Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[CH2:20][NH2:21])[CH:6]=[CH:7][CH:8]=1.C(N(C(C)C)CC)(C)C.[CH:33]([S:36](Cl)(=[O:38])=[O:37])([CH3:35])[CH3:34]>ClCCl>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([C:9]#[C:10][C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][C:12]=2[CH2:20][NH:21][S:36]([CH:33]([CH3:35])[CH3:34])(=[O:38])=[O:37])[CH:6]=[CH:7][CH:8]=1
Reactant: NCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NCc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.7 %

Procedure:
0.08 g (0.239 mmol) of (3-((3-(trifluoromethyl)phenyl) ethynyl) imidazo[1,2-a]pyridin-2-yl) methanamine (prepared according to steps 1 to 4 of Example 11) were solubilised in 2 ml of dichloromethane with magnetic stirring, 0.208 ml (1.193 mmol) of diisopropylethylamine and 0.083 ml (0.716 mmol) of isopropylsulfonyl chloride were added. The mixture was stirred at r.t. for 16 h. A supplement of 0.083 ml (0.716 mmol) of isopropylsulfonyl chloride was added and the mixture was stirred at r.t. for 1 h before being concentrated in vacuo. The crude residue was directly purified by flash chromatography on a silica gel cartridge (eluent: dichloromethane/methanol 95/5, v/v). 0.048 g (yield=22%) of N-((3-((3-(trifluoromethyl)phenyl)ethynyl) imidazo[1,2-a]pyridin-2-yl)methyl)propane-2-sulfonamide were obtained as a white solid. LC-MS: m/z=422 (MH+); UV purity at 254 nm=98%. 1H NMR (300 MHz, DMSO) δ 8.75 (d, J=6.8 Hz, 1H), 8.13 (s, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.85-7.61 (m, 4H), 7.53-7.38 (m, 1H), 7.15 (t, J=6.8 Hz, 1H), 4.44 (d, J=5.9 Hz, 2H), 3.25 (dd, J=13.6, 6.8 Hz, 1H), 1.21 (d, J=6.8 Hz, 6H).
Reaction SMILES: [NH:1]1[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](Cl)=[O:15].[OH-].[Na+]>O>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]([N:1]1[CH2:3][CH2:2]1)=[O:15]
Reactant: O=C(Cl)c1cccs1
Reactant: C1CN1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(c1cccs1)N1CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a cooled (0° c) mixture of 338 parts of a solution of aziridine in water 0.875 N and 22 parts of sodium hydrogen carbonate are added dropwise, during a 45 minutes-period, 87 parts of 2-thiophenecarbonyl chloride while stirring vigorously. Upon completion, stirring is continued for 45 minutes without cooling. The reaction mixture is warmed to room temperature and alkalized with a diluted sodium hydroxide solution till pH 8 is reached. The product is extracted three times with trichloromethane. The combined extracts are washed with water, dried, filtered and evaporated, yielding 42 parts of 1-(2-thienylcarbonyl)aziridine as a residue.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:29])[CH:5]([CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[NH:6][C:7](=[O:21])[CH2:8][N:9]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH3:10].C(N(CC)CC)C.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)(Cl)Cl.Cl>[CH3:2][O:3][C:4](=[O:29])[CH:5]([CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:25][CH2:24]1)[NH:6][C:7](=[O:21])[CH2:8][N:9]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH3:10]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)C(CC1CCNCC1)NC(=O)CN(C)S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)C(CC1CCN(C(=O)c2ccccc2)CC1)NC(=O)CN(C)S(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 86.6 %

