Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]C1CC(C=O)CC=C1.C[CH:11]1[CH2:16][CH:15]([CH:17]2[O:21][C:20](=[O:22])[NH:19][C:18]2=[O:23])[CH2:14][CH:13]=[CH:12]1>>[CH3:1][C:12]1[CH2:11][CH2:16][CH:15]([CH:17]2[O:21][C:20](=[O:22])[NH:19][C:18]2=[O:23])[CH2:14][CH:13]=1
Reactant: CC1C=CCC(C=O)C1
Reactant: CC1C=CCC(C2OC(=O)NC2=O)C1
Product: CC1=CCC(C2OC(=O)NC2=O)CC1

Procedure:
By the same three step procedures of the preceding Examples, 5-methyl-3-cyclohexene-1-carbaldehyde is inverted to 5-(5-methyl-3-cyclohexen-1-yl)oxazolidine-2,4-dione.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([F:18])[CH:17]=1)[C:12](O)=[O:13])(=[O:8])=[O:7]>CN(C)C=O>[Cl:5][S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([F:18])[CH:17]=1)[C:12]([Cl:3])=[O:13])(=[O:8])=[O:7]
Reactant: O=C(O)c1cc(F)cc(S(=O)(=O)Cl)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(F)cc(S(=O)(=O)Cl)c1
Temperature: 75 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
One drop of N,N-dimethylformamide was added to a thionyl chloride (2.03 g) suspension of 3-(chlorosulfonyl)-5-fluorobenzoic acid (1.36 g), followed by stirring at 75° C. for 1 hour. The solvent was evaporated, and this was azeotroped with toluene to obtain 3-(chlorosulfonyl)-5-fluorobenzoyl chloride (1.47 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[O:10][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2c(Br)cc(C=O)cc2Br)cc1
Temperature: 60 °C
Reaction time: 0.21 h
Yield: 88 %

Procedure:
To a stirred solution of 3,5-dibromo-4-hydroxybenzaldehyde (5.30 g, 18.9 mmol) in anhydrous DMF (15 mL) under nitrogen was added potassium carbonate (5.50 g, 19.9 mmol) and the mixture was stirred for 10-15 min during which time vigorous effervescence was observed. 4-methoxybenzyl chloride (2.70 mL, 19.9 mL) was then added and the mixture was heated at 60° C. for 20 h. The mixture was filtered and the filtrate was evaporated. The residual oil was then poured into water (100 mL) and the mixture was stirred for 1-2 h. The resulting solid was collected by filtration, washed with water and dried under vacuum at 60° C. to leave 6.63 g (88%) of the title compound as a pale brown solid. 1H NMR (DMSO-d6) 3.82 (3 H, s), 5.06 (2 H, s), 7.02 (2 H, d), 7.53 (2 H, d), 8.24 (2 H, s), 9.95 (1 H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1F)[CH3:2].C(N(C(C)C)CC)(C)C.C[N:26]1C(=O)[CH2:29][CH2:28][CH2:27]1>>[N+:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:26]3[C@H:2]([CH2:1][O:3][C:4](=[O:15])[C:5]=2[CH:10]=1)[CH2:29][CH2:28][CH2:27]3)([O-:13])=[O:12]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OC[C@@H]2CCCN2c2ccc([N+](=O)[O-])cc21
Temperature: 100 °C
Reaction time: 3 h

