Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[C:4]([NH:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])=[O:5].[C:23](Cl)(Cl)=[O:24].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[C:4]1[O:5][C:23](=[O:24])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:15])([F:16])[F:17])[N:6]=1
Reactant: O=C(NNc1ccccc1C(F)(F)F)c1c(F)cccc1Cl
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1oc(-c2c(F)cccc2Cl)nn1-c1ccccc1C(F)(F)F

Procedure:
2.5 g (7.5 mmol) of 2-chloro-6-fluoro-N'-(α,α,α-trifluoro-o-tolyl)-benzhydrazide are heated to reflux temperature (internal temperature 80° C.) for 16 hours in 35 ml of a 20% solution of phosgene (67 mmol) in toluene. Excess phosgene and toluene are then distilled off, and the residue is dissolved in 30 ml of methylene chloride and heated to reflux temperature for 30 minutes with the addition of 6.7 ml (48 mmol) of triethylamine. The mixture is subsequently washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. After chromatographic purification of the crude product with toluene/n-hexane (1:1) as the eluent and recrystallization from methylene chloride/n-hexane there is obtained pure 5-(2-chloro-6-fluorophenyl)-3-(α,α,α-trifluoro-o-tolyl)-1,3,4-oxadiazol-2(3H)-one, m.p. 109°-109.5° C.; IR spectrum: 1792 cm-1 ; mass spectrum: 358(14), 314(23), 159(100).
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]2[C:6]([CH3:9])=[CH:7][O:8][C:4]=2[CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17]Br.C(N(C(C)C)C(C)C)C>C(O)C>[Cl:12][C:11]1[C:2]([N:1]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:3][C:4]2[O:8][CH:7]=[C:6]([CH3:9])[C:5]=2[CH:10]=1
Reactant: BrCCCCBr
Reactant: Cc1coc2cc(N)c(Cl)cc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1coc2cc(N3CCCC3)c(Cl)cc12

Procedure:
A mixture of 9.1 g (50 mmole) of 6-amino-5-chloro-3-methylbenzofuran, 11.8 ml (0.1 mole) of 1,4-dibromobutane, 17.1 ml (0.1 mole) of N-ethyldiisopropylamine and 60 ml of ethanol is boiled under reflux for 24 hours and then concentrated by evaporation in vacuo. The residue is partitioned between methylene chloride and saturated sodium bicarbonate solution. The crude product obtained after drying and concentration by evaporation of the methylene chloride is chromatographed with petroleum ether/ether over silica gel. Subsequent distillation in a bulb tube (150°/10-1 torr) yields 5-chloro-3-methyl-6-(pyrrolidin-1-yl)-benzofuran having a melting point of 50°-52°.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([O-:15])=O)=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+].N1C=CC=CC=1.C(Cl)(=O)C([Cl:26])=O>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:12]([C:13]([Cl:26])=[O:15])=[N:11][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C([O-])c1nnnn1Cc1ccccc1
Agent: [K+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1nnnn1Cc1ccccc1
Reaction time: 2 h

Procedure:
A stirred mixture of potassium 1-benzyl-1H-tetrazole-5-carboxylate (3.6 g; prepared as described in the specification of Belgian Pat. No. 845612), dry pyridine (0.75 ml) and dry toluene (65 ml) was cooled to 5° C. and treated with oxalyl chloride (12.5 ml). Stirring was maintained and the temperature was allowed to rise to 15° C. during a period of 2 hours. The mixture was filtered and the residue was washed with dry toluene. Evaporation of the combined toluene filtrate and washings, under diminished pressure, gave crude 1-benzyl-1H-tetrazole-5-carbonyl chloride in the form of an oil, which was used without further purification.
Reaction SMILES: [O:1]1[C:8]2[CH:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:5][C:4]=2[CH:3]=[CH:2]1.Br[CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>>[CH3:12][O:11][C:9]([C:6]1[N:5]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)[C:4]2[CH:3]=[CH:2][O:1][C:8]=2[CH:7]=1)=[O:10]
Reactant: BrCc1cccc2ccccc12
Reactant: COC(=O)c1cc2occc2[nH]1
Product: COC(=O)c1cc2occc2n1Cc1cccc2ccccc12

