Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH:17]([NH2:21])[CH:18]([CH3:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:22]=[C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=[O:32])[N:24]1[CH2:33][CH2:34][CH:35]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH:17]([NH:21][CH2:35][CH2:34][CH2:33][N:24]1[C:25](=[O:32])[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]1=[O:22])[CH:18]([CH3:19])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(N)c1nc2ccccc2n1Cc1ccccc1
Reactant: O=CCCN1C(=O)c2ccccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)C(NCCCN1C(=O)c2ccccc2C1=O)c1nc2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-(1-benzyl-1H-benzimidazol-2-yl)-2-methyl-propylamine (160 mg, 0.56 mmol) and 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionaldehyde (114 mg, 0.56 mmol) in dry DCM (3 ml) at room temperature, was added sodium triacetoxyborohydride (119 mg, 0.56 mmol). After 10 minutes, acetic acid (34 μl, 0.56 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the solid was dissolved in ethyl acetate. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography to give material that was used in Example 5g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Cl:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].[F-].[K+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[Cl:12])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: Nc1ccccc1Cl
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)ccc1Nc1ccccc1Cl
Temperature: 180 °C

Procedure:
A mixture of 1-bromo-4-fluoro-3-nitrobenzene (3.00 mL, 13.6 mmol), 2-chloroaniline (2.87 mL, 27.3 mmol) and potassium fluoride (0.792 g, 13.6 mmol) was heated at 180° C. for 48 h. Upon cooling the mixture, DCM (300 mL) was added and the mixture was successively washed with water (100 mL), 10% HCl (2×50 mL) and brine (50 mL). The resulting organic solution was dried over magnesium sulfate and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography on SiO2(DCM:hexanes=25:75) to afford the title compound as a red crystalline solid. MS (ESI, pos. ion) m/z: 328.9 (M+1).
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[CH3:27][C:28]1[S:29][CH:30]=[C:31]([C:33](Cl)=[O:34])[N:32]=1.Cl>>[CH3:27][C:28]1[S:29][CH:30]=[C:31]([C:33]([N:21]2[CH2:20][CH2:19][C:16]3([C:15](=[O:24])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=4)[CH2:18][CH2:17]3)[CH2:23][CH2:22]2)=[O:34])[N:32]=1
Reactant: Cc1nc(C(=O)Cl)cs1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc(C(=O)N2CCC3(CC2)CCN(c2ccc(OC(F)(F)F)cc2)C3=O)cs1

Procedure:
The title compound was prepared in analogy to example 7 step A from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and 2-methyl-thiazole-4-carbonyl chloride; hydrochloride. Off-white solid. MS (ESI): 440.2 (MH+).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][CH3:3].[C:11]([OH:15])(=[O:14])[CH:12]=[CH2:13].[OH-].[Na+]>O>[C:5]1([N:4]([CH2:13][CH2:12][C:11]([OH:15])=[O:14])[CH2:1][CH2:2][CH3:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=CC(=O)O
Reactant: CCCNc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCN(CCC(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A mixture of N-propyl aniline (5.0 g), acrylic acid (5.1 ml) and water (7 ml) was stirred for 2 hours under reflux. After cooling to room temperature, the aqueous solution was adjusted to pH 11 with 5N aqueous sodium hydroxide and washed four times with ether. The aqueous layer was acidified to pH 3 with concentrated hydrochloric acid and extracted three times with ethyl acetate. The combined organic layer was washed with saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 7.2 g (94%) of the objective compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH:37][CH:38]=1)[CH2:25][N:26]1[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][C:27]1=[O:35]>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:32]([C:29]3[CH:30]=[CH:31][N:26]([CH2:25][C:24]4[CH:36]=[CH:37][CH:38]=[C:22]([Cl:21])[CH:23]=4)[C:27](=[O:35])[CH:28]=3)=[O:33])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccn(Cc2cccc(Cl)c2)c(=O)c1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccn(Cc2cccc(Cl)c2)c(=O)c1