Procedure:
By adopting a similar procedure as described in “Mueller, W; Stauss, U.; Forschungsinst, W.; Bern, S. Helvetica Chimica Acta 1982, 65, 2118.” (S)-8-Nitro-2,3,3a,4-tetrahydro-1H-5-oxa-10b-aza-benzo[e]azulen-6-one was prepared as follows. A mixture of 2-fluoro-5-nitro-benzoic acid ethyl ester (1.16 g, 5.44 mmol), S-prolinol (638 mg, 6.31 mmol) and diisopropylethylamine (1.5 mL, 8.62 mmol) in dry NMP (20 mL) was stirred at 100° C. for 3 h. Solvent was removed and the mixture was partition between EtOAc and water. Organic layer was extracted two more times with EtOAc. Combined organic was washed successively with water (twice) and brine. After drying over magnesium sulfate, solvent was evaporated. The product, (S)-8-Nitro-2,3,3a,4-tetrahydro-1H-5-oxa-10b-aza-benzo[e]azulen-6-one was obtained as a solid (1.08 g, 80%). 12b) (S)-8-Nitro-2,3,3a,4-tetrahydro-1H-5-oxa-10b-aza-benzo[e]azulen-6-one (1 g, 4 mol) was taken in MeOH (50 mL) and was cooled to 0° C. Sodium borohydride (1 g, 26.43 mmol, 300 mg was added in portion in the first phase, 700 mg after 4 h at RT) was added and the cooling bath was removed. After stirring overnight at RT, the mixture was quenched with water. The mixture was treated with 1N Na2CO3 solution (100 mL) and dichloromethane (100 mL). The mixture was extracted from dichloromethane (twice). Combined organic was washed successively with water (twice) and brine. After drying over magnesium sulfate, solvent was evaporated. A gum was obtained which was taken in 50% H2SO4 (20 mL). The mixture was stirred at 120° C. for 45 minutes. The mixture was cooled to RT and was neutralized with NaHCO3 solution and was extracted from EtOAc. Combined organic was washed successively with water (twice) and brine. After drying over magnesium sulfate, solvent was evaporated. The crude product was purified by flash chromatography (hexane:EtOAc 3:1). The product (S)-8-Nitro-2,3,3a,4-tetrahydro-1H-5-oxa-10b-aza-benzo[e]azulen-6-one was obtained as an yellow solid (451 mg, 48% in two steps); 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J=9.1 Hz, 1H), 8.00 (s, 1H), 6.75 (d, J=9.09 Hz, 1H0, 5.14 (d, J=14.14 Hz, 1H), 4.36 (d, J=13.89 Hz, 1H), 5.14 (d, J=14.14 Hz, 1H0, 4.36 (d, J=13.89 Hz, 1H), 4.07 (m, 1H0, 3.93 (m, 1H), 3.41 (m, 1H), 3.35-3.31 (2m, 2H), 2.17-1.89 (2m, 3H), 1.57 (m, 1H); MS (m/e) 235 (M+H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.S(O[CH:37]1[CH2:41][CH2:40][O:39][CH2:38]1)(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[O:19]([C:16]1[CH:15]=[CH:14][C:13]([C:12]2[C:5]3[C:4]([NH2:3])=[N:9][CH:8]=[N:7][C:6]=3[N:10]([CH:37]3[CH2:41][CH2:40][O:39][CH2:38]3)[CH:11]=2)=[CH:18][CH:17]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: Cc1ccc(S(=O)(=O)OC2CCOC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCOC1
Temperature: 95 °C

Procedure:
Sodium hydride (120 mg, of a 60% dispersion in mineral oil) was added to a solution of 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (906 mg) and dimethylformamide (30 ml) with stirring under nitrogen. The mixture was stirred for 30 minutes and then a solution of 3-(tosyloxy) tetrahydrofuran (750 mg) in dimethyl formamide (10 ml) was added with stirring. The mixture was stirred and heated at 95° C. for 18 hours and then evaporated under vacuum. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, dried and evaporated to give a residual gummy solid which was triturated with ether and filtered to give 5-(4-phenoxyphenyl)-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine m.p. 196-196.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[C:13]2[N:21]=[N:20][N:19]([CH2:22][CH2:23][CH3:24])[C:14]=2[N:15]=[C:16]([CH3:18])[N:17]=1.[H-].[Na+].[CH2:27](I)[CH3:28]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:27][CH3:28])[C:12]1[C:13]2[N:21]=[N:20][N:19]([CH2:22][CH2:23][CH3:24])[C:14]=2[N:15]=[C:16]([CH3:18])[N:17]=1
Reactant: CCI
Reactant: CCCn1nnc2c(Nc3ccc(C(C)C)cc3Br)nc(C)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1nnc2c(N(CC)c3ccc(C(C)C)cc3Br)nc(C)nc21
Reaction time: 0.08 h