Procedure:
N-(Toluene4-sulfonyl)sarcosyl-β-(piperidin-4-yl)-D,L-alanine methyl ester hydrochloride (see Preparative Example C (109)) (65 mg, 0.15 mmol) was dissolved in CHCl3 (3 mL) and cooled in an ice bath. Triethylamine (61 μL) and benzoyl chloride (21 mg, 0.15 mmol) were added and the mixture was stirred for 1 hr. The mixture was diluted with 1N HCl (20 mL) and extracted with EtOAc (2×25 mL). The extracts were dried (Na2SO4), filtered and evaporated in vacuo to give a residue which was purified by silica gel flash chromatography (95:5 CH2Cl2/MeOH) to yield N-(toluene4-sulfonyl)sarcosyl-β-(N-benzoylpiperidin-4-yl)-D,L-alanine methyl ester (67 mg, 89%). The title compound was prepared via hydrolysis of the methyl ester using LiOH in THF/water (71 mg, 100%).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])(C)(C)C.[CH2:25]([C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1)[CH3:26].[Cl-].[NH4+]>C1COCC1.CCCCC>[CH2:25]([C:27]1[CH:34]=[CH:33][C:30]([CH:31]([C:2]2[C:7]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:32])=[CH:29][CH:28]=1)[CH3:26]
Reactant: CC[Si](CC)(CC)CCOCOc1cccnc1Br
Reactant: CCc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCc1ccc(C(O)c2ncccc2OCOCC[Si](CC)(CC)CC)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 33.7 %

Procedure:
Next, to a solution of 2-bromo-3-[2-(triethylsilyl)ethoxymethoxy]pyridine (2.0 g, 6.57 mmol) in THF (22 mL), a 1.47 M n-pentane solution of tert-butyllithium (9.6 mL, 14.1 mmol) was slowly added dropwise at −78° C. After 20 minutes, a solution of 4-ethylbenzaldehyde (1.0 g, 7.45 mmol) in THF (5 mL) was added dropwise to the reaction mixture. After stirring at −78° C. for 10 minutes, the reaction mixture was warmed to room temperature and saturated aqueous ammonium chloride was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 4-ethylphenyl-[3-[2-(triethylsilyl)ethoxymethoxy]]pyridin-2-yl-methanol (0.89 g, 38%).
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][CH2:9][O:10][C:11]([C:13]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:17]([C:26](O)=[O:27])=[C:16]([CH3:29])[NH:15][C:14]=2[CH3:30])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:37]1[CH2:43][CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.CCN=C=NCCCN(C)C.Cl.CN(C=O)C>ClCCl>[C:31]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][O:10][C:11](=[O:12])[C:13]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[C:17]([C:26]([N:37]3[CH2:43][CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[O:27])[C:16]([CH3:29])=[N:15][C:14]=2[CH3:30])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C1CNCCNC1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)OCCC(c2ccccc2)c2ccccc2)=C(C)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(C)c(C(=O)N2CCCNCC2)c(-c2cccc(Cl)c2)c1C(=O)OCCC(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
200 mg (0.398 mmol) of 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid mono (3,3-diphenylpropyl) ester, 120 mg (1.20 mmol) of homopiperazine and 230 mg (1.20 mmol) of WSC hydrochloride were stirred in 6 ml of dichloromethane at room temperature overnight. 0.8 ml of DMF was added and stirred at 60° C. for 5 hours. After concentration under reduced pressure, chloroform was added. After being washed with saturated aqueous sodium hydrogencarbonate solution, the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained substance was dissolved in 5 ml of dichloromethane. 2 ml of trifluoroacetate was added and stirred at room temperature for 30 minutes. After concentration under reduced pressure, ethyl acetate was added and the reaction mixture was washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the thin layer silica gel chromatography (dichloromethane/methanol=9/1) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:24])[NH:4][C:5]2[C:11]([O:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([NH2:23])=[CH:15][CH:14]=3)=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1.[C:25]([C:29]1[CH:33]=[C:32]([N:34]=[C:35]=[O:36])[N:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:30]=1)([CH3:28])([CH3:27])[CH3:26]>>[NH2:1][C:2]1[C:3](=[O:24])[NH:4][C:5]2[C:11]([O:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([NH:23][C:35]([NH:34][C:32]4[N:31]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[N:30]=[C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:33]=4)=[O:36])=[CH:15][CH:14]=3)=[CH:10][CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: Nc1nc2nccc(Oc3ccc(N)c4ccccc34)c2[nH]c1=O
Reactant: CC(C)(C)c1cc(N=C=O)n(-c2ccccc2)n1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc4nc(N)c(=O)[nH]c34)c3ccccc23)n(-c2ccccc2)n1
Yield: 44 %

