Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:28]I>CN(C=O)C.C([O-])(O)=O.[Na+]>[C:3]([O:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][C:15]([N:19]([C:20](=[O:27])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH3:28])=[CH:16][CH:17]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)c3ccccc3)ccc21
Reactant: CI
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccccc1)c1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
Sodium hydride (60 mg, 1.5 eq.) was added to a mixture of 5-benzoylamino-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (570 mg, 1.68 mmol) and methyl iodide (0.42 mL, 4.0 eq.) in DMF (10 mL) at 0° C. and the resulting mixture was stirred for 20 min. After concentration, the residue from reaction mixture was diluted with sat. NaHCO3 and extracted with 3×EtOAc. The combined extracts were dried over Na2SO4, filtered, concentrated and the product was purified by chromatography (30% EtOAc-hexanes) to give 5-(benzoyl-methyl-amino)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (547 mg, 93%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][N:11]3[CH2:14][C:13](=[CH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=4[Cl:25])[CH2:12]3)[CH:8]=2)[CH:3]=[CH:2]1.CCN(C(C)C)C(C)C.[C:35]([O:39][C:40](=[O:49])[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[NH2:48])([CH3:38])([CH3:37])[CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][N:11]3[CH2:14][C:13](=[CH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([NH:48][C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=5[NH:41][C:40](=[O:49])[O:39][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:21])=[CH:18][C:17]=4[Cl:25])[CH2:12]3)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: O=C(O)c1ccc(C=C2CN(Cc3ccc4cc[nH]c4c3)C2)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=C2CN(Cc3ccc4cc[nH]c4c3)C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
To a solution of 4-((1-((1H-indol-6-yl)methyl)azetidin-3-ylidene)methyl)-3-chlorobenzoic acid (0.26 g, 0.74 mmol) in DCM (25 mL) was added DIPEA (0.29 g, 2.22 mmol), tert-butyl-2-aminophenylcarbamate (0.27 g, 1.18 mmol) and HATU (0.37 g, 0.96 mmol). The reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. After completion of the reaction as indicated by HPLC, the mixture was washed with saturated sodium bicarbonate (2×20 mL) and brine (1×15 mL). It was dried (Na2SO4), filtered and evaporated to give the crude product which was purified by column chromatography (10% MeOH: 90% DCM). After evaporation of pooled fractions of pure product, tert-butyl (2-(4-((1-((1H-indol-6-yl)methyl)azetidin-3-ylidene)methyl)-3-chlorobenzamido)phenyl)carbamate (0.2 g) was isolated as an off-white solid. ES+(M+H)+ 543.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:13][CH2:14]Cl)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:28]=[CH:27][C:26](=[O:29])[N:25]([CH2:30][CH3:31])[C:24]2=[O:32])=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+].C(O)CCC>O>[CH2:30]([N:25]1[C:26](=[O:29])[CH:27]=[CH:28][N:23]([C:20]2[CH:21]=[CH:22][C:17]([N:16]3[CH2:14][CH2:13][N:4]([C:5]4[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=4)[CH2:3][CH2:2]3)=[CH:18][CH:19]=2)[C:24]1=[O:32])[CH3:31]
Reactant: COc1ccc(N(CCCl)CCCl)cc1
Reactant: CCn1c(=O)ccn(-c2ccc(N)cc2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: CCn1c(=O)ccn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Reaction time: 24 h
Yield: 37 %

