Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O>C(Cl)Cl>[C:20]([O:19][C:17]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:13](=[O:15])[CH3:14])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)=[O:16])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Product: CC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
A mixture of 1-(4-piperazin-1-yl-phenyl)-ethanone (513 mg, 2.51 mmol), BOC2O (820 mg, 3.76 mmol) and TEA (0.698 ml, 5.02 mmol) in DCM (20 ml) was stirred at room temperature overnight. The resulting solution was concentrated in vacuo and then partitioned between water and AcOEt. The organic phase was dried over Na2SO4, evaporated in vacuo and the crude reaction mixture was purified by column chromatography (eluent: petroleum ether/AcOEt) to give 701 mg of 4-(4-acetyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH2:7][N:8]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl.O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH2:7][N:8]2[CH2:12][CH2:11][C@H:10]([O:13][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CCN(CCc2ccc(Cl)cc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)O[C@H]1CCN(CCc2ccc(Cl)cc2)C1

Procedure:
(S)-1-(4-Chlorophenethyl)-3-hydroxypyrrolidine (190 mg, 0.84 mmol) was dissolved in dichloromethane (6 ml). Triethylamine (110 mg, 1.09 mmol) and methanesulfonyl chloride (125 mg, 1.09 mmol) were added to the obtained solution under stirring under cooling on ice. They were stirred at 0° C. for 1 hour. The reaction liquid was distributed in dichloromethane and water. The organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane and then with a solvent mixture of dichloromethane and methanol (50:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (S)-1-(4-chlorophenethyl)-3-methanesulfonyloxypyrrolidine in the form of a light yellow oil (252 mg, 99%).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[CH2:8]([O:10][C:11]1[C:16]([CH3:17])=[CH:15][N+:14]([O-])=C(C)[CH:12]=1)[CH3:9]>C(Cl)(Cl)Cl>[C:5]([O:4][CH2:1][C:2]1[CH:12]=[C:11]([O:10][CH2:8][CH3:9])[C:16]([CH3:17])=[CH:15][N:14]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1cc(C)[n+]([O-])cc1C
Solvent: ClC(Cl)Cl
Product: CCOc1cc(COC(C)=O)ncc1C

Procedure:
20 ml of acetic anhydride were added dropwise at room temperature to a solution of 7.8 g of 4-ethoxy-2,5-dimethylpyridine 1-oxide in 30 ml of chloroform. After boiling under reflux for 3 hours the solution was evaporated, the residue was dissolved in 50 ml of toluene and again evaporated. The residue was taken up in 50 ml of ethyl acetate, whereupon the solution was extracted three times with 20 ml of saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and evaporated in vacuo. The product was chromatographed on 50 g of silica gel with ether and there was obtained (4-ethoxy-5-methyl-2-pyridyl)methyl acetate in the form of an oil.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)([CH2:14]OS(C)(=O)=O)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[CH3:26][C:27]([S-:30])(C)[CH3:28].[Na+].O.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>CN(C=O)C.C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[CH:20]1([C:11]2([CH2:14][S:30][CH:27]([CH3:28])[CH3:26])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC(C)(C)[S-]
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)(C2CCCCC2)CC1
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)SCC1(C2CCCCC2)CCNCC1

Procedure:
To a stirred solution of Intermediate 1d (4 mmol) in DMF (25 mL) at rt was added sodium 2-methyl-2-propanethiolate (2 g, 20 mmol). The resultant suspension was stirred at rt for 18 hr then poured into water (75 mL) and extracted with EtOAc (2×75 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated. Chromatography over silica eluting with 5:95 EtOAc/hexane furnished the N-protected product as a clear colourless oil. The N-Boc-protected sulfide was dissolved in CH2Cl2 (120 mL) and TFA (30 mL) was added. The resultant solution was stirred at rt for 1 hr. Volatiles were removed in vacuo to furnish the title compound as a clear colourless gum (1.34 g, 3.8 mmol). ESI-MS calcd for C15H29NS: 255; found 297 (M+H+MeCN).
Reaction SMILES: [CH2:1]([Zn]CC)C.C(C(O)=O)(F)(F)F.C(I)I.[NH2:16][C:17]1[N:21]([CH3:22])[C:20](=[O:23])[C:19]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[CH:37][CH:36]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[C:26](/[CH:30]=[CH:31]/[CH2:32][O:33][CH3:34])[CH:25]=2)[N:18]=1>C(Cl)Cl>[NH2:16][C:17]1[N:21]([CH3:22])[C:20](=[O:23])[C:19]([C:35]2[CH:36]=[CH:37][C:38]([O:41][CH:42]([F:44])[F:43])=[CH:39][CH:40]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]3[CH2:1][CH:31]3[CH2:32][O:33][CH3:34])[CH:25]=2)[N:18]=1
Reactant: CC[Zn]CC
Reactant: COC/C=C/c1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ICI
Product: COCC1CC1c1cccc(C2(c3ccc(OC(F)F)cc3)N=C(N)N(C)C2=O)c1
Reaction time: 0.33 h
Yield: 16 %