Procedure:
The title compound from Example 1 (0.30 g) was dissolved in dry DMF (10 mL) and added NaH (62 mg; 60% in oil) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 5 mins., and then added EtI (0.2 mL) and continued for an additional 24 h. The reaction mixture was partitioned between ethyl acetate (25 mL) and water (25 mL), washed the organic layer with brine, dried, and stripped in vacuum to yield a pale yellow oil. The sample was purified by flash column chromatography (1:100 MeOH +CH2Cl2) to afford the title compound as a colorlesss oil (0.16 g). Elemental analysis for C19H25BrN6 : Theory C: 54.68, H: 6.05 Found: C: 54.66, H: 6.02.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH2:15](OC(OCC)OCC)C>C(O)(=O)C>[F:13][C:11]([F:12])([F:14])[CH2:10][C:4]1[S:3][C:2]2[N:1]=[CH:15][NH:9][C:7](=[O:8])[C:6]=2[CH:5]=1
Reactant: NC(=O)c1cc(CC(F)(F)F)sc1N
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1[nH]cnc2sc(CC(F)(F)F)cc12

Procedure:
8.4 g of 2-amino-5-(2,2,2-trifluoroethyl)thiophene-3-carboxamide was refluxed in a mixture of 28 mL of triethylorthoformate and 20 mL of acetic acid for 4 hs. Solvents were removed under reduced pressure and the residue was triturated hexane-ethyl acetate mixture (1:1). The solid was filtered off to afford 5.7 g of 6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4(3H)-one. 1H NMR MeOH-d4 (300 MHz): 12.6 (br, 1H), 8.14 (s, 1H), 7.42 (s, 1H), 4.07 (q, 2H, J 11.0 Hz). 13C NMR MeOH-d4 (75 MHz): 164.5, 157.01, 146.1, 128.4, 124.6, 123.5, 33.6 (q, J31.5 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6].Cl.[CH2:13](O)[CH3:14]>>[CH2:13]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([I:11])=[C:2]([OH:1])[CH:3]=1)[CH3:14]
Reactant: O=C(O)c1ccc(I)c(O)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(I)c(O)c1
Yield: 99 %

Procedure:
Reflux 3-hydroxy-4-iodo-benzoic acid (38 g, 144 mmol) and saturated solution of HCl in ethanol (600 mL) overnight. Evaporate the solvent yielding 42 g, 99% of 3-hydroxy -4-iodo-benzoic acid ethyl ester. 1H NMR (300 MHz, CDCl3): δ 1.39 (t, J=7.1 Hz, 3H), 4.36 (q, J=7.1 Hz, 2H), 7.33 (dd, J=8.3 and 2.0 Hz, 1H), 7.64 (d, J=2.0 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H). Add ethyl iodide (33.8 g, 216 mmol) to a solution of 3-hydroxy -4-iodo-benzoic acid ethyl ester (42 g, 144 mmol) and K2CO3 (39.9 g, 288 mmol) in acetonitrile (400 mL) under magnetic stirring. Heat the reaction mixture at 65° C. for 2 hours, allow the mixture to cool and maintain at RT overnight. Evaporate the solvent and add ethyl acetate to the crude. Filter the solid through Celite® and evaporate the solvent. Yield 42 g, 96%. 1H NMR (300 MHz, CDCl3): δ 1.39 (t, J=7.1 Hz, 3H), 1.50 (t, J=7.0 Hz, 3H), 4.16 (q, J=7.0 Hz, 2H), 4.37 (q, J=7.1 Hz, 2H), 7.36 (dd, J=8.1 and 1.8 Hz, 1H), 7.42 (d, J=1.8 Hz, 1H), 7.84 (d, J=8.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].O[C:11]1[CH:12]=[C:13]([CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:14]=[CH:15][C:16]=1[NH2:17]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]1[O:5][C:11]2[CH:12]=[C:13]([CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:14]=[CH:15][C:16]=2[N:17]=1
Reactant: CCOC(=O)C(C)c1ccc(N)c(O)c1
Reactant: O=Cc1ccccc1Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)c1ccc2nc(-c3ccccc3Cl)oc2c1