Procedure:
A mixture of 17.47 parts of N,N-bis(2-chloroethyl)-4-methoxybenzenamine, 16.3 parts of 1-(4-aminophenyl)-3-ethyl-2,4(1H,3H)-pyrimidinedione, 11.83 parts of sodium hydrogen carbonate and 240 parts of 1-butanol was stirred for 24 hours at reflux temperature. After cooling, 150 parts of water were added. The product was filtered off and crystallized from methylbenzene. The product was filtered off and dried in vacuo at 60° C., yielding 10.6 parts (37.0%) of 3-ethyl-1-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-2,4(1H,3H)-pyrimidinedione; mp. 210.2° C. (int. 26).
Reaction SMILES: [CH:1](/[C:14]1[CH:25]=[CH:24][C:17]([CH:18]=[CH:19][C:20]([O:22]C)=[O:21])=[CH:16][CH:15]=1)=[CH:2]\[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].O.[OH-].[Li+].Cl>O1CCCC1>[CH:1](/[C:14]1[CH:15]=[CH:16][C:17]([CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[CH:24][CH:25]=1)=[CH:2]\[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCC/C=C/c1ccc(C=CC(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCC/C=C/c1ccc(C=CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-[(E)-1-tridecenyl]cinnamate (342 mg, 1 mmole from Example 16 in 50% aqueous tetrahydrofuran (25 ml) was added lithium hydroxide monohydrate (420 mg, 10 equivalents) and the mixture was stirred at room temperature overnight. The cloudy mixture was acidified with dilute hydrochloric acid and extracted with ether. The extracts were washed with brine, dried (magnesium sulphate) and evaporated to a white crystalline solid. Yield 330 mg (100%). Recrystallisation from methanol afforded material of mp 107° C., νmax (mull) 2600 (broad), 1710, 1680, 1625, 1425, 1308, 1285 cm-1 ; δ(DMSO-d6) 0.82 (3H, distorted t, CH3), 1.25 (18H, m. alkylene chain), 2.18 (2H, m, allylic CH2), 6.37 (2H, distorted s), 6.48 (1H, d, J 15 Hz, C=CHCO2), 7.52 (4H, AB quartet, J 7.5 Hz, Δν 18 Hz, aromatics), 7.60 (1H, d, J 15 Hz, ArCH=C--CO2) λmax (MeOH) 307 (31,200), 226 (12,200) nm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([S:14](O)(=[O:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:4]([F:18])[CH:3]=1.CN(C=O)C.C1(C)C=CC=CC=1.S(Cl)([Cl:33])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([S:14]([Cl:33])(=[O:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:4]([F:18])[CH:3]=1
Reactant: O=S(=O)(O)c1ccccc1-c1ccc(Br)cc1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=S(=O)(Cl)c1ccccc1-c1ccc(Br)cc1F

Procedure:
4′-Bromo-2′-fluorobiphenyl sulfonic acid (5 g) was refluxed in thionyl chloride (30 mL) with a catalytic quantity of DMF (0.5 mL) for 4 hours. Toluene was added and the solvents evaporated under vacuum. The residue collected was recrystallised from petrol/ethyl acetate to give white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1
Reactant: Brc1cccc2[nH]ncc12
Reactant: CSc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nccc(-n2ncc3c(Br)cccc32)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
To a solution of 4-bromo-1H-indazole (8.831 g, 44.82 mmol) in DMF (100 mL) was added NaH (60% suspension in mineral oil, 74.7 mmol, 2.988 g) followed by 4-chloro-2-methylsulfanyl-pyrimidine (4.34 mL, 37.35 mmol). The resulting mixture was allowed to stir at RT for 2 h; the solid precipitate was collected by filtration, washed and dried under reduced pressure to give 10.7 g (89% yield) of 4-bromo-1-(2-methylsulfanyl-pyrimidin-4-yl)-1H-indazole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:10])[CH3:9].[C:11]([Cu])#[N:12]>CN(C=O)C>[CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[N:12])([CH3:10])[CH3:9]
Reactant: CC(C)c1ccccc1Br
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: CC(C)c1ccccc1C#N
Temperature: 25 °C
Yield: 81.9 %