Procedure:
Method F2 was used with 3-amino-8-(4-aminonaphthalen-1-yloxy)pyrido[2,3-b]pyrazin-2(1H)-one and 3-tert-butyl-5-isocyanato-1-phenyl-1H-pyrazole to afford the title compound as a yellow/orange solid (46 mg, 44%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[N:13][C:12]([C:15]#[N:16])=[CH:11][N:10]=2)=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[C:3]([O:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:4][C:5]([NH:8][C:9]2[N:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc(Nc3cnc(C#N)cn3)ncc2N)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cnc(Nc2cc(OCC3CCNCC3)c(N)cn2)cn1

Procedure:
A solution of tert-butyl 4-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-yloxy)methyl)piperidine-1-carboxylate (16 mg, 0.038 mmol) in 10 mL dichloromethane (10 mL) was treated over 45 minutes with 2 mL trifluoroacetic acid. After concentration of the solution in vacuo, the required product was isolated by SPE using a MP-TsOH cartridge, eluting with 2N ammonia in methanol. Concentration of the eluent gave the required product as a yellow solid (10 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)[N:10]=[C:9]2[CH3:22])[CH:5]=[CH:4][N:3]=1.[OH-:23].[K+]>C(O)(C)(C)C>[CH3:22][C:9]1[N:8]([C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:23])[CH:7]=2)[CH:12]=[C:11]([C:13]#[C:14][C:15]2[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=2)[N:10]=1
Reactant: [OH-]
Reactant: Cc1cccc(C#Cc2cn(-c3ccnc(Cl)c3)c(C)n2)c1
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1cccc(C#Cc2cn(-c3cc[nH]c(=O)c3)c(C)n2)c1

Procedure:
The title compound, white solid, MS: m/e=290.1 (M+H+), was prepared in accordance with the general method of example 1a from 2-chloro-4-(2-methyl-4-m-tolylethynyl-imidazol-1-yl)-pyridine and KOH in tert-butanol.
Reaction SMILES: [N:1]1[C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=[CH:3][C:2]=1[C:10](Cl)=[O:11].[Cl-].[Cl-].[Cl-].[Al+3].O.[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:10]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:7](=[O:8])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:1]=1)(=[O:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccccc1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(c1ccccc1)c1cccc(C(=O)c2ccccc2)n1
Reaction time: 4 h

Procedure:
20.0 g (98 mmol) pyridine-2,6-dicarboxylic acid chloride in 250 ml of dry benzene were mixed with 32.4 g (243 mmol) of anhydrous aluminum trichloride under an argon atmosphere in a 500 ml round-bottom flask fitted with a reflux condenser. The batch was stirred for 4 hours under reflux, was then cooled and stirred overnight at room temperature (“RT”), and was then stirred for a further 6 hours under reflux. After cooling, the batch was carefully poured into 500 ml of iced water. The organic phase was separated and the aqueous phase was washed twice with 100 ml diethyl ether each time. The combined organic phases were washed twice with 100 ml water each time and were then dried over sodium sulphate. The solvents were removed in a rotary evaporator and the product was recrystallized from diethyl ether. Yield: 16.80 g.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[Cl:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[C:48]=1O>C1COCC1>[Cl:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[C:48]=1[O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1c(Cl)cccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(Cl)cccc2Cl)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 75 %