Procedure:
1-(3-Chloro-benzyl)-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 1-(3-chloro-benzyl)-2-oxo-1,2-dihydro-pyridine-4-carboxylic acid. MS calcd. for C29H22Cl2N3O3 [(M+H)+] 530.1, obsd. 530.0.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4](/[C:7](/I)=[CH:8]/[CH2:9][S:10][C:11]2[CH:23]=[CH:22][C:14]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])=[C:13]([CH3:24])[CH:12]=2)=[CH:3][CH:2]=1.[S:32]1[C:36]([Sn](CCCC)(CCCC)CCCC)=[CH:35][C:34]2[CH:50]=[CH:51][CH:52]=[CH:53][C:33]1=2.C(Cl)(Cl)Cl.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C1CCCCC1.[F-].[K+]>CN(C)C=O.C(OCC)(=O)C>[S:32]1[C:36]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:6][CH:5]=2)=[CH:8][CH2:9][S:10][C:11]2[CH:23]=[CH:22][C:14]([O:15][CH2:16][C:17]([OH:19])=[O:18])=[C:13]([CH3:24])[CH:12]=2)=[CH:35][C:34]2[CH:50]=[CH:51][CH:52]=[CH:53][C:33]1=2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2ccccc2s1
Reactant: CCOC(=O)COc1ccc(SC/C=C(\I)c2ccc(-c3ccccc3)cc2)cc1C
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1cc(SCC=C(c2ccc(-c3ccccc3)cc2)c2cc3ccccc3s2)ccc1OCC(=O)O
Temperature: 50 °C
Reaction time: 10 h

Procedure:
To a solution of ethyl (Z)-[4-[3-(biphenyl-4-yl)-3-iodoallylsulfanyl]-2-methylphenoxy]-acetate (419 mg, 0.770 mmol; example 5, step D-E) and (benzo[b]thiophen-2-yl)-tributyltin (335 mg, 0.792 mmol, prepared according to Morimoto et al.: J. Med. Chem. 44, 3355 (2001)) in dry N,N-dimethylformamide (9 mL) Pd2(dba)3.CHCl3 (23.1 mg, 0.023 mmol) was added. Traces of moisture and oxygen were removed and 0.20M solution of tri(tert.butyl)phosphine in cyclohexane (0.39 mL, 0.098 mmol) was added under atmosphere of nitrogen and the whole mixture was stirred at 50° C. for 10 h and then left stand overnight. The dark solution was poured into 10% aqueous solution of potassium fluoride (30 mL) and subsequently ethyl acetate (40 mL) was added. The layers were separated, the aqueous layer was washed with ethyl acetate (2×15 mL) and the collected organic layers were washed with brine (10 mL), 10% solution of potassium fluoride (20 mL), water (20 mL) and brine (20 mL). The organic solution was dried with anhydrous sodium sulfate and its evaporation gave an oil that was purified by column chromatography (silica gel Fluka 60, hexane/ethyl acetate 93:7).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:14]([O:16][CH2:17][CH2:18]Cl)=[CH2:15].[OH-].[Na+].C(N(CC)CC)C>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:14]([O:16][CH2:17][CH2:18][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:12][CH:11]=1)=[CH2:15]
Reactant: Oc1ccc(C2CCCCC2)cc1
Reactant: C=COCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=COCCOc1ccc(C2CCCCC2)cc1

Procedure:
In 300 ml of toluene, 83.1 g (0.5 moles) of p-cyclohexylphenol was dissolved, to which were then added 150 g of 2-chloroethyl vinyl ether, 25 g of sodium hydroxide, 5 g of tetrabutylammonium bromide and 60 g of triethylamine, and the mixture was reacted at 120° C. for 5 hours. The reaction solution was washed with water, the excessive 2-chloroethyl vinyl ether and toluene were distilled off, and the resulting oil was purified by distillation in vacuo to obtain 4-cyclohexylphenoxyethyl vinyl ether.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.O[C:17]1[CH:32]=[CH:31][C:20]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[CH:19][CH:18]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][C:17]3[CH:32]=[CH:31][C:20]([C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[CH:19][CH:18]=3)=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: CC1(C)CCSc2ccc(C(=O)O)cc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)CCSc2ccc(C(=O)Oc3ccc(C(=O)OCc4ccccc4)cc3)cc21