Procedure:
To a dry, N2 purged 100 mL round bottom flask attached with condenser was added 1-bromo-2-isopropylbenzene (10.0 g, 50.2 mmol), anhydrous DMF (26 mL), and CuCN (5.85 g, 653 mmol) The reaction slurry was stirred at reflux under N2 for 4 hrs prior to analysis by GCMS. The reaction mixture was cooled to room temperature and poured into an ice/aq NH4Cl solution. The resulting precipitates were removed by vacuum filtration through a Buchner funnel. The aqueous filtrate was extracted with EtOAc (150 mL×3). The combined organic phase was dried over Na2SO4, filtered and concentrated on the Rotavapor to afford 5.97 g (82% yield) of 2-isopropylbenzonitrile. The product was used in the next step without further purification. GCMS m/z=145 [M+].
Reaction SMILES: N[C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:5]2[N:6]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[C:23]([Cu])#[N:24].N(OC(C)(C)C)=O.O>CS(C)=O>[Cl:16][C:12]1[CH:11]=[C:10]([N:6]2[C:5]3[C:17]([C:19]([F:21])([F:22])[F:20])=[CH:18][C:2]([C:23]#[N:24])=[CH:3][C:4]=3[NH:8][C:7]2=[O:9])[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1cccc(Cl)c1
Reactant: N#C[Cu]
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1cccc(Cl)c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 24.4 %

Procedure:
5-Amino-1-(3-chlorophenyl)-7-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one (125.1 mg) was dissolved in dimethyl sulfoxide (5 ml), and to the solution was added CuCN (102.6 mg). The mixture was heated at 55° C. At the same temperature, t-butyl nitrite (0.134 ml) was added dropwise during 30 minutes. After the addition was completed, the mixture was stirred at 60° C. for 1 hour. After allowing to cool, to the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by preparative TLC (2 mm, 20×20 cm, CHCl3:methanol=10:1) and then preparative TLC (2 mm, 20×20 cm, hexane:ethyl acetate=2:1) to give the title compound (31.4 mg, 24%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.Br[CH2:10][C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:7]=1
Reactant: COC(=O)CBr
Reactant: Oc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Cn1cc(Br)ccc1=O
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of 5-bromopyridin-2-ol (100 mg, 0.57 mmol), methyl 2-bromoacetate (168 mg, 1.1 mmol) and potassium carbonate (238 mg, 1.7 mmol) in acetone (5 mL) was stirred at 60° C. for 3 h. The solution was allowed to cool to room temperature, filtered and the filter cake was washed with acetone (5 mL×2). The filtrate was collected and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (PE: EA=15:1) to afford the title compound: LC/MS m/z=246.1 [M+H]+
Reaction SMILES: C(O[C:4]1[CH:9]=[CH:8][N:7]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[S:12][CH2:11]2)[C:6](=[O:17])[N:5]=1)C.[NH3:18].CO>>[OH:16][CH2:15][C@@H:13]1[S:12][CH2:11][C@H:10]([N:7]2[CH:8]=[CH:9][C:4]([NH2:18])=[N:5][C:6]2=[O:17])[O:14]1
Reactant: CCOc1ccn([C@H]2CS[C@@H](CO)O2)c(=O)n1
Reactant: N
Solvent: CO
Product: Nc1ccn([C@H]2CS[C@@H](CO)O2)c(=O)n1
Temperature: 70 °C
Yield: 89 %

Procedure:
A solution of (2S*,5R*)-4-ethoxy-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one (0.21 g) in ammonia/methanol (8 mL of methanol saturated with ammonia gas at 0° C. for 45 minutes) was placed in a steel bomb with a teflon liner, sealed and heated at 70° C. for 18 hours. Solvent was evaporated in vacuo and the residue subjected to flash chromatography to give the desired product (0.16 g, 89%) as a white solid: mp 184-185° C.; 1H NMR (DMSO-d6): δ 3.00 (dd, J=11.8, 5.0 Hz, 1H), 3.38 (dd, J=11.8, 5.5 Hz, 1H), 3.63-3.80 (m, 2H), 5.15 (t, J=4.5 Hz, 1H), 5.30 (t, J=6.0 Hz, 1H), 5.70 (d, J=7.3 Hz, 1H); 6.18 (t, J=5.0 Hz, 1H), 7.20 (brd, 2H, NH2), 7.79 (d, J=7.3 Hz, 1H); MS m/z 229.8 (M+1, 4%), 112 (100%). Anal. Calcd. for C8H11N3O3S: C, 41.91; H, 4.84; N. 18.33; S, 13.99. Found: C, 41.97; H, 4.83; N, 18.24; S, 13.93
Reaction SMILES: C(OC([NH:8]CC1CCN(CCNS(C)(=O)=O)C1)=O)(C)(C)C.N[C:23]1[C:31](Cl)=[CH:30][C:26]([C:27](O)=[O:28])=[C:25](OC)[CH:24]=1>>[C:27]([NH2:8])(=[O:28])[C:26]1[CH:30]=[CH:31][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCNS(C)(=O)=O)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: NC(=O)c1ccccc1