Procedure:
Using general procedure B, methyl 4H-furo[3,2-b]pyrrole-5-carboxylate was coupled with 1-bromomethyl-naphthalene to give 4-naphthalen-1-ylmethyl-4H-furo[3,2-b]pyrrole-5-carboxylic acid methyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white solid. MS: 290.3 ([M−H]−).
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[N:10]=[C:11]=[S:12])C.[CH2:13]([NH:15][CH2:16][C:17](O)=[O:18])[CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:13]([N:15]1[CH2:16][C:17](=[O:18])[N:10]([C:4]2[CH:3]=[CH:8][CH:7]=[CH:6][C:5]=2[CH3:9])[C:11]1=[S:12])[CH3:14]
Reactant: CCc1cccc(C)c1N=C=S
Reactant: CCNCC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2ccccc2C)C1=S

Procedure:
The title compound was prepared by the procedure described in Example 28 using 17.7 g of 2-ethyl-6-methylphenyl-isothiocyanate, 18.4 g of N-ethyl glycine, 20.2 g of triethyl amine, and 300 mL of chloroform. The residue was further purified by flash chromatography on silica gel (20% ethyl acetate in hexane).The title compound was obtained (8.6 g) as a light peach solid, m.p. 82°-84° C. Anal. Calcd. for. C14H18N2O S: C, 64.09; H, 6.92; N, 10.68. Found: C, 64.27; H, 7.04; N, 10.60. Mass spectrum (EI, M.+) m/z 262.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:35]=[CH:34][N:33](S(C5C=CC(C)=CC=5)(=O)=O)[C:13]=4[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:29][CH2:28][N:27]([C:30](=[O:32])[CH3:31])[CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[N:16]=3)[CH:8]=2)[CH:3]=[N:2]1.[OH-].[K+]>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:35]=[CH:34][NH:33][C:13]=4[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([N:24]5[CH2:25][CH2:26][N:27]([C:30](=[O:32])[CH3:31])[CH2:28][CH2:29]5)=[CH:20][CH:19]=4)[N:16]=3)[CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4ccc5cn[nH]c5c4)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4ccc5cn[nH]c5c4)c4cc[nH]c4n3)cc2)CC1
Temperature: 60 °C
Yield: 46.3 %

Procedure:
To a solution of 1-(4-(4-(4-(1H-indazol-6-ylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (60 mg, 0.097 mmol) in methanol (MeOH) (4 mL), aq. 1N potassium hydroxide (KOH) (1.0 mL, 1.0 mmol) was added. The mixture was heated at 60° C. for 5 h before it was concentrated in vacuo. The residue was acidified with acetic acid (HOAc) (1 mL) before being purified by HPLC to give 1-(4-(4-(4-(1H-indazol-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone (21 mg), MS 468.2 (M+H) (Compound 1-1); and N4-(1H-indazol-6-yl)-N2-(4-(piperazin-1-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (3 mg), MS 426.3 (M+H) (Compound 1-2).
Reaction SMILES: [CH2:1]([N:5]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:26])[CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[C:9]([N+:27]([O-])=O)[CH:8]=1)[CH:2]([CH3:4])[CH3:3]>[Pd].C(OCC)(=O)C.C(O)C>[NH2:27][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[NH:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:26])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)[C:6]([N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:30]
Reactant: CC(C)CN(CC(C)C)C(=O)c1ccc(NCCCN(C)CCc2ccccn2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)CN(CC(C)C)C(=O)c1ccc(NCCCN(C)CCc2ccccn2)c(N)c1
Reaction time: 7 h

Procedure:
N,N-diisobutyl-4-({3-[methyl(2-pyridin-2-ylethyl)amino]propyl}amino)-3-nitrobenzamide (2.9 g) in solution in an ethyl acetate/ethanol mixture (100 ml), and 10% palladium on carbon (290 mg) are added together in an autoclave. After stirring for 7 hours under a hydrogen atmosphere (3 bars), the catalyst is eliminated by filtration on Celite and the filtrate is concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of an oil (2.5 g, 92% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]([CH3:17])([CH:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]([CH3:9])([CH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)[CH3:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(C)(C)C1CCC(O)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 93.4 %

Procedure:
2.91 g of [1-Methyl-1-(4-oxo-cyclohexyl)-ethyl]-carbamic acid tert-butyl ester (20) were dissolved in 60 mL of ethanol and 473 mg of sodium borohydride were added at −20° C. The mixture was allowed to warm to room temperature and stirred for 3.5 h. The mixture was evaporated, the residue was dissolved in ethyl acetate and washed twice with 2N hydrochloric acid and once with brine. The organic layer was dried over sodium sulphate and evaporated to dryness to give 2.74 g of (21). Rt=1.27 min (Method 5). Detected mass: 194 (M-Isobutene-H2O+H+).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[N:3]=[N:4][C:5]([CH2:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[C:6]([CH3:9])[C:7]=2[CH3:8])=[CH:20][CH:19]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1c(Cl)nnc(Cc2ccncc2)c1C
Product: Cc1c(Cc2ccncc2)nnc(Nc2ccc(Cl)cc2)c1C
Temperature: 25 °C

Procedure:
A solution of 0.070 g 3-chloro-4,5-dimethyl-6-(pyridin-4-yl)methylpyridazine and 0.153 g para-chioroaniline is heated in a sealed tube for 20h to 130° C. After cooling to RT, the solution is concentrated by evaporation, the residue diluted with 100 ml CH2Cl2 and then extracted with 100 ml sat. aqueous NaHCO3 solution. The organic phase is dried over MgSO4, concentrated by evaporation, and the residue purified by flash chromatography (FC) on silica gel in CH2Cl2/methanol 19/1. The title compound is obtained: m.p. 196-199° C. 1H-NMR (250 MHz, CDCl3): δ=8.45 (s, wide, 2H); 7.55 (d, 2H); 7.25 (d, 2H); 7.10 (d, 2H); 6.20 (s, wide, 1H); 4.25 (s, 2H); 2.15 (s, 3H); 2.10 (s, 3H). ES-MS 325, 327 (M+H for 35Cl and 37Cl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH2:12]([N:20]=[C:21]=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C([N-]C(C)C)(C)C.[Li+]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH2:10][C:21]([NH:20][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:22]
Reactant: CCCCCCCCN=C=O
Reactant: CC(=O)c1ccc(F)cc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCCCCCCCNC(=O)CC(=O)c1ccc(F)cc1F
Yield: 40.6 %

Procedure:
The title compound was prepared from 2',4'-difluoroacetophenone (5.0 g, 0.032 mol), octyl isocyanate (4.97 g, 0.032 mol), and lithium diisopropylamide (0.032 mol) using the procedure described in Example 1. Purification by flash chromatography (silica gel, 20% EtoAc/hexane) yielded 4.25 g (0.013 mol, 42.6%) of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH:9]([CH3:18])[C:10]3[CH:16]=[C:15]([CH3:17])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2].C(Cl)(Cl)Cl.C1(C=CC(O)=CC=1)O.C1C(=O)N([Br:38])C(=O)C1>CC(O)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH:9]([CH3:18])[C:10]3[C:16]([Br:38])=[C:15]([CH3:17])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC2c3sc(C)cc3C(C)C2C1
Reactant: O=C1CCC(=O)N1Br
Agent: Oc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)N1CC2c3sc(C)c(Br)c3C(C)C2C1
Yield: 17 %

Procedure:
A solution of the product from step k) (110 mg, 0.42 mmol) in AcOH (1 ml) and CHCl3 (1 ml) was treated with hydroquinone (5 mg) and NBS (77.8 mg, 0.437 mmol) at 40° C. for 3 hours in the dark. Next, the reaction mixture was carefully quenched with sat. NaHCO3 (5 ml) and extracted with EtOAc (3×20 ml). The combined organic extracts were dried (MgSO4) and purified by preparative TLC hexanes:EtOAc (1:1) to give the subtitle compound (24.2 mg, 17%). MS calculated for C14H18BrNO2S+H 344, observed 344, 346.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Br:13])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[Br:14].C[N+]1([O-])CC[O:19]CC1>C(#N)C.[Cl-].[Na+].O>[Br:14][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([Br:13])[C:3]=1[CH:2]=[O:19])[C:7]([O:9][CH3:10])=[O:8]
Reactant: C[N+]1([O-])CCOCC1
Reactant: COC(=O)c1cc(Br)c(CBr)c(Br)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Br)c(C=O)c(Br)c1
Temperature: 50 °C

Procedure:
Methyl 3,5-dibromo-4-(bromomethyl)benzoate (INTERMEDIATE 24) (3.9 g) was dissolved in acetonitrile (100 mL) and to this was added 4 Å molecular sieves and N-methylmorpholine N-oxide (1.18 g) and the reaction heated to 50° C. for 12 h. The reaction mixture was poured into brine and extracted into ethyl acetate, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography eluting with 90% hexane:10% ethyl acetate to give the title compound. 1H NMR (500 MHz, CDCl3): δ 10.27 (s, 1H); 8.29 (s, 2H); 3.99 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][C:22]([CH3:29])([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][OH:24]>>[OH:24][CH2:23][C:22]([NH:21][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:29])[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC(C)CC(C)(N)CO
Product: CC(C)CC(C)(CO)NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 2-amino-2,4-dimethylpentan-1-ol (CAN 13893-55-5) as starting materials. MS (EI): m/e=398.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[CH:9][O:10][C:6]=2[C:5]([CH3:18])=[C:4]([CH3:19])[CH:3]=1>C1COCC1.CO>[CH3:1][C:2]1[C:7]2[CH:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[CH2:9][O:10][C:6]=2[C:5]([CH3:18])=[C:4]([CH3:19])[CH:3]=1
Reactant: Cc1ccc(-c2coc3c(C)c(C)cc(C)c23)cc1
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C2COc3c(C)c(C)cc(C)c32)cc1
Yield: 81 %

Procedure:
Using 4,6,7-trimethyl-3-(4-methylphenyl)-1-benzofuran obtained in Reference Example 191, the title compound was synthesized in the same manner as in Reference Example 144. Yield 81%. Melting point: 65-66° C. (THF-methanol).
Reaction SMILES: [Na].[CH3:2][NH:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[NH:6][CH:7]=[N:8]2.[C:13]1([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27]Cl)[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)(C)C>[CH3:2][NH:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH2:27][CH2:26][CH2:25][N:22]1[CH2:23][CH2:24][N:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:20][CH2:21]1
Reactant: CNc1ncnc2nc[nH]c12
Reactant: ClCCCN1CCN(c2ccccc2)CC1
Agent: [Na]
Solvent: CC(C)O
Product: CNc1ncnc2c1ncn2CCCN1CCN(c2ccccc2)CC1
Yield: 45.1 %

Procedure:
1.38 g (0.06 mole) of sodium are dissolved in 120 ml of isopropanol. 8.9 g (0.06 mole) of N6 -methyl-adenine are added to this solution, which is then heated under reflux for 10 minutes, cooled and 15.8 g (0.066 mole) of 3-(4-phenyl-piperazino)-propyl chloride in 30 ml of isopropanol are added thereto. This reaction mixture is heated under reflux for 6 hours. Thereafter, it is cooled, suction filtered and sodium chloride washed out from the residue with water. After washing with water and drying, the product is recrystallized from isopropanol. There are obtained 9.5 g (45% of theory) of N6 -methyl-9-[3-(4-phenyl-piperazino)-propyl]-adenine, which has a melting point of 162°-163° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Br:25][C:26]1[CH:27]=[C:28]([CH:32]=O)[S:29][C:30]=1[Cl:31]>ClCCCl>[Br:25][C:26]1[CH:27]=[C:28]([CH2:32][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[S:29][C:30]=1[Cl:31]
Reactant: C1COCCN1
Reactant: O=Cc1cc(Br)c(Cl)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Clc1sc(CN2CCOCC2)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
Morpholine (15.2 mL), acetic acid (9.1 mL), and then sodium triacetoxyborohydride (50.3 g) is added to a solution of 4-bromo-5-chloro-2-thiophenecarbaldehyde (Preparation 61, 35.7 g) in 1,2-dichloroethane (600 mL) at 0° C. The mixture is allowed to warm to room temperature, and after 18 h, it is quenched with a 2N NaOH solution (200 mL) with ice bath cooling. The organic layer is separated and washed with 1 N NaOH solution (2×200 mL). The aqueous layers are extracted with CH2Cl2 (2×100 mL). The combined organic layers are extracted with 0.25 M HCl solution (2 L) and the resulting aqueous layer is made basic with 2N NaOH solution. The mixture is then extracted with CH2Cl2 (2 L) and the organic layer is dried (Na2SO4) and concentrated to afford 39.24 g (84%) of the title compound as a light yellow oil. Physical characteristics: 1H NMR (400 MHz, DMSO-d6) δ7.03, 3.63, 3.57, 2.42; 13C NMR (100 MHz, CDCl3) δ140.9, 127.3, 125.9, 109.2, 66.9, 57.6, 53.3; MS (ESI+) m/z 296 (72, (M+H)+), 298 (100).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[C:13](O)=[O:14])=[O:6])#[N:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>CO>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][OH:14])=[O:6])#[N:2]
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CN1CCOCC1
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CO
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
(1R,2R)-2-{[(Cyanomethyl)amino]carbonyl}cyclohexanecarboxylic acid (97 mg, 0.46 mmol) in a 25 mL round bottom flask was fitted with a rubber septum and the flask was flushed with nitrogen. After adding tetrahydrofuran (1 mL), the reaction mixture was cooled to −78° C. and 4-methylmorpholine (51 μL, 0.47 mmol) and isobutyl chloroformate (51 μL, 0.46 mmol) were added. After 5 min, the reaction mixture was warmed quickly to 0° C. for 30 minutes. After recooling to −78° C., sodium borohydride (45 mg, 1.2 mmol) and methanol (1 mL) were added. After 5 min., the reaction mixture was allowed to warm to ambient temperature over 2 h. After quenching with 1 mL saturated aqueous ammonium chloride, the reaction mixture was partitioned between saturated aqueous sodium chloride solution and ethyl acetate. The organic layer was separated, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. Toluene (5 mL) was added and stirring was carried out overnight. The solution was decanted and the residue was dried to give (1R,2R)-N-(cyanomethyl)-2-(hydroxymethyl)cyclohexanecarboxamide as a colorless powder.
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:16]/[CH:17]=[CH:18]/[CH3:19])([C:11]([O:13]CC)=[O:12])[C:6]([O:8]CC)=[O:7])(=[O:3])[CH3:2].[OH-].[Na+]>C(O)C.O>[C:1]([NH:4][C:5]([CH2:16]/[CH:17]=[CH:18]/[CH3:19])([C:11]([OH:13])=[O:12])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: C/C=C/CC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C/C=C/CC(NC(C)=O)(C(=O)O)C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
39.63 g (146 mmol) of diethyl (E)-2-acetamido-2-(2-butenyl)malonate were dissolved in 200 ml of ethanol and a solution of 19.24 g (481 mmol) of sodium hydroxide in 100 ml of water was added. The mixture was stirred for 2 hours at 60° C., evaporated to dryness under a vacuum and theresidue was partitioned between diethyl ether and water. The aqueous phase was acidified with 2M hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over magnesium sulphate and the solvent was removed by evaporation under a vacuum to give 26.1 g of (E)-2-acetamido-2-(2-butenyl)malonic acid as a white solid which was used in the next step without further purification. 1 H NMR (250 MHz, MeOD) δ: 1.65 (d, 3 H), 2.0 (s, 3 H), 2.9 (d, 2 H), 5.25 (m, 1 H), 5.5 (m,1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:28])[C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C1COCC1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:30]=[CH:29][C:7]([C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18](=[O:28])[C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(OCCCCCCOC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)OCCCCCCOC(=O)c2ccc(N)cc2)cc1
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
40.1 g 6-[(4-nitrobenzoyl)oxy]hexyl 4-nitrobenzoate (96.3 mM) were suspended in 300 ml of ethyl acetate and 300 ml of THF and 4.0 g of palladium on charcoal (10%) were added. The resulting mixture was hydrogenated at atmospheric pressure until the theoretical amount of hydrogen was consumed. The mixture was then filtered, the cake was washed with DMF and the filtrate was evaporated. The residue was suspended in 200 of cyclohexane. It was stirred for 30 min. and then the solids were filtered off, washed with cyclohexane and dried to give 33.2 g (93.1 mM, 97%) of 6-[(4-aminobenzoyl)oxy]hexyl 4-aminobenzoate as beige crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[S:21](Cl)(=[O:23])=[O:22]>>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[S:21]([NH:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5])(=[O:23])=[O:22]
Reactant: COC(=O)c1ccc(Br)cc1N
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Product: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1c(F)cccc1F

Procedure:
Methyl 2-amino-4-bromobenzoate was sulfonylated with 2,6-difluorobenzenesulfonyl chloride and hydrolyzed as in EXAMPLE 1, Part B. 1H NMR (400 MHz, acetone-d6): 11.65 (s, 1H), 8.02 (d, J=8.5, 1H), 7.93 (d, J=1.8, 1H), 7.74-7.82 (m, 1H), 7.38 (dd, J=8.5, 1.9, 1H), 7.28-7.23 (m, 2H).
Reaction SMILES: [CH:1]1([Li])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH2:7]([N:9]1[CH:13]=[CH:12][C:11]([SiH:15]([CH3:17])[CH3:16])(Cl)[B:10]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:8]>C1COCC1>[CH2:7]([N:9]1[CH:13]=[CH:12][CH:11]([Si:15]([CH:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)([CH3:17])[CH3:16])[B:10]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:8]
Reactant: [Li]C1C=CC=C1
Reactant: CCN1C=CC(Cl)([SiH](C)C)B1c1ccccc1
Solvent: C1CCOC1
Product: CCN1C=CC([Si](C)(C)C2C=CC=C2)B1c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.1 %

Procedure:
A solution of cyclopentadienyl lithium (0.16 g, 2.27 mmol) in 10 mL of THF was added slowly to a solution of 1-ethyl-3-chlorodimethylsilyl-2,3-dihydro-2-phenyl-1H-1,2-azaborole (0.60 g, 2.27 mmol) in 10 mL of THF at −50° C. The reaction mixture wag slowly warmed to 25° C. and stirred for 12 h. The solvent was removed in vacuo and the residue was extracted with pentane. Solvent was removed from the extracts leaving the desired product as a brown oil (0.58 g, 87 percent).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([NH:9]C(=O)C(C)(C)C)[CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=[O:17].[K+].[K+]>OS(O)(=O)=O>[NH2:9][C:7]1[N:8]=[C:3]([CH2:2][OH:17])[CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(CBr)n1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Nc1cccc(CO)n1
Temperature: 25 °C
Yield: 71 %

Procedure:
The product of Example 2 (24.89 g, 96 mmol) and 10% (v/v) H2SO4 (100 mL) were combined in a 250 mL flask. The reaction was heated to reflux for 8 h and then cooled to room temperature. The reaction was made basic with aq K2CO3 and extracted with EtOAc. The extracts were dried (MgSO4), decolorized with activated charcoal, and filtered. Removal of all solvent in vacuo gave 8.49 g (71%) of the desired product.