Procedure:
A solution of 786 mg (3.54 mmol) of 4,4-dimethyl-6-carboxythiochroman, 804 mg (3.53 mmol) of benzyl 4-hydroxybenzoate, 800 mg (3.88 mmol) of 1, 3-dicyclohexylcarbodiimide and 60 mg (0.49 mmol) of 4-dimethylaminopyridine in 50 ml of methylene chloride was stirred at room temperature for 2 hours. The reaction mixture was then filtered and the residue washed with 20 ml of methylene chloride. The filtrate was concentrated in-vacuo and the resultant crude product was purified by flash chromatography (silica, 20% ethyl acetate in hexanes) followed by recrystallization from a mixture of hexanes and ethyl acetate to give the title compound as a white, crystalline solid. PMR (CDCl3): δ1.39 (6H, s), 1.98 (2H, m), 3.08 (2H, m), 5.37 (2H, s), 7.20 (1H, d, J~8.3 Hz), 7.28 (2H, d, J~8.0 Hz), 7.34-7.48 (5 H, m), 7.82 (1H, dd, J~8.3, 2.0 Hz), 8.14 (2H, d, J~8.0 Hz), 8.16 (1H, d, J~2.0 Hz).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][NH:12][C:13](=[O:28])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:5]=1.[OH-].[Na+].Cl>CO.O>[N:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([NH:12][O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:29])=[O:2])=[O:28])=[CH:23][CH:24]=1
Reactant: COC(=O)c1cccc(CONC(=O)c2ccccc2NCc2ccncc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(CONC(=O)c2ccccc2NCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a stirred solution of 3-{2-[(Pyridin-4-ylmethyl)-amino]-benzoylaminooxymethyl}-benzoic acid methyl ester (see example 402, 89 mg) in methanol (3 ml) was added 2M sodium hydroxide (1 ml). The reaction mixture was stirred at room temperature for 7 hours. The mixture was diluted with water (12 ml) and acidified with 4M HCl aq. The resulting precipitated material was isolated by filtration and dried under vacuum, affording the title compound. 13C-NMR (DMSO-d6) δ 167.2, 167.1, 149.5, 149.0, 148.3, 136.4, 133.1, 132.5, 130.8, 129.7, 129.1, 128.5, 128.0, 121.9, 114.8, 113.3, 111.4, 76.3, 44.7.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13].C(N(CC)CC)C.O>CN(C=O)C>[C:1]([O:11][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=1)(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=C(O)[C@H](O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)[C@H](O)c1ccccc1
Yield: 68.2 %

Procedure:
A solution of 15.2 g (100 mmol) of D-mandelic acid, 21.6 g (100 mmol) of 4-nitrobenzyl bromide, and 14.0 ml (100 mmol) of triethylamine in 300 ml of DMF was stirred for 8 hours at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with 2N hydrochloric acid and water and recrystallized from ether-petroleum ether to give 19.6 g of the aimed product D-4 in 68% yield.
Reaction SMILES: [OH:1][CH:2]([CH:6]([NH:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[C:22]1[N:23]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:25][CH:26]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](O)=[O:4].[CH:34]1([NH2:37])[CH2:36][CH2:35]1.ClCCl.CCN(C(C)C)C(C)C>>[CH:34]1([NH:37][C:3](=[O:4])[CH:2]([OH:1])[CH:6]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][C:17]=2[C:22]2[N:23]=[C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[S:25][CH:26]=2)[CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:36][CH2:35]1
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-c1csc(-c2ccccc2)n1
Reactant: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC(Cc1ccccc1)C(O)C(=O)NC1CC1)c1cccnc1-c1csc(-c2ccccc2)n1
Temperature: 5 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a solution of 2-hydroxy-4-phenyl-3-(2-(2-phenylthiazol-4-yl)nicotinamido)butanoic acid (230 mg, 0.501 mmol) and cyclopropylamine (40 μL, 0.570 mmol) in dichloromethane (30 ml) 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU) (230 mg, 0.605 mmol) and DIPEA (100 μL, 0.605 mmol) were added at 5° C. The mixture was stirred for 1 hour at 5° C. and then for 5 hours at room temperature. The mixture was concentrated under reduced pressure, 40 ml of water added, the precipitate formed filtered off with suction, washed with water and dried in vacuo to give 227 mg of a white amorphous solid;
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:10][C:11]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=1>>[Cl:10][C:11]1[C:16]([O:17][C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Oc1cccnc1Cl
Reactant: N#Cc1cccnc1F
Product: N#Cc1cccnc1Oc1cccnc1Cl