Procedure:
3-tert-Butoxycarbonylaminomethyl-1-(2-methylsulfonylaminoethyl)pyrrolidine (2 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (1.25 g) to give 4-amino-5-chloro-2-methoxy-N-(2-methylsulfonylaminoethyl)pyrrolidin-3-ylmethyl)benzamide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH2:17][OH:18])[CH:16]=2)[CH:5]=1.[OH:20][C:21]1[C:26]([CH2:27][CH2:28][CH3:29])=[C:25](O)[CH:24]=[CH:23][C:22]=1[C:31](=[O:33])[CH3:32]>>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH2:17][O:18][C:25]3[CH:24]=[CH:23][C:22]([C:31](=[O:33])[CH3:32])=[C:21]([OH:20])[C:26]=3[CH2:27][CH2:28][CH3:29])[CH:16]=2)[CH:5]=1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: COC(=O)c1cccc(Sc2cncc(CO)c2)c1
Product: CCCc1c(OCc2cncc(Sc3cccc(C(=O)OC)c3)c2)ccc(C(C)=O)c1O
Yield: 62.7 %

Procedure:
Using the procedure essentially of Preparation 117 using 3-(5-hydroxymethyl-pyridin-3-ylsulfanyl)-benzoic acid methyl ester (370 mg, 1.34 mmol), 1-(2,4-dihydroxy-3-propyl-phenyl)-ethanone (261 mg, 1.34 mmol) provides the title compound as colorless oil (379 mg, 0.84 mmol): MS (m/z): 452 (M+1).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([I:11])=[C:7]([CH:10]=1)[CH2:8]Br.[C-:14]#[N:15].[Na+]>CCO.O>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([I:11])=[C:7]([CH2:8][C:14]#[N:15])[CH:10]=1
Reactant: FC(F)(F)c1ccc(I)c(CBr)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1cc(C(F)(F)F)ccc1I
Temperature: 25 °C

Procedure:
A solution of 5-trifluoromethyl-2-iodobenzyl bromide (55 g, 0.15 mol) in EtOH (200 mL) is stirred at room temperature and a solution of sodium cyanide (16 g, 0.33 mol) in water (60 mL) is added. The reaction mixture is heated to reflux temperature for 3 hours and then cooled to room temperature. Most of the ethanol is removed by rotary evaporator and the residue partitioned between EtOAc (500 mL) and water (200 mL). The organic layer is washed with brine (250 mL), dried (MgSO4) and the solvent is removed by rotary evaporator. The residue is purified using flash chromatography (1:9 EtOAc/hexanes) to give 5-trifluoromethyl-2-iodophenylacetonitrile as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=O)[O:5][CH:6]=1.COC(Cl)[Cl:13]>>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([Cl:13])=[O:9])[O:5][CH:6]=1
Reactant: COC(Cl)Cl
Reactant: O=C(O)c1cc(Br)co1
Product: O=C(Cl)c1cc(Br)co1
Temperature: 25 °C