Procedure:
A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (3.7 g, 23 mmol) and triphenyl phosphine (12.23 g, 46 mmol) in 50 ml THF was mixed in an ice-H2O bath. A solution of diethyl azodicarboxylate (8.37 g, 46 mmol) in 50 ml THF was added drop-wise, followed by 2,6-dichlorophenol (3.87 g, 23 mmol). The mixture was warmed up to room temperature and stirred for 22 hr. Solvent was removed under vacuum and crude product was purified with column chromatography. tert-Butyl 4-(2,6-dichlorophenoxy)piperidine-1-carboxylate was obtained in 75% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:21])[NH:11][C:12]([CH3:20])=[CH:13][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:21])[N:11]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:12]([CH3:20])=[CH:13][C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(C)[nH]c(=O)c1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)n(CC(=O)OC(C)(C)C)c(=O)c1OCc1ccccc1
Temperature: 4 °C
Reaction time: 96 h

Procedure:
To a stirred solution of 3-benzyloxy-4-ethoxycarbonyl-6-methyl-2-pyridinone from step 1 above (17 g, 59 mmol) and tert-butyl bromoacetate (8.1 g, 59 mmol) in DMF (350 mL) at 0° C. was added cesium carbonate (19.3 g, 59 mmol). The mixture was stirred at 4° C. for 96 h. The salts were removed by filtration and the filtrate solvent was removed in vacuo. The residue was purified by flash column chromatography using 1:4 EtOAc:hexanes as eluant to give the title compound as an oil (9.5 g; HPLC RT=23.58, method B).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:36])=[C:23]([N:25]4[CH2:34][CH2:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][C:31]=5[F:35])[CH2:26]4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.CCOCC>[F:35][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:32]=1[CH2:33][CH2:34][N:25]([C:23]1[C:22]([NH2:36])=[N:21][CH:20]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH:18]=3)[CH:24]=1)[CH2:26]2
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(N4CCc5c(F)cccc5C4)c3)cn2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1N1CCc2c(F)cccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{4-[6-Amino-5-(5-fluoro-3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (34 mg) was dissolved in MeOH (20 mL), 1.0 M of HCl in Et2O (20 mL) was added, and the mixture was stirred at rt overnight. The solvent was removed in vacuo to give a brown oil. It was purified by Gilson HPLC eluting with H2O/CH3CN/0.1% formic acid mixtures to give the title compound contaminated with the corresponding formamide. This material was dissolved in MeOH (2 ml), aqueous NaOH (10 N, 2 ml) was added, and the solution was stirred at rt overnight. It was then treated with water (5 ml) and extracted with DCM (3×20 ml). The extracts were washed with water (2×20 ml), brine (20 ml), dried over MgSO4, filtered, and concentrated in vacuo, to give the title compound as a beige solid. 1H NMR (400 MHz, CD3OD): δ=1.79-1.92 (m, 2H), 1.98-2.06 (m, 2H), 2.63-2.70 (m, 2H), 2.90 (t, J=6.0 Hz, 2H), 3.06-3.14 (m, 2H), 3.18-3.24 (m, 2H), 4.06 (s, 2H), 4.15-4.23 (m, 1H), 6.82 (d, J=8.8 Hz, 1H), 6.85-6.88 (m, 1H), 7.05-7.12 (m, 1H), 7.44 (d, J=2.4 Hz, 1H), 7.66 (d, J=0.8 Hz, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.91 (d, J=0.4 Hz, 1H). MS(ES+): m/z=394.14 (45) [MH+]. HPLC: tR=2.21 min (ZQ2, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[O:11]1[C:13]2[CH2:14][CH2:15][CH2:16][C:12]1=2.CO>[Pd].O1CCCC1>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:15]1[CH2:16][CH:12]([OH:11])[CH:13]=[CH:14]1
Reactant: C1CC2=C(C1)O2
Reactant: Clc1ncnc2nc[nH]c12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: OC1C=CC(n2cnc3c(Cl)ncnc32)C1
Yield: 25 %