Procedure:
A 1M solution of diethyl zinc (4.92 ml, 4.92 mmol) in dry CH2Cl2 at 0° C. is treated very slowly with a solution of CF3CO2H (0.56 g, 4.92 mmol) in dry CH2Cl2, stirred for 20 min, treated dropwise with a solution of CH2I2 (0.66 g, 2.46 mmol) in dry CH2Cl2, stirred for 20 min, treated with a solution of 2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(1E)-3-methoxyprop-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-imidazol-4-one (197 mg, 0.492 mmol) in dry CH2Cl2, allowed to come to room temperature, stirred for 2 h at room temperature, quenched with aqueous NH4Cl and extracted with CH2Cl2. The combined extracts are dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by SCX cartridge and preparative HPLC to give the title compound as a white solid, 32 mg (16% yield), identified by NMR and mass spectral analyses. (1H-NMR 300 MHz, DMSO): 7.46(d, 2H); 7.24-7.13(m, 3H); 7.16(t, 1H); 7.10(d, 2H); 6.88(m, 1H); 6.64(s br, 2H); 3.44-3.34(m, 2H); 3.24(m, 1H); 3.23(s, 3H); 2.97(s, 3H); 1.76(m, 1H); 0.90-0.76(m, 2H). MS [M+H]+ 416.1
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].[Br:11][C:12]1[N:13]=[C:14]([CH3:19])[NH:15][C:16]=1[CH:17]=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.O>[Br:11][C:12]1[N:13]=[C:14]([CH3:19])[N:15]([CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[C:16]=1[CH:17]=[O:18]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cc1nc(Br)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1nc(Br)c(C=O)n1Cc1ccc(C#N)cc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
4-Cyanobenzylbromide (1.05 g, 5.39 mmol) was added to a solution of 4-bromo-2-methylimidazole-5-carboxaldehyde (1.02 g, 5.39 mmol) (Step A) in dimethylacetamide (15 mL). The solution was cooled to −10° C. and powdered potassium carbonate (0.745 g, 5.39 mmol) added. The reaction was stirred at −10° C. for 2 h, and a further 4 h at 20° C. The reaction was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, saturated brine, and dried over magnesium sulfate. Solvent evaporation yielded a white solid.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:31][CH:32]([F:34])[F:33])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=O)[CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[OH-].[Li+]>O1CCCC1.O>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH2:17][CH3:18])[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH:27]([CH3:28])[CH3:29])=[CH:24][CH:25]=1)=[C:8]2[O:31][CH:32]([F:34])[F:33]
Reactant: CCc1nc2c(Cl)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(C(=O)C(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2c(Cl)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(CC(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
A solution of [8-chloro-4-difluoromethoxy-2-ethyl-3-(4-isobutyrylbenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.22 g) in tetrahydrofuran (5.0 mL) and water (1.0 mL) was treated with 1.0M aqueous lithium hydroxide solution (0.86 mL), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated to low bulk under reduced pressure, and the pH adjusted to 4-5 by the addition of 1.0M aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate, and the combined extracts were dried over magnesium sulfate and then concentrated under reduced pressure. Purification of the residue by preparative reverse-phase HPLC gave title compound (0.18 g).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([NH:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[CH:24][CH:25]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: Oc1ccc(CCNCc2ccccc2)cc1
Product: N#Cc1ccc(Oc2ccc(CCNCc3ccccc3)cc2)cc1

