moles) was added to cap the residual isocyanate and the temperature of the kettle was increased to 77° C. After another two hours, a sample was withdrawn for analysis. The remainder was transferred to a bottle and stored in darkness.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][NH2:13])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH:14]1[N:19]=[C:18](Cl)[C:17]2[N:21]=[CH:22][N:23]([C@@H:24]3[O:28][C@H:27]([CH2:29][OH:30])[C@@H:26]([OH:31])[C@H:25]3[OH:32])[C:16]=2[N:15]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][O:12][NH:13][C:18]2[C:17]3[N:21]=[CH:22][N:23]([C:16]=3[N:15]=[CH:14][N:19]=2)[C@@H:24]2[O:28][C@H:27]([CH2:29][OH:30])[C@@H:26]([OH:31])[C@H:25]2[OH:32])=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NOCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(CONc2ncnc3c2ncn3[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1

Procedure:
The title compound was prepared according to Method A described above (R2, R3 =H) by reacting O-[(4-nitrophenyl)methyl]hydroxylamine hydrochloride (1.43 g, 7 mmol) with 6-chloropurine riboside (i.e. 9-β-D-ribofuranosyl-6-chloro-9H-purine) (1.0 g, 3.5 mmol) in DMF (40 ml) at 110° C. for 2 h with diisopropylethylamine (1.80 g, 14 mmol) present. The reaction mixture was evaporated and to the resultant residue was added saturated sodium bicarbonate solution (20 ml) and water (20 ml). Methanol was gradually added until the residue dissolved, and the solid which gradually precipitated was removed by filtration. The flitrate was concentrated to a residue which was purified by flash chromatography on silica gel. Elution with ethyl acetate/ethanol (30/1) initially, followed by a (8/1) mixture of these solvents provided a solid which was recrystallized from ethanol. The first crop of material was discarded, but the second crop was confirmed as the title compound (70 mg, 7%) mp 115°-117 ° C. TLC rf 0.20 [SiO2, ethyl acetate/methanol (9/1)]; 1H NMR (DMSO-d6)γ 3.46-3.57 (2H, m, H-5'a and H-5'b), 3.90 (1H, q, H-4'), 4.08 (1H, q, H-3'), 4.43 (1H, q, H-2'), 5.07 (1H, t, 5'-OH), 5.44, 5.74 (2H, 2d, 2'and 3'-OH), 5.82 (1H, d, H-1'), 7.67 (2H, d, Ar-H), 8.08 (1h, s, H-8), 8.22 (2H, d, Ar-H), 9.34 (1H, br s, N-H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([C:16]([C:19](OCC)=[O:20])([CH3:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[NH3:25]>C(O)C>[C:19]([C:16]([CH3:18])([CH3:17])[C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])([OH:24])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)(=[O:20])[NH2:25]
Reactant: CCOC(=O)C(C)(C)C(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: N
Solvent: CCO
Product: CC(C)(C(N)=O)C(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reaction time: 192 h

Procedure:
To a solution of 2-(2,4-dichlorophenyl)-3-ethoxycarbonyl-3-methyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (75 mg) in ethanol (5 ml), aqueous ammonia (sp. gr. 0.88, 12 ml.) was added and the solution was left at room temperature (20° C.) for eight days. The solvent was then evaporated in vacuo, the residue was partitioned between methylene chloride and water, and the organic extracts were washed with brine and dried (MgSO4). Removal of solvent followed by flash chromatography on silica (30 g) and elution with a mixture of methylene chloride/methanol/ammonia (93:7:1) gave the title compound, m.p. 162°-163° C. (34.5 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:9]#C)[CH:8]=1)#[N:2].[Mn]([O-])(=O)(=O)=[O:12].[K+].C[C:18](C)=[O:19]>>[C:9]([C:7]1[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[N:5][CH:6]=1)([O:19][CH3:18])=[O:12]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: C#Cc1cncc(C#N)c1
Reactant: CC(C)=O
Agent: [K+]
Product: COC(=O)c1cncc(C#N)c1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
3-Cyano-5-ethynylpyridine (1.28 g) (see Example 2) was dissolved in acetone (20 ml), and an aqueous solution (40 ml) of potassium permanganate (350 mg) was added dropwise. After the addition was completed, the reaction mixture was heated to 100° C. and filtered. The filtrate was concentrated under reduced pressure, and the residue was dissolved in DMF (20 ml). Potassium carbonate (1.6 g) and dimethyl sulfate (1 ml) were added to the solution, and the mixture was stirred at room temperature for 10 minutes. Water (10 ml) was added to the reaction mixture, and resulting mixture was extracted with diethyl ether (30 ml×3). The diethyl ether layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (Wako Gel C-200, 10 g; eluted with hexane:diethyl ether=1:1) to give 5-carbomethoxy-3-cyanopyridine (670 mg; yield, 41%) as colorless solids. IR (KBr) cm-1 : 2210, 1730.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([CH3:18])([CH3:17])[CH2:5][CH2:6][S:7][C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(=O)([O-])O.[Na+]>ClCCl>[CH3:26][S:27]([O:1][CH2:2][CH2:3][C:4]([CH3:18])([CH3:17])[CH2:5][CH2:6][S:7][C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[CH:10][CH:9]=1)(=[O:29])=[O:28]
Reactant: CC(C)(CCO)CCSc1cccc2nccn12
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CCOS(C)(=O)=O)CCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 304 mg (1.15 mmol) of 5-(5-hydroxy-3,3-dimethylpentylthio)imidazo[1,2-a]pyridine and 0.16 ml (1.15 mmol) of triethylamine in 5 ml of dichloromethane, 89 μl (1.15 mmol) of methanesulfonyl chloride was added at 0° C., followed by stirring at room temperature for 1 hour, after which saturated aqueous sodium hydrogen carbonate was added. The mixture was extracted with dichloromethane and dried, after which the solvent was distilled off to yield 5-(5-methanesulfonyloxy-3,3-dimethylpentylthio)imidazo[1,2-a]pyridine.