Procedure:
Trimethylsilylated 6-chloropurine (prepared from 50 g (0.32 mol) of 6-chloropurine) is stirred with 5 mol % of the palladium(0) catalyst described above and an equivalent amount of epoxycyclopentene in tetrahydrofuran at room temperature for 24 hours. The reaction solution is heated with methanol for 1.5 hours, the precipitate formed is filtered off with suction, the resulting solution is concentrated and the residue is chromatographed over silica gel using methylene chloride/methanol 20/1. 18.9 g (25% of theory) of 6-chloro-9-[(1RS,4SR)-4-hydroxy-cyclopent-2-en-1-yl]purine (Example 1.5.1.) are obtained as yellowish crystals of melting point 118° C. 1H-NMR (270 MHz, d6 -DMSO), δ[ppm]: 8.80 (s, 1H), 8.62 (s, 1H), 6.25 (m, 1H), 6.08 (m, 1H), 5.60 (m, 1H), 5.31 (d, 1H), 4.76 (m, 1H), 2.95 (m, 1H), 1.81 (m, 1H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(P(=O)(OCC)OCC)#N.CN1CCOCC1.[NH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[C:41]([S:42]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:44])=[O:43])[C:36]=2[S:35][N:34]=1>C(Cl)Cl>[C:46]([NH:45][S:42]([C:41]1[C:36]2[S:35][N:34]=[C:33]([NH:32][CH2:31][CH2:30][CH2:29][NH:28][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([I:1])=[CH:10][CH:9]=3)[C:37]=2[CH:38]=[CH:39][CH:40]=1)(=[O:43])=[O:44])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc2c(NCCCN)nsc12
Reactant: O=C(O)c1ccc(I)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1cccc2c(NCCCNC(=O)c3ccc(I)cc3)nsc12
Reaction time: 0.25 h
Yield: 77.5 %

Procedure:
To a solution of 4-iodobenzoic acid (270 mg, 0.8 mmol) in methylene chloride (2 mL), diethyl cyanophosphonate (130 μL, 0.9 mmol) and 4-methylmorpholine (182 μL, 1.7 mmol) were added at room temperature and allowed to stir for 15 min. A solution of 3-(3-aminopropylamino)-N-t-butylbenzo[d]isothiazole-7-sulfonamide (270 mg, 0.8 mmol) in methylene chloride (4 mL) was then added and the resulting reaction mixture was allowed to stir overnight. The reaction mixture with diluted with methylene chloride (20 mL), washed with 10% HCl aqueous solution and brine, dried anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography, on silica gel, eluting with 6:4 ethyl acetate:hexanes provided N-(3-(7-(N-tert-butylsulfamoyl)benzo[d]isothiazol-3-ylamino)propyl)-4-iodobenzamide (355 mg). 1H NMR (300 MHz, CDCl3): 8.01 (dd, 1H), 7.96 (d, 1H), 7.78 (d, 2H), 7.59 (d, 2H), 7.53 (t, 1H), 7.44 (t, 1H), 6.15 (t, 1H), 5.09 (s, 1H), 3.70 (dd, 2H), 3.57 (dd, 2H), 1.90-1.99 (m, 2H), 1.24 ppm (s, 9H). MS (m/z): 573 (M+H)+ confirmed by LC-MS, tr=13.92 min (Method Y) MW=572 confirmed by LC-MS, tr=13.92 min (Method Y) MH+=573.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:18]([CH2:20][CH3:21])[CH3:19])=[N:5][S:6][C:7]=1[NH:8][C:9](=[O:17])OC1C=CC=CC=1)#[N:2].[CH3:22][N:23](C)[CH:24]=O>>[CH3:22][N:23]([CH3:24])[C:9]([NH:8][C:7]1[S:6][N:5]=[C:4]([N:18]([CH2:20][CH3:21])[CH3:19])[C:3]=1[C:1]#[N:2])=[O:17]
Reactant: CCN(C)c1nsc(NC(=O)Oc2ccccc2)c1C#N
Reactant: CN(C)C=O
Product: CCN(C)c1nsc(NC(=O)N(C)C)c1C#N
Temperature: 25 °C