Procedure:
Reaction of 4-fluorobenzonitrile with the compound of Example 4, step 1 following the procedure of Example 1, step 2. affords the title compound, 4-[4-(2-Benzylamino-ethyl)-phenoxy]-benzonitrile, (2.7 g): 1H NMR (CDCl3, 300.00 MHz): 7.65-7.58 (m, 2H), 7.41-7.25 (m, 7H), 7.06-6.98 (m, 4H), 3.86 (s, 2H), 3.01-2.83 (m, 4H), m/z=328.9 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([C:24]2[S:25][CH:26]=[C:27]([CH:29]=[O:30])[N:28]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH3:23])[CH3:13].[Cl-].[NH4+]>O1CCCC1>[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([C:24]2[S:25][CH2:26][C:27](=[C:29]([OH:30])[C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=3)[N:28]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH3:23])[CH3:13]
Reactant: COc1ccc(Br)cc1OC
Reactant: CCOc1ccc(-c2nc(C=O)cs2)cc1OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOc1ccc(C2=NC(=C(O)c3ccc(OC)c(OC)c3)CS2)cc1OCC
Yield: 48.9 %

Procedure:
60 ml of a tetrahydrofuran solution of a Grignard reagent prepared from 2.4 g of 1-bromo-3,4-dimethoxybenzene was stirred with ice-cooling. Thereto was added 20 ml of a tetrahydrofuran solution of 3 g of 2-(3,4-diethoxyphenyl)-4-formylthiazole. The mixture was stirred at the same temperature for 1 hour and at room temperature for 3 hours. 10 ml of a saturated aqueous ammonium chloride solution was added. The solvent was removed by distillation. The residue was extracted with 100 ml of chloroform. The extract was washed with 20 ml of water and 20 ml of a saturated aqueous sodium chloride solution, and dried. The solvent was removed by distillation. The residue was purified by silica gel column chromatography (elutant: dichloromethane/acetone=99/1 by v/v) and recrystallized from diethyl ether to obtain 2.2 g of 2-(3,4-diethoxyphenyl)4-[1-hydroxy-1-(3, 4-dimethoxyphenyl)methlyl]thiazole.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[CH:5]=[O:6].[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17]Cl>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[O:10][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[CH:5]=[O:6]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: COCCOCCl
Product: COCCOCOc1c(C)cc(C=O)cc1C
Yield: 74 %

Procedure:
The hydroxyl group of 3,5-dimethyl-4-hydroxybenzaldehyde (2.3 g) was protected by use of 2-methoxyethoxymethyl chloride (3.4 g) in accordance with (production process 1), to thereby produce 3,5-dimethyl-4-methoxyethoxymethoxybenzaldehyde (2.7 g, yield: 62%). The thus-produced 3,5-dimethyl-4-methoxyethoxymethoxybenzaldehyde (2.0 g) and 3,4-dimethoxybenzyl cyanide (1.5 g) were subjected to condensation in accordance with process A of (production process 2), to thereby yield an MEM form of the target product. Subsequently, the protective group was removed from the MEM form in accordance with (production process 3), to thereby produce the target product (1.5 g, yield: 57%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([CH2:17][OH:18])[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([CH:12]=1)[C:10]#[N:11].Cl[C:20]1[CH:21]=[C:22]2[N:29]([CH3:30])[C@@H:28]([CH3:31])[CH2:27][N:23]2[C:24](=[O:26])[N:25]=1>>[CH3:30][N:29]1[C:22]2[N:23]([C:24](=[O:26])[N:25]=[C:20]([O:18][CH2:17][C:15]3[CH:14]=[CH:13][C:3]([O:4][C:5]4[CH:6]=[N:7][CH:8]=[C:9]([CH:12]=4)[C:10]#[N:11])=[C:2]([F:1])[CH:16]=3)[CH:21]=2)[CH2:27][C@@H:28]1[CH3:31]
Reactant: N#Cc1cncc(Oc2ccc(CO)cc2F)c1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4cncc(C#N)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 5-(2-fluoro-4-(hydroxymethyl)phenoxy)nicotinonitrile and (S)-7-chloro-1,2-dimet-hyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:23].[CH3:24][O:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[C:26]([O:25][CH3:24])=[N:27][CH:28]=[CH:29][CH:30]=5)[C:3]([CH3:23])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: COc1ncccc1B(O)O
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ncccc1-c1nc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)ccc1C
Yield: 72.2 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (95 mg, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added 2-methoxypyridin-3-ylboronic acid (66 mg, 0.4 mmol), tetrakis(triphenylphosphine)palladium (0) (33 mg, 0.03 mmol), and 2 M sodium carbonate (0.45 mL, 0.9 mmol). The reaction mixture was irradiated in the microwave at 120° C. for twenty minutes. The reaction mixture was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The crude reaction mixture was purified by silica gel chromatography (eluting with 0-50% ethyl acetate in hexanes) to yield the product (87 mg, 75%). ESI-MS m/z calc. 401.17. found 402.1 (M+1)+. Retention time 1.79 minutes.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17]([CH:19]3[CH2:22][CH2:21]C3)=[O:18])[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.Cl.N[C@H]1C[C@@H](N2C=NC3C2=NC(Cl)=NC=3NCC(C2C=CC=CC=2)C2C=CC=CC=2)[C@H](O)[C@@H]1O.ClC1N=C2C(N=CN2)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1.[O:99]1C(C(Cl)=O)=CC=[N:100]1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([NH:16][C:17]([C:19]3[O:99][N:100]=[CH:21][CH:22]=3)=[O:18])[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:3]=1
Reactant: O=C(N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O)C1CCC1
Reactant: O=C(Cl)c1ccno1
Agent: Cl
Agent: Clc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Agent: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Product: O=C(N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O)c1ccno1