Procedure:
A solution of o-chlorobenzaldehyde (4.3 g.) and ethyl 2-(3-hydroxy-4-aminophenyl)propionate (6 g.) in toluene (100 ml.) was heated, using a Dean and Stark apparatus to collect the water formed. After 30 minutes the solution was evaporated to dryness. The residue was dissolved in acetic acid (100 ml.), lead tetracetate (15 g.) was added and the solution was heated on a steam bath for 1 hour. The solution was poured into ice/water and extracted with ether to give the oil, ethyl 2-(2-o-chlorophenyl-6-benzoxazolyl)propionate, a sample of which gave a satisfactory micro-analysis.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[C:10]([CH2:18][CH3:19])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([N:8]1[C:16]2[CH:15]=[CH:14][C:13]([Cl:20])=[C:12]([NH2:17])[C:11]=2[C:10]([CH2:18][CH3:19])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1nn(Cc2ccccc2)c2cccc(N)c12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CCc1nn(Cc2ccccc2)c2ccc(Cl)c(N)c12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a reaction vial was added 1-benzyl-3-ethyl-1H-indazol-4-amine (20.0 mg, 0.0796 mmol) (prepared as in Example 2, steps A-B), N-chlorosuccinimide (12.8 mg, 0.0955 mmol) and acetonitrile (0.4 mL). The reaction vial was sealed and heated, with magnetic stirring, at 60° C. for 4 hours. The mixture was stirred at ambient temperature for 16 hours. The solvent was removed under a stream of nitrogen. The resulting material was purified using preparative thin layer chromatography on silica, eluting with 5% methanol in chloroform containing 0.5% ammonium chloride solution. The desired mono-chlorination product, 1-benzyl-5-chloro-3-ethyl-1H-indazol-4-amine (MS, APCI, m/z=286.1, M+H) was isolated as lower eluting component (8.7 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)[CH2:6][OH:7].[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>C(OC)(C)(C)C.[Pd]>[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:23])[NH:11][C:10]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: Cc1ccccc1N=C=O
Reactant: COc1cc(CO)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: COC(C)(C)C
Product: COc1cc(CO)ccc1NC(=O)Nc1ccccc1C
Reaction time: 0.5 h

Procedure:
15 g (81.8 mmol) of 3-methoxy-4-nitrobenzyl alcohol were hydrogenated over 1.3 g of palladium/carbon (10% strength; 50% water) in 500 mL of methyl tert-butyl ether with ice cooling. After the absorption of hydrogen was complete, the catalyst was filtered off and 10.14 mL (81.8 mmol) of 2-methylphenyl isocyanate were added to the filtrate with stirring in the course of 30 minutes. The reaction mixture was allowed to stand overnight, and the precipitated solid was filtered off with suction and washed with methyl tert-butyl ether. Yield: 20.5 g (88%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[N:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][C:14]2[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[N:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COc1ccc(CO)cn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(COc2ccc(Br)cc2)cn1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
4-Bromophenol (1.37 g, 7.90 mmol) was added to a solution of (6-methoxypyridin-3-yl)methanol (1.0 g, 7.16 mmol) in THF (100 mL). Triphenylphosphine (1.88 g, 7.19 mmol) was added followed by triethylamine (0.727 g, 7.19 mmol). The resulting solution was cooled to 0° C. and DIAD (1.45 g, 7.19 mmol) was added by drop-wise addition and was maintained at 0° C. for 30 minutes, then warmed to room temperature and stirred for two days. The reaction was quenched by addition of water and extracted with ether (2×100 mL). The organic layer was washed with water (2×100 mL) then brine (1×100 mL), dried (MgSO4), filtered and concentrated to give a yellow oil. The crude material was purified by flash column chromatography on a Biotage SNAP cartridge Kp-sil 100 g column (hexanes/ethyl acetate 9:1) to give a white solid. Mass/Yield—1.78 g/84% TLC (hexanes/ethyl acetate=8:2) Rf=0.12, UV active. LCMS MS ES+294.4/296.4. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.93 (s, 3H) 4.93 (s, 2H) 6.72-6.78 (m, 1H) 6.81-6.86 (m, 2H) 7.33-7.42 (m, 2H) 7.58-7.65 (m, 1H) 8.18 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C@@H:18]([OH:26])[C@H:17]2[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]=1)=[O:6].[S:43](Cl)([CH3:46])(=[O:45])=[O:44]>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:46][S:43]([NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C@@H:18]([OH:26])[C@H:17]2[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]=1)=[O:6])(=[O:45])=[O:44]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNS(C)(=O)=O)nc32)[C@H](O)[C@@H]1O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (2-amino-ethyl)-amide (0.01 g, 0.017 mmol) in chloroform (1 ml) is treated with mesyl chloride (1 ml of a 3 mg/ml solution in chloroform) and TEA (0.003 ml). After stirring at 5° C. for 1 hour, the reaction mixture is diluted with DCM and extracted with 1 M HCl. The organic portion is isolated and concentrated in vacuo to yield the title product. (MH+ 651.5)
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2.[CH:21]([Si:24](Cl)([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])([CH3:23])[CH3:22].O>O1CCCC1>[Br:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([Si:24]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:21]([CH3:23])[CH3:22])[CH:16]=[CH:15]2
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Brc1ccc2[nH]ccc2c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Reaction time: 0.08 h
Yield: 92 %