Procedure:
A solution of 10.6 g of phenyl (4-cyano-3-(ethylmethylamino)-5-isothiazolyl)carbamate and 25 ml of dimethylformamide was placed in a pressure bottle. This solution was cooled and 5 ml of dimethylamine (previously collected in a dry-ice trap) were added. The pressure bottle was sealed and allowed to warm slowly to room temperature. The reaction mixture was then heated at 80° for approximately 16 hours. The reaction mixture was cooled in a dry ice bath and the vessel was opened. The reaction mixture was concentrated under reduced pressure until a small amount of material crystallized. Collection of the crystals produced 2.3 g of 1,1-dimethyl-3-(4-cyano-3-(ethylmethylamino)-5-isothiazolyl)urea, mp 115°-130° (decomposes). The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13](Cl)(=O)=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.P(OC)(OC)O[CH3:21].CO.[OH-].[K+]>C1(C)C=CC=CC=1>[CH3:21][S:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: COP(OC)OC
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CSc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 60 °C
Yield: 76.6 %

Procedure:
4-(4′-Chlorophenoxy)phenyl sulfonyl chloride (3.0 kg), 3, was dissolved in three liters of toluene and the solution was added dropwise, with stirring, to 3.6 kg of trimethyl phosphite which had been preheated to 60° C. The reaction was exothermic and the reaction was allowed to heat to 80°-90° C. during the addition. Thin layer chromatography indicated a mixture of the desired thioether and two baseline products. The mixture was refluxed until the pot temperature rose to ˜130° C. The mixture was cooled to ˜60° C. and 1 liter of methanol was added. Potassium hydroxide solution (4.5 kg of 45% aqueous solution) was added dropwise, slowly, with rapid stirring to the reaction mixture. The addition was very exothermic and the pot temperature was controlled to 65°-80° C. The mixture was then refluxed for 2 hrs. More toluene (6 liters) was added and the mixture cooled to 60° C. The lower aqueous layer was separated and the organic layer washed with 3 liters of water. The organic layer was stripped to a low volume and 9 liters of isopropanol charged to the hot mixture. The solution as distilled until ˜3.5 liters of distillate had been collected. The mixture was held at 45° C. for several hours and was then cooled to ˜−10° C. and stirred several hours. The white, crystalline product was collected, washed with cold isopropanol and dried to yield 1.9 kg of 4-(4′-chlorophenoxy)phenyl methyl sulfide, 4.
Reaction SMILES: [CH2:1]1[N:6]2[CH2:7][N:8]3[CH2:10][N:4]([CH2:5]2)[CH2:3][N:2]1[CH2:9]3.[Cl:11][C:12]1[S:13][C:14]([CH2:17]Cl)=[CH:15][CH:16]=1>C(Cl)(Cl)Cl>[Cl:11][C:12]1[S:13][C:14]([CH2:17][CH:1]2[N:6]3[CH2:5][N:4]4[CH2:10][N:8]([CH2:9][N:2]2[CH2:3]4)[CH2:7]3)=[CH:15][CH:16]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: C1N2CN3CN1CN(C2)C3
Solvent: ClC(Cl)Cl
Product: Clc1ccc(CC2N3CN4CN(C3)CN2C4)s1
Yield: 99.5 %

Procedure:
To a suspension of hexamethylenetetramine (HMTA) (3.12 g, 22.2 mmol) in CHCl3 (35 mL) was added 2-chloro-5-chloromethylthiophene (1.02 mL, 8.46 mmol). The reaction mixture was heated at reflux for 4 hr, cooled, and filtered to give white solid 5-chloro-2-[(1,3,5,7-tetraazatricyclo-[3.3.1.1(3,7)]decyl) methyl]thiophene (2.28 g, 88%). ES-MS (M)+=271, 273 (Cl). 1H-NMR (DMSO-d6): δ 4.27 (s, 2H), 4.39-4.57 (ABq, 6H), 5.06 (s, 6H), 7.21-7.24 (ABq, 2H).