Procedure:
2-Fluoro-nicotinonitrile was reacted with 2-chloro-pyridin-3-ol according to the method of Example 85A to provide the title compound. MS (DCI/NH3) m/z 232 (M)+, 234 (M+2)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:5]([NH2:6])=[CH:4][C:3]=1[N:12]1[CH:17]=[CH:16][C:15](=[O:18])[CH:14]=[CH:13]1.O.Cl>[Fe].C(O)C>[Cl:1][C:2]1[C:3]([N:12]2[CH:17]=[CH:16][C:15](=[O:18])[CH:14]=[CH:13]2)=[CH:4][C:5]([NH2:6])=[C:7]([NH2:9])[CH:8]=1
Reactant: Nc1cc(-n2ccc(=O)cc2)c(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)c(-n2ccc(=O)cc2)cc1N

Procedure:
First, a mixture containing 3.0 g of 4-chloro-3-(4-oxo-4H-pyridin-1-yl)-6-nitroaniline, 3.78 g of iron powder, 10 ml of water, 90 ml of ethanol, and 1.15 ml of 2N hydrochloric acid was refluxed by heating in an oil bath for 3 hours. Then, 135 ml of ethanol was added to the mixture, and insoluble substances were filtered with Hyflo Super-Cel (trade name) and the solvent was removed.
Reaction SMILES: O.[OH-].[Na+].[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:20]([O-:22])=[O:21])[CH2:15][CH2:16][C:17]([O-:19])=[O:18])=[O:12].Cl>CO>[O:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:20]([OH:22])=[O:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:12]
Reactant: O=C([O-])CC[C@H](NC(=O)C=Cc1ccco1)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CC[C@H](NC(=O)C=Cc1ccco1)C(=O)O
Temperature: 25 °C
Yield: 90 %

Procedure:
To a mixture of 400 ml of water, 80 ml of methanol and 45 g of sodium hydroxide was added 100 g of the dimethyl DL-N-[β-(2-furyl)acryloyl]glutamate, and the resulting mixture was heated at 60° C. to 65° C. for 4 hours to hydrolyze the ester. The reaction mixture was cooled to room temperature and acidified with hydrochloric acid, and thereafter the precipitated crystals were collected by filtration to obtain 80 g (yield 90%) of DL-N-[β-(2-furyl)acryloyl]glutamic acid having a melting point of 166°-170° C.
Reaction SMILES: [F:1][C:2]([F:12])([CH3:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[BH4-].[Na+].Cl>C1(C)C=CC=CC=1>[F:1][C:2]([F:12])([CH3:11])[CH:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)C(C)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(O)C(C)(F)F
Temperature: 0 °C
Reaction time: 8 h
Yield: 70588.2 %

Procedure:
Ethyl 4,4-difluoro-3-oxo-pentanoate (12.4 g, 0.068 mmol) was dissolved in toluene (100 ml) and cooled to 0° C. Sodium borohydride (3.12 g, 0.083 g) was added portionwise, and the mixture was allowed to reach room temperature overnight with stirring. The mixture was then cooled to 0° C. and acidified with 1M HCl. The phases were separated, the aqueous phase was extracted two times with ethyl acetate, the combined organic phases were dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was dissolved in a minimum amount of methanol, the resulting solution was evaporated to dryness under reduced pressure to yield 8.76 g of a residue (0.048 mol, 70%) that were used directly in the next step.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@H:16]2[CH:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][C:24]#[CH:25])[O:17]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1I.CCN(CC)CC>C1COCC1.[Cu]I>[CH:1]1([NH:6][C:7]2[N:15]=[CH:14][N:13]=[C:12]3[C:8]=2[N:9]=[CH:10][N:11]3[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([CH2:23][C:24]#[C:25][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[F:26])[O:17]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Fc1ccccc1I
Reactant: C#CC[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)ncnc32)C(O)[C@@H]1O
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O[C@@H]1[C@H](O)[C@@H](CC#Cc2ccccc2F)O[C@H]1n1cnc2c(NC3CCCC3)ncnc21
Temperature: 75 °C
Reaction time: 48 h