Procedure:
Lithium hexamethyldisilazane [1.0 M] (44.7 mL, 44.4 mmol) was added to a solution of 5-bromo-1H-indole (7.30 g, 37.0 mmol) in tetrahydrofuran (50 mL) at room temperature. After stirring for 5 minutes, triisopropylsilyl chloride (8.62 g, 44.4 mmol) was added to reaction mixture and stirred for 30 minutes. Water was added to quench the reaction and the solvent was removed under reduced pressure to give the crude mixture, which was purified via column chromatography on silica gel (9:1 hexane/ethyl acetate) to give the title compound in 92% yield. 1H NMR (CDCl3) δ 7.74 (d, J=1.8, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.22 (m, 2H), 6.55 (d, J=3.1 Hz, 1H), 1.65 (m, 3H), 1.12 (d, J=7.5 Hz, 18H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][C:10]=1[F:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH:27]([CH3:38])[C@@H:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH3:29]>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:23]=[C:22]([O:24][CH:27]([CH3:38])[C@@H:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH3:29])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][C:10]=1[F:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc2nc(-c3ccc(OCc4ccccc4)c(F)c3)oc2c1
Reactant: CC(O)[C@H](C)NC(=O)OC(C)(C)C
Product: CC(Oc1ccc2nc(-c3ccc(OCc4ccccc4)c(F)c3)oc2c1)[C@H](C)NC(=O)OC(C)(C)C