Procedure:
The title compound is prepared by the same method as cyclobutanecarboxylic acid {(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-amide from (1S,2R,3S,5R)-3-amino-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopentane-1,2-diol hydrochloride (an intermediate for preparing the compound of Example 22) and isoxazole-5-carbonyl chloride to afford the title compound. LCMS (electrospray): m/z [MH+] 560.28.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][C@H:22]([CH2:24]O)[O:21][C:20]4=[O:26])=[CH:15][C:14]=3[F:27])=[CH:9][N:8]=2)=[N:3]1.C(N(S(F)(F)[F:34])CC)C.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:23][C@H:22]([CH2:24][F:34])[O:21][C:20]4=[O:26])=[CH:15][C:14]=3[F:27])=[CH:9][N:8]=2)=[N:3]1
Reactant: Cn1nnc(-c2ccc(-c3ccc(N4C[C@H](CO)OC4=O)cc3F)cn2)n1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1nnc(-c2ccc(-c3ccc(N4C[C@H](CF)OC4=O)cc3F)cn2)n1
Reaction time: 24 h
Yield: 75.5 %

Procedure:
In 5 ml of methylenchloride was dissolved 100 mg of the compound 10. The solution was added with 43 mg of diethylaminosulfurtrifloride (DAST) and 0.078 ml of triethylamine and then stirred for 24 hours. After being concentrating, the reaction mixture was purified by column chromatography to obtain the title compound 75 mg. Yield 75%.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[CH:8]([CH3:16])[C:9]([O:11]C(C)(C)C)=[O:10].Cl>O1CCOCC1>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[CH:8]([CH3:16])[C:9]([OH:11])=[O:10]
Reactant: CC(C(=O)OC(C)(C)C)n1ccccc1=O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C(=O)O)n1ccccc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a stirred suspension of 16.6 g (74.4 mmol) of tert-butyl 2-(2-oxopyridin-1(2H)-yl)propanoate from step A above in 10 mL of anhydrous 1,4-dioxane under an atmosphere of nitrogen was added 150 mL of a 4.0 M hydrogen chloride solution in 1,4-dioxane. The resulting solution was stirred overnight at ambient temperature then evaporated to dryness in vacuo to afford the title compound as a white solid (12.4 g, quantitative yield). LC-MS: m/z (ES) 168 (MH)+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][S:11]([NH:14][CH2:15][CH2:16][CH3:17])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl[C:19]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[N:22]=[CH:21][N:20]=1>CN(C=O)C>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:23]1[N:22]=[CH:21][N:20]=[C:19]([NH:1][C:4]2[CH:5]=[C:6]([CH2:10][S:11]([NH:14][CH2:15][CH2:16][CH3:17])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:24]=1
Reactant: CCCNS(=O)(=O)Cc1cccc([N+](=O)[O-])c1
Reactant: COc1ccccc1-c1cc(Cl)ncn1
Solvent: CN(C)C=O
Product: CCCNS(=O)(=O)Cc1cccc(Nc2cc(-c3ccccc3OC)ncn2)c1
Temperature: 80 °C