Procedure:
The crude 4-bromofuran-2-carboxylic acid was placed in a 250 mL round bottom flask equipped with a magnetic stirring bar and a reflux condenser, and the flask was alternately evacuated and filled with nitrogen several times. To the stirred solid was carefully added α,α-dichloromethyl methyl ether (50 mL, 563 mmol). The addition was accompanied by vigorous gas evolution and was very exothermic, bringing the temperature of the resulting brown frothy mixture nearly to reflux. The gas evolution was allowed to subside, then the brown mixture was slowly heated to reflux using a heating mantle. The thick, partially solidified reaction mixture was then diluted with additional α,α-dichloromethyl methyl ether (20 mL, 225 mmol) to afford a dark brown solution containing some large black solid chunks. After heating at reflux for 135 minutes, the reaction was allowed to cool to ambient temperature, and then concentrated under reduced pressure. The resulting dark brown semi-solid was held under high vacuum to remove the last traces of solvents. While being held under vacuum at ambient temperature, some large colorless prisms appeared on the upper walls of the flask. The crude 4-bromofuran-2-carbonyl chloride was obtained as a dark brown semi-solid, and was used in the next step without purification.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]1[OH:13].[OH:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[O:32][CH3:33].C(N(CC)CC)C>C(O)CCC>[OH:20][CH2:21][CH2:22][N:23]([CH2:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[O:32][CH3:33])[C:2]1[C:3]2[N:4]=[CH:5][N:6]([C:7]=2[N:8]=[CH:9][N:10]=1)[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]1[OH:13]
Reactant: COc1ccc(Cl)cc1CNCCO
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1CN(CCO)c1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
5.7 g. 6-Chloro-9-(β-D-ribofuranosyl)-purine, 6 g. N-(2-hydroxyethyl)-2-methoxy-5-chlorobenzylamine and 2.5 g. triethylamine were heated under reflux for 2 hours in 100 ml. n-butanol. Subsequently, the solvent was removed in a vacuum and the residue taken up in 100 ml. chloroform. The chloroform phase was washed several times with water, initially with the addition of some dilute hydrochloric acid and thereafter with a dilute solution of sodium bicarbonate. From the so purified chloroform solution, there crystallized out 4.9 g. (53% of theory) N(6)-(2-hydroxyethyl)-N(6)-(2-methoxy-5-chlorobenzyl)-adenosine, which melted at 98°-100°C.
Reaction SMILES: [Na].[SH:2][C:3]1[NH:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]=1.[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CO>[C:13]1([CH2:12][S:2][C:3]2[NH:4][C:5]3[CH:10]=[CH:9][N:8]=[CH:7][C:6]=3[N:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Sc1nc2cnccc2[nH]1
Reactant: ClCc1ccccc1
Agent: [Na]
Solvent: O
Solvent: CO
Product: c1ccc(CSc2nc3cnccc3[nH]2)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 1.26 g (0.055 g atom) of sodium in 300 mL of methanol was added 7.56 g (0.05 mol) of 2-mercapto-1H-imidazo[4,5-c]pyridine with stirring. After 20 minutes, the reaction mixture was evaporated to dryness in a rotary evaporator. Dimethyl formamide (200 mL) was added to the residue. To the resulting solution was added dropwise 6.33 g (0.05 mol) of benzylchloride. The reaction mixture was stirred for 5 hours at room temperature and was then poured into 1500 mL of water. The product was removed by filtration and amounted to 9.5 g, m.p. 175°-177° C. The product was triturated with hot ethyl acetate and refiltered. The product amounted to 8.11 g, m.p. 175°-177° C. A portion recrystallized from ethyl acetate gave the analytical sample (m.p. 175°-177° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Sn](C)(C)C)=[CH:4][CH:3]=1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:20][C:19]([F:22])([F:21])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Reactant: FC(F)(F)c1ccccc1Br
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2C(F)(F)F)cc1