Procedure:
Using 2-(4-(benzyloxy)-3-fluorophenyl)-1,3-benzoxazol-6-ol and tert-butyl ((2S)-3-hydroxybutan-2-yl)carbamate, and in the same manner as in Step C of Example 1, the title compound was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:8]([CH2:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=2[N+:18]([O-:20])=[O:19])[CH:7]=[N:6][CH:5]=1.CCN(CC)CC.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([CH2:9][N:8]2[C:4]([CH2:3][CH2:2][O:1][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:5][N:6]=[CH:7]2)=[C:11]([N+:18]([O-:20])=[O:19])[CH:12]=1)#[N:15]
Reactant: N#Cc1ccc(Cn2cncc2CCO)c([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cncn1Cc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
The crude residue, 4-[5-(2-hydroxyethyl)imidazol-1-ylmethyl]-3-nitrobenzonitrile, is then taken up in CH2Cl2 (10 mL), cooled to 0° C., and treated with Et3N (0.58 mL, 4.19 mmol). To this solution is added methanesulfonyl chloride (0.13 mL, 1.68 mmol). After 0.5 h the solution is diluted with CH2Cl2 (10 mL) and saturated aqueous NaHCO3 (20 mL). The organic layer is further extracted with CH2Cl2 (3×20 mL) and the combined layers are dried (Na2SO4) and concentrated to give crude methanesulfonic acid 2-[3-(4-cyano-2-nitrobenzyl)-3H-imidazol-4-yl]ethyl ester. A suspension of the methanesulfonic acid 2-[3-(4-cyano-2-nitrobenzyl)-3H-imidazol-4-yl]-ethyl ester residue, DMF (17 mL), sodium iodide (0.630 g, 4.19 mmol), Et3N (0.58 mL, 4.19 mmol), and potassium carbonate (0.580 g, 4.19 mmol) is heated to 60° C. for 1 hour and then 75° C. for an additional 2 h. At that point the suspension is concentrated and diluted with CH2Cl2 (20 mL) and saturated aqueous NaHCO3 (20 mL). The organic layer is further extracted with CH2Cl2 (3×20 mL) and the combined layers are dried (Na2SO4). The residue is then purified via HPLC (reversed phase, CH3CN/H2O) to give 4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-nitrobenzonitrile as a solid. MS (ESI) m/z 254.9 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 2.48-2.57 (m, 1H), 2.81-2.92 (m, 1H), 2.92-3.01 (m, 1H), 3.35-3.47 (m, 1H), 6.03 (dd, J=8.6, 3.5 Hz, 1H), 6.80 (d, J=8.3 Hz, 1H), 6.89 (s, 1H), 7.36 (s, 1H), 7.81 (dd, J=7.8, 1.8 Hz, 1H), 8.41 (d, J=1.8 Hz, 1H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH:12]=O)[C:9]#[N:10])=[CH:4][CH:3]=1.[CH3:14][NH:15][CH3:16].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)CCl>[CH3:14][N:15]([CH3:16])[CH2:12][CH2:11][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)[C:9]#[N:10]
Reactant: CNC
Reactant: N#CC(CC=O)c1ccc(I)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C)CCC(C#N)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4iodophenyl)-4oxobutyronitrile (2.03 g, 7.1 mmol) in ClCH2CH2Cl (50 mL) was added dimethylamine (14.3 mL, 2M in THF, 28.6 mmol, 4 eq) and the mixture was left stirring at room temperature for 1 h. Na(OAc)3BH (6.04 g, 28.6 mmol, 4 eq) was added and the mixture was stirred at room temperature for 16 h. The reaction was quenched by adding aqueous saturated NaHCO3 (50 mL) and the mixture was extracted with EtOAc (50 mL×3). The organic layer was washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated. The crude product was purified by silica gel chromatography (50% EtOAc/hexanes) to give 4dimethylamino-2-(4iodophenyl)-butyronitrile as a dark brown solid, 2.09 g (94%). 1H NMR (300 MHz, CDCl3): δ 7.83 (d, 2H), 7.22 (d, 2H), 4.10 (t, 1H), 2.56 (m, 1H), 2.41 (m, 1H), 2.34 (s, 6H), 2.20 (m, 1H), 2.05 (m, 1H).
Reaction SMILES: CC([N:5]([C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[O:15][CH3:16])[C:6](=[O:8])[O-:7])(C)C.[F:17][C:18]1[CH:19]=[N:20][C:21]2[C:26]([C:27]=1[C:28](=[CH2:33])[C:29]([O:31][CH3:32])=[O:30])=[N:25][C:24]([O:34][CH3:35])=[CH:23][CH:22]=2>>[CH3:18][C:27]([O:7][C:6]([NH:5][C@H:9]1[CH2:14][CH2:13][N:12]([CH2:33][CH:28]([C:27]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:34][CH3:35])[N:25]=3)[N:20]=[CH:19][C:18]=2[F:17])[C:29]([O:31][CH3:32])=[O:30])[CH2:11][C@H:10]1[O:15][CH3:16])=[O:8])([CH3:28])[CH3:26]
Reactant: C=C(C(=O)OC)c1c(F)cnc2ccc(OC)nc12
Reactant: CO[C@@H]1CNCC[C@@H]1N(C(=O)[O-])C(C)(C)C
Product: COC(=O)C(CN1CC[C@H](NC(=O)OC(C)(C)C)[C@H](OC)C1)c1c(F)cnc2ccc(OC)nc12
Yield: 142.8 %

Procedure:
The title compound was prepared according to the general method of Example 2(d) from 1,1-dimethylethyl[(3R,4S)-3-(methyloxy)-4-piperidinyl]carbamate (1.29 g, 5.63 mmol) and methyl 2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-2-propenoate (1.48 g, 5.63 mmol) to give the desired product (1.98 g, 71%).