Procedure:
A mixture of (3-nitrophenyl)-N-propylmethanesulfonamide (0.114 g, 0.5 mmol) and 4-chloro-6-(2-methoxyphenyl)-pyrimidine (0.110 g, 0.5 mmol) in DMFA (3 mL) was stirred at 80° C. till the end of the reaction (TLC control) and then concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica to afford the (3-[6-(2-methoxyphenyl)-4-pyrimidinyl]aminophenyl)-N-propylmethanesulfonamide.
Reaction SMILES: C(C1OC2C=CC(Br)=CC=2C=1)C1C=CC=CC=1.C(Cl)(=O)C1C=CC(OC)=CC=1.[CH2:29]([C:36]1[O:37][C:38]2[CH:54]=[CH:53][C:52]([Br:55])=[CH:51][C:39]=2[C:40]=1[C:41](=[O:50])[C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[CH2:56]([N:58]([CH2:63][CH3:64])[CH2:59][CH2:60]CCl)[CH3:57]>>[CH2:29]([C:36]1[O:37][C:38]2[CH:54]=[CH:53][C:52]([Br:55])=[CH:51][C:39]=2[C:40]=1[C:41](=[O:50])[C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][CH2:57][CH2:56][N:58]([CH2:63][CH3:64])[CH2:59][CH3:60])=[CH:44][CH:43]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCN(CC)CCCCl
Reactant: COc1ccc(C(=O)c2c(Cc3ccccc3)oc3ccc(Br)cc23)cc1
Agent: Brc1ccc2oc(Cc3ccccc3)cc2c1
Agent: COc1ccc(C(=O)Cl)cc1
Product: CCN(CC)CCCOc1ccc(C(=O)c2c(Cc3ccccc3)oc3ccc(Br)cc23)cc1

Procedure:
2-Benzyl-5-bromobenzofuran is acylated with p-anisoyl chloride as described above and the resulting 2-benzyl-5-bromo-3-(4-methoxybenzoyl)benzofuran is demethylated and the product reacted with 3-diethylaminopropyl chloride as previously described to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17]>C1COCC1>[CH2:16]([O:15][C:14](=[O:18])[CH2:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1)[CH3:17]
Reactant: Cc1cccc(Cl)n1
Reactant: CCOC(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cccc(Cl)n1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 3.8 %

Procedure:
To a solution of 6-chloro-2-picoline (2.0 g, 15.7 mmol) in THF (60 mL) at −20° C. was added n-butyllithium (2.5M in hexanes, 9.4 mL, 23.5 mmol). The resulting dark red solution was stirred at −20° C. for 15 minutes, then cooled to −78° C. and diethyl carbonate (2.85 mL, 23.5 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 30 minutes then slowly warmed to r.t. overnight. The reaction mixture was quenched with sat. aqueous ammonium chloride solution (100 mL) and extracted with EtOAc (3×60 mL). The combined organic fractions were washed with brine (60 mL), dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (SiO2, 0-40% EtOAc/heptane, followed by SiO2, 20% EtOAc/heptane) gave the title compound (120 mg, 25%) as a pale yellow oil. LCMS (ES+) 321.11 (M+H)+, RT 4.43 min (Method 1).
Reaction SMILES: [OH:1][C:2]([CH3:14])([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][CH:6]=1)=[O:4].N1C=CC=CC=1.Cl[C:22]([O:24][CH3:25])=[O:23].O>O1CCCC1>[CH3:25][O:24][C:22](=[O:23])[O:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[C:2]([OH:1])([CH3:14])[CH3:13])=[CH:6][CH:7]=1
Reactant: COC(=O)Cl
Reactant: CC(C)(O)C(=O)c1ccc(CO)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)OCc1ccc(C(=O)C(C)(C)O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
Under argon gas, 3.0 g (15.5 mmol) of 2-hydroxy-1-(4-hydroxymethyl-phenyl)-2-methyl-propan-1-one and 1.5 g (19 mmol) of pyridine in 50 ml of tetrahydrofuran are introduced into a 100 ml reaction flask. The pale-yellow solution is cooled to 0° C., and 1.6 g (17 mmol) of methyl chloroformate diluted with 5 ml of tetrahydrofuran are added dropwise between 0 and 2° C. over 45 minutes. A whitish-yellow suspension is formed, which is further stirred overnight in an ice bath. After warming up to room temperature, the reaction mixture is poured into 50 ml of water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. The crude product is purified by means of flash chromatography on silica gel (eluant: mixed hexanes:ethyl acetate 2:1). 2.3 g of carbonic acid 4-(2-hydroxy-2-methyl-propionyl)-benzyl ester methyl ester are obtained as a pale-yellow liquid. The structure is confirmed using a 1H NMR spectrum.