Procedure:
A solution of 388 mg (1.52 mmol,1.4 eq.) of 4-methylphenyltrimethylstannane (Example 69, Step A) in 5 mL of toluene under a nitrogen atmosphere was treated with 238 mg of 2-bromobenzotrifluoride (1.06 mmol) and 64 mg of tetrakis(triphenylphosphine) palladium(0) and the resulting solution heated at reflux for 14 hours. The mixture was cooled, filtered and concentrated under vacuum to give an amber oil that was chromatographed on silica, eluting with hexane, to give the product. 1H NMR (300 MHz,CDCl3): 2.41 (s,3H), 7.2-7.8 (m,8H). EI-MS: calculated for C14H11F3 236; found 236 (M+,100%).
Reaction SMILES: [CH3:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([NH:17][CH2:18][C:19](O)=[O:20])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:13]([O:12][C:10](=[O:11])[NH:17][CH2:18][C:19](=[O:20])[NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:2]=1[CH3:1])([CH3:16])([CH3:14])[CH3:15]
Reactant: Cc1c(N)cccc1Cl
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1NC(=O)CNC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
To a mixture of 2-methyl-3-chloroaniline (14.16 g, 100 mmol, 1 equiv), Boc-glycine (17.52 g, 1 equiv), BOP reagent (48.6 g, 1.1 equiv) in 50 mL of DMF was added TEA (42 mL, 3 equiv). After overnight, standard aqueous workup followed by flash chromatography gave 20 g of [(3-chloro-2-methyl-phenylcarbamoyl)-methyl]-carbamic acid tert-butyl ester, which was treated with ˜300 mL of 4N HCl in dioxane overnight to afford 2-amino-N-(3-chloro-2-methyl-phenyl)-acetamide (74).
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].C(O[CH:9]1[NH:12][C:11](=[O:13])[CH:10]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)C>[OH-].[Na+].O1CCOCC1>[C:1]([S:3][CH:9]1[NH:12][C:11](=[O:13])[CH:10]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:4])[CH3:2]
Reactant: CC(=O)OC1NC(=O)C1Cc1ccccc1
Reactant: CC(O)=S
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)SC1NC(=O)C1Cc1ccccc1
Reaction time: 3 h

Procedure:
A solution of 0.76 g (10 mmole) of thioacetic acid in 10 ml of 1N sodium hydroxide solution is added dropwise to a solution of 2.19 g (10 mmole) of 4-acetoxy-3-benzylazetidin-2-one (racemic mixture of cis- and trans-isomer in the ratio of 9:13) in 10 ml of dioxan at room temperature under a nitrogen atmosphere, and the mixture is stirred at the same temperature for 3 hours. The reaction mixture is exhaustively extracted with methylene chloride. The combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed over silica gel with toluene/ethyl acetate (9:1) and yields a cis-trans mixture of the title compound in the ratio of 2:10. By recrystallisation from methylene chloride/hexane at -10° the pure trans-compound having a melting point of 42°-43° is obtained.
Reaction SMILES: [C:1]1([S:11](Cl)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:15]([C:17]1[CH:39]=[CH:38][C:20]([O:21][C:22]2[CH:27]=[C:26]([O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=3)[CH:25]=[CH:24][C:23]=2[NH2:37])=[CH:19][CH:18]=1)#[N:16]>>[C:15]([C:17]1[CH:39]=[CH:38][C:20]([O:21][C:22]2[CH:27]=[C:26]([O:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=3)[CH:25]=[CH:24][C:23]=2[NH:37][S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:13])=[O:12])=[CH:19][CH:18]=1)#[N:16]
Reactant: N#Cc1ccc(Oc2ccc(N)c(Oc3ccc(C#N)cc3)c2)cc1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Product: N#Cc1ccc(Oc2ccc(NS(=O)(=O)c3cccc4ccccc34)c(Oc3ccc(C#N)cc3)c2)cc1
Yield: 68 %

Procedure:
1-Naphthalene sulfonyl chloride (0.148 g, 0.65 mmol) was added to a stirred solution of 1,5-bis-(4-cyano-phenoxy)-2-aminobenzene (0.175 g, 0.54 mmol) along with other reagents as mentioned in Example 20(c) to afford 0.19 g of the required product. 1H NMR (DMSO-d6): δ 6.45 (3H, m), 7.16 (5H, m), 7.42 (6H, m), 7.75 (2H, dd), 7.85 (3H, m).