Procedure:
To a stirred solution of (4S,2R,5R)-2-[6-(cyclopentylamino)purin-9-yl]-5-prop-2-ynyloxolane-3,4-diol (0.017 g, 0.05 mmol) and 1-fluoro-2-iodobenzene (0.02 mL, 0.13 mmol) in THF (3.50 mL) under an atmosphere of N2 was added catalytic amount of dichlorobis(triphenylphosphine) palladium (II) and copper (I) iodide. Et3N (0.20 mL) was then added. The resulting mixture was stirred under N2 at 75° C. for 2 days. The solvent was removed under reduced pressure, and the residue was purified by preparative thin layer chromatography to give (4S,2R,3R,5R)-2-[6-(cyclopentylamino)purin-9-yl]-5-[3-(2-fluorophenyl)prop-2-ynyl]oxolane-3,4-diol, a compound of Formula I.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6]NC2C3C(=CC=CC=3)N=C(C)C=2C(=O)C)=[CH:4][CH:3]=1.[NH2:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[CH3:35])[N:28]=[C:27]([CH3:36])[C:26]=1[C:37]([O:39][CH3:40])=[O:38].BrC1C=CC(CBr)=CC=1>>[Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][C:33]=3[CH3:35])[N:28]=[C:27]([CH3:36])[C:26]=2[C:37]([O:39][CH3:40])=[O:38])=[CH:4][CH:3]=1
Reactant: CC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)cc1
Reactant: COC(=O)c1c(C)nc2cccc(C)c2c1N
Agent: BrCc1ccc(Br)cc1
Product: COC(=O)c1c(C)nc2cccc(C)c2c1NCc1ccc(Br)cc1

Procedure:
Methyl 4-(4-bromobenzylamino)-2,5-dimethylquinoline-3-carboxylate was synthesized by the same process as described for 1-(4-(4-bromobenzylamino)-2-methylquinolin-3-yl)ethanone (Example 1, Intermediate 2c) starting from methyl 4-amino-2,5-dimethylquinoline-3-carboxylate and 4-bromobenzyl bromide. Melting point: 150° C.; MS(Cl+): 399/401.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[Cl:26])=[C:16]([C:27]([O:29]CC)=O)[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[Cl:26])=[C:16]([C:27]([N:42]3[CH2:43][CH2:44][CH:39]([C:36]4[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=4)[CH2:40][CH2:41]3)=[O:29])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1cccc(Cl)c1Cl
Reactant: Fc1ccc(C2CCNCC2)cc1
Product: CC(C)(C)NS(=O)(=O)c1cnn2c(Nc3cccc(Cl)c3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 77.8 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(2,3-dichlorophenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (4.56 g, 9.38 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (2.31 g, 12.9 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (4.52 g, 85%) was obtained.
Reaction SMILES: O1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Al+3].[Cl-].[Cl-].[Cl-]>CCOCC>[CH3:9][O:8][C:6]([C:2]1[C:15]2[C:14](=[CH:13][CH:12]=[C:11]([Cl:10])[CH:16]=2)[CH:5]=[CH:4][CH:3]=1)=[O:7]
Reactant: COC(=O)c1ccco1
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: COC(=O)c1cccc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 50 ml of methyl 2-furoate and 400 ml of chlorobenzene is stirred at 0° for 30 minutes, at RT for 1.5 hours and at 100° for 16 hours. 121 g of anhydrous AlCl3 are added by portion at 0°. The solution obtained is cooled, poured in an ice-bath and stirred for 30 minutes before extraction of the aq. phase with ether. The organic phase obtained is washed with aq. 10% NaHCO3 solution and brine, dried and solvent is evaporated. The residue obtained is purified by flash chromatography on silica gel (eluent: cyclohexane/EtOAc 99/1 to 95/5) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[C:12]([O:16][C:17](=[O:25])[N:18]([CH2:22][CH2:23][OH:24])[CH2:19][CH2:20][CH3:21])([CH3:15])([CH3:14])[CH3:13].[H-].[Li+]>C1(C)C=CC=CC=1>[C:12]([O:16][C:17](=[O:25])[N:18]([CH2:22][CH2:23][O:24][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[N:7]=1)[CH2:19][CH2:20][CH3:21])([CH3:13])([CH3:14])[CH3:15]
Reactant: CCCN(CCO)C(=O)OC(C)(C)C
Reactant: Cc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CCCN(CCOc1ccc([N+](=O)[O-])c(C)n1)C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 4 h
Yield: 70.2 %

Procedure:
A mixture of 6-chloro-2-methyl-3-nitro-pyridine (1 g, 5.79 mmol), (2-hydroxyethyl)-propyl-carbamic acid tert-butyl ester (1.18 g, 5.79 mmol) and lithium hydride (0.05 g, 6.37 mmol) in toluene (5 ml) was stirred at 90° C. for 4 h. After evaporation of the solvent under reduced pressure the residue was purified by silica gel chromatography with heptane/ethyl acetate (10:0; 8:2; 0:10) as eluent to provide 1.38 g (70.2